Recent developments in the antiprotozoal and anticancer activities of the 2-alkynoic fatty acids

Science.gov (United States)

Carballeira, Néstor M.

2013-01-01

The 2-alkynoic fatty acids are an interesting group of synthetic compounds that display antimycobacterial, antifungal, anticancer, and pesticidal activities but their antiprotozoal activity has received little attention until recently. In this review we have summarized our present knowledge of the biomedical potential of the 2-hexadecynoic acid (2-HDA) and 2-octadecynoic acid (2-ODA) together with several mechanistic pieces of work attesting to the fact that these compounds, and their metabolites, are good fatty acid biosynthesis inhibitors. The antiprotozoal activity of 2-HDA and 2-ODA against Leishmania donovani and Plasmodium falciparum, parasites responsible for visceral leishmaniasis and malaria, respectively, is also reviewed. The evidence obtained so far supports the fact that these fatty acids are good inhibitors of the L. donovani DNA topoisomerase IB enzyme (LdTopIB) and the potency of LdTopIB inhibition is chain length dependent. We also demonstrate the generality of the antiprotozoal activity of 2-HDA and 2-ODA against P. falciparum, and review our present knowledge of their inhibition of key P. falciparum enzymes such as PfFabZ, PfFabG, and PfFabI together with some possible modes of inhibition. Recent research by our group has also demonstrated that 2-ODA displays antineoplastic activity, specifically against the neuroblastoma SH-SY5Y cell line via lactate dehydrogenase (LDH) release, which is a cell death mechanism principally associated to necrosis. This is the first comprehensive review of the medicinal chemistry of this interesting group of acetylenic fatty acids. PMID:23727443

Recent developments in the antiprotozoal and anticancer activities of the 2-alkynoic fatty acids.

Science.gov (United States)

Carballeira, Néstor M

2013-01-01

The 2-alkynoic fatty acids are an interesting group of synthetic compounds that display antimycobacterial, antifungal, anticancer, and pesticidal activities but their antiprotozoal activity has received little attention until recently. In this review we have summarized our present knowledge of the biomedical potential of the 2-hexadecynoic acid (2-HDA) and 2-octadecynoic acid (2-ODA) together with several mechanistic pieces of work attesting to the fact that these compounds, and their metabolites, are good fatty acid biosynthesis inhibitors. The antiprotozoal activity of 2-HDA and 2-ODA against Leishmania donovani and Plasmodium falciparum, parasites responsible for visceral leishmaniasis and malaria, respectively, is also reviewed. The evidence obtained so far supports the fact that these fatty acids are good inhibitors of the L. donovani DNA topoisomerase IB enzyme (LdTopIB) and the potency of LdTopIB inhibition is chain length dependent. We also demonstrate the generality of the antiprotozoal activity of 2-HDA and 2-ODA against P. falciparum, and review our present knowledge of their inhibition of key P. falciparum enzymes such as PfFabZ, PfFabG, and PfFabI together with some possible modes of inhibition. Recent research by our group has also demonstrated that 2-ODA displays antineoplastic activity, specifically against the neuroblastoma SH-SY5Y cell line via lactate dehydrogenase (LDH) release, which is a cell death mechanism principally associated to necrosis. This is the first comprehensive review of the medicinal chemistry of this interesting group of acetylenic fatty acids. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Strokes attributable to underuse of warfarin and antiplatelets

DEFF Research Database (Denmark)

Olsen, Tom Skyhøj; Rasmussen, Berit Hammershaimb; Kammersgaard, Lars Peter

2007-01-01

atrial fibrillation, prior myocardial infarction, angina, or prior stroke transient ischemic attack (TIA). Sufficient information on cardiovascular risk factors before stroke was available in 404 patients. A total of 54 patients had atrial fibrillation known before the stroke. Of these, 16 had...... fibrillation could have been prevented if warfarin or antiplatelets had been given before stroke. A total of 147 patients had known stroke/TIA and/or myocardial infarction/angina before stroke (41 patients had not received antiplatelets on admission). If antiplatelet therapy had been given before stroke, 10...

ANTIPLATELET THERAPY IN THE PREVENTION OF CEREBROVASCULAR ACCIDENTS

Directory of Open Access Journals (Sweden)

O. V. Rodionova

2017-01-01

Full Text Available Currently the problem of preventing cerebrovascular disorders, in which antiplatelet therapy takes one of the leading places, remains relevant. The efficiency of the therapy depends on a large number of modifiable and non-modifiable factors. There are many methods to assess the severity of the response to antiplatelet therapy, but there is no common approach to the assessment of the results and their prognostic significance. Further studies of this issue are essential with the aim of individualization of antiplatelet therapy thereby increasing its efficiency and safety.

Immunomodulating and Antiprotozoal Effects of Different Extracts of the Oyster Culinary-Medicinal Mushroom Pleurotus ostreatus (Higher Basidiomycetes) Against Coccidiosis in Broiler.

Science.gov (United States)

Ullah, Muhammad Irfan; Akhtar, Masood; Iqbal, Zafar; Shahid, Muhammad; Awais, Mian Muhammad

2015-01-01

The culinary-medicinal oyster mushroom Pleurotus ostreatus, procured from local sources, was processed for hot water and methanolic extraction. Extracts obtained were subjected to proximate analysis to determine the amount of crude protein, crude fiber, ash, ether, and nitrogen-free extracts. These extracts were evaluated for immunomodulating and antiprotozoal effects against coccidiosis in a broiler. Cellular immune investigation revealed significantly higher (P 0.05) findings were observed in investigations of lymphoid organs. Antiprotozoal studies revealed a significantly higher (P < 0.05) percentage of protection against coccidiosis in groups administered P. ostreatus extracts when compared with controls. Moreover, lesion scoring and oocysts per gram of droppings observed in the control group were significantly higher (P < 0.05) compared with those in groups administered hot water and methanolic extracts of P. ostreatus. Results concluded that hot water and methanolic extracts of P. ostreatus had strong immune-enhancing activities. Further, these extracts also had excellent antiprotozoal activities against coccidiosis in a broiler.

Improving the antiprotozoal effect of saponins in the rumen by combination with glycosidase inhibiting iminosugars or by modification of their chemical structure

Science.gov (United States)

de la Fuente, Gabriel; Nash, Robert J.; Braganca, Radek; Duval, Stephane; Bouillon, Marc E.; Lahmann, Martina; Newbold, C. Jamie

2017-01-01

The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to sapogenins by rumen microorganisms they become inactive. We hypothesised that the combination of saponins with glycosidase-inhibiting iminosugars might potentially increase the effectiveness of saponins over time by preventing their deglycosylation in the rumen. Alternatively, modifying the structure of the saponins by substituting the sugar moiety with other small polar residues might maintain their activity as the sugar substitute would not be enzymatically cleaved. The aim of this in vitro study was to evaluate the acute antiprotozoal effect and the stability of this effect over a 24 h incubation period using ivy saponins, a stevia extract rich in iminosugars, ivy saponins with stevia extract, and a chemically modified ivy saponin, hederagenin bis-succinate (HBS). The effects on fermentation parameters and rumen bacterial communities were also studied. Ivy saponins with stevia and HBS had a greater antiprotozoal effect than ivy saponins, and this effect was maintained after 24 h of incubation (Pstevia extracts was more effective in shifting the fermentation pattern towards higher propionate (+39%) and lower butyrate (-32%) and lower ammonia concentration (-64%) than the extracts incubated separately. HBS caused a decrease in butyrate (-45%) and an increase in propionate (+43%) molar proportions. However, the decrease in ammonia concentration (-42%) observed in the presence of HBS was less than that caused by ivy saponins, either alone or with stevia. Whereas HBS and stevia impacted on bacterial population in terms of community structure, only HBS had an effect in terms of biodiversity (Pstevia and the modified saponin HBS had a strong antiprotozoal effect, although they differed in their effects on fermentation parameters and bacteria communities. Ivy saponins combined with an iminosugar-rich stevia extract and/or HBS should be evaluated to determine their antiprotozoal

Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke

DEFF Research Database (Denmark)

Søndergaard, Lars; Kasner, Scott E; Rhodes, John F

2017-01-01

BACKGROUND: The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new...... brain infarctions. METHODS: In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group......). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month...

Synthesis and SAR studies of very potent imidazopyridine antiprotozoal agents.

Science.gov (United States)

Biftu, Tesfaye; Feng, Dennis; Fisher, Michael; Liang, Gui-Bai; Qian, Xiaoxia; Scribner, Andrew; Dennis, Richard; Lee, Shuliang; Liberator, Paul A; Brown, Chris; Gurnett, Anne; Leavitt, Penny S; Thompson, Donald; Mathew, John; Misura, Andrew; Samaras, Samantha; Tamas, Tamas; Sina, Joseph F; McNulty, Kathleen A; McKnight, Crystal G; Schmatz, Dennis M; Wyvratt, Matthew

2006-05-01

Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.

Marine products with anti-protozoal activity: a review.

Science.gov (United States)

García, Marley; Monzote, Lianet

2014-01-01

The marine organisms are a rich source of varied natural products with unique functionality. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna for treatment and/or prevention of human diseases. The present review briefly illustrates current status of marine products as antiprotozoal agents. The in vitro and in vivo studies of marine algae, invertebrates and micro-organism against different protozoa parasites are included. The marine products studied, according to international criterions for selection of more promisory products in the different models reported, demonstrated their potentialities as antiprozoal agents. Herein, the interest of scientific community to search new alternatives from marine environment has been demonstrated.

In vivo anti-malarial activity of hydroalcoholic extracts from ...

African Journals Online (AJOL)

Administrator

There is, thus, the need to initiate further in-depth investigation by using different experimental ... antiprotozoal compounds, a sapogenin (muzanzagenin) and lignan ((+) .... The microscope had an. Ehrlich's ... 100 red blood cells per field.

Antimalarial drug induced decrease in creatinine clearance

NARCIS (Netherlands)

Landewé, R. B.; Vergouwen, M. S.; Goeei The, S. G.; van Rijthoven, A. W.; Breedveld, F. C.; Dijkmans, B. A.

1995-01-01

To confirm the antimalarial drug induced increase of creatinine to determine the factors contributing to this effect. Patients with rheumatoid arthritis (RA) (n = 118) who have used or still use antimalarials (chloroquine or hydroxychloroquine). Serum creatinines prior to antimalarials and serum

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids

Directory of Open Access Journals (Sweden)

Birgit Viira

2016-06-01

Full Text Available Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

Science.gov (United States)

Viira, Birgit; Gendron, Thibault; Lanfranchi, Don Antoine; Cojean, Sandrine; Horvath, Dragos; Marcou, Gilles; Varnek, Alexandre; Maes, Louis; Maran, Uko; Loiseau, Philippe M; Davioud-Charvet, Elisabeth

2016-06-29

Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery.

Update on antiplatelet agents, including MATCH, CHARISMA, and ESPRIT.

Science.gov (United States)

Skliut, Maryna; Jamieson, Dara G

2008-02-01

Despite recent advances in the acute treatment of stroke, prevention and risk factor modification remain the mainstays of management for patients with ischemic stroke and transient ischemic attack. The majority of noncardioembolic ischemic strokes are atherothrombotic, presumed to be associated with the activation and aggregation of platelets. Antiplatelet medications have been shown to be effective in the secondary prevention of stroke of presumed arterial origin, both as monotherapy and in combination. Among combination of antiplatelet agents, aspirin plus extended-release dipyridamole has demonstrated statistically significant additive benefit over monotherapy with each agent. Clopidogrel plus aspirin does not prevent recurrent ischemic stroke over each component individually, and the combination increases the risk of hemorrhagic side effects. This article reviews the most recent studies on antiplatelet medications, including the combination of aspirin and clopidogrel or extended-release dipyridamole, and discusses some of the controversies that still exist with the use of antiplatelet agents.

Long-term use of antiplatelet drugs by stroke patients

DEFF Research Database (Denmark)

Ostergaard, Kamilla; Hallas, Jesper; Bak, Søren

2012-01-01

PURPOSE: Treatment with antiplatelet drugs is a key element of secondary stroke prevention. We investigated long-term antiplatelet drug use in stroke patients with a focus on non-persistence. METHODS: Population-based prescription register data were used to determine antiplatelet drug use...... the dosage of a previous prescription had run out, or within 180 days after discharge. Cox regression was used to identify risk factors for non-persistence. RESULTS: The cohort comprised 503 patients with ischaemic stroke discharged in 1999-2001. During follow-up (median 2.8 years, interquartile range 0......-persistent. Stroke severity was inversely associated with the risk of non-persistence [NIHSS score on admission 0-3 (reference); 4-6: hazard risk (HR) 0.87, 95 % confidence interval (CI) 0.61-1.25; 7+: HR 0.47, 95 % CI 0.29-0.74]. CONCLUSIONS: Long-term non-persistence with antiplatelet treatment was high and more...

Improving the antiprotozoal effect of saponins in the rumen by combination with glycosidase inhibiting iminosugars or by modification of their chemical structure.

Directory of Open Access Journals (Sweden)

Eva Ramos-Morales

Full Text Available The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to sapogenins by rumen microorganisms they become inactive. We hypothesised that the combination of saponins with glycosidase-inhibiting iminosugars might potentially increase the effectiveness of saponins over time by preventing their deglycosylation in the rumen. Alternatively, modifying the structure of the saponins by substituting the sugar moiety with other small polar residues might maintain their activity as the sugar substitute would not be enzymatically cleaved. The aim of this in vitro study was to evaluate the acute antiprotozoal effect and the stability of this effect over a 24 h incubation period using ivy saponins, a stevia extract rich in iminosugars, ivy saponins with stevia extract, and a chemically modified ivy saponin, hederagenin bis-succinate (HBS. The effects on fermentation parameters and rumen bacterial communities were also studied. Ivy saponins with stevia and HBS had a greater antiprotozoal effect than ivy saponins, and this effect was maintained after 24 h of incubation (P<0.001. The combination of ivy and stevia extracts was more effective in shifting the fermentation pattern towards higher propionate (+39% and lower butyrate (-32% and lower ammonia concentration (-64% than the extracts incubated separately. HBS caused a decrease in butyrate (-45% and an increase in propionate (+43% molar proportions. However, the decrease in ammonia concentration (-42% observed in the presence of HBS was less than that caused by ivy saponins, either alone or with stevia. Whereas HBS and stevia impacted on bacterial population in terms of community structure, only HBS had an effect in terms of biodiversity (P<0.05. It was concluded that ivy saponins with stevia and the modified saponin HBS had a strong antiprotozoal effect, although they differed in their effects on fermentation parameters and bacteria communities. Ivy saponins combined with an

The peri-operative management of anti-platelet therapy in elective, non-cardiac surgery.

Science.gov (United States)

Alcock, Richard F; Naoum, Chris; Aliprandi-Costa, Bernadette; Hillis, Graham S; Brieger, David B

2013-07-31

Cardiovascular complications are important causes of morbidity and mortality in patients undergoing elective non-cardiac surgery, with adverse cardiac outcomes estimated to occur in approximately 4% of all patients. Anti-platelet therapy withdrawal may precede up to 10% of acute cardiovascular syndromes, with withdrawal in the peri-operative setting incompletely appraised. The aims of our study were to determine the proportion of patients undergoing elective non-cardiac surgery currently prescribed anti-platelet therapy, and identify current practice in peri-operative management. In addition, the relationship between management of anti-platelet therapy and peri-operative cardiac risk was assessed. We evaluated consecutive patients attending elective non-cardiac surgery at a major tertiary referral centre. Clinical and biochemical data were collected and analysed on patients currently prescribed anti-platelet therapy. Peri-operative management of anti-platelet therapy was compared with estimated peri-operative cardiac risk. Included were 2950 consecutive patients, with 516 (17%) prescribed anti-platelet therapy, primarily for ischaemic heart disease. Two hundred and eighty nine (56%) patients had all anti-platelet therapy ceased in the peri-operative period, including 49% of patients with ischaemic heart disease and 46% of patients with previous coronary stenting. Peri-operative cardiac risk score did not influence anti-platelet therapy management. Approximately 17% of patients undergoing elective non-cardiac surgery are prescribed anti-platelet therapy, the predominant indication being for ischaemic heart disease. Almost half of all patients with previous coronary stenting had no anti-platelet therapy during the peri-operative period. The decision to cease anti-platelet therapy, which occurred commonly, did not appear to be guided by peri-operative cardiac risk stratification. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies.

Science.gov (United States)

Ashok, Penta; Ganguly, Swastika; Murugesan, Sankaranarayanan

2014-11-01

The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of β-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and -resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids. Copyright © 2014 Elsevier Ltd. All rights reserved.

Antimalarial Activity of Plant Metabolites.

Science.gov (United States)

Pan, Wen-Hui; Xu, Xin-Ya; Shi, Ni; Tsang, Siu Wai; Zhang, Hong-Jie

2018-05-06

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum . As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Antimalarial Activity of Plant Metabolites

Directory of Open Access Journals (Sweden)

Wen-Hui Pan

2018-05-01

Full Text Available Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002 reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Interactions of DB75, a Novel Antimalarial Agent, with Other Antimalarial Drugs In Vitro▿

OpenAIRE

Purfield, Anne E.; Tidwell, Richard R.; Meshnick, Steven R.

2008-01-01

Pafuramidine is a novel orally active antimalarial. To identify a combination partner, we measured the in vitro antimalarial activities of the active metabolite, DB75, with amodiaquine, artemisinin, atovaquone, azithromycin, chloroquine, clindamycin, mefloquine, piperaquine, pyronaridine, tafenoquine, and tetracycline. None of the drugs tested demonstrated antagonistic or synergistic activity in combination with pafuramidine.

The Tropical Brown Alga Lobophora variegata: A Source of Antiprotozoal Compounds

Science.gov (United States)

Cantillo-Ciau, Zulema; Moo-Puc, Rosa; Quijano, Leovigildo; Freile-Pelegrín, Yolanda

2010-01-01

Lobophora variegata, a brown alga collected from the coast of the Yucatan peninsula, Mexico, was studied for antiprotozoal activity against Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. The whole extract showed the highest activity against T. vaginalis, with an IC50 value of 3.2 μg/mL. For the fractions, the best antiprotozoal activity was found in non-polar fractions. The chloroform fraction of the extract contained a major sulfoquinovosyldiacylglycerol (SQDG), identified as 1-O-palmitoyl-2-O-myristoyl-3-O-(6‴-sulfo-α-d-quinovopyranosyl)-glycerol (1), together with small amounts of 1,2-di-O-palmitoyl-3-O-(6‴-sulfo-α-d-quinovopyranosyl)-glycerol (2) and a new compound identified as 1-O-palmitoyl-2-O-oleoyl-3-O-(6‴-sulfo-α-d-quinovopyranosyl)-glycerol (3). Their structures were elucidated on the basis of chemical and enzymatic hydrolysis and careful analysis of FAB-MS and NMR spectroscopic data. This is the first report on the isolation of SQDGs from L. variegata. The mixture of 1–3 showed good activity against E. histolytica and moderate activity against T. vaginalis with IC50s of 3.9 and 8.0 μg/mL, respectively, however, the activity of 1–3 is not as effective as metronidazole. These results afford ground information for the potential use of the whole extract and fractions of this species in protozoal infections. PMID:20479979

The Tropical Brown Alga Lobophora variegata: A Source of Antiprotozoal Compounds

Directory of Open Access Journals (Sweden)

Zulema Cantillo-Ciau

2010-04-01

Full Text Available Lobophora variegata, a brown alga collected from the coast of the Yucatan peninsula, Mexico, was studied for antiprotozoal activity against Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. The whole extract showed the highest activity against T. vaginalis, with an IC50 value of 3.2 mg/mL. For the fractions, the best antiprotozoal activity was found in non-polar fractions. The chloroform fraction of the extract contained a major sulfoquinovosyldiacylglycerol (SQDG, identified as 1-O-palmitoyl-2-O-myristoyl-3-O-(6´´´-sulfo-a-D-quinovopyranosyl-glycerol (1, together with small amounts of 1,2-di-O-palmitoyl-3-O-(6´´´-sulfo-a-D-quinovopyranosyl-glycerol (2 and a new compound identified as 1-O-palmitoyl-2-O-oleoyl-3-O-(6´´´-sulfo-a-D-quinovopyranosyl-glycerol (3. Their structures were elucidated on the basis of chemical and enzymatic hydrolysis and careful analysis of FAB-MS and NMR spectroscopic data. This is the first report on the isolation of SQDGs from L. variegata. The mixture of 1–3 showed good activity against E. histolytica and moderate activity against T. vaginalis with IC50s of 3.9 and 8.0 mg/mL, respectively, however, the activity of 1–3 is not as effective as metronidazole. These results afford ground information for the potential use of the whole extract and fractions of this species in protozoal infections.

Anticancer Effect of AntiMalarial Artemisinin Compounds | Das ...

African Journals Online (AJOL)

A PubMed search of about 127 papers on anti‑cancer effects of antimalarials has revealed that this class of drug, including other antimalarials, have several biological characteristics that include anticancer properties. ... Keywords: Anticancer agents, Antimalarials, Antitumor activity, Artemisinins, Novel chemotherapy ...

Plants as antimalarial agents in Sub-Saharan Africa.

Science.gov (United States)

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.

Cost-effectiveness of oral antiplatelet agents--current and future perspectives.

Science.gov (United States)

Arnold, Suzanne V; Cohen, David J; Magnuson, Elizabeth A

2011-08-09

Cardiovascular disease is both highly prevalent and exceedingly costly to treat. Several novel antiplatelet agents have been found to be effective in reducing the morbidity and mortality associated with cardiovascular disease. Understanding both the economic and the clinical implications of these novel therapies is particularly important. In this article, the results of published evaluations of the cost-effectiveness of oral antiplatelet strategies for use across a range of clinical conditions and treatment settings are reviewed. The results of these studies support the use of aspirin for primary prevention in high-risk patients and for secondary prevention in all patients with previous cardiovascular events. Although the optimal duration of dual antiplatelet therapy after an event remains uncertain, favorable cost-effectiveness estimates have been demonstrated for aspirin plus clopidogrel versus aspirin alone after a myocardial infarction or percutaneous coronary intervention. Moreover, prasugrel has been shown to be more cost-effective than clopidogrel for patients with an acute coronary syndrome and planned percutaneous coronary intervention. As novel antiplatelet agents emerge and existing agents are tested in different patient populations, the evaluation of the relative economic efficiency of these oral antiplatelet treatment strategies will continue to be instrumental to optimally inform clinical and health-policy decision-making.

Pattern and predictors of dual antiplatelet use after coronary artery bypass graft surgery.

Science.gov (United States)

Mori, Makoto; Shioda, Kayoko; Yun, James J; Mangi, Abeel A; Darr, Umer; Geirsson, Arnar

2018-02-01

Resumption of dual antiplatelet therapy after coronary artery bypass grafting in patients presenting with acute coronary syndrome is recommended, but the current practice pattern in the United States remains unknown. We aimed to investigate the current pattern of dual antiplatelet therapy use after coronary artery bypass grafting at the Yale-New Haven Hospital. We conducted a single-center retrospective review of patients who presented with acute coronary syndrome and underwent coronary artery bypass grafting between 2014 and 2016. The primary outcome was hospital discharge with dual antiplatelet therapy. Mixed-effect multivariate logistic regression was used to evaluate predictors of dual antiplatelet therapy use or nonuse, accounting for surgeon-specific preference. The discriminatory ability of the model was evaluated with receiver operating characteristics analysis. Of 572 patients included, only 29% were discharged with dual antiplatelet therapy. In the mixed-effect multivariate model isolating surgeon preferences, increase in age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; P dual antiplatelet therapy use. Off-pump coronary artery bypass grafting compared with on-pump coronary artery bypass grafting was associated with increased odds of dual antiplatelet therapy use (odds ratio, 31.5; 95% confidence interval, 12.8-77.2; P dual antiplatelet therapy use in patients with acute coronary syndrome who underwent coronary artery bypass grafting was low and variable among surgeons. The use or nonuse was guided by previously established risk factors of recurrent ischemia and bleeding, along with surgeon preference. Published by Elsevier Inc.

Antimalarial drugs in pregnancy: a review

NARCIS (Netherlands)

Nosten, François; McGready, Rose; d'Alessandro, Umberto; Bonell, Ana; Verhoeff, Francine; Menendez, Clara; Mutabingwa, Thenonest; Brabin, Bernard

2006-01-01

In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine,

Phytochemicalassay and Antiplatelet Activity of Fractions of Velvet Bean Seeds (Mucuna pruriens L.

Directory of Open Access Journals (Sweden)

WAHYU WIDOWATI

2010-06-01

Full Text Available Platelet aggregation is an important factor contributing to the formation of thrombus due to an uncontrolled blood clotting. An antiplatelet agent is a compound which decreases platelet aggregation and inhibits thrombus formation. The objectives of this study were to determine the class of compound employing phytochemical assay and to determine the in vitro antiplatelet activity of four fraction, namely hexane, ethyl acetate, butanol, and water fractions of velvet bean seeds (Mucuna pruriens L. using epinephrine (EPN as agonist of platelet aggregation. The antiplatelet activities were tested in human platelet rich plasma with hyperaggregation. To determine the activities, EPN was arranged at 4 level of concentrations (300, 150, 75, and 30 ì M, and antiplatelet agents were at 500 µg/ml. The results indicated that ethyl acetate, butanol and water fraction contained high flavonoids and moderate phenols. The water, butanol and ethyl acetate fractions of velvet bean seeds exhibited potential inhibition of EPN-induced platelet aggregation at all concentrations. The strongest antiplatelet agent was water fraction and had the same antiplatelet activity as aspirin at level 150, 75, and 30 ì M of EPN. Butanol fraction had the same antiplatelet activity as aspirin at the lowest EPN (30 ì M.

Antimalarial Activity of Azadipeptide Nitriles

OpenAIRE

Löser, Reik; Gut, Jiri; Rosenthal, Philip J.; Frizler, Maxim; Gütschow, Michael; Andrews, Katherine T.

2009-01-01

Azadipeptide nitriles – novel cysteine protease inhibitors – display structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine-resistant lines of cultured Plasmodium falciparum malaria parasites. Inhibition of parasite’s haemoglobin-degrading cysteine proteases was also investigated, revealing the azadipeptide nitriles as potent inhibitors of falcipain-2 and -3. A correlation between the cysteine protease-inhibiting activity and the antimalarial potential of...

Antiplatelet effects of Cyperus rotundus and its component (+)-nootkatone.

Science.gov (United States)

Seo, Eun Ji; Lee, Dong-Ung; Kwak, Jong Hwan; Lee, Sun-Mee; Kim, Yeong Shik; Jung, Yi-Sook

2011-04-26

Cyperus rotundus, a well-known oriental traditional medicine, has been reported to exhibit wide spectrum activity in biological systems including the circulatory system, however, little information is available on its antiplatelet activity. This study was undertaken to investigate the antiplatelet effects of Cyperus rotundus EtOH extract (CRE) and its constituent compounds. The antiplatelet activities of CRE and its eight constituent compounds were evaluated by examining their effects on rat platelet aggregations in vitro and ex vivo, and on mice tail bleeding times. During the in vitro platelet aggregation study, CRE showed significant and concentration-dependent inhibitory effects on collagen-, thrombin-, and/or AA-induced platelet aggregation. Of its eight components, (+)-nootkatone was found to have the most potent inhibitory effect on collagen-, thrombin-, and AA-induced platelet aggregation. In addition, CRE- and (+)-nootkatone-treated mice exhibited significantly prolonged bleeding times. Furthermore, (+)-nootkatone had a significant inhibitory effect on rat platelet aggregation ex vivo. This study demonstrates the antiplatelet effects of CRE and its active component (+)-nootkatone, and suggests that these agents might be of therapeutic benefit for the prevention of platelet-associated cardiovascular diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Some Pharmacological Aspects of Antimalarial Drugs

African Journals Online (AJOL)

1974-06-15

Jun 15, 1974 ... Some Pharmacological Aspects of Antimalarial. Drugs. D.BOTHA. SUMMARY. A short review is given of antimalarial drugs currently in use. S. Air. Med. l., 48, 1263 (1974). CLASSIFICATION. The chemotherapy of malaria may be conveniently classi- fied as (i) casual prophylaxis; (ii) suppressive treatment;.

Absolute configuration and antiprotozoal activity of minquartynoic acid

DEFF Research Database (Denmark)

Rasmussen, H B; Christensen, Søren Brøgger; Kvist, L P

2000-01-01

Minquartynoic acid (1) was isolated as an antimalarial and antileishmanial constituent of the Peruvian tree Minquartia guianensis and its absolute configuration at C-17 established to be (+)-S through conversion to the known (+)-(S)-17-hydroxystearic acid (2) and confirmed using Mosher's method....

Urological surgery and antiplatelet drugs after cardiac and cerebrovascular accidents.

Science.gov (United States)

Eberli, Daniel; Chassot, Pierre-Guy; Sulser, Tullio; Samama, Charles Marc; Mantz, Jean; Delabays, Alain; Spahn, Donat R

2010-06-01

The perioperative treatment of patients on dual antiplatelet therapy after myocardial infarction, cerebrovascular event or coronary stent implantation represents an increasingly frequent issue for urologists and anesthesiologists. We assess the current scientific evidence and propose strategies concerning treatment of these patients. A MEDLINE and PubMed search was conducted for articles related to antiplatelet therapy after myocardial infarction, coronary stents and cerebrovascular events, as well as the use of aspirin and/or clopidogrel in the context of surgery. Early discontinuation of antiplatelet therapy for secondary prevention is associated with a high risk of coronary thrombosis, which is further increased by the hypercoagulable state induced by surgery. Aspirin has recently been recommended as a lifelong therapy. Clopidogrel is mandatory for 6 weeks after myocardial infarction and bare metal stents, and for 12 months after drug-eluting stents. Surgery must be postponed beyond these waiting periods or performed with patients receiving dual antiplatelet therapy because withdrawal therapy increases 5 to 10 times the risk of postoperative myocardial infarction, stent thrombosis or death. The shorter the waiting period between revascularization and surgery the greater the risk of adverse cardiac events. The risk of surgical hemorrhage is increased approximately 20% by aspirin and 50% by clopidogrel. The risk of coronary thrombosis when antiplatelet agents are withdrawn before surgery is generally higher than the risk of surgical hemorrhage when antiplatelet agents are maintained. However, this issue has not yet been sufficiently evaluated in urological patients and in many instances during urological surgery the risk of bleeding can be dangerous. A thorough dialogue among surgeon, cardiologist and anesthesiologist is essential to determine all risk factors and define the best possible strategy for each patient. Copyright 2010 American Urological Association

Benefits of a Pharmacology Antimalarial Reference Standard and Proficiency Testing Program Provided by the Worldwide Antimalarial Resistance Network (WWARN)

Science.gov (United States)

Lourens, Chris; Lindegardh, Niklas; Barnes, Karen I.; Guerin, Philippe J.; Sibley, Carol H.; White, Nicholas J.

2014-01-01

Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modeling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures is necessary for verification of assay results. Within the Worldwide Antimalarial Resistance Network (WWARN), the goal of the quality assurance/quality control (QA/QC) program is to facilitate and sustain high-quality antimalarial assays. The QA/QC program consists of an international PT program for pharmacology laboratories and a reference material (RM) program for the provision of antimalarial drug standards, metabolites, and internal standards for laboratory use. The RM program currently distributes accurately weighed quantities of antimalarial drug standards, metabolites, and internal standards to 44 pharmacology, in vitro, and drug quality testing laboratories. The pharmacology PT program has sent samples to eight laboratories in four rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC program has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases. PMID:24777099

Terahertz absorption spectra of commonly used antimalarial drugs

Science.gov (United States)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-06-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Terahertz absorption spectra of commonly used antimalarial drugs

Science.gov (United States)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-03-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Antibacterial and antiprotozoal effect of Artemisia annua extracts

DEFF Research Database (Denmark)

Ivarsen, E.; Fretté, X. C.; Engberg, R. M.

2012-01-01

be banned in the EU. Extracts of aerial parts of Artemisia annua (AA) showed antimicrobial activity in overnight cultures of CP strains isolated from diseased broilers. The hexane extract (HEX) gave the strongest inhibition (MIC=185ppm) while the dichloromethane extract (DCM) gave a weaker inhibition (MIC......=270ppm). The dietary incorporation of HEX reduced the population of CP and the severity of the associated small intestinal lesions (P>0.05) in broilers when applying a NE disease model. The antibacterial compounds from HEX and DCM, chrysosplenol and ponticaepoxide, were isolated. This is the first...... report of activity against CP for these compounds. HEX, DCM and artemisinin were also tested against HM. The two latter showed highest antiprotozoal effect in vitro (MLC=1.0mg/ml and IC50=1.3mg/ml respectively), and were tested in vivo in infected poultry. However, no effect against HM at the given...

Phytochemical Assay and Antiplatelet Activity of Fractions of Velvet Bean Seeds (Mucuna pruriens L.

Directory of Open Access Journals (Sweden)

VICTOR IMMANUEL

2010-06-01

Full Text Available Platelet aggregation is an important factor contributing to the formation of thrombus due to an uncontrolled blood clotting. An antiplatelet agent is a compound which decreases platelet aggregation and inhibits thrombus formation. The objectives of this study were to determine the class of compound employing phytochemical assay and to determine the in vitro antiplatelet activity of four fraction, namely hexane, ethyl acetate, butanol, and water fractions of velvet bean seeds (Mucuna pruriens L. using epinephrine (EPN as agonist of platelet aggregation. The antiplatelet activities were tested in human platelet rich plasma with hyperaggregation. To determine the activities, EPN was arranged at 4 level of concentrations (300, 150, 75, and 30 μM, and antiplatelet agents were at 500 µg/ml. The results indicated that ethyl acetate, butanol and water fraction contained high flavonoids and moderate phenols. The water, butanol and ethyl acetate fractions of velvet bean seeds exhibited potential inhibition of EPN-induced platelet aggregation at all concentrations. The strongest antiplatelet agent was water fraction and had the same antiplatelet activity as aspirin at level 150, 75, and 30 μM of EPN. Butanol fraction had the same antiplatelet activity as aspirin at the lowest EPN (30 μM.

Synergistic In Vitro Antimalarial Activity of Omeprazole and Quinine

OpenAIRE

Skinner-Adams, T.; Davis, T. M. E.

1999-01-01

Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.

N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.

Science.gov (United States)

Pérez, Bianca C; Teixeira, Cátia; Albuquerque, Inês S; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Prudêncio, Miguel; Gomes, Paula

2013-01-24

The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

ANTIPROTOZOAL ACTIVITY OF EXTRACTS OF ELAEODENDRON TRICHOTOMUM (CELASTRACEAE).

Science.gov (United States)

Roca-Mézquita, Carolina; Graniel-Sabido, Manlio; Moo-Puc, Rosa E; Leon-Déniz, Lorena V; Gamboa-León, Rubí; Arjona-Ruiz, Carely; Tun-Garrido, Juan; Mirón-López, Gumersindo; Mena-Rejón, Gonzalo J

2016-01-01

Chagas disease, amebiasis, giardiasis and trichomoniasis represent a serious health problem in Latin America. The drugs employed to treat these illnesses produce important side effects and resistant strains have appeared. The present study was aimed to evaluate the antiprotozoal activity of leaves, stem bark and root bark of Elaeodendron trichotomum , a celastraceus, that is used in Mexico as an anti-infective in febrile-type diseases. Dichloromethane and methanol extracts of leaves, bark and roots of Elaeodendron trichotomum were tested against Entamoeba histolytica , Giardia lamblia , Trichomonas vaginalis , and Trypanosoma cruzi . A quantitative HPLC analysis of pristimerin and tingenone was performed. The dichloromethane extract of roots was active against E. histolytica , G. lamblia , T. vaginalis , and T. cruzi , at IC50's of 0.80, 0.44, 0.46, and 2.68 μg/mL, respectively. The HPLC analysis revealed the presence of tingenone (3.84%) and pristimerin (0.14%). The dichloromethane extract of the roots bark showed significant activity against all screened protozoa.

Antiplasmodial and antimalarial activities of quinolone derivatives: An overview.

Science.gov (United States)

Fan, Yi-Lei; Cheng, Xiang-Wei; Wu, Jian-Bing; Liu, Min; Zhang, Feng-Zhi; Xu, Zhi; Feng, Lian-Shun

2018-02-25

Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Is anti-platelet therapy interruption a real clinical issue? Its implications in dentistry and particularly in periodontics

Directory of Open Access Journals (Sweden)

Kumar A

2009-01-01

Full Text Available The use of anti-platelet therapy has reduced the mortality and morbidity of cardiovascular disease remarkably. A considerable number of patients presenting before a dentist or periodontist give a history of anti-platelet therapy. A clinical dilemma whether to discontinue the anti-platelet therapy or continue the same always confronts the practitioner. Diverse opinions exist regarding the management of such patients. While one group of researchers advise continuation of anti-platelet therapy rather than invite remote, but possible, thromboembolic events, another group encourages discontinuation for variable periods. This study aims at reviewing the current rationale of anti-platelet therapy and the various options available to a clinician, with regard to the management of a patient under anti-platelet therapy. Current recommendations and consensus favour no discontinuation of anti-platelet therapy. This recommendation, however, comes with a rider to use caution and consider other mitigating factors as well. With a large number of patients giving a history of anti-platelet therapy, the topic is of interest and helps a clinician to arrive at a decision.

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

Science.gov (United States)

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.

Quinoline hybrids and their antiplasmodial and antimalarial activities.

Science.gov (United States)

Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

2017-10-20

Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Individual patient data meta-analysis of antiplatelet regimens after noncardioembolic stroke or TIA : Rationale and design

NARCIS (Netherlands)

Greving, Jacoba P.; Diener, Hans Christoph; Csiba, László; Hacke, Werner; Kappelle, L. Jaap; Koudstaal, Peter J.; Leys, Didier; Mas, Jean Louis; Sacco, Ralph L.; Sivenius, Juhani; Algra, Ale

2015-01-01

Background: The Cerebrovascular Antiplatelet Trialists' Collaborative Group was formed to obtain and analyze individual patient data from the major randomized trials of common antiplatelet regimens after cerebral ischemia. Although the risk of stroke can be reduced by antiplatelet drugs, there

Awareness of antiplatelet resistance in patient with repeated episodes of thrombotic events

Science.gov (United States)

Dalimunthe, N. N.; Hamonangan, R.; Antono, D.; Prasetya, I.; Rusdi, L.

2018-03-01

Antiplatelet has been the cornerstones management of acute coronary syndrome. However, numbers of patients on these agents had episodes of adverse cardiovascular events. A 65-year-old woman post cardiac coronary bypass surgery on dual antiplatelet therapy, Aspirin, and Clopidogrel underwent several episodes of thrombotic events despite good adhered to thedailyantiplatelet regimen.These recurrent events had led to clinical suspicious of antiplatelet resistance. Platelet function test was performed which indicates a poor platelet response to Clopidogrel. Clopidogrelwas discontinued and Ticagrelor was prescribed together with Aspirin. During two months of follow up, there is no episode of chest discomfort.

Steam-cooking rapidly destroys and reverses onion-induced antiplatelet activity

Directory of Open Access Journals (Sweden)

Hansen Emilie A

2012-09-01

Full Text Available Abstract Background Foods in the diet that can aid in the prevention of diseases are of major interest. Onions are key ingredients in many cuisines around the world and moreover, onion demand has trended higher over the past three decades. An important pharmacological aspect of onion is the ability to inhibit platelet aggregation. Raw onions inhibit platelet aggregation; however, when onions are boiled or heated, antiplatelet activity may be abolished. Methods Onion quarters were steamed for 0, 1, 3, 6, 10, and 15 min. The in vitro antiplatelet activity of a yellow hybrid storage onion was examined at these times on the blood of 12 human subjects using in vitro whole blood aggregometry. Results Contrary to findings reported for boiling, antiplatelet activity was destroyed between 3 and 6 min of steaming, and at 10 min of steaming, cooked onions stimulated platelet activity. Extracts from cooked onion had the potential to reverse the inhibitory effect on blood platelets by 25%. Responses were consistent across all donors. Total polyphenolic concentration and soluble solids were not affected by steaming time. Conclusions The potential value of cooked onion preparations may result in destruction or reversal of antiplatelet activity, without affecting the polyphenolic concentration.

Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin.

Science.gov (United States)

Park, Gab-Man; Park, Hyun; Oh, Sangtae; Lee, Seokjoon

2017-12-01

We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.

Antimalarial drug policy in India: Past, present & future

Directory of Open Access Journals (Sweden)

Anupkumar R Anvikar

2014-01-01

Full Text Available 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.

QSAR modeling and chemical space analysis of antimalarial compounds

Science.gov (United States)

Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

2017-05-01

Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

Aspidosperma species as sources of antimalarials. Part III. A review of traditional use and antimalarial activity.

Science.gov (United States)

de Paula, Renata Cristina; Dolabela, Maria Fâni; de Oliveira, Alaíde Braga

2014-03-01

Several plant species belonging to the genus Aspidosperma are traditionally used in Brazil and other Meso- and South American countries for the treatment of malaria and fevers. These traditional uses were motivation for this review. A literature survey completed for this review has identified scientific bibliographical references to the use of 24 Aspidosperma species to treat malaria/fevers and to 19 species that have had their extracts and/or alkaloids evaluated, with good results, for in vitro and/or in vivo antimalarial activity. Indole alkaloids are typical constituents of Aspidosperma species. However, only 20 out of more than 200 known indole alkaloids isolated from this genus have been assayed for antimalarial activity. These data support the potential of Aspidosperma species as sources of antimalarials and the importance of research aimed at validating their use in the treatment of human malaria. Georg Thieme Verlag KG Stuttgart · New York.

The interaction of x-rays and antimalarials

International Nuclear Information System (INIS)

Geoghegan, D.S.; Skinner-Adams, T.; Davis, T.M.E.

2001-01-01

Full text: The radiation sensitivity of malaria parasites has three potential clinical applications, namely i) to prevent the transmission of malaria by blood transfusion, ii) as adjunctive therapy when a radioactive isotope is complexed to a conventional antimalarial drug, and iii) to attenuate the pathogenicity of specific parasite stages as part of the development of a vaccine. In the first two applications, detailed information relating to parasite radiosensitivity and the interaction of ionising radiation with antimalarials is of vital importance because dosimetry must allow for the exposure of normal cells. Malaria parasite cultures (Plasmodium falciparum) were exposed to a logarithmic series of concentrations of antimalarial agents and irradiated using a Siemens Stabilipan orthovoltage radiotherapy unit. The irradiation was performed at room temperature and ambient oxygen concentration. Control samples were also irradiated. The DNA synthesis in each culture was measured 48 hours post irradiation by using a 3 H-hypoxanthine incorporation assay. The antimalarials studied are: artesunate, quinine, retinol and chloroquine. The radiosensitivity of Plasmodium falciparum is not dependent on the strain of parasite with the dose required to inhibit 50% of DNA synthesis (ID 50 ) equal to 24.7 ± 3.0 Gy. This applies equally for the drug resistant and drug sensitive strains studied. Because the measured radiosensitivity is dependent on the sera oxygen concentration, the reported value for the ID 50 may not apply in hypoxic situations. The interaction of ionising radiation with the antimalarials shows synergy with retinol and choloquine, additivity with quinine and slight antagonism with artesunate. Radionuclide therapy may emerge as a novel treatment for malaria. If this does occur, then, although all strains appear to be equally radiosensitive, care must be taken when combining ionising radiation with existing antimalarials for the treatment of malaria. Copyright

Antiplatelet therapy in STEMI undergoing primary PCI, when, which one and how long.

Science.gov (United States)

Baralis, Giorgio; Rossini, Roberta; Musumeci, Giuseppe

2018-02-19

Reperfusion therapy for patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) involves primary percutaneous coronary intervention (PPCI) and concomitant dual antiplatelet therapy (DAPT) with combination of a P2Y12 inhibitor and acetylsalicylic acid (ASA). Decision regarding DAPT can be challenging clinically in the modern era with the evolution of newer stents, more potent antiplatelet agents and novel anticoagulant drugs in addition to an older patient population with multiple comorbidities. This review outlines the currently available antiplatelet treatments, and their place within the therapeutic timeline of a patient presenting with STEMI.

Does anti-malarial drug knowledge predict anti-malarial dispensing practice in drug outlets? A survey of medicine retailers in western Kenya

Directory of Open Access Journals (Sweden)

Rusk Andria

2012-08-01

Full Text Available Abstract Background Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial. Methods To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of the Webuye Health and Demographic Surveillance Site in the Bungoma East District of western Kenya. Results Most of the medicine retailers surveyed (65% were able to identify artemether-lumefantrine (AL as the Kenyan Ministry of Health recommended first-line anti-malarial therapy for uncomplicated malaria. Retailers who correctly identified this treatment were also more likely to recommend AL to adult and paediatric customers. However, the proportion of medicine retailers who recommend the correct treatment is disappointingly low. Only 48% would recommend AL to adults, and 37% would recommend it to children. It was discovered that customer demand has an influence on retailer behaviour. Retailer training and education were found to be correlated with anti-malarial drug knowledge, which in turn is correlated with dispensing practices. Medicine retailer behaviour, including patient referral practice and dispensing practices, are also correlated with knowledge of the first-line anti-malarial medication. The Kenya Ministry of Health guidelines were found to influence retailer drug stocking and dispensing behaviours. Conclusion Most medicine retailers could identify the recommended first-line treatment for uncomplicated malaria, but the percentage that could

Synthesis and evaluation of antimalarial activity of curcumin derivatives

International Nuclear Information System (INIS)

Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla

2014-01-01

ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC 50 values ranging from 1.7 to 15.2 μg mL -1 ), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

Synthesis and antimalarial evaluation of novel isocryptolepine derivatives.

Science.gov (United States)

Whittell, Louise R; Batty, Kevin T; Wong, Rina P M; Bolitho, Erin M; Fox, Simon A; Davis, Timothy M E; Murray, Paul E

2011-12-15

A series of mono- and di-substituted analogues of isocryptolepine have been synthesized and evaluated for in vitro antimalarial activity against chloroquine sensitive (3D7) and resistant (W2mef) Plasmodium falciparum and for cytotoxicity (3T3 cells). Di-halogenated compounds were the most potent derivatives and 8-bromo-2-chloroisocryptolepine displayed the highest selectivity index (106; the ratio of cytotoxicity (IC(50)=9005 nM) to antimalarial activity (IC(50)=85 nM)). Our evaluation of novel isocryptolepine compounds has demonstrated that di-halogenated derivatives are promising antimalarial lead compounds. Copyright © 2011 Elsevier Ltd. All rights reserved.

A review of the use of common antiplatelet agents in orthopaedic practice.

LENUS (Irish Health Repository)

Dineen, P F

2010-09-01

Antiplatelet agents are widely prescribed for the primary and secondary prevention of cardiovascular events. A common clinical problem facing orthopaedic and trauma surgeons is how to manage patients receiving these agents who require surgery, either electively or following trauma. The dilemma is to balance the risk of increased blood loss if the antiplatelet agents are continued peri-operatively against the risk of coronary artery\\/stent thrombosis and\\/or other vascular event if the drugs are stopped. The traditional approach of stopping these medications up to two weeks before surgery appears to pose significant danger to patients and may require review. This paper covers the important aspects regarding the two most commonly prescribed antiplatelet agents, aspirin and clopidogrel.

Ferroquine and its derivatives: new generation of antimalarial agents.

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Wani, Waseem A; Jameel, Ehtesham; Baig, Umair; Mumtazuddin, Syed; Hun, Lee Ting

2015-08-28

Malaria has been teasing human populations from a long time. Presently, several classes of antimalarial drugs are available in market, but the issues of toxicity, lower efficacy and the resistance by malarial parasites have decreased their overall therapeutic indices. Thus, the search for new promising antimalarials continues, however, the battle against malaria is far from over. Ferroquine is a derivative of chloroquine with antimalarial properties. It is the most successful of the chloroquine derivatives. Not only ferroquine, but also its derivatives have shown promising potential as antimalarials of clinical interest. Presently, much research is dedicated to the development of ferroquine derivatives as safe alternatives to antimalarial chemotherapy. The present article describes the structural, chemical and biological features of ferroquine. Several classes of ferroquine derivatives including hydroxyferroquines, trioxaferroquines, chloroquine-bridged ferrocenophanes, thiosemicarbazone derivatives, ferrocene dual conjugates, 4-N-substituted derivatives, and others have been discussed. Besides, the mechanism of action of ferroquine has been discussed. A careful observation has been made into pharmacologically significant ferroquine derivatives with better or equal therapeutic effects to that of chloroquine and ferroquine. A brief discussion of the toxicities of ferroquine derivatives has been made. Finally, efforts have been made to discuss the current challenges and future perspectives of ferroquine-based antimalarial drug development. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

World Antimalarial Resistance Network (WARN IV: Clinical pharmacology

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Gbotosho Grace O

2007-09-01

Full Text Available Abstract A World Antimalarial Resistance Network (WARN database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics. By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component

Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties

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Karène Urgin

2017-01-01

Full Text Available With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me2 or -N(Et2 in different positions (ortho, meta and para on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties.

Science.gov (United States)

Urgin, Karène; Jida, Mouhamad; Ehrhardt, Katharina; Müller, Tobias; Lanzer, Michael; Maes, Louis; Elhabiri, Mourad; Davioud-Charvet, Elisabeth

2017-01-19

With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N -arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal - N (Me)₂ or - N (Et)₂ in different positions ( ortho , meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N -arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para -position of the substituent remains the most favourable position on the benzyl chain and the carbamate - N HBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei -infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

Synthesis of febrifugine derivatives and development of an effective and safe tetrahydroquinazoline-type antimalarial.

Science.gov (United States)

Kikuchi, Haruhisa; Horoiwa, Seiko; Kasahara, Ryota; Hariguchi, Norimitsu; Matsumoto, Makoto; Oshima, Yoshiteru

2014-04-09

Febrifugine, a quinazoline alkaloid isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. Although the use of ferifugine as an antimalarial drug has been precluded because of its severe side effects, its potent antimalarial activity has stimulated medicinal chemists to pursue its derivatives instead, which may provide valuable leads for novel antimalarial drugs. In the present study, we synthesized new derivatives of febrifugine and evaluated their in vitro and in vivo antimalarial activities to develop antimalarials that are more effective and safer. As a result, we proposed tetrahydroquinazoline-type derivative as a safe and effective antimalarial candidate. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials.

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Gomes, Ana; Machado, Marta; Lobo, Lis; Nogueira, Fátima; Prudêncio, Miguel; Teixeira, Cátia; Gomes, Paula

2015-08-01

In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment.

Science.gov (United States)

Andrews, Katherine T; Fisher, Gillian M; Sumanadasa, Subathdrage D M; Skinner-Adams, Tina; Moeker, Janina; Lopez, Marie; Poulsen, Sally-Ann

2013-11-15

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite. Copyright © 2013 Elsevier Ltd. All rights reserved.

4-aminoquinoline analogues and its platinum (II) complexes as antimalarial agents.

Science.gov (United States)

de Souza, Nicolli Bellotti; Carmo, Arturene M L; Lagatta, Davi C; Alves, Márcio José Martins; Fontes, Ana Paula Soares; Coimbra, Elaine Soares; da Silva, Adilson David; Abramo, Clarice

2011-07-01

The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of β-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

[Retrospective analysis of correlative factors between digestive system injury and anticoagulant or antiplatelet-agents].

Science.gov (United States)

Cui, Ning; Luo, Hesheng

2014-05-27

To explore the correlative factors and clinical characteristics of digestive system injury during the treatment of anticoagulant and (or) antiplatelet-agents. A total of 1 443 hospitalized patients on anticoagulant and (or) antiplatelet-agents from January 2010 to December 2013 at Renmin Hospital of Wuhan University were analyzed retrospectively. Their length of hospital stay was from 5 to 27 days. Most of them were elderly males (n = 880, 61.0%) with an average age of (62 ± 6) years. 1 138 patients (78.9%) were farmers, workers or someone without a specific occupation. During the treatment of anticoagulant/antiplatelet-agents, statistical difference existed (P = 0.01) between positively and negatively previous digestive disease groups for actively newly occurring digestive system injury (16.0% (41/256) vs 15.9% (189/1 187)). After the dosing of anticoagulant and (or) antiplatelet-agents, 57 (66.3%, 57/86) patients were complicated by hemorrhage of digestive tract, taking 62.9% (61/97) of all positive result patients for Helicobacter pylori test. Comparing preventive PPI group with no PPI group, there was no marked statistical differences (P = 2.67) for digestive system complication (including hemorrhage of digestive tract) while receiving anticoagulant and (or) antiplatelet-agents (13.9% (74/533) vs 17.1% (156/910)). During anticoagulant and/or antiplatelet-agent therapy, 185 patients (12.8%) were complicated by peptic ulcer or peptic ulcer with bleeding, 40 patients (2.8%) had erosive gastritis and 5 (0.3%) developed acute gastric mucosal lesions. And 42 of 76 patients complicated by hemorrhage of digestive tract underwent endoscopic hemostasis while 2 patients were operated. Ninety-seven patients (6.7%) died, including 61 (62.9%, 61/97) from hemorrhage of digestive tract. The remainder became cured, improved and discharged. Moreover, no significant statistical differences existed (P = 2.29) among three combination group (aspirin, clopidogrel, warfarin), two

Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.

Science.gov (United States)

Tanaka, Takeshi Q; Guiguemde, W Armand; Barnett, David S; Maron, Maxim I; Min, Jaeki; Connelly, Michele C; Suryadevara, Praveen Kumar; Guy, R Kiplin; Williamson, Kim C

2015-03-01

Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs.

Science.gov (United States)

Piscianz, Elisa; Cuzzoni, Eva; Sharma, Rajan; Tesser, Alessandra; Sapra, Pooja; Tommasini, Alberto

2017-09-11

The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGAS-STING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Risk and benefit of dual antiplatelet treatment among non-revascularized myocardial infarction patients in different age groups.

Science.gov (United States)

Juul, Nikolai; Gislason, Gunnar; Olesen, Jonas Bjerring; Lamberts, Morten; Hansen, Morten Lock; Karasoy, Deniz; Christiansen, Christine Benn; Torp-Pedersen, Christian; Sorensen, Rikke

2017-09-01

Dual anti-platelet treatment with clopidogrel and aspirin is indicated for most patients after myocardial infarction. We examined the risk/benefit relationship of dual anti-platelet treatment according to age in a nationwide cohort of 30,532 myocardial infarction patients without revascularization. Patients admitted with first-time myocardial infarction in 2002-2010, not undergoing revascularization, were identified from nationwide Danish registers. Dual anti-platelet treatment use was assessed by claimed prescriptions. Stratified into age groups, risk of bleeding, all-cause mortality and a combined endpoint of cardiovascular death, recurrent myocardial infarction and ischaemic stroke was analysed by Cox proportional-hazard models and tested in a propensity-score matched population. A total of 21,302 users and 9230 non-users of dual anti-platelet treatment were included (mean age 67.02 (±13.8) years and 64.7% males). Use of dual anti-platelet treatment decreased with age: 80% (79 years). We found a reduced risk of cardiovascular death, recurrent myocardial infarction and ischaemic stroke in users 79 years (HR=0.92; 95% CI 0.84-1.01, NS). Risk of bleeding increased with dual anti-platelet treatment use in patients aged 79 years (HR=1.46; 95% CI 1.22-1.74). Similar tendencies in all four age groups were found in the propensity-matched population. Dual anti-platelet treatment use was less likely among elderly patients although similar effects regarding both risk and benefit were found in all age groups. Increased focus on initiating dual anti-platelet treatment in elderly, non-invasively treated myocardial infarction patients is warranted.

Update: Acute coronary syndromes (V). Personalized antiplatelet therapy.

Science.gov (United States)

Gurbel, Paul A; Rafeedheen, Rahil; Tantry, Udaya S

2014-06-01

It is well established that high on-treatment platelet reactivity to adenosine diphosphate during clopidogrel therapy is an independent risk factor for ischemic event occurrences in a postpercutaneous coronary intervention patients. However, the precise role of platelet function testing remains debated. Platelet function testing to ensure optimal platelet inhibition has been recommended by some authorities to improve outcomes in patients treated with clopidogrel. Recent prospective, randomized trials of personalized antiplatelet therapy have failed to demonstrate a benefit of platelet function testing in improving outcomes. In this review article, we discuss the mechanisms responsible for clopidogrel nonreponsiveness, recent trials of platelet function testing, and other new developments in the field of personalized antiplatelet therapy. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Spontaneous subdural hematoma and antiplatelet therapy: Does efficacy of Ticagrelor come with added risk?

Directory of Open Access Journals (Sweden)

Pattanagere Manjunatha Suryanarayana Sharma

2015-12-01

Full Text Available Antiplatelet therapy has established clinical benefit on cardiovascular outcome and has reduced the rates of re-infarction/in stent thrombosis following percutaneous coronary intervention in acute coronary syndromes. Major bleeding episodes can occur with antiplatelet therapy and intracranial hemorrhage (ICH is one of the most feared complications resulting in significant morbidity and mortality. Identification of high risk groups and judicious use of antiplatelet therapy reduces the bleeding risk. Ticagrelor is a newer P2Y12 receptor antagonist with established clinical benefit. However, risks of having an ICH with these newer molecules cannot be ignored. Here, we report a case of spontaneous acute subdural hematoma developing in a patient on antiplatelet therapy with aspirin and ticagrelor. Early recognition, discontinuation of the medication and appropriate management resulted in resolution of hematoma and good clinical outcome. Authors have reviewed the antithrombotic drugs and their tendencies in causing intracranial bleeds from a neurophysicians perspective.

Estimated Under-Five Deaths Associated with Poor-Quality Antimalarials in Sub-Saharan Africa

Science.gov (United States)

Renschler, John P.; Walters, Kelsey M.; Newton, Paul N.; Laxminarayan, Ramanan

2015-01-01

Many antimalarials sold in sub-Saharan Africa are poor-quality (falsified, substandard, or degraded), and the burden of disease caused by this problem is inadequately quantified. In this article, we estimate the number of under-five deaths caused by ineffective treatment of malaria associated with consumption of poor-quality antimalarials in 39 sub-Saharan countries. Using Latin hypercube sampling our estimates were calculated as the product of the number of private sector antimalarials consumed by malaria-positive children in 2013; the proportion of private sector antimalarials consumed that were of poor-quality; and the case fatality rate (CFR) of under-five malaria-positive children who did not receive appropriate treatment. An estimated 122,350 (interquartile range [IQR]: 91,577–154,736) under-five malaria deaths were associated with consumption of poor-quality antimalarials, representing 3.75% (IQR: 2.81–4.75%) of all under-five deaths in our sample of 39 countries. There is considerable uncertainty surrounding our results because of gaps in data on case fatality rates and prevalence of poor-quality antimalarials. Our analysis highlights the need for further investigation into the distribution of poor-quality antimalarials and the need for stronger surveillance and regulatory efforts to prevent the sale of poor-quality antimalarials. PMID:25897068

High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

Science.gov (United States)

Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

2015-01-01

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.

OpenAIRE

Rosenthal, P J; Olson, J E; Lee, G K; Palmer, J T; Klaus, J L; Rasnick, D

1996-01-01

We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or...

Antimalarial activity of plumbagin in vitro and in animal models.

Science.gov (United States)

Sumsakul, Wiriyaporn; Plengsuriyakarn, Tullayakorn; Chaijaroenkul, Wanna; Viyanant, Vithoon; Karbwang, Juntra; Na-Bangchang, Kesara

2014-01-12

Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.

Antiplatelet antibody may cause delayed transfusion-related acute lung injury

Directory of Open Access Journals (Sweden)

Torii Y

2011-09-01

Full Text Available Yoshitaro Torii1, Toshiki Shimizu1, Takashi Yokoi1, Hiroyuki Sugimoto1, Yuichi Katashiba1, Ryotaro Ozasa1, Shinya Fujita1, Yasushi Adachi2, Masahiko Maki3, Shosaku Nomura11The First Department of Internal Medicine, Kansai Medical University, Osaka, 2Department of Clinical Pathology, Toyooka Hospital, Hyogo, 3First Department of Pathology, Kansai Medical University, Osaka, JapanAbstract: A 61-year-old woman with lung cancer developed delayed transfusion-related acute lung injury (TRALI syndrome after transfusion of plasma- and leukoreduced red blood cells (RBCs for gastrointestinal bleeding due to intestinal metastasis. Acute lung injury (ALI recurred 31 days after the first ALI episode. Both ALI episodes occurred 48 hours after transfusion. Laboratory examinations revealed the presence of various antileukocyte antibodies including antiplatelet antibody in the recipient's serum but not in the donors' serum. The authors speculate that antiplatelet antibodies can have an inhibitory effect in the recipient, which can modulate the bona fide procedure of ALI and lead to a delay in the onset of ALI. This case illustrates the crucial role of a recipient's platelets in the development of TRALI.Keywords: delayed TRALI syndrome, recurrence, anti-platelet antibody

Antimalarial Drug: From its Development to Deface.

Science.gov (United States)

Barik, Tapan Kumar

2015-01-01

Wiping out malaria is now the global concern as about three billion people are at risk of malaria infection globally. Despite of extensive research in the field of vaccine development for malaria, till now, no effective vaccine is available for use and hence only antimalarial drugs remain our best hope for both treatment and prevention of malaria. However, emergence and spread of drug resistance has been a major obstacle for the success of malaria elimination globally. This review will summarize the information related to antimalarial drugs, drug development strategies, drug delivery through nanoparticles, few current issues like adverse side effects of most antimalarial drugs, non availability of drugs in the market and use of fake/poor quality drugs that are hurdles to malaria control. As we don't have any other option in the present scenario, we have to take care of the existing tools and make them available to almost all malaria affected area.

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products

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Eduardo Fuentes

2013-01-01

Full Text Available Platelets are no longer considered simply as cells participating in thrombosis. In atherosclerosis, platelets are regulators of multiple processes, with the recruitment of inflammatory cells towards the lesion sites, inflammatory mediators release, and regulation of endothelial function. The antiplatelet therapy has been used for a long time in an effort to prevent and treat cardiovascular diseases. However, limited efficacy in some patients, drug resistance, and side effects are limitations of current antiplatelet therapy. In this context, a large number of natural products (polyphenols, terpenoids, alkaloids, and fatty acids have been reported with antiplatelet activity. In this sense, the present paper describes mechanisms of antiplatelet action of natural products on platelet P-selectin expression through cAMP levels and its role as peroxisome proliferator-activated receptors agonists.

Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan to improve antiplatelet therapy

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Pepinghege Fenena

2011-01-01

Full Text Available Abstract Background Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm. Methods Platelet function testing using whole blood aggregometry (Chronolog 590 was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP 5 μM and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily, and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance. Results Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all

Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

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Avinaba Mukherjee

2016-03-01

Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

QSAR models for anti-malarial activity of 4-aminoquinolines.

Science.gov (United States)

Masand, Vijay H; Toropov, Andrey A; Toropova, Alla P; Mahajan, Devidas T

2014-03-01

In the present study, predictive quantitative structure - activity relationship (QSAR) models for anti-malarial activity of 4-aminoquinolines have been developed. CORAL, which is freely available on internet (http://www.insilico.eu/coral), has been used as a tool of QSAR analysis to establish statistically robust QSAR model of anti-malarial activity of 4-aminoquinolines. Six random splits into the visible sub-system of the training and invisible subsystem of validation were examined. Statistical qualities for these splits vary, but in all these cases, statistical quality of prediction for anti-malarial activity was quite good. The optimal SMILES-based descriptor was used to derive the single descriptor based QSAR model for a data set of 112 aminoquinolones. All the splits had r(2)> 0.85 and r(2)> 0.78 for subtraining and validation sets, respectively. The three parametric multilinear regression (MLR) QSAR model has Q(2) = 0.83, R(2) = 0.84 and F = 190.39. The anti-malarial activity has strong correlation with presence/absence of nitrogen and oxygen at a topological distance of six.

In vivo Antimalarial Activity of Methanol and Water Extracts of ...

African Journals Online (AJOL)

Conclusions: The possible active compounds responsible for the observed chemosupression may be flavonoids, terpeneoids and anthraquinones which are present in the extract. This is the first report on the in vivo antimalarial activity of E. thorifolium. Keywords: Antimalarial, Eryngium thorifolium, Plasmodium berghei, ...

Antiprotozoal activity of extracts and isolated triterpenoids of 'carnauba' (Copernicia prunifera) wax from Brazil.

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de Almeida, Buana C; Araújo, Bruno Q; Carvalho, Adonias A; Freitas, Sâmya Danielle L; Maciel, Dayany da S Alves; Ferreira, Ari José S; Tempone, Andre G; Martins, Ligia F; Alexandre, Tatiana R; Chaves, Mariana H; Lago, João Henrique G

2016-12-01

'Carnauba' wax is a natural product obtained from the processing of the powder exuded from Copernicia prunifera (Miller) H. E. Moore (Arecaceae). This material is widely used in the Brazilian folk medicine, including the treatment of rheumatism and syphilis. To investigate the antiprotozoal activity of hexane and EtOH extracts from the 'carnauba' wax as well as from the isolated compounds from the bioactive extracts. Two different samples of 'carnauba' (C. prunifera) waxes - types 1 and 4 - were individually extracted using hexane (EH) and EtOH (EE). Aliquots of hexane (type 1 - EH-1 and EH-4) and EtOH (type 4 - EE-1 and EE-4) extracts were tested against promastigote (2-200 μg/mL in DMSO during 48 h at 24 °C) and amastigote (3-150 μg/mL in DMSO during 120 h at 37 °C) forms of Leishmania infantum as well as against trypomastigote (3-150 μg/mL in DMSO during 24 h at 37 °C) forms of Trypanosoma cruzi. Bioactive extracts EH-1 and EE-4 were subjected to a bioactivity-guided fractionation to afford three dammarane-type triterpenoids (1-3). The in vitro antiprotozoal activities of the obtained compounds were evaluated as described above. Additionally, the cytotoxicity activity of compounds 1-3 against mammalian conjunctive cells (NCTC - 2-200 μg/mL in DMSO during 48 h at 37 °C) was determined. From the bioactive hexane and EtOH extracts from the 'carnauba' (C. prunifera) wax, were isolated three dammarane-type triterpenoids: (24R*)-methyldammar-25-ene-3β,20-diol (carnaubadiol, 1), (24R*)-methyldammara-20,25-dien-3-one (2) and (24R*)-methyldammara-20,25-dien-3α-ol (3). These compounds were identified based on the analysis of NMR and MS spectroscopic data. Compounds 1-3 were effective against the intracellular amastigotes of L. infantum, with IC 50 values ranging from 8 to 52 μM, while compounds 1 and 3 displayed activity against trypomastigote forms of T. cruzi with IC 50 values of 15 and 35 μM, respectively. The mammalian

Natural cocoa as diet-mediated antimalarial prophylaxis.

Science.gov (United States)

Addai, F K

2010-05-01

The Maya of Central America are credited with the first consumption of cocoa and maintaining its ancient Olmec name kakawa translated in English as "God Food", in recognition of its multiple health benefits. The legend of cocoa is receiving renewed attention in recent years, on account of epidemiological and scientific studies that support its cardiovascular health benefits. Increasing numbers of scientific reports corroborating cocoa's antiquated reputation as health food persuaded this author to promote regular consumption of cocoa in Ghana since 2004. Cocoa is readily available in Ghana; the country is the second largest producer accounting for 14% of the world's output. Numerous anecdotal reports of reduced episodic malaria in people who daily drink natural unsweetened cocoa beverage prompted a search for scientific mechanisms that possibly account for cocoa's antimalarial effects. This paper presents the outcome as a hypothesis. Internet search for literature on effects of cocoa's ingredients on malaria parasites and illness using a variety of search tools. Evidential literature suggests five mechanisms that possibly underpin cocoa's anecdotal antimalarial effects. (i) Increased availability of antioxidants in plasma, (ii) membrane effects in general and erythrocyte membrane in particular, (iii) increased plasma levels of nitric oxide, (iv) antimalarial activity of cocoa flavanoids and their derivatives, and (v) boosted immune system mediated by components of cocoa including cocoa butter, polyphenols, magnesium, and zinc. A hypothesis is formulated that cocoa offers a diet-mediated antimalarial prophylaxis; and an additional novel tool in the fight against the legendary scourge.

Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic

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Alexandre Manirakiza

2011-01-01

Full Text Available Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%, artemisinin-based combinations (26.8% and artemisinin monotherapy (14.4%. Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9% and (13.3%. respectively. Conclusion. This study showed a relatively high rate (>80% of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested.

Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic

Science.gov (United States)

Manirakiza, Alexandre; Soula, Georges; Laganier, Remi; Klement, Elise; Djallé, Djibrine; Methode, Moyen; Madji, Nestor; Heredeïbona, Luc Salva; Le Faou, Alain; Delmont, Jean

2011-01-01

Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%), artemisinin-based combinations (26.8%) and artemisinin monotherapy (14.4%). Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9%) and (13.3%). respectively. Conclusion. This study showed a relatively high rate (>80%) of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested. PMID:22312567

Apixaban with antiplatelet therapy after acute coronary syndrome

NARCIS (Netherlands)

Alexander, J.H.; Lopes, R.D.; James, S.; Kilaru, R.; He, Y.; Mohan, P.; Bhatt, D.L.; Goodman, S.; Verheugt, F.W.A.; Flather, M.; Huber, K.; Liaw, D.; Husted, S.E.; Lopez-Sendon, J.; De Caterina, R.; Jansky, P.; Darius, H.; Vinereanu, D.; Cornel, J.H.; Cools, F.; Atar, D.; Leiva-Pons, J.L.; Keltai, M.; Ogawa, H.; Pais, P.; Parkhomenko, A.; Ruzyllo, W.; Diaz, R.; White, H.; Ruda, M.; Geraldes, M.; Lawrence, J.; Harrington, R.A.; Wallentin, L.

2011-01-01

BACKGROUND: Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg

Quinoline-Based Hybrid Compounds with Antimalarial Activity

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Xhamla Nqoro

2017-12-01

Full Text Available The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies.

A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.

Science.gov (United States)

Sadashiva, Maralinganadoddi P; Gowda, Raghavendra; Wu, Xianzhu; Inamdar, Gajanan S; Kuzu, Omer F; Rangappa, Kanchugarakoppal S; Robertson, Gavin P; Gowda, D Channe

2015-08-01

Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM. Several carboxylic group-derivatives of abietic acid were moderately active with IC50 values of ~8.2 to ~13.3 µM. These results suggest that a detailed understanding of the structure-activity relationship of abietane diterpenoids might provide strategies to exploit this class of compounds for malaria treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement.

Science.gov (United States)

Shen, Shuo; Liu, Shu-Zhi; Zhang, Yu-Shi; Du, Mao-Bo; Liang, Ai-Hua; Song, Li-Hua; Ye, Zu-Guang

2015-01-01

Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem-ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data obtained in this study showed that the application of ethosomal technology to antimalarial cataplasm could improve the transdermal delivery of drug, enhance the efficacy, and facilitate practical application in clinic.

Docking, synthesis and antimalarial activity of novel 4-anilinoquinoline derivatives.

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Vijayaraghavan, Shilpa; Mahajan, Supriya

2017-04-15

A series of 4-anilinoquinoline triazine derivatives were designed, synthesized and screened for in vivo antimalarial activity against a chloroquine-sensitive strain of Plasmodium berghei. The compounds were further subjected to in vitro antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum and β-haematin inhibition studies. All the compounds exhibited in vivo antimalarial activity better than that shown by the standard drug, chloroquine. Twelve out of fifteen compounds showed better inhibition than that of chloroquine against chloroquine-resistant W2 strain of Plasmodium falciparum. Ten compounds showed β-haematin inhibition, better than that of chloroquine, with IC 50 values in the range of 18-25µM. One compound, 3k, was found to be better than artemisinin against W2 strain of Plasmodium falciparum and also displayed the best β-haematin inhibitory activity, thereby becoming eligible to be explored as a potential lead for antimalarial chemotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of antimalarial properties of novel 4-aminoquinoline hybrid compounds.

Science.gov (United States)

Fisher, Gillian M; Tanpure, Rajendra P; Douchez, Antoine; Andrews, Katherine T; Poulsen, Sally-Ann

2014-10-01

Pharmacophore hybridization has recently been employed in the search for antimalarial lead compounds. This approach chemically links two pharmacophores, each with their own antimalarial activity and ideally with different modes of action, into a single hybrid molecule with the goal to improve therapeutic properties. In this paper, we report the synthesis of novel 7-chloro-4-aminoquinoline/primary sulfonamide hybrid compounds. The chlorinated 4-aminoquinoline scaffold is the core structure of chloroquine, an established antimalarial drug, while the primary sulfonamide functional group has a proven track record of efficacy and safety in many clinically used drugs and was recently shown to exhibit some antimalarial activity. The activity of the hybrid compounds was determined against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. While the hybrid compounds had lower antimalarial activity when compared to chloroquine, they demonstrated a number of interesting structure-activity relationship (SAR) trends including the potential to overcome the resistance profile of chloroquine. © 2014 John Wiley & Sons A/S.

Poisoning by anti-malarial drugs

African Journals Online (AJOL)

had taken chloroquine: no other anti-malarial drugs were involved [1]. ... and angio-oedema have been described. Itching without a ... 15mg/L the risk of permanent visual damage and cardiac dysrhythmias is ... to use an alternative method.

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

NARCIS (Netherlands)

Baigent, C; Sudlow, C; Collins, R; Peto, R

2002-01-01

Objective To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Design Collaborative meta-analyses (systematic overviews). Inclusion criteria Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another

Contemporary Parenteral Antiplatelet Bridging Strategies: A Single-Center Real-World Experience at a Tertiary Care Center.

Science.gov (United States)

Stern, Gretchen; Rimsans, Jessica; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2018-03-13

Oral antiplatelet therapy may require interruption soon after percutaneous coronary intervention (PCI) or acute coronary syndrome. The optimal parenteral antiplatelet bridge strategy with glycoprotein IIb/IIIa inhibitors or cangrelor, a P2Y12 inhibitor, is unclear. We explore real-world use of cangrelor or eptifibatide for antiplatelet bridging at a large tertiary-care center. Thirty-one patients (9 eptifibatide, 20 cangrelor, and 2 both) received bridge therapy from October 2015 to June 2017. Primary bridge therapy indications included surgery (68%), limited enteral access/absorption (16%), and high-perceived bleed risk (16%). Median duration of bridge therapy was 61 (20-100) hours for cangrelor and 83 (19-98) hours for eptifibatide. Severe/life-threatening bleeding or stent thrombosis was not observed. GUSTO-defined bleeding occurred in 30% (cangrelor) and 27% (eptifibatide). Initial dosing errors occurred in 23% of patients. Death during hospitalization occurred in 16% of patients. Parenteral antiplatelet bridging was used for ~3 days in this single-center, tertiary care experience, commonly for unplanned surgery following PCI. Despite high-risk presentations with >15% in-hospital mortality, efficacy profiles were reassuring with no identified stent thrombosis, but bleeding and dosing errors were common. Antiplatelet bridging should only be used in well-selected patients at the appropriate dose for the minimal necessary duration.

Titration of antiplatelet treatment in pregnant women at risk of preeclampsia.

Science.gov (United States)

Sullivan, M H; Clark, N A; de Swiet, M; Nelson-Piercy, C; Elder, M G

1998-04-01

We recruited 111 patients who were considered to be at significantly increased risk of preeclampsia on the basis of previous obstetric history or preexisting medical disorders. All patients were treated with low dose aspirin (75 mg/day) from the first occasion the patient attended the antenatal clinic, regardless of gestational age. If the maternal mean platelet volume (MPV) increased significantly (by > 0.8 fl) from the baseline, antiplatelet treatment was increased. Five pregnancies were lost during the second trimester and 106 of the treated patients had live infants. The incidence of neonatal death (3/106 infants) was much lower than in the previous pregnancies in these patients (32/134 infants). Patients who were treated from the first trimester of pregnancy (group A, 89 patients) did substantially better than those treated from the second trimester (group B, 17 patients) as assessed by the incidence of pre-eclampsia or intrauterine growth restriction (IUGR), gestational age and birthweight at delivery. These data suggest that longitudinal monitoring of the MPV may identify the women who could benefit from increased antiplatelet treatment, and that antiplatelet treatment may be more effective when initiated in the first trimester rather than later in pregnancy.

Discontinuation of antiplatelet treatment and risk of recurrent stroke and all-cause death

DEFF Research Database (Denmark)

Ostergaard, Kamilla; Pottegård, Anton; Hallas, Jesper

2014-01-01

use and followed them up for stroke recurrence, or all-cause death. Person-time was classified by antiplatelet drug use into current use, recent use (≤150 days after last use), and non-use (>150 days after last use). Lipid-lowering drug (LLD) use was classified by the same rules. We used Cox......BACKGROUND: We wished to examine the impact of antiplatelet drug discontinuation on recurrent stroke and all-cause mortality. METHODS: We identified a cohort of incident ischaemic stroke patients in a Danish stroke registry, 2007-2011. Using population-based registries we assessed subjects' drug...... proportional hazard models to calculate the adjusted hazard ratio (HR) and corresponding 95% confidence intervals (CIs) for the risk of recurrent stroke or death associated with discontinuation of antiplatelet or LLD drugs. RESULTS: Among 4,670 stroke patients followed up for up a median of 1.5 years, 237...

Application of Feedback System Control Optimization Technique in Combined Use of Dual Antiplatelet Therapy and Herbal Medicines

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Wang Liu

2018-05-01

Full Text Available Aim: Combined use of herbal medicines in patients underwent dual antiplatelet therapy (DAPT might cause bleeding or thrombosis because herbal medicines with anti-platelet activities may exhibit interactions with DAPT. In this study, we tried to use a feedback system control (FSC optimization technique to optimize dose strategy and clarify possible interactions in combined use of DAPT and herbal medicines.Methods: Herbal medicines with reported anti-platelet activities were selected by searching related references in Pubmed. Experimental anti-platelet activities of representative compounds originated from these herbal medicines were investigated using in vitro assay, namely ADP-induced aggregation of rat platelet-rich-plasma. FSC scheme hybridized artificial intelligence calculation and bench experiments to iteratively optimize 4-drug combination and 2-drug combination from these drug candidates.Results: Totally 68 herbal medicines were reported to have anti-platelet activities. In the present study, 7 representative compounds from these herbal medicines were selected to study combinatorial drug optimization together with DAPT, i.e., aspirin and ticagrelor. FSC technique first down-selected 9 drug candidates to the most significant 5 drugs. Then, FSC further secured 4 drugs in the optimal combination, including aspirin, ticagrelor, ferulic acid from DangGui, and forskolin from MaoHouQiaoRuiHua. Finally, FSC quantitatively estimated the possible interactions between aspirin:ticagrelor, aspirin:ferulic acid, ticagrelor:forskolin, and ferulic acid:forskolin. The estimation was further verified by experimentally determined Combination Index (CI values.Conclusion: Results of the present study suggested that FSC optimization technique could be used in optimization of anti-platelet drug combinations and might be helpful in designing personal anti-platelet therapy strategy. Furthermore, FSC analysis could also identify interactions between different

Cajachalcone: An Antimalarial Compound from Cajanus cajan Leaf Extract

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E. O. Ajaiyeoba

2013-01-01

Full Text Available Cajanus cajan L, a member of the family Fabaceae, was identified from the Nigerian antimalarial ethnobotany as possessing antimalarial properties. The bioassay-guided fractionation of the crude methanol extract of C. cajan leaves was done in vitro using the multiresistant strain of Plasmodium falciparum (K1 in the parasite lactate dehydrogenase assay. Isolation of compound was achieved by a combination of chromatographic techniques, while the structure of the compound was elucidated by spectroscopy. This led to the identification of a cajachalcone, 2′,6′-dihydroxy-4-methoxy chalcone, as the biologically active constituent from the ethyl acetate fraction. Cajachalcone had an IC50 value of 2.0 μg/mL (7.4 μM and could be a lead for anti-malarial drug discovery.

Antiplatelet therapy and vascular disease: an update.

Science.gov (United States)

Buch, Mamta H; Prendergast, Bernard D; Storey, Robert F

2010-08-01

Atherosclerosis is a diffuse, systemic disorder of the large and medium-sized arterial vessels, affecting the coronary, cerebral and peripheral circulation. Chronic inflammatory processes are the central pathophysiological mechanism largely driven by lipid accumulation, and provide the substrate for occlusive thrombus formation. The clinical sequelae of acute arterial thrombosis, heart attack and stroke, are the most common causes of morbidity and mortality in the industrialized world. Such acute events are characterized by rupture or erosion of the atherosclerotic plaque leading to acute thrombosis. The atherosclerotic process and associated thrombotic complications are collectively termed atherothrombosis. The platelet is a pivotal mediator of various endothelial, immune, thrombotic and inflammatory responses and therefore a key player in the initiation and progression of atherothrombosis. A robust evidence base supports the clear clinical benefits of antiplatelet agents in the primary and secondary therapy of atherothrombotic disorders. Percutaneous coronary and peripheral interventions have an established central role in the management of atherothrombotic disease and demand a greater understanding of platelet biology. In this article, we provide a clinically orientated overview of the pathophysiology of arterial thrombosis and the evidence supporting the use of the various established antiplatelet therapies, and discuss new and future agents.

Survey of chemical compounds tested in vitro against rumen protozoa for possible control of bloat.

Science.gov (United States)

Willard, F L; Kodras, R

1967-09-01

Over 170 chemical agents were screened for antiprotozoal action in bovine ruminal fluid. Compounds were tested at 0.1 and 0.05% concentrations. Tested compounds included inorganic compounds, antibiotics, biocides, neuromuscular agents, arsenicals, plant and animal hormones, antimalarials, surface-active agents, anthelmintics, and many others. The most active compounds were cupric sulfate, nickel sulfate, nitrofurazone, hydrogen peroxide, dodecyl sodium sulfate, pelargonic acid, iodoacetic acid, 1-diethylaminoethylamino-4-methylthiaxanthrone, sodium arsanilate, sodium arsenate, bismuth glycolyl arsanilate, 1-beta-hydroxyethyl-2-methyl-5-nitroimidazole, and p-nitroaniline. Copper ion was not particularly effective against entodinia; nickel ion had no effect on holotrichs. Hydrogen peroxide and iodoacetic acid were effective at a concentration of 0.005%. Anionic surface-active agents were very effective, especially long-chain sulfates and phosphates. These antiprotozoal agents warrant further in vivo studies for possible use in treating or curing bloat in ruminants.

Antimalarial Anthrone and Chromone from the Leaf Latex of Aloe ...

African Journals Online (AJOL)

In Ethiopian traditional medicine, the leaf latex of Aloe debranan Chrstian is used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the leaf latex of A. debrana was tested for its in vivo antimalarial activity, in a 4-day suppressive assay ...

Antimalarial Activity of Methanolic Leaf Extract of Piper betle L.

Directory of Open Access Journals (Sweden)

Adel A. Amran

2010-12-01

Full Text Available The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50–400 mg/kg was investigated for its antimalarial activity against Plasmodium berghei (NK65 during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P < 0.05 schizonticidal activity in all three antimalarial evaluation models. Phytochemical screening showed that the leaf extract contains some vital antiplasmodial chemical constituents. The extract also exhibited a potent ability to scavenge the free radicals. The results of acute toxicity showed that the methanol extract of Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439).

Science.gov (United States)

Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J; Chiu, Francis C K; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L; Urwyler, Heinrich; Charman, William N; Matile, Hugues; Wittlin, Sergio; Charman, Susan A; Vennerstrom, Jonathan L

2017-04-13

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK a and lower log D 7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D 7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.

HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

NARCIS (Netherlands)

Ramcharan, A.S.; van Stralen, K.J.; Snoep, J.D.; Mantel-Teeuwisse, A.K.; Doggen, Catharina Jacoba Maria

2009-01-01

Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet

Safety of percutaneous nephrolithotomy in patients on chronic anticoagulant or antiplatelet therapy.

Science.gov (United States)

Fernández-Baltar, C; Pérez-Fentes, D; Sánchez-García, J F; García-Freire, C

2018-01-22

In developed countries, the incidence of cardiovascular disease is increasing, therefore, anticoagulant and antiplatelet drugs are a widespread treatment nowadays. Percutaneous nephrolithotomy (PNL) is the first-line treatment for large or complex stones (> 2 cm) and remains an alternative for the smaller ones. The objective of this study is to analyze whether PNL surgery is a safe procedure in patients under a treatment discontinuation protocol for anticoagulant or antiplatelet therapies. We retrospectively studied 301 patients who underwent PNL in our hospital between 2008 and 2016 and identified 46 patients on chronic antiplatelet or anticoagulation treatment. With respect to PNL outcomes, the stone-free rate was similar (78 vs 74%, p = 0.762) in both groups, without any significant differences in the overall postoperative complications (17 vs 26%, p = 0.203). The incidence of hemorrhagic complications was similar between groups (12 vs 9%, p = 0.492), as demonstrated by the mean drop in hemoglobin (Hb), which was comparable in both cohorts (2.2 ± 1.3 vs 2.0 ± 1.4 p = 0.270) and the blood transfusion rate (14% in group A and 8% in group B, p = 0.205). No thromboembolic events were found within the year after the PNL procedure. PNL is a safe and effective intervention in patients under a treatment discontinuation protocol for anticoagulant or antiplatelet therapies. Although our study demonstrates the feasibility of this protocol, new scientific evidence aims to stratify the thromboembolic and bleeding risk of each patient to individualize the perioperative management thereafter.

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones.

Science.gov (United States)

Sarkar, Souvik; Siddiqui, Asim A; Saha, Shubhra J; De, Rudranil; Mazumder, Somnath; Banerjee, Chinmoy; Iqbal, Mohd S; Nag, Shiladitya; Adhikari, Susanta; Bandyopadhyay, Uday

2016-07-01

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (KD [equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [(3)H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Spontaneous pulmonary hematoma in a patient with sepsis treated with dual antiplatelet therapy.

Science.gov (United States)

Vlaović, Janko; Voga, Gorazd

2016-12-01

A 72-year-old patient was admitted to the medical intensive care unit due to a right-sided, hospital-acquired pneumonia and septic shock with respiratory failure and deterioration of chronic renal failure. During hospitalization the patient required hemodynamic support with norepinephrine and dobutamine, mechanical ventilation and hemodialysis. The patient suffered a non-ST segment elevation myocardial infarction (NSTEMI) and received dual antiplatelet therapy. After 14 days an acute intrapulmonary infiltrate of unknown origin developed, accompanied by fever and a significant increase of the C‑reactive protein (CRP) level. Chest radiography and a computed tomography (CT) scan showed a well-defined, round, high-attenuation lesion in the lungs and a suspected infected pulmonary hematoma, which was confirmed by percutaneous aspiration biopsy. There was no evidence of trauma and it is believed that the hematoma occurred spontaneously, probably because of the dual antiplatelet therapy. Double antibiotic treatment was started but no surgery was performed after consultation with a thoracic surgeon. The antiplatelet drugs were temporarily withdrawn until the size of the hematoma showed no further increase and then antiplatelet therapy was continued. After stabilization the patient was discharged from hospital and 6 months later a follow-up chest X‑ray showed almost complete resolution of the hematoma.

TIPdb: A Database of Anticancer, Antiplatelet, and Antituberculosis Phytochemicals from Indigenous Plants in Taiwan

Directory of Open Access Journals (Sweden)

Ying-Chi Lin

2013-01-01

Full Text Available The unique geographic features of Taiwan are attributed to the rich indigenous and endemic plant species in Taiwan. These plants serve as resourceful bank for biologically active phytochemicals. Given that these plant-derived chemicals are prototypes of potential drugs for diseases, databases connecting the chemical structures and pharmacological activities may facilitate drug development. To enhance the utility of the data, it is desirable to develop a database of chemical compounds and corresponding activities from indigenous plants in Taiwan. A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan was constructed. The database, TIPdb, is composed of a standardized format of published anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. A browse function was implemented for users to browse the database in a taxonomy-based manner. Search functions can be utilized to filter records of interest by botanical name, part, chemical class, or compound name. The structured and searchable database TIPdb was constructed to serve as a comprehensive and standardized resource for anticancer, antiplatelet, and antituberculosis compounds search. The manually curated chemical structures and activities provide a great opportunity to develop quantitative structure-activity relationship models for the high-throughput screening of potential anticancer, antiplatelet, and antituberculosis drugs.

TIPdb: a database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan.

Science.gov (United States)

Lin, Ying-Chi; Wang, Chia-Chi; Chen, Ih-Sheng; Jheng, Jhao-Liang; Li, Jih-Heng; Tung, Chun-Wei

2013-01-01

The unique geographic features of Taiwan are attributed to the rich indigenous and endemic plant species in Taiwan. These plants serve as resourceful bank for biologically active phytochemicals. Given that these plant-derived chemicals are prototypes of potential drugs for diseases, databases connecting the chemical structures and pharmacological activities may facilitate drug development. To enhance the utility of the data, it is desirable to develop a database of chemical compounds and corresponding activities from indigenous plants in Taiwan. A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan was constructed. The database, TIPdb, is composed of a standardized format of published anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. A browse function was implemented for users to browse the database in a taxonomy-based manner. Search functions can be utilized to filter records of interest by botanical name, part, chemical class, or compound name. The structured and searchable database TIPdb was constructed to serve as a comprehensive and standardized resource for anticancer, antiplatelet, and antituberculosis compounds search. The manually curated chemical structures and activities provide a great opportunity to develop quantitative structure-activity relationship models for the high-throughput screening of potential anticancer, antiplatelet, and antituberculosis drugs.

Dentists' approach to patients on anti-platelet agents and warfarin: a survey of practice.

LENUS (Irish Health Repository)

Murphy, James

2010-04-23

In everyday practice, dentists are confronted with the dilemma of patients on anti-platelet agents and warfarin who require invasive dental procedures and, more pertinently, dental extractions. There may be a divergence of opinion among dentists regarding how they manage these patients. AIMS: To assess general dental practitioners\\' approach to the management of patients taking anti-platelet agents and\\/or warfarin who are undergoing invasive dental procedures. METHODS AND DATA: A semi-structured questionnaire was designed to survey general dental practitioners in a large Irish urban area. RESULTS: A response rate of 89% was achieved in a study population of 54 general dental practitioners. A total of 25% of respondents who carry out extractions on warfarinised patients do not check the INR prior to invasive dental procedures. Some 90% of respondents stop anti-platelet agents prior to extractions. CONCLUSIONS: A significant proportion of respondents fail to check warfarinised patients\\' INR prior to invasive dental procedures. Furthermore, a trend of stopping anti-platelet agents was noted, which is in contrast with current recommendations in the dental literature. Certain practices in this small study population proved alarming and highlight the need for improved awareness of current guidelines. A further large-scale study may be justified, as variation in practice may have clinical and medico-legal repercussions.

Subdural haematoma complicating shunting for normal pressure hydrocephalus in the setting of concomitant antiplatelet medication

DEFF Research Database (Denmark)

Birkeland, Peter; Lauritsen, Jens; Poulsen, Frantz Rom

2016-01-01

OBJECTIVE: To report on the occurrence and management of subdural haematoma after shunt implantation for normal pressure hydrocephalus and to determine the risk of recurrence in the setting of antiplatelet medication. METHODS: From a consecutive series of 80 patients implanted with a cerebrospinal...... fluid shunt for normal pressure hydrocephalus, records from 11 patients taking antiplatelet drugs, who subsequently had surgery for subdural haematoma were extracted and retrospectively reviewed. RESULTS: Patients were followed up for a mean of 1819 days after shunt implantation. Subdural haematomas...... reoperations done before the subdural collection disappeared. Only one patient had a late recurrence almost 11 years after shunt implantation. CONCLUSIONS: Subdural haematoma in the setting of a ventriculoperitoneal implantation for normal pressure hydrocephalus and concomitant antiplatelet medication can...

Analgesic, anti-inflammatory and anti-platelet activities of Buddleja crispa.

Science.gov (United States)

Bukhari, Ishfaq A; Gilani, Anwar H; Meo, Sultan Ayoub; Saeed, Anjum

2016-02-25

Buddleja crispa Benth (Buddlejaceae) is a dense shrub; several species of genus Buddleja have been used in the management of various health conditions including pain and inflammation. The present study was aimed to investigate the analgesic, anti-inflammatory and anti-platelet properties of B. crispa. Male rats (220-270 gm,) and mice (25-30 gm) were randomly divided into different groups (n = 6). Various doses of plant extract of B. crispa, its fractions and pure compounds isolated from the plant were administered intraperitoneally (i.p). The analgesic, anti-inflammatory and anti-platelet activities were assessed using acetic acid and formalin-induced nociception in mice, carrageenan-induced rat paw edema and arachidonic acid-induced platelets aggregation tests. The intraperitoneal administration of the methanolic extract (50 and 100 mg/kg), hexane fraction (10 and 25 mg/kg i.p) exhibited significant inhibition (P < 0.01) of the acetic acid-induced writhing in mice and attenuated formalin-induced reaction time of animals in second phase of the test. Pure compounds BdI-2, BdI-H3 and BH-3 isolated from B. crispa produced significant (P < 0.01) analgesic activity in acetic acid-induced and formalin tests. The crude extract of B. crispa (50-200 mg/kg i.p.) and its hexane fraction inhibited carrageenan-induced rat paw edema with maximum inhibition of 65 and 71% respectively (P < 0.01). The analgesic and anti-inflammatory effect of the plant extract and isolated pure compounds were comparable to diclofenac sodium. B. crispa plant extract (0.5-2.5 mg/mL) produced significant anti-platelet effect (P < 0.01) with maximum inhibition of 78% at 2.5 mg/ml. The findings from our present study suggest that B. crispa possesses analgesic, anti-inflammatory and anti-platelet properties. B. crispa could serve a potential novel source of compounds effective in pain and inflammatory conditions.

Quinine conjugates and quinine analogues as potential antimalarial agents.

Science.gov (United States)

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.

Novel series of 1,2,4-trioxane derivatives as antimalarial agents.

Science.gov (United States)

Rudrapal, Mithun; Chetia, Dipak; Singh, Vineeta

2017-12-01

Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC 50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski's rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

Compound antimalarial ethosomal cataplasm: preparation, evaluation, and mechanism of penetration enhancement

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Shen S

2015-06-01

Full Text Available Shuo Shen, Shu-Zhi Liu, Yu-Shi Zhang, Mao-Bo Du, Ai-Hua Liang, Li-Hua Song, Zu-Guang Ye Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China Abstract: Malaria is still a serious public health problem in some parts of the world. The problems of recurrence and drug resistance are increasingly more serious. Thus, it is necessary to develop a novel antimalarial agent. The objectives of this study were to construct a novel compound antimalarial transdermal nanosystem–ethosomal cataplasm, to investigate its characteristics and efficiency, and to systematically explore the penetration-enhancing mechanisms of ethosomal cataplasm. Artesunate-loaded ethosomes and febrifugine-loaded ethosomes were prepared, and their characteristics were evaluated. Drug-loaded ethosomes were incorporated in the matrix of cataplasm to form the compound antimalarial ethosomal cataplasm. With the help of ethosomal technology, the accumulated permeation quantity of artesunate significantly increased at 8 hours after administration, which was 1.57 times as much as that of conventional cataplasm. Soon after administration, the ethosomal cataplasm could make a large quantity of antimalarial drug quickly penetrate through skin, then the remaining drug in the ethosomal cataplasm could be steadily released. These characteristics of ethosomal cataplasm are favorable for antimalarial drugs to kill Plasmodium spp. quickly and prevent the resurgence of Plasmodium spp. As expected, the ethosomal cataplasm showed good antimalarial efficiency in this experiment. The negative conversion rates were 100% and the recurrence rates were 0% at all dosages. The mechanism of penetration enhancement of the ethosomal cataplasm was systematically explored using an optics microscope, polarization microscope, and transmission electron microscopy. The microstructure, ultrastructure, and birefringent structure in skin were observed. Data

Acridine and Acridinones: Old and New Structures with Antimalarial Activity

OpenAIRE

Valdés, Aymé Fernández-Calienes

2011-01-01

Since emergence of chloroquine-resistant Plasmodium falciparum and reports of parasite resistance to alternative drugs, there has been renewed interest in the antimalarial activity of acridines and their congeners, the acridinones. This article presents literature compilation of natural acridinone alkaloids and synthetic 9-substituted acridines, acridinediones, haloalcoxyacridinones and 10-N-substituted acridinones with antimalarial activity. The review also provides an outlook to antimalaria...

Effect of Tomato Industrial Processing on Phenolic Profile and Antiplatelet Activity

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Iván Palomo

2013-09-01

Full Text Available Background: Regular consumption of fruits and vegetables (e.g., tomatoes has been shown to be beneficial in terms of reducing the incidence of cardiovascular diseases. The industrial processing of tomatoes into tomato-based products includes several thermal treatments. Very little is known on the effect of tomato industrial processing on antiaggregatory activity and phenolic profile. Methods: It was assessed the effect of tomato and by-products extracts on platelet aggregation induced by ADP, collagen, TRAP-6 and arachidonic acid. These in vitro antithrombotic properties were further supported in an in vivo model of thrombosis. A set of antiplatelet compounds has been selected for HPLC analysis in the different extracts. Results: Some natural compounds such as chlorogenic, caffeic, ferulic and p-coumaric acids were identified by HPLC in tomatoes and its products may inhibit platelet activation. Red tomatoes, tomato products (sauce, ketchup and juice and by-products extracts inhibited platelet aggregation induced adenosine 5'-diphosphate, collagen, thrombin receptor activator peptide-6 and arachidonic acid, but to a different extent. Also, pomace extract presents antithrombotic activity. Conclusions: Processed tomatoes may have a higher content of health-benefiting compounds than fresh ones. Pomace even presents the best antiplatelet activity. Finally, tomato products may be used as a functional ingredient adding antiplatelet activities to processed foods.

Antimalarial activity of methanolic leaf extract of Piper betle L.

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Al-Adhroey, Abdulelah H; Nor, Zurainee M; Al-Mekhlafi, Hesham M; Amran, Adel A; Mahmud, Rohela

2010-12-28

The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

In Vivo Antimalarial Activity of Solvent Fractions of the Leaves of ...

African Journals Online (AJOL)

Increasing resistance of Plasmodium falciparum to almost all the available antimalarial drugs urges a search for newer antimalarial drugs. Justicia schimperiana Hochst. Ex Nees is traditionally used for the treatment of malaria and a study conducted previously on the crude leaf extract confirmed that the plant is endowed ...

Synthetic Antimalarial Maculopathy: A Case Report

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Aziz El Ouaf

2017-04-01

Full Text Available Antimalarial drug-induced retinopathy was first described in the 1950s. Screening for preclinical poisoning prevents evolution to irreversible maculopathy. We discuss, through the case of maculopathy with antimalarial (AM revealed by progressive bilateral decrease in vision in a patient with lupus, the modalities of monitoring patients treated with AM and the management of a potential intoxication. All authors stress the need for clinical and paraclinical ophthalmological monitoring regularly to detect early signs of impaired retinal function at a reversible stage. Indeed, at a more severe retinal intoxication, impaired visual function remains irreversible and can lead to blindness. A full ophthalmologic assessment is necessary before starting long course treatment with AM, possibly coupled with additional tests (central visual field, colour vision and/or electrophysiological examinations.

Comparison of antimalarial activity of Artemisia turanica extract with current drugs in vivo.

Science.gov (United States)

Taherkhani, Mahboubeh; Rustaiyan, Abdolhossein; Nahrevanian, Hossein; Naeimi, Sabah; Taherkhani, Tofigh

2013-03-01

The purpose of this study was to compare antimalarial activity of Artemisia turanica Krasch as Iranian flora with current antimalarial drugs against Plasmodium berghei in vivo in mice. Air-dried aerial parts of Iranian flora A. turanica were collected from Khorasan, northeastern Iran, extracted with Et2O/MeOH/Petrol and defatted. Toxicity of herbal extracts was assessed on male NMRI mice, and their antimalarial efficacy was compared with antimalarial drugs [artemether, chloroquine and sulfadoxinepyrimethamine (Fansidar)] on infected P. berghei animals. All the groups were investigated for parasitaemia, body weight, hepatomegaly, splenomegaly and anemia. The significance of differences was determined by Analysis of Variances (ANOVA) and Student's t-test using Graph Pad Prism software. The inhibitory effects of A. turanica extract on early decline of P. berghei parasitaemia highlights its antimalarial activity, however, this effect no longer can be observed in the late infection. This may be due to the metabolic process of A. turanica crude extract by mice and reduction of its concentration in the body. Crude extract of A. turanica represented its antisymptomatic effects by stabilization of body, liver and spleen weights. This study confirmed antimalarial effects of A. turanica extracts against murine malaria in vivo during early infection, however, there are more benefits on pathophysiological symptoms by this medication.

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands.

Science.gov (United States)

Hubin, Timothy J; Amoyaw, Prince N-A; Roewe, Kimberly D; Simpson, Natalie C; Maples, Randall D; Carder Freeman, TaRynn N; Cain, Amy N; Le, Justin G; Archibald, Stephen J; Khan, Shabana I; Tekwani, Babu L; Khan, M O Faruk

2014-07-01

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development. Published by Elsevier Ltd.

Dual Antiplatelet Therapy in Secondary Prevention of Ischemic Stroke: A Ghost from the Past or a New Frontier?

Directory of Open Access Journals (Sweden)

Clotilde Balucani

2010-01-01

Full Text Available With majority of ischemic strokes attributable to atherothrombosis and many being predictable after transient ischemic attacks (TIA, the role of early secondary prevention with antiplatelet agents is under renewed investigation. Prior major clinical trials of various secondary stroke prevention regimens pointed to a greater efficacy of dual antiplatelet agents if initiated early from symptom onset. This paper examines data and rationale behind dual antiplatelet regimens across the completed clinical trials. The safety of dual antiplatelets approach is of concern, but it could be outweighed, at least in early management, by a greater reduction in recurrence of ischemic events since this risk is “front loaded” after minor stroke or TIA. Aspirin monotherapy, though considered standard of care, is compared to aspirin-extended release dipiridamole and its combination with clopidogrel in early-phase completed and efficacy-phase ongoing clinical trials.

Antimalarial activity of HIV-1 protease inhibitor in chromone series.

Science.gov (United States)

Lerdsirisuk, Pradith; Maicheen, Chirattikan; Ungwitayatorn, Jiraporn

2014-12-01

Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65μM), was found to be the most potent antimalarial compound with IC50=0.95μM while primaquine and tafenoquine showed IC50=2.41 and 1.95μM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=-13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis and antiplatelet activity of thioaryloxyacids analogues of clofibric acid.

Science.gov (United States)

Ammazzalorso, Alessandra; Amoroso, Rosa; Baraldi, Mario; Bettoni, Giancarlo; Braghiroli, Daniela; De Filippis, Barbara; Giampietro, Letizia; Tricca, Maria L; Vezzalini, Francesca

2005-09-01

The thiophene-, benzothiazole- and pyridine-thioaryloxyacids analogues of clofibric acid were synthesized and their antiplatelet activity was screened. Some compounds exhibited antiaggregating properties. The platelet-related haemostasis was measured on a PFA-100 analyzer using bull blood.

Substandard anti-malarial drugs in Burkina Faso

Directory of Open Access Journals (Sweden)

Sie Ali

2008-05-01

Full Text Available Abstract 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

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

Science.gov (United States)

Meyers, Marvin J; Anderson, Elizabeth J; McNitt, Sarah A; Krenning, Thomas M; Singh, Megh; Xu, Jing; Zeng, Wentian; Qin, Limei; Xu, Wanwan; Zhao, Siting; Qin, Li; Eickhoff, Christopher S; Oliva, Jonathan; Campbell, Mary A; Arnett, Stacy D; Prinsen, Michael J; Griggs, David W; Ruminski, Peter G; Goldberg, Daniel E; Ding, Ke; Liu, Xiaorong; Tu, Zhengchao; Tortorella, Micky D; Sverdrup, Francis M; Chen, Xiaoping

2015-08-15

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria

NARCIS (Netherlands)

Newton, Paul N.; van Vugt, Michele; Teja-Isavadharm, Paktiya; Siriyanonda, Duangsuda; Rasameesoroj, Maneerat; Teerapong, Pramote; Ruangveerayuth, Ronatrai; Slight, Thra; Nosten, Francois; Suputtamongkol, Yupin; Looareesuwan, Sornchai; White, Nicholas J.

2002-01-01

Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ

An investigation of the antiplatelet effects of succinobucol (AGI-1067).

Science.gov (United States)

Houston, Stephanie A; Ugusman, Azizah; Gnanadesikan, Sukanya; Kennedy, Simon

2017-05-01

Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10 -5 -10 -4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.

In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra.

Directory of Open Access Journals (Sweden)

Komal Kalani

Full Text Available Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69 µg/ml anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250 mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.

Modelling the impact of antimalarial quality on the transmission of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum

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Aleisha R. Brock

2017-05-01

Full Text Available Background: The use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s can theoretically promote the emergence and transmission of drug resistant parasites. Methods: We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant and both poor quality and good quality (artemether-lumefantrine antimalarial use. Findings: The model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy. Interpretation: Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria. Keywords: Deterministic compartmental model, Falsified antimalarial medicine, Substandard antimalarial treatments, Antimalarial quality, Plasmodium falciparum malaria, Drug resistance

Antimalarial activity of selected Ethiopian medicinal plants in mice

Directory of Open Access Journals (Sweden)

Eshetu M. Bobasa

2018-02-01

Full Text Available Context: Parasites are the leading killers in subtropical areas of which malaria took the lion share from protozoan diseases. Measuring the impact of antimalarial drug resistance is difficult, and the impact may not be recognized until it is severe, especially in high transmission areas. Aims: To evaluate the in vivo antimalarial activities of hydroalcoholic extracts of the roots of Piper capense and Adhatoda schimperiana, against Plasmodium berghei in mice. Methods: Four-day suppressive and curative test animal models were used to explore the antimalarial activities of the plants. 200, 400, and 600 mg/kg of each plant extract was administered to check the activities versus vehicle administered mice. Mean survival time and level of parasitemia were the major variables employed to compare the efficacy vs. negative control. Results: In both models the 400 and 600 mg/kg doses of Adhatoda schimperiana and the 600 mg/kg dose Piper capense. showed significant parasitemia suppression and increased in mean survival time at p≤0.05. The middle dose of Piper capense had a border line inhibition where the extracts were considered active when parasitemia was reduced by ≥ 30%. Conclusions: The hydroalcoholic extracts of the roots of Adhatoda schimperiana and Piper capense possess moderate antimalarial activities, which prove its traditional claims. Thus, further studies should be done to isolate the active constituents for future use in the modern drug discovery.

The ACTwatch project: methods to describe anti-malarial markets in seven countries.

Science.gov (United States)

Shewchuk, Tanya; O'Connell, Kathryn A; Goodman, Catherine; Hanson, Kara; Chapman, Steven; Chavasse, Desmond

2011-10-31

Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012.ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate findings widely for decision

The ACTwatch project: methods to describe anti-malarial markets in seven countries

Directory of Open Access Journals (Sweden)

Chapman Steven

2011-10-01

Full Text Available Abstract Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT and malaria diagnostics including rapid diagnostic tests (RDTs. To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the

The ACTwatch project: methods to describe anti-malarial markets in seven countries

Science.gov (United States)

2011-01-01

Background Policy makers, governments and donors are faced with an information gap when considering ways to improve access to artemisinin-based combination therapy (ACT) and malaria diagnostics including rapid diagnostic tests (RDTs). To help address some of these gaps, a five-year multi-country research project called ACTwatch was launched. The project is designed to provide a comprehensive picture of the anti-malarial market to inform national and international anti-malarial drug policy decision-making. Methods The project is being conducted in seven malaria-endemic countries: Benin, Cambodia, the Democratic Republic of Congo, Madagascar, Nigeria, Uganda and Zambia from 2008 to 2012. ACTwatch measures which anti-malarials are available, where they are available and at what price and who they are used by. These indicators are measured over time and across countries through three study components: outlet surveys, supply chain studies and household surveys. Nationally representative outlet surveys examine the market share of different anti-malarials passing through public facilities and private retail outlets. Supply chain research provides a picture of the supply chain serving drug outlets, and measures mark-ups at each supply chain level. On the demand side, nationally representative household surveys capture treatment seeking patterns and use of anti-malarial drugs, as well as respondent knowledge of anti-malarials. Discussion The research project provides findings on both the demand and supply side determinants of anti-malarial access. There are four key features of ACTwatch. First is the overlap of the three study components where nationally representative data are collected over similar periods, using a common sampling approach. A second feature is the number and diversity of countries that are studied which allows for cross-country comparisons. Another distinguishing feature is its ability to measure trends over time. Finally, the project aims to disseminate

Pyrimidines in antimalarial drug design

CSIR Research Space (South Africa)

Moleele, SS

2008-09-01

Full Text Available of the routes attempted are shown in Scheme 1. Pyrimidines In Antimalarial Drug Design S S Moleele1, D Gravestock1, A L Rousseau1, R L Van Zyl2 1Discovery Chemistry, CSIR, Biosciences, Private Bag X2, Modderfontein, 1645, South Africa; SMoleele@csir.co.za 2...

Naturally occurring cobalamins have antimalarial activity.

Science.gov (United States)

Chemaly, Susan M; Chen, Chien-Teng; van Zyl, Robyn L

2007-05-01

The acquisition of resistance by malaria parasites towards existing antimalarials has necessitated the development of new chemotherapeutic agents. The effect of vitamin B(12) derivatives on the formation of beta-haematin (synthetic haemozoin) was determined under conditions similar to those in the parasitic food vacuole (using chloroquine, a known inhibitor of haemozoin formation for comparison). Adenosylcobalamin (Ado-cbl), methylcobalamin (CH(3)-cbl) and aquocobalamin (H(2)O-cbl) were approximately forty times more effective inhibitors of beta-haematin formation than chloroquine, cyanocobalamin (CN-cbl) was slightly more inhibitory than chloroquine, while dicyanocobinamide had no effect. It is proposed that the cobalamins exert their inhibitory effect on beta-haematin formation by pi-interactions of their corrin ring with the Fe(III)-protoporphyrin ring and by hydrogen-bonding using their 5,6-dimethylbenzimidazole/ribose/sugar side-chain. The antimalarial activity for the cobalamins (Ado-cbl>CH(3)-cbl>H(2)O-cbl>CN-cbl) was found to be less than that for chloroquine or quinine. Ado-cbl, CH(3)-cbl and CN-cbl do not accumulate in the parasite food vacuole by pH trapping, but H(2)O-cbl does. Unlike humans, the malaria parasite has only one enzyme that uses cobalamin as a cofactor, namely methionine synthase, which is important for growth and metabolism. Thus cobalamins in very small amounts are necessary for Plasmodium falciparum growth but in larger amounts they display antimalarial properties.

Antiplatelet therapy for recurrent stroke prevention: newer perspectives based on (MATCH), (CHARISMA), and (ESPRIT).

Science.gov (United States)

Gorelick, Philip B

2008-01-01

Antiplatelet therapy is an important component of our armamentarium for recurrent stroke prevention. Aspirin is a safe and effective antiplatelet drug for recurrent stroke prevention, however, it has been challenged recently by the thienopyridine derivative, clopidogrel, and the combination agent, aspirin plus extended release dipyridamole. In this review, we discuss recent studies of thienopyridine derivatives and aspirin plus extended-release dipyridamole in stroke prevention and evidence-based guidelines for the administration of these agents in practice for recurrent stroke prevention.

Antiprotozoal activity of medicinal plants used by Iquitos-Nauta road communities in Loreto (Peru).

Science.gov (United States)

Vásquez-Ocmín, Pedro; Cojean, Sandrine; Rengifo, Elsa; Suyyagh-Albouz, Soulaf; Amasifuen Guerra, Carlos A; Pomel, Sébastien; Cabanillas, Billy; Mejía, Kember; Loiseau, Philippe M; Figadère, Bruno; Maciuk, Alexandre

2018-01-10

In the Peruvian Amazon, the use of medicinal plants is a common practice. However, there is few documented information about the practical aspects of their use and few scientific validation. The starting point for this work was a set of interviews of people living in rural communities from the Peruvian Amazon about their uses of plants. Protozoan diseases are a public health issue in the Amazonian communities, who partly cope with it by using traditional remedies. Validation of these traditional practices contributes to public health care efficiency and may help identify new antiprotozoal compounds. to inventory and validate the use of medicinal plants by rural people of Loreto region. Rural mestizos were interviewed about traditional medication of parasite infections with medicinal plants. Ethnopharmacological surveys were undertaken in two villages along Iquitos-Nauta road (Loreto region, Peru), namely 13 de Febrero and El Dorado communities. Forty-six plants were collected according to their traditional use for the treatment of parasitic diseases, 50 ethanolic extracts (different parts for some of the plants) were tested in vitro on Plasmodium falciparum (3D7 sensitive strain and W2 chloroquine resistant strain), Leishmania donovani LV9 strain and Trypanosoma brucei gambiense. Cytotoxic assessment (HUVEC cells) of the active extracts was performed. Two of the most active plants were submitted to preliminary bioguided fractionation to ascertain and explore their activities. From the initial plants list, 10 were found to be active on P. falciparum, 15 on L. donovani and 2 on the three parasites. The ethanolic extract from Costus curvibracteatus (Costaceae) leaves and Grias neuberthii (Lecythidaceae) bark showed strong in vitro activity on P. falciparum (sensitive and resistant strain) and L. donovani and moderate activity on T. brucei gambiense. The Amazonian forest communities in Peru represents a source of knowledge on the use of medicinal plants. In this work

A New In Vivo Screening Paradigm to Accelerate Antimalarial Drug Discovery

Science.gov (United States)

Jiménez-Díaz, María Belén; Viera, Sara; Ibáñez, Javier; Mulet, Teresa; Magán-Marchal, Noemí; Garuti, Helen; Gómez, Vanessa; Cortés-Gil, Lorena; Martínez, Antonio; Ferrer, Santiago; Fraile, María Teresa; Calderón, Félix; Fernández, Esther; Shultz, Leonard D.; Leroy, Didier; Wilson, David M.; García-Bustos, José Francisco; Gamo, Francisco Javier; Angulo-Barturen, Iñigo

2013-01-01

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task

A new in vivo screening paradigm to accelerate antimalarial drug discovery.

Directory of Open Access Journals (Sweden)

María Belén Jiménez-Díaz

Full Text Available The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR, which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0 of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1 or induce parasite clearance (PRR >1 with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a

Deployment of ACT antimalarials for treatment of malaria: challenges and opportunities

Directory of Open Access Journals (Sweden)

Leslie Toby

2008-12-01

Full Text Available Abstract Following a long period when the effectiveness of existing mono-therapies for antimalarials was steadily declining with no clear alternative, most malaria-endemic countries in Africa and Asia have adopted artemisinin combination therapy (ACT as antimalarial drug policy. Several ACT drugs exist and others are in the pipeline. If properly targeted, they have the potential to reduce mortality from malaria substantially. The major challenge now is to get the drugs to the right people. Current evidence suggests that most of those who need the drugs do not get them. Simultaneously, a high proportion of those who are given antimalarials do not in fact have malaria. Financial and other barriers mean that, in many settings, the majority of those with malaria, particularly the poorest, do not access formal healthcare, so the provision of free antimalarials via this route has only limited impact. The higher cost of ACT creates a market for fake drugs. Addressing these problems is now a priority. This review outlines current evidence, possible solutions and research priorities.

Current practice of antiplatelet and anticoagulation management in post-cardiac surgery patients: a national audit.

Science.gov (United States)

Hosmane, Sharath; Birla, Rashmi; Marchbank, Adrian

2012-04-01

The Audit and Guidelines Committee of the European Association for Cardio-Thoracic Surgery recently published a guideline on antiplatelet and anticoagulation management in cardiac surgery. We aimed to assess the awareness of the current guideline and adherence to it in the National Health Service through this National Audit. We designed a questionnaire consisting of nine questions covering various aspects of antiplatelet and anticoagulation management in post-cardiac surgery patients. A telephonic survey of the on-call cardiothoracic registrars in all the cardiothoracic centres across the UK was performed. All 37 National Health Service hospitals in the UK with 242 consultants providing adult cardiac surgical service were contacted. Twenty (54%) hospitals had a unit protocol for antiplatelet and anticoagulation management in post-cardiac surgery. Only 23 (62.2%) registrars were aware of current European Association for Cardio-Thoracic Surgery guidelines. Antiplatelet therapy is variable in the cardiac surgical units across the country. Low-dose aspirin is commonly used despite the recommendation of 150-300 mg. The loading dose of aspirin within 24 h as recommended by the guideline is followed only by 60.7% of surgeons. There was not much deviation from the guideline with respect to the anticoagulation therapy.

Synthesis and biological evaluation of febrifugine analogues as potential antimalarial agents.

Science.gov (United States)

Zhu, Shuren; Zhang, Quan; Gudise, Chandrashekar; Wei, Lai; Smith, Erika; Zeng, Yuling

2009-07-01

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Adverse side effects have precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated for acute toxicity and in vitro and in vivo antimalarial efficacy. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drug chloroquine and are expected to possess wide therapeutic windows. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.

Baseline characteristics of the 3096 patients recruited into the 'Triple Antiplatelets for Reducing Dependency after Ischemic Stroke' trial

DEFF Research Database (Denmark)

Bath, Philip Mw; Appleton, Jason P; Beridze, Maia

2017-01-01

Background The risk of recurrence following ischemic stroke or transient ischemic attack is highest immediately after the event. Antiplatelet agents are effective in reducing the risk of recurrence and two agents are superior to one in the early phase after ictus. Design The triple antiplatelets...

QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors.

Science.gov (United States)

Hou, X; Chen, X; Zhang, M; Yan, A

2016-01-01

Plasmodium falciparum, the most fatal parasite that causes malaria, is responsible for over one million deaths per year. P. falciparum dihydroorotate dehydrogenase (PfDHODH) has been validated as a promising drug development target for antimalarial therapy since it catalyzes the rate-limiting step for DNA and RNA biosynthesis. In this study, we investigated the quantitative structure-activity relationships (QSAR) of the antimalarial activity of PfDHODH inhibitors by generating four computational models using a multilinear regression (MLR) and a support vector machine (SVM) based on a dataset of 255 PfDHODH inhibitors. All the models display good prediction quality with a leave-one-out q(2) >0.66, a correlation coefficient (r) >0.85 on both training sets and test sets, and a mean square error (MSE) antimalarial activity. The models are capable of predicting inhibitors' antimalarial activity and the molecular descriptors for building the models could be helpful in the development of new antimalarial drugs.

Anticancer Effect of AntiMalarial Artemisinin Compounds

African Journals Online (AJOL)

Artemisinin is a naturally occurring antimalarial showing anticancer properties. ..... Artemisinins usually promote apoptosis rather than necrosis in most cases ... artemisinin-mediated inhibition of vascular endothelial growth factor C (VEGF-C).

Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials.

Science.gov (United States)

Zhang, Yiqun; Clark, Julie A; Connelly, Michele C; Zhu, Fangyi; Min, Jaeki; Guiguemde, W Armand; Pradhan, Anupam; Iyer, Lalitha; Furimsky, Anna; Gow, Jason; Parman, Toufan; El Mazouni, Farah; Phillips, Margaret A; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

2012-05-10

Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis.

Science.gov (United States)

Lee, Meng; Saver, Jeffrey L; Hong, Keun-Sik; Rao, Neal M; Wu, Yi-Ling; Ovbiagele, Bruce

2017-09-01

Optimal antiplatelet therapy after an ischemic stroke or transient ischemic attack while on aspirin is uncertain. We, therefore, conducted a systematic review and meta-analysis. We searched PubMed (1966 to August 2016) and bibliographies of relevant published original studies to identify randomized trials and cohort studies reporting patients who were on aspirin at the time of an index ischemic stroke or transient ischemic attack and reported hazard ratio for major adverse cardiovascular events or recurrent stroke associated with a switch to or addition of another antiplatelet agent versus maintaining aspirin monotherapy. Estimates were combined using a random effects model. Five studies with 8723 patients with ischemic stroke or transient ischemic attack were identified. Clopidogrel was used in 4 cohorts, and ticagrelor was used in 1 cohort. Pooling results showed that addition of or a switch to another antiplatelet agent, versus aspirin monotherapy, was associated with reduced risks of major adverse cardiovascular events (hazard ratio, 0.68; 95% confidence interval, 0.54-0.85) and recurrent stroke (hazard ratio, 0.70; 95% confidence interval, 0.54-0.92). Each of the strategies of addition of and switching another antiplatelet agent showed benefit versus continued aspirin monotherapy, and studies with regimen initiation in the first days after index event showed more homogenous evidence of benefit. Among patients who experience an ischemic stroke or transient ischemic attack while on aspirin monotherapy, the addition of or a switch to another antiplatelet agent, especially in the first days after index event, is associated with fewer future vascular events, including stroke. © 2017 American Heart Association, Inc.

Analytical sample preparation strategies for the determination of antimalarial drugs in human whole blood, plasma and urine

DEFF Research Database (Denmark)

Casas, Mònica Escolà; Hansen, Martin; Krogh, Kristine A

2014-01-01

Abstract Antimalarial drugs commonly referred to as antimalarials , include a variety of compounds with different physicochemical properties. There is a lack of information on antimalarial distribution in the body over time after administration, eg the drug ...

Chitosan-based nanocarriers for antimalarials

Science.gov (United States)

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.

Antimalarial sesquiterpene lactones from oncosiphon piluliferum

CSIR Research Space (South Africa)

Pillay, P

2006-02-01

Full Text Available for the treatment of malaria. Through this consortium, an indigenous plant, Oncosiphon piluliferum, was identified as a potential source of new antimalarial drugs. Bio-assay-guided fractionation based on in vitro antiplasmodial activity led to the isolation of five...

In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents.

Science.gov (United States)

Patel, Navin B; Patel, Jignesh N; Purohit, Amit C; Patel, Vatsal M; Rajani, Dhanji P; Moo-Puc, Rosa; Lopez-Cedillo, Julio Cesar; Nogueda-Torres, Benjamin; Rivera, Gildardo

2017-09-01

A new series of N-(substituted-phenyl)-2-[5-(quinoxalin-2-yloxymethyl)-[1,3,4] oxadiazol-2-ylsulfanyl]-acetamides (5a-o) was designed and synthesised from the parent compound 2-hydroxy quinoxaline (1) through a multistep reaction sequence and was characterised by spectral and elemental analyses. All of the compounds synthesised were evaluated for their antimicrobial and antiprotozoal activities. The results revealed that quinoxaline-based 1,3,4-oxadiazoles displayed promising antibacterial, antifungal and anti-Trypanosoma cruzi activities compared with reference drugs, particularly the lead compound 5l in a short-term in vivo model in T. cruzi. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Synthesis and Evaluation of Some New Isoquine Analogues for Antimalarial Activity

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Chandra Nath Saha

2009-01-01

Full Text Available Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI, which binds to cellular macromolecules leading to hepatotoxicity and agranulocytosis. Interchange of the 3ʼ hydroxyl and the 4ʼ Mannich side-chain function of amodiaquine provides an amodiaquine regioisomer (isoquine that cannot form toxic quinoneimine metabolites. By a simple two-step procedure, four isoquine analogues were synthesized and subsequently evaluated against the chloroquine sensitive RKL-2 strain of Plasmodium falciparum in vitro. All synthesized analogues demonstrated differential level of antimalarial activity against the test strain. However, no compound was found to exhibit better antimalarial property as compared to chloroquine.

In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria.

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Nondo, Ramadhani S O; Erasto, Paul; Moshi, Mainen J; Zacharia, Abdallah; Masimba, Pax J; Kidukuli, Abdul W

2016-01-01

Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L.) Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 × 10(7) erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day) and solvent (5 mL/kg/day) were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s). In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria.

In vivo antimalarial activity of extracts of Tanzanian medicinal plants used for the treatment of malaria

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Ramadhani SO Nondo

2016-01-01

Full Text Available Plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. The aim of this study was to evaluate in vivo antimalarial activity of four plants; Erythrina schliebenii Harms, Holarrhena pubescens Buch-Ham, Phyllanthus nummulariifolius Poir, and Caesalpinia bonducella (L. Flem used for treatment of malaria in Tanzania. In vivo antimalarial activity was assessed using the 4-day suppressive antimalarial assay. Mice were infected by injection via tail vein with 2 Χ 10 7 erythrocytes infected with Plasmodium berghei ANKA. Extracts were administered orally, once daily, for a total of four daily doses from the day of infection. Chloroquine (10 mg/kg/day and solvent (5 mL/kg/day were used as positive and negative controls, respectively. The extracts of C. bonducella, E. schliebenii, H. pubescens, and P. nummulariifolius exhibited dose-dependent suppression of parasite growth in vivo in mice, with the highest suppression being by C. bonducella extract. While each of the plant extracts has potential to yield useful antimalarial compounds, the dichloromethane root extract of C. bonducella seems to be the most promising for isolation of active antimalarial compound(s. In vivo antimalarial activity presented in this study supports traditional uses of C. bonducella roots, E. schliebenii stem barks, H. pubescens roots, and P. nummulariifolius for treatment of malaria.

Antimalarial activity of Garcinia mangostana L rind and its synergistic effect with artemisinin in vitro.

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Tjahjani, Susy

2017-02-28

Malaria especially falciparum malaria still causes high morbidity and mortality in tropical countries. Several factors have been linked to this situation and the most important one is the rapid spread of parasite resistance to the currently available antimalarials, including artemisinin. Artemisinin is the main component of the currently recommended antimalarial, artemisinin based combination therapy (ACT), and it is a free radical generating antimalarial. Garcinia mangostana L (mangosteen) rind contain a lot of xanthone compounds acting as an antioxidant and exhibited antimalarial activity. The aim of this study was to evaluate the antimalarial activity of mangosteen rind extract and its fractions and their interaction with artemisinin against the 3D7 clone of Plasmodium falciparum in vitro. Dry ripe mangosteen rind was extracted with ethanol followed by fractionation with hexane, ethylacetate, buthanol, and water consecutively to get ethanol extract, hexane, athylacetate, buthanol, and water fractions. Each of these substances was diluted in DMSO and examined for antimalarial activity either singly or in combination with artemisinin in vitro against Plasmodium falciparum 3D7 clone. Synergism between these substances with artemisinin was evaluated according to certain formula to get the sum of fractional inhibitory concentration 50 (∑FIC 50 ). Analysis of the parasite growth in vitro indicated that IC 50 of these mangosteen rind extract, hexane, ethylacetate, buthanol, and water fraction ranged from 0.41 to > 100 μg/mL. All of the ∑FIC50 were antimalarial activity of the extract and fractions of G.mangostana L rind and its synergistic effect with artemisinin. Further study using lead compound(s) isolated from extract and fractions should be performed to identify more accurately their mechanism of antimalarial activities.

Case management of malaria fever in Cambodia: results from national anti-malarial outlet and household surveys

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Littrell Megan

2011-10-01

Full Text Available Abstract Background Continued progress towards global reduction in morbidity and mortality due to malaria requires scale-up of effective case management with artemisinin-combination therapy (ACT. The first case of artemisinin resistance in Plasmodium falciparum was documented in western Cambodia. Spread of artemisinin resistance would threaten recent gains in global malaria control. As such, the anti-malarial market and malaria case management practices in Cambodia have global significance. Methods Nationally-representative household and outlet surveys were conducted in 2009 among areas in Cambodia with malaria risk. An anti-malarial audit was conducted among all public and private outlets with the potential to sell anti-malarials. Indicators on availability, price and relative volumes sold/distributed were calculated across types of anti-malarials and outlets. The household survey collected information about management of recent "malaria fevers." Case management in the public versus private sector, and anti-malarial treatment based on malaria diagnostic testing were examined. Results Most public outlets (85% and nearly half of private pharmacies, clinics and drug stores stock ACT. Oral artemisinin monotherapy was found in pharmacies/clinics (9%, drug stores (14%, mobile providers (4% and grocery stores (2%. Among total anti-malarial volumes sold/distributed nationally, 6% are artemisinin monotherapies and 72% are ACT. Only 45% of people with recent "malaria fever" reportedly receive a diagnostic test, and the most common treatment acquired is a drug cocktail containing no identifiable anti-malarial. A self-reported positive diagnostic test, particularly when received in the public sector, improves likelihood of receiving anti-malarial treatment. Nonetheless, anti-malarial treatment of reportedly positive cases is low among people who seek treatment exclusively in the public (61% and private (42% sectors. Conclusions While data on the anti-malarial

Trends in Ambulatory Prescribing of Antiplatelet Therapy among US Ischemic Stroke Patients: 2000–2007

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Sudeep Karve

2012-01-01

Full Text Available Objective. Study objectives were to assess temporal trends and identify patient- and practice-level predictors of the prescription of antiplatelet medications in a national sample of ischemic stroke (IS patients seeking ambulatory care. Methods. IS-related outpatient visits by adults were identified using the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey for the years 2000–2007. We assessed prescribing of antiplatelet medications using the generic drug code and drug entry codes in these data. Temporal trends in antiplatelet prescribing were assessed using the Cochran-Mantel-Haenszel test for trend. Results. We identified 9.5 million IS-related ambulatory visits. Antiplatelet medications were prescribed at 35.5% of visits. Physician office prescribing of the clopidogrel-aspirin combination increased significantly from 0.5% in 2000 to 22.0% in 2007 (P=0.05, whereas prescribing of aspirin decreased from 17.9% to 7.0% (P=0.50 during the same period. Conclusion. We observed a continued increase in prescription of the aspirin-clopidogrel combination from 2000 to 2007. Clinical trial evidence suggests that the aspirin-clopidogrel combination does not provide any additional benefit compared with clopidogrel alone; however, our study findings indicate that even with lack of adequate clinical evidence physician prescribing of this combination has increased in real-world community settings.

The clinical value of antiplatelet therapy for patients with hemorrhage after thrombolysis based on susceptibility-weighted imaging: A prospective pilot study

International Nuclear Information System (INIS)

Lu, Jing; Li, Yue-Hua; Li, Yong-Dong; Li, Ming-Hua; Zhao, Jun-Gong; Chen, Shi-Wen

2012-01-01

Purpose: To evaluate treatment decision-making based on susceptibility-weighted imaging (SWI) in patients with hemorrhage after thrombolysis. Materials and methods: One hundred and forty-six patients without intracranial hemorrhage on CT after receiving recombinant tissue plasminogen activator (rt-PA) were allocated to two groups: antiplatelets (n = 72), who received antiplatelet therapy 24 h after rt-PA for 10 days; and non-antiplatelets (n = 74), who received no antiplatelet therapy. Twenty-two patients with SWI-detected microbleeds (MBs) or hemorrhagic transformation (HT) in the antiplatelets group (Group A) and 28 with MB or HT in the non-antiplatelets group (Group B) were included in this study. Results: Sixteen patients had MB and six HT in Group A; 18 had MB, six HT, and four parenchymal hemorrhage (PH) in Group B. National Institutes of Health Stroke Scale (NIHSS) scores at 7 and 14 days and the Modified Rankin Scale (mRS) at 90 days post-rt-PA were significantly lower in Group B than in Group A, duration of hospitalization was significantly shorter, and the favorable outcome rate was higher at 90 days (P < 0.05). There were no other significant differences. SWI evaluation at 14 days revealed eight patients with MB, 11 HT, and three PH in Group A; in Group B, 16 had MB, five HT, and one PH, with resolution of hemorrhage in six patients. Conclusions: Treatment decision-making based on SWI in acute stroke after thrombolysis was validated by the significantly reduced NIHSS score after 7/14 days, improved outcome, and reduced mRS in hemorrhage patients without antiplatelet therapy.

Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum

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Langer, Christine; Goodman, Christopher D.; McFadden, Geoffrey I.

2013-01-01

Most current antimalarials for treatment of clinical Plasmodium falciparum malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion in vitro. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for in vitro assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials. PMID:23318799

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity.

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Ke, Hangjun; Morrisey, Joanne M; Qu, Shiwei; Chantarasriwong, Oraphin; Mather, Michael W; Theodorakis, Emmanuel A; Vaidya, Akhil B

2017-01-01

Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents. Copyright © 2016 American Society for Microbiology.

Anti-Platelet Aggregation and Vasorelaxing Effects of the Constituents of the Rhizomes of Zingiber officinale

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Tian-Shung Wu

2012-07-01

Full Text Available In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty-nine compounds including one new compound, O-methyldehydrogingerol (1. Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol (13 and [6]-shogaol (17 exhibited potent anti-platelet aggregation bioactivity. In addition, [10]-gingerol (15 inhibited the Ca²⁺-dependent contractions in high K⁺ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism.

Risk and benefit of dual antiplatelet treatment among nonrevascularized myocardial infarction patients in different age groups

DEFF Research Database (Denmark)

Juul, Nikolai; Gislason, Gunnar; Olesen, Jonas Bjerring

2017-01-01

revascularization. METHODS: Patients admitted with first-time myocardial infarction in 2002-2010, not undergoing revascularization, were identified from nationwide Danish registers. Dual anti-platelet treatment use was assessed by claimed prescriptions. Stratified into age groups, risk of bleeding, all.......63; 95% CI 1.17-2.26), 60-69 years (HR=1.22; 95% CI 0.97-1.59, NS), 70-79 years (HR=1.42; 95% CI 1.17-1.72) and >79 years (HR=1.46; 95% CI 1.22-1.74). Similar tendencies in all four age groups were found in the propensity-matched population. CONCLUSION: Dual anti-platelet treatment use was less likely...... among elderly patients although similar effects regarding both risk and benefit were found in all age groups. Increased focus on initiating dual anti-platelet treatment in elderly, non-invasively treated myocardial infarction patients is warranted....

High prevalence of ulcer bleeding risk factors in dual antiplatelet-treated patients after percutaneous coronary intervention

DEFF Research Database (Denmark)

Jensen, Berit Elin S; Hansen, Jane M; Junker, Anders B

2015-01-01

INTRODUCTION: Dual antiplatelet therapy is standard treatment following percutaneous coronary intervention (PCI) and stenting. However, such therapy increases the risk of upper gastrointestinal bleeding (UGIB). The risk factors of UGIB are well-documented and proton pump inhibitor (PPI) treatment...... reduces the risk. The aim was to describe the prevalence of risk factors of UGIB in dual antiplatelet-treated patients. METHODS: A questionnaire was used to assess the prevalence of risk factors of upper gastrointestinal bleeding among dual antiplatelet-treated first-time PCI patients in Western Denmark......: A total of 1,358 patients with a mean age of 64.1 years (range: 33-92 years) were included. The distribution of risk factors was as follows: dyspepsia: 681 patients (50.1%); previous ulcer: 110 (8.1%; 2.3% with bleeding); use of NSAIDs: 214 (15.8%); corticosteroids (2.9%), SSRIs (5.8%) and anticoagulants...

Semiquantitative dynamic computed tomography to predict response to anti-platelet therapy in acute cerebral infarction

International Nuclear Information System (INIS)

Chokyu, K.; Shimizu, K.; Fukumoto, M.; Mori, T.; Mokudai, T.; Mori, K.

2002-01-01

We investigated whether dynamic computed tomography (CT) in patients with acute cerebral infarction could identify patients likely to respond to anti-platelet therapy. Seventy patients underwent semiquantitative dynamic CT within 6 h as well as cerebral angiography. All then received anti-platelet therapy with a thromboxane A2 synthetase inhibitor. Peak value (pv) and time-to-peak (tp) (time-density curves) for the Sylvian fissure were extracted from dynamic CT data and standardizing interpatient data, two indices, PV/TP index and TP index, were prepared following a standard semiquantitative manner. Both PV/TP index and TP index were effective in discriminating between 48 responders (modified Rankin scale (mRS): 0 to 2) and 22 non-responders (mRS: 3 to 5, or death: 6; both P 1.1) and non-compensated rCBF. Intermediate PV/TP values could not predict outcome. Dynamic CT prior to therapy can identify patients with acute cerebral infarction who are treatable with anti-platelet therapy alone. (orig.)

From crystal to compound: structure-based antimalarial drug discovery.

Science.gov (United States)

Drinkwater, Nyssa; McGowan, Sheena

2014-08-01

Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

Mechanochemical Synthesis, In vivo Anti-malarial and Safety Evaluation of Amodiaquine-zinc Complex

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Arise Rotimi Olusanya

2017-09-01

Full Text Available So far, some prospective metal-based anti-malarial drugs have been developed. The mechanochemical synthesis and characterization of Zn (II complex with amodiaquine and its anti-malarial efficacy on Plasmodium berghei-infected mice and safety evaluation were described in this study.

Initiation and persistence with dual antiplatelet therapy after acute myocardial infarction

DEFF Research Database (Denmark)

Green, Anders; Pottegård, Anton; Broe, Anne

2016-01-01

OBJECTIVES: The study investigated dual antiplatelet therapy (DAPT) patterns over time and patient characteristics associated with the various treatments in a myocardial infarction (MI) population. DESIGN: A registry-based observational cohort study was performed using antecedent data. SETTING: T...

Antimalarial properties of imipramine and amitriptyline

International Nuclear Information System (INIS)

Dutta, P.; Siegel, L.; Pinto, J.; Meshnick, S.

1986-01-01

This laboratory has previously demonstrated that imipramine (IM) and amitriptyline (AM), inhibit the conversion of riboflavin to its coenzymic derivatives. Several other laboratories have shown that dietary riboflavin deficiency is protective against malarial infection. In the present investigation, the authors determined whether IM and AM exert antimalarial effects similar to that of riboflavin deficiency, as they have hypothesized. In addition, they evaluated whether these drugs, like other antimalarial agents, increase the hemolytic response to ferriprotoporphyrin IX (FP). The growth of P. falciparum (FCR3) in the absence or presence of these drugs (80 μM) was measured by incubating parasitized erythrocytes for 48 h in RPMI 1640 medium. Parasitemia was determined by counting erythrocyte smears and monitoring ( 3 H)hypoxanthine uptake. With no drug, parasitemia was 20.3 +/- 5.3%, whereas in the presence of IM and AM, parasitemia was reduced to 7.3 +/- 0.8% and 13.6 +/- 2.8%, respectively. The uptake of ( 3 H)hypoxanthine was reduced to 47 +/- 3.6% and 54 +/- 2.9% of control by IM and AM, respectively. Assays of hemolysis were conducted by incubating 0.5% RBC suspension in NaCl-Tris buffer for 3 h at 37 0 C with variable concentrations of drugs and/or FP (1-7 μM). Both drugs at 10 to 100 μM significantly enhanced hemolysis induced by FP. No hemolysis by these drugs was detected in the absence of FP. It is concluded that the tricyclic antidepressants, IM and AM, possess substantial antimalarial properties, thereby supporting the hypothesis that drugs which interfere with riboflavin metabolism should also provide protection against malaria

Prehospital antiplatelet use and functional status on admission of patients with non-haemorrhagic moyamoya disease: a nationwide retrospective cohort study (J-ASPECT study)

Science.gov (United States)

Onozuka, Daisuke; Hagihara, Akihito; Nishimura, Kunihiro; Kada, Akiko; Nakagawara, Jyoji; Ogasawara, Kuniaki; Ono, Junichi; Shiokawa, Yoshiaki; Aruga, Toru; Miyachi, Shigeru; Nagata, Izumi; Toyoda, Kazunori; Matsuda, Shinya; Suzuki, Akifumi; Kataoka, Hiroharu; Nakamura, Fumiaki; Kamitani, Satoru; Nishimura, Ataru; Kurogi, Ryota; Sayama, Tetsuro; Iihara, Koji

2016-01-01

Objectives To elucidate the association between antiplatelet use in patients with non-haemorrhagic moyamoya disease before hospital admission and good functional status on admission in Japan. Design Retrospective, multicentre, non-randomised, observational study. Setting Nationwide registry data in Japan. Participants A total of 1925 patients with non-haemorrhagic moyamoya disease admitted between 1 April 2012 and 31 March 2014 in Japan. Main outcome measure We performed propensity score-matched analysis to examine the association between prehospital antiplatelet use and no significant disability on hospital admission, as defined by a modified Rankin Scale score of 0 or 1. Results Propensity-matched patients who received prehospital antiplatelet drugs were associated with a good outcome on hospital admission (OR adjusted for all covariates, 3.82; 95% CI 1.22 to 11.99) compared with those who did not receive antiplatelet drugs prior to hospital admission. Conclusions Prehospital antiplatelet use was significantly associated with good functional status on hospital admission among patients with non-haemorrhagic moyamoya disease in Japan. Our results suggest that prehospital antiplatelet use should be considered when evaluating outcomes of patients with non-haemorrhagic moyamoya disease. PMID:27008684

Epidemiology and Management of Patients With Acute Coronary Syndromes in Contemporary Real-World Practice: Evolving Trends From the EYESHOT Study to the START-ANTIPLATELET Registry.

Science.gov (United States)

Calabrò, Paolo; Gragnano, Felice; di Maio, Marco; Patti, Giuseppe; Antonucci, Emilia; Cirillo, Plinio; Gresele, Paolo; Palareti, Gualtiero; Pengo, Vittorio; Pignatelli, Pasquale; Pennacchi, Mauro; Granatelli, Antonino; De Servi, Stefano; De Luca, Leonardo; Marcucci, Rossella

2018-01-01

The epidemiology and management of patients with acute coronary syndromes (ACSs) have evolved. We aimed to describe recent demographics and therapeutic changes in the Italian ACS population. We analyzed data from 2 multicenter consecutive Italian registries (the EYESHOT [EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalised in iTalian cardiac care units] and START-ANTIPLATELET registries) enrolling patients with ACS between December 2013 and June 2016. An overall population of 3756 patients with ACS was enrolled: 2585 in the EYESHOT and 1171 in the START-ANTIPLATELET. Compared with the EYESHOT, patients in the START-ANTIPLATELET registry presented more frequently with ST-segment elevation myocardial infarction and were more often smokers and dyslipidemic (all P START-ANTIPLATELET (all P START-ANTIPLATELET compared with the EYESHOT. The START-ANTIPLATELET and EYESHOT registries provide consecutive snapshots in the contemporary management of patients with ACS in Italy, showing important changes in both demographic characteristics and treatment strategies.

Synthesis and exploration of novel curcumin analogues as anti-malarial agents.

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Mishra, Satyendra; Karmodiya, Krishanpal; Surolia, Namita; Surolia, Avadhesha

2008-03-15

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.

Prior antiplatelet therapy and outcome following intracerebral hemorrhage: a systematic review

DEFF Research Database (Denmark)

Thompson, B B; Béjot, Y; Caso, V

2010-01-01

Antiplatelet therapy (APT) promotes bleeding; therefore, APT might worsen outcome in patients with intracerebral hemorrhage (ICH). We performed a systematic review and meta-analysis to address the hypothesis that pre-ICH APT use is associated with mortality and poor functional outcome following ICH....

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

Science.gov (United States)

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

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

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Harparkash Kaur

Full Text Available 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

Augmentation of the Differentiation Response to Antitumor Antimalarials

National Research Council Canada - National Science Library

Rahim, Rayhana

2003-01-01

.... We have shown that the quinoline antimalarials chloroquine (CO) and hydroxychioroquine (HCQ) inhibit proliferation and induce differentiation in breast cancer cell lines without toxicity to normal MCF-10A cells...

The counterfeit anti-malarial is a crime against humanity: a systematic review of the scientific evidence.

Science.gov (United States)

Karunamoorthi, Kaliyaperumal

2014-06-02

The counterfeiting of anti-malarials represents a form of attack on global public health in which fake and substandard anti-malarials serve as de facto weapons of mass destruction, particularly in resource-constrained endemic settings, where malaria causes nearly 660,000 preventable deaths and threatens millions of lives annually. It has been estimated that fake anti-malarials contribute to nearly 450,000 preventable deaths every year. This crime against humanity is often underestimated or ignored. This study attempts to describe and characterize the direct and indirect effects of counterfeit anti-malarials on public health, clinical care and socio-economic conditions. A search was performed using key databases, WHO documents, and English language search engines. Of 262 potential articles that were identified using a fixed set of criteria, a convenience sample of 105 appropriate articles was selected for this review. Artemisinin-based combination therapy (ACT) is an important tool in the fight against malaria, but a sizable number of patients are unable to afford to this first-line treatment. Consequently, patients tend to procure cheaper anti-malarials, which may be fake or substandard. Forensic palynology reveals that counterfeits originate in Asia. Fragile drug regulations, ineffective law-enforcement agencies and corruption further burden ailing healthcare facilities. Substandard/fake anti-malarials can cause (a) economic sabotage; (b) therapeutic failure; (c) increased risk of the emergence and spread of resistant strains of Plasmodium falciparum and Plasmodium vivax; (d) an undermining of trust/confidence in healthcare stakeholders/systems; and, (e) serious side effects or death. Combating counterfeit anti-malarials is a complex task due to limited resources and poor techniques for the detection and identification of fake anti-malarials. This situation calls for sustainable, global, scientific research and policy change. Further, responsible stakeholders in

Ristocetin induces phosphorylated-HSP27 (HSPB1) release from the platelets of type 2 DM patients: Anti-platelet agent-effect on the release.

Science.gov (United States)

Tokuda, Haruhiko; Kuroyanagi, Gen; Onuma, Takashi; Enomoto, Yukiko; Doi, Tomoaki; Iida, Hiroki; Otsuka, Takanobu; Ogura, Shinji; Iwama, Toru; Kojima, Kumi; Kozawa, Osamu

2018-04-01

It has been previously reported that HSP27 is released from platelets in type 2 diabetes mellitus (DM) patients according to phosphorylation. In the present study, we investigated the effect of ristocetin, a glycoprotein (GP)Ib/IX/V activator, on the release of HSP27 and the effect of anti-platelet agents, such as acetylsalicylic acid (ASA), on this release. Forty-six patients with type 2 DM were recruited, and classified into two groups depending on administration of anti-platelet agents, resulting in 31 patients without these agents (control group) and 15 patients with them (anti-platelet group). Ristocetin potently induced the aggregation of platelets in the two groups. Ristocetin-induced changes of the area under the curve of light transmittance and the ratio of the size of platelet aggregates in the anti-platelet group were slightly different from those in the control group. On the other hand, the levels of phosphorylated-HSP27 induced by ristocetin in the platelets from a patient of the anti-platelet group taking ASA were significantly lower than those from a patient of the control group. The levels of HSP27 release from the ristocetin-stimulated platelets were significantly correlated with the levels of phosphorylated-HSP27 in the platelets from patients in the two groups. The levels of HSP27 release and those of platelet-derived growth factor-AB (PDGF-AB) secretion stimulated by ristocetin in the anti-platelet group were lower than those in the control group. In addition, the levels of HSP27 release and those of PDGF-AB secretion stimulated by ADP in the anti-platelet group were lower than those in the control group. These results strongly suggest that anti-platelet agents inhibit the HSP27 release from platelets stimulated by ristocetin but not the aggregation in type 2 DM patients.

Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents.

Science.gov (United States)

Mane, Uttam R; Mohanakrishnan, D; Sahal, Dinkar; Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

2014-05-22

Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin-3-yl)carbamate (21, IC50 value 33 μM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 μM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

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Mariana Conceição Souza

2015-06-01

Full Text Available A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3 inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

A SAR and QSAR study of new artemisinin compounds with antimalarial activity.

Science.gov (United States)

Santos, Cleydson Breno R; Vieira, Josinete B; Lobato, Cleison C; Hage-Melim, Lorane I S; Souto, Raimundo N P; Lima, Clarissa S; Costa, Elizabeth V M; Brasil, Davi S B; Macêdo, Williams Jorge C; Carvalho, José Carlos T

2013-12-30

The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs) and molecular docking were used to investigate the interaction between ligands and the receptor (heme). Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE), the charge on the O11 oxygen atom (QO11), the torsion angle O1-O2-Fe-N2 (D2) and the maximum rate of R/Sanderson Electronegativity (RTe+). These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

Antimalarial activity of medicinal plants from the Democratic Republic of Congo: A review.

Science.gov (United States)

Memvanga, Patrick B; Tona, Gaston L; Mesia, Gauthier K; Lusakibanza, Mariano M; Cimanga, Richard K

2015-07-01

Malaria is the most prevalent parasitic disease and the foremost cause of morbidity and mortality in the Democratic Republic of Congo. For the management of this disease, a large Congolese population recourses to traditional medicinal plants. To date the efficacy and safety of many of these plants have been validated scientifically in rodent malaria models. In order to generate scientific evidence of traditional remedies used in the Democratic Republic of Congo for the management of malaria, and show the potential of Congolese plants as a major source of antimalarial drugs, this review highlights the antiplasmodial and toxicological properties of the Congolese antimalarial plants investigated during the period of 1999-2014. In doing so, a useful resource for further complementary investigations is presented. Furthermore, this review may pave the way for the research and development of several available and affordable antimalarial phytomedicines. In order to get information on the different studies, a Google Scholar and PubMed literature search was performed using keywords (malaria, Congolese, medicinal plants, antiplasmodial/antimalarial activity, and toxicity). Data from non-indexed journals, Master and Doctoral dissertations were also collected. Approximately 120 extracts and fractions obtained from Congolese medicinal plants showed pronounced or good antiplasmodial activity. A number of compounds with interesting antiplasmodial properties were also isolated and identified. Some of these compounds constituted new scaffolds for the synthesis of promising antimalarial drugs. Interestingly, most of these extracts and compounds possessed high selective activity against Plasmodium parasites compared to mammalian cells. The efficacy and safety of several plant-derived products was confirmed in mice, and a good correlation was observed between in vitro and in vivo antimalarial activity. The formulation of several plant-derived products also led to some clinical trials

In vitro antimalarial activity of Calophyllum bicolor and hemozoin crystals observed by Transmission Electron Microscope (TEM)

OpenAIRE

Abbas Jamilah

2018-01-01

Objective : In continuation of our antimalarial candidate drug discovery program on Indonesia medicinal plants especially from stem bark of Calophyllum bicolor. Metode : We extracted of bioactive crude extract with hexane, acetone and methanol from stem bark of Calophyllum bicolor and evaluated their antimalarial activity by using parasite Plasmodium falciparum in vitro. Results: Methanol fraction showed most active and potent antimalarial activity dose dependent in in vitro experiments with ...

Prehospital antiplatelet use and functional status on admission of patients with non-haemorrhagic moyamoya disease: a nationwide retrospective cohort study (J-ASPECT study).

Science.gov (United States)

Onozuka, Daisuke; Hagihara, Akihito; Nishimura, Kunihiro; Kada, Akiko; Nakagawara, Jyoji; Ogasawara, Kuniaki; Ono, Junichi; Shiokawa, Yoshiaki; Aruga, Toru; Miyachi, Shigeru; Nagata, Izumi; Toyoda, Kazunori; Matsuda, Shinya; Suzuki, Akifumi; Kataoka, Hiroharu; Nakamura, Fumiaki; Kamitani, Satoru; Nishimura, Ataru; Kurogi, Ryota; Sayama, Tetsuro; Iihara, Koji

2016-03-15

To elucidate the association between antiplatelet use in patients with non-haemorrhagic moyamoya disease before hospital admission and good functional status on admission in Japan. Retrospective, multicentre, non-randomised, observational study. Nationwide registry data in Japan. A total of 1925 patients with non-haemorrhagic moyamoya disease admitted between 1 April 2012 and 31 March 2014 in Japan. We performed propensity score-matched analysis to examine the association between prehospital antiplatelet use and no significant disability on hospital admission, as defined by a modified Rankin Scale score of 0 or 1. Propensity-matched patients who received prehospital antiplatelet drugs were associated with a good outcome on hospital admission (OR adjusted for all covariates, 3.82; 95% CI 1.22 to 11.99) compared with those who did not receive antiplatelet drugs prior to hospital admission. Prehospital antiplatelet use was significantly associated with good functional status on hospital admission among patients with non-haemorrhagic moyamoya disease in Japan. Our results suggest that prehospital antiplatelet use should be considered when evaluating outcomes of patients with non-haemorrhagic moyamoya disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses.

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Melissa Li

Full Text Available The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s(-1 and therapy concentrations (0-2.4 µM for eptifibatide, 0-2 mM for acetyl-salicylic acid (ASA, 3.5-40 Units/L for heparin using a microfluidic device. We also measured complete blood counts (CBC and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose. Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment.

Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity.

Science.gov (United States)

Gilson, Paul R; Tan, Cyrus; Jarman, Kate E; Lowes, Kym N; Curtis, Joan M; Nguyen, William; Di Rago, Adrian E; Bullen, Hayley E; Prinz, Boris; Duffy, Sandra; Baell, Jonathan B; Hutton, Craig A; Jousset Subroux, Helene; Crabb, Brendan S; Avery, Vicky M; Cowman, Alan F; Sleebs, Brad E

2017-02-09

Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.

Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

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Mpimbaza Arthur

2008-06-01

Full Text Available Abstract Background New antimalarial regimens, including artemisinin-based combination therapies (ACTs, have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials. Case description Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity. Discussion and evaluation Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported. Conclusion Although the World Health Organization has supported the development of

Quantitative Structure ‒ Antiprotozoal Activity Relationships of Sesquiterpene Lactones

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Reto Brun

2009-06-01

Full Text Available Prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (STLs against Trypanosoma brucei rhodesiense (which causes East African sleeping sickness, we have now conducted a structure-(in-vitro-activity study on a set of 40 STLs against T. brucei rhodesiense, T. cruzi, Leishmania donovani and Plasmodium falciparum. Furthermore, cytotoxic activity against L6 rat skeletal myoblast cells was assessed. Some of the compounds possess high activity, especially against T. brucei (e.g. helenalin and some of its esters with IC50-values of 0.05-0.1 µM, which is about 10 times lower than their cytotoxic activity. It was found that all investigated antiprotozoal activities are significantly correlated with cytotoxicity and the major determinants for activity are a,b-unsaturated structural elements, also known to be essential for other biological activities of STLs. It was observed, however, that certain compounds are considerably more toxic against protozoa than against mammalian cells while others are more cytotoxic than active against the protozoa. A comparative QSAR analysis was therefore undertaken, in order to discern the antiparasitic activity of STLs against T. brucei and cytotoxicity. Both activities were found to depend to a large extent on the same structural elements and molecular properties. The observed variance in the biological data can be explained in terms of subtle variations in the relative influences of various molecular descriptors.

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

Science.gov (United States)

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.

Anticancer Properties of Distinct Antimalarial Drug Classes

Science.gov (United States)

Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

2013-01-01

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

Anticancer properties of distinct antimalarial drug classes.

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Rob Hooft van Huijsduijnen

Full Text Available We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor, emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.

ANALYZES OF ANTIPLATELETS AND ANTICOAGULANTS UTILIZATION IN PATIENTS TREATED IN CARDIOVASCULAR REHABILITATION CENTER FROM CROATIA

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Boban Marko

2016-07-01

Full Text Available Purpose: Discordance with the guidelines and underutilization of pharmacotherapy for secondary prevention frequently exists in clinical practice. Aim of our study was to assess the prescription routine and drug utilization patterns for antiplatelets and peroral anticoagulants in tertiary medical center specialized for cardiovascular rehabilitation. Methods: study included 96 consecutive patients scheduled for cardiovascular rehabilitation in period 1-6 months after the acute treatment for ischemic 87(80.2% and valvular heart disease 18(19.8%. Patients were divided according to etiology of heart disease and type of acute cardiovascular treatments (conservative, percutaneous coronary interventions (PCI and surgery. Results: Dual antiplatelet therapy was the most commonly applied regimen in 84(87.5% of conservatively treated myocardial infarctions, 47(61.9% of percutaneous coronary interventions (PCI and 13(58.9% of surgically treated group (p>0.05. Among studied group of patients significant differences in utilization were found for warfarin, or combinations of antiplatelets with warfarin(p0.05. All four of patients that received triple therapy (4.17% were from surgical group. Underutilization of antiplatelets in ischemic heart disease was at 11(14.3% what was congruent with the developed industrial nations. Conclusions: Acute cardiovascular treatment type, but not heart disease etiology, had significant influence on subsequent prescription routine. Decreased use of pharmacological agents for secondary prevention in surgical patients was revealed. Drug utilization analyzes can offer improvement in optimizing medical treatments, quality of care and decrease unnecessary polypragmasia, as well as improve economical efficiency of medical management.

24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis

DEFF Research Database (Denmark)

Würtz, Morten; Hvas, Anne-Mette; Jensen, Lisette O

2014-01-01

OBJECTIVE: Once-daily aspirin is standard treatment, but recent studies point towards increased platelet function at the end of the dosing interval. Stent thrombosis (ST) has been linked with reduced antiplatelet effect of aspirin, so we investigated if platelet inhibition by aspirin declines...... with 100 patients with stable coronary artery disease and 50 healthy volunteers. All participants were on aspirin 75 mg/day mono antiplatelet therapy. Platelet aggregation was measured 1 and 24 h after aspirin intake using platelet aggregometry (Multiplate® Analyzer). Cyclooxygenase-1 activity, platelet...... activation, immature platelets, and thrombopoietin were measured. RESULTS: Platelet aggregation increased by 109±150 (arachidonic acid) and 47±155 (collagen) aggregation units per minute from 1 to 24 h after aspirin intake (p-values

In vitro antimalarial activity of novel semisynthetic nocathiacin I antibiotics.

Science.gov (United States)

Sharma, Indu; Sullivan, Margery; McCutchan, Thomas F

2015-01-01

Presently, the arsenal of antimalarial drugs is limited and needs to be replenished. We evaluated the potential antimalarial activity of two water-soluble derivatives of nocathiacin (BMS461996 and BMS411886) against the asexual blood stages of Plasmodium falciparum. Nocathiacins are a thiazolyl peptide group of antibiotics, are structurally related to thiostrepton, have potent activity against a wide spectrum of multidrug-resistant Gram-positive bacteria, and inhibit protein synthesis. The in vitro growth inhibition assay was done using three laboratory strains of P. falciparum displaying various levels of chloroquine (CQ) susceptibility. Our results indicate that BMS461996 has potent antimalarial activity and inhibits parasite growth with mean 50% inhibitory concentrations (IC50s) of 51.55 nM for P. falciparum 3D7 (CQ susceptible), 85.67 nM for P. falciparum Dd2 (accelerated resistance to multiple drugs [ARMD]), and 99.44 nM for P. falciparum K1 (resistant to CQ, pyrimethamine, and sulfadoxine). Similar results at approximately 7-fold higher IC50s were obtained with BMS411886 than with BMS461996. We also tested the effect of BMS491996 on gametocytes; our results show that at a 20-fold excess of the mean IC50, gametocytes were deformed with a pyknotic nucleus and growth of stage I to IV gametocytes was arrested. This preliminary study shows a significant potential for nocathiacin analogues to be developed as antimalarial drug candidates and to warrant further investigation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Dual antiplatelet therapy with prasugrel or ticagrelor versus clopidogrel in interventional cardiology

DEFF Research Database (Denmark)

Clemmensen, Peter; Dridi, Nadia Paarup; Holmvang, Lene

2013-01-01

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater effica...

A qualitative assessment of the challenges of WHO prequalification for anti-malarial drugs in China.

Science.gov (United States)

Huang, Yangmu; Pan, Ke; Peng, Danlu; Stergachis, Andy

2018-04-03

While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China.

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

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Newton Paul N

2011-12-01

Full Text Available Abstract Background Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. Methods Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis and botanical investigations were performed. Results Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA containing paracetamol (acetaminophen, counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. Conclusions Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems.

A SAR and QSAR Study of New Artemisinin Compounds with Antimalarial Activity

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Cleydson Breno R. Santos

2013-12-01

Full Text Available The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs and molecular docking were used to investigate the interaction between ligands and the receptor (heme. Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE, the charge on the O11 oxygen atom (QO11, the torsion angle O1-O2-Fe-N2 (D2 and the maximum rate of R/Sanderson Electronegativity (RTe+. These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.

Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf

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Helen Bitew

2017-11-01

Full Text Available Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl-2-(3,4-dihydroxybut-1-ynyl-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl-2-(3-chloro-4-acetoxy-but-1-yn-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs.

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

Science.gov (United States)

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

Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum

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Garavito G.

2007-06-01

Full Text Available Methylene blue (MB is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

Baseline characteristics of the 3096 patients recruited into the 'Triple Antiplatelets for Reducing Dependency after Ischemic Stroke' trial.

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Bath, Philip Mw; Appleton, Jason P; Beridze, Maia; Christensen, Hanne; Dineen, Robert A; Duley, Lelia; England, Timothy J; Heptinstall, Stan; James, Marilyn; Krishnan, Kailash; Markus, Hugh S; Pocock, Stuart; Ranta, Annemarei; Robinson, Thompson G; Flaherty, Katie; Scutt, Polly; Venables, Graham S; Woodhouse, Lisa J; Sprigg, Nikola

2017-07-01

Background The risk of recurrence following ischemic stroke or transient ischemic attack is highest immediately after the event. Antiplatelet agents are effective in reducing the risk of recurrence and two agents are superior to one in the early phase after ictus. Design The triple antiplatelets for reducing dependency after ischemic stroke trial was an international multicenter prospective randomized open-label blinded-endpoint trial that assessed the safety and efficacy of short-term intensive antiplatelet therapy with three agents (combined aspirin, clopidogrel and dipyridamole) as compared with guideline treatment in acute ischemic stroke or transient ischemic attack. The primary outcome was stroke recurrence and its severity, measured using the modified Rankin Scale at 90 days. Secondary outcomes included recurrent vascular events, functional measures (cognition, disability, mood, quality of life), and safety (bleeding, death, serious adverse events). Data are number (%) or mean (standard deviation, SD). Results Recruitment ran from April 2009 to March 2016; 3096 patients were recruited from 106 sites in four countries (Denmark 1.6%, Georgia 2.7%, New Zealand 0.2%, UK 95.4%). Randomization characteristics included: age 69.0 (10.1) years; male 1945 (62.8%); time onset to randomization 29.4 (11.9) h; stroke severity (National Institutes for Health Stroke Scale) 2.8 (3.6); blood pressure 143.5 (18.2)/79.5 (11.4) mmHg; IS 2143 (69.2%), transient ischemic attack 953 (30.8%). Conclusion Triple antiplatelets for reducing dependency after ischemic stroke was a large trial of intensive/triple antiplatelet therapy in acute ischemic stroke and transient ischemic attack, and included participants from four predominantly Caucasian countries who were representative of patients in many western stroke services.

Research Article Antimalarial Drugs for Pediatrics - Prescribing and ...

African Journals Online (AJOL)

Erah

2011-03-23

Mar 23, 2011 ... is a need to institute measures to ensure rational prescribing, dispensing and use of antimalarial drugs in pediatrics. ... facilities, strategies to control behaviour in the private sector are ..... changes were implemented in 2006 in.

Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity.

Science.gov (United States)

Vyas, V K; Qureshi, G; Ghate, M; Patel, H; Dalai, S

2016-06-01

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere-Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents.

Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN

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Barnes Karen I

2010-12-01

Full Text Available Abstract Background The Worldwide Antimalarial Resistance Network (WWARN is a global collaboration to support the objective that anyone affected by malaria receives effective and safe drug treatment. The Pharmacology module aims to inform optimal anti-malarial drug selection. There is an urgent need to define the drug exposure - effect relationship for most anti-malarial drugs. Few anti-malarials have had their therapeutic blood concentration levels defined. One of the main challenges in assessing safety and efficacy data in relation to drug concentrations is the comparability of data generated from different laboratories. To explain differences in anti-malarial pharmacokinetics in studies with different measurement laboratories it is necessary to confirm the accuracy of the assay methods. This requires the establishment of an external quality assurance process to assure results that can be compared. This paper describes this process. Methods The pharmacology module of WWARN has established a quality assurance/quality control (QA/QC programme consisting of two separate components: 1. A proficiency testing programme where blank human plasma spiked with certified reference material (CRM in different concentrations is sent out to participating bioanalytical laboratories. 2. A certified reference standard programme where accurately weighed amounts of certified anti-malarial reference standards, metabolites, and internal standards are sent to participating bioanalytical and in vitro laboratories. Conclusion The proficiency testing programme is designed as a cooperative effort to help participating laboratories assess their ability to carry out drug analysis, resolve any potential problem areas and to improve their results - and, in so doing, to improve the quality of anti-malarial pharmacokinetic data published and shared with WWARN. By utilizing the same source of standards for all laboratories, it is possible to minimize bias arising from poor

Antimalarial Drugs for Pediatrics - Prescribing and Dispensing ...

African Journals Online (AJOL)

Purpose: To assess dispensing and prescribing practices with regard to antimalarial drugs for pediatrics in private pharmacies and public hospitals in Dar es Salaam, Tanzania. Methods: This was a cross-sectional, descriptive study that assessed the knowledge and practice of 200 drug dispensers in the private community ...

Synthesis and evaluation of 1-amino-6-halo-β-carbolines as antimalarial and antiprion agents.

Science.gov (United States)

Thompson, Mark J; Louth, Jennifer C; Little, Susan M; Jackson, Matthew P; Boursereau, Yohan; Chen, Beining; Coldham, Iain

2012-04-01

Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Efficacy And Safety of Dabigatran Etexilate Utilization With Concomitant Dual Antiplatelet Therapy In Atrial Fibrillation.

Science.gov (United States)

Centurión Md PhD Facc, Osmar Antonio

2014-01-01

The necessity to add two antiplatelet agents to an oral anticoagulant (OAC) often arises in patients with atrial fibrillation (AF) in routine clinical practice. The majority of AF patients have an indication for continuous OAC, and coronary artery disease co-exists in 25% of these patients. The increasing use of drug-eluting stents to minimize intrastent restenosis necessitates long-term dual antiplatelet therapy with Aspirin plus Clopidogrel to reduce the risk of early and late stent thrombosis. Combined aspirin-clopidogrel therapy, however, is less effective in preventing stroke compared with OAC alone in AF patients, and OAC alone is insufficient to prevent stent thrombosis. The management of AF patients presenting with an acute coronary syndrome poses similar management complexities. Since AF and coronary artery disease with stent placement are common, it is relatively frequent to treat patients with both these conditions, where triple antithrombotic therapy with Aspirin, Clopidogrel and an OAC would be needed. Dabigatran etexilate, an oral direct thrombin inhibitor, has shown that compared with Warfarin given at a dose of 150 mg twice daily significantly reduces stroke with less intracranial bleeding, and at a dose of 110 mg twice daily has similar efficacy with less bleeding. Although, Dabigatran maintained its overall favorable profile compared with Warfarin in patients on dual antiplatelet therapy, we should always bear in mind for the sake of our AF patients that combining dual antiplatelet therapy with chronic anticoagulation with Dabigatran, as well as with Warfarin, significantly increases bleeding risk. This triple therapy association should be evaluated in the individual patient after carefully balancing bleeding versus thrombotic risk.

Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5'-carboxamidoadenosine analogues.

Science.gov (United States)

Rodenko, Boris; Detz, Remko J; Pinas, Victorine A; Lambertucci, Catia; Brun, Reto; Wanner, Martin J; Koomen, Gerrit-Jan

2006-03-01

The rapid increase of resistance to drugs commonly used in the treatment of tropical diseases such as malaria and African sleeping sickness calls for the prompt development of new safe and efficacious drugs. The pathogenic protozoan parasites lack the capability of synthesising purines de novo and they take up preformed purines from their host through various transmembrane transporters. Adenosine derivatives constitute a class of potential therapeutics due to their selective internalisation by these transporters. Automated solid-phase synthesis can speed up the process of lead finding and we pursued the solid-phase synthesis of di- and trisubstituted 5'-carboxamidoadenosine derivatives by using a safety-catch approach. While efforts with Kenner's sulfonamide linker remained fruitless, successful application of the hydrazide safety-catch linker allowed the construction of two representative combinatorial libraries. Their antiprotozoal evaluation identified two compounds with promising activity: N(6)-benzyl-5'-N-phenylcarboxamidoadenosine with an IC(50) value of 0.91 microM against Trypanosoma brucei rhodesiense and N(6)-diphenylethyl-5'-phenylcarboxamidoadenosine with an IC(50) value of 1.8 microM against chloroquine resistant Plasmodium falciparum.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

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Arezoo Rafiee Parhizgar

2017-03-01

Full Text Available Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ and amodiaquine (AQ, have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

Science.gov (United States)

Parhizgar, Arezoo Rafiee; Tahghighi, Azar

2017-03-01

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

A review on comparative study of PPI and PAMAM dendrimers

International Nuclear Information System (INIS)

Kaur, Daljeet; Jain, Keerti; Mehra, Neelesh Kumar; Kesharwani, Prashant; Jain, Narendra K.

2016-01-01

Dendrimers are hyperbranched, monodispersed macromolecules with multivalent functional end groups. Dendrimers have been explored as carrier for many drugs like anticancer, antiviral, antimalarial, antiprotozoal, anti tubercular drugs. Although a number of different types of dendrimers containing different core molecules, branching monomers and surface functional groups have been designed till date for drug delivery applications, yet the poly(propyleneimine) (PPI) and poly(amidoamine) (PAMAM) dendrimers have been the most explored dendrimers in this regard. In this review, we have summarized a comparative data on PPI and PAMAM dendrimers particularly relevant to their properties, synthesis, toxicity, biomedical applications and drug delivery attributes.

A review on comparative study of PPI and PAMAM dendrimers

Energy Technology Data Exchange (ETDEWEB)

Kaur, Daljeet; Jain, Keerti, E-mail: keertijain02@gmail.com; Mehra, Neelesh Kumar [ISF College of Pharmacy, Pharmaceutical Nanotechnology Research Laboratory (India); Kesharwani, Prashant [Wayne State University, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (United States); Jain, Narendra K., E-mail: jnarendr@yahoo.co.in, E-mail: dr.jnarendr@gmail.com [ISF College of Pharmacy, Pharmaceutical Nanotechnology Research Laboratory (India)

2016-06-15

Dendrimers are hyperbranched, monodispersed macromolecules with multivalent functional end groups. Dendrimers have been explored as carrier for many drugs like anticancer, antiviral, antimalarial, antiprotozoal, anti tubercular drugs. Although a number of different types of dendrimers containing different core molecules, branching monomers and surface functional groups have been designed till date for drug delivery applications, yet the poly(propyleneimine) (PPI) and poly(amidoamine) (PAMAM) dendrimers have been the most explored dendrimers in this regard. In this review, we have summarized a comparative data on PPI and PAMAM dendrimers particularly relevant to their properties, synthesis, toxicity, biomedical applications and drug delivery attributes.

Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata

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Vangelis Smyrniotopoulos

2017-08-01

Full Text Available Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1, a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcaria bifurcata. The gross structure of this new natural product was elucidated based on its spectroscopic data (IR, 1D and 2D-NMR, HRMS. Its absolute configuration was identified by experimental and computational vibrational circular dichroism (VCD spectroscopy, combined with the calculation of 13C-NMR chemical shielding constants. Bifurcatriol (1 was tested for in vitro antiprotozoal activity towards a small panel of parasites (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, and Leishmania donovani and cytotoxicity against mammalian primary cells. The highest activity was exerted against the malaria parasite P. falciparum (IC50 value 0.65 μg/mL with low cytotoxicity (IC50 value 56.6 μg/mL. To our knowledge, this is the first successful application of VCD and DP4 probability analysis of the calculated 13C-NMR chemical shifts for the simultaneous assignment of the absolute configuration of multiple stereogenic centers in a long-chain acyclic natural product.

Sweet Marjoram

Science.gov (United States)

Bina, Fatemeh; Rahimi, Roja

2016-01-01

Origanum majorana L. commonly known as sweet marjoram has been used for variety of diseases in traditional and folklore medicines, including gastrointestinal, ocular, nasopharyngeal, respiratory, cardiac, rheumatologic, and neurological disorders. Essential oil containing monoterpene hydrocarbons and oxygenated monoterpenes as well as phenolic compounds are chemical constituents isolated and detected in O majorana. Wide range of pharmacological activities including antioxidant, hepatoprotective, cardioprotective, anti-platelet, gastroprotective, antibacterial and antifungal, antiprotozoal, antiatherosclerosis, anti-inflammatory, antimetastatic, antitumor, antiulcer, and anticholinesterase inhibitory activities have been reported from this plant in modern medicine. This article summarizes comprehensive information concerning traditional uses, phytochemistry, and pharmacological activities of sweet marjoram. PMID:27231340

Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Science.gov (United States)

2014-10-01

OCT 2014 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone...Prescribed by ANSI Std Z39-18 Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone and Arterolane, against Multidrug-Resistant...potent antimalarial activity (2, 3). Despite having a rapid mecha- nism of action, artemisinin resistance eventually emerged and was first detected

In vitro and in vivo assessment of the anti-malarial activity of Caesalpinia pluviosa

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Eberlin Marcos N

2011-05-01

Full Text Available Abstract Background To overcome the problem of increasing drug resistance, traditional medicines are an important source for potential new anti-malarials. Caesalpinia pluviosa, commonly named "sibipiruna", originates from Brazil and possess multiple therapeutic properties, including anti-malarial activity. Methods Crude extract (CE was obtained from stem bark by purification using different solvents, resulting in seven fractions. An MTT assay was performed to evaluate cytotoxicity in MCF-7 cells. The CE and its fractions were tested in vitro against chloroquine-sensitive (3D7 and -resistant (S20 strains of Plasmodium falciparum and in vivo in Plasmodium chabaudi-infected mice. In vitro interaction with artesunate and the active C. pluviosa fractions was assessed, and mass spectrometry analyses were conducted. Results At non-toxic concentrations, the 100% ethanolic (F4 and 50% methanolic (F5 fractions possessed significant anti-malarial activity against both 3D7 and S20 strains. Drug interaction assays with artesunate showed a synergistic interaction with the F4. Four days of treatment with this fraction significantly inhibited parasitaemia in mice in a dose-dependent manner. Mass spectrometry analyses revealed the presence of an ion corresponding to m/z 303.0450, suggesting the presence of quercetin. However, a second set of analyses, with a quercetin standard, showed distinct ions of m/z 137 and 153. Conclusions The findings show that the F4 fraction of C. pluviosa exhibits anti-malarial activity in vitro at non-toxic concentrations, which was potentiated in the presence of artesunate. Moreover, this anti-malarial activity was also sustained in vivo after treatment of infected mice. Finally, mass spectrometry analyses suggest that a new compound, most likely an isomer of quercetin, is responsible for the anti-malarial activity of the F4.

N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

Science.gov (United States)

Gomes, Ana; Pérez, Bianca; Albuquerque, Inês; Machado, Marta; Prudêncio, Miguel; Nogueira, Fátima; Teixeira, Cátia; Gomes, Paula

2014-02-01

Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 μM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The antimalarial drug quinine interferes with serotonin biosynthesis and action

DEFF Research Database (Denmark)

Islahudin, Farida; Tindall, Sarah M.; Mellor, Ian R.

2014-01-01

The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmit......The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor...... tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells....

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity.

Science.gov (United States)

Wicht, Kathryn J; Combrinck, Jill M; Smith, Peter J; Egan, Timothy J

2015-08-15

A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against Plasmodium falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5000 commercially available compounds (Aldrich(CPR)) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively. Copyright © 2014 Elsevier Ltd. All rights reserved.

A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides.

Science.gov (United States)

Bachi, Mario D; Korshin, Edward E; Hoos, Roland; Szpilman, Alex M; Ploypradith, Poonsakdi; Xie, Suji; Shapiro, Theresa A; Posner, Gary H

2003-06-05

The syntheses and in vitro antimalarial screening of 50 bridged, bicyclic endoperoxides of types 9-13 are reported. In contrast to antimalarial trioxanes of the artemisinin family, but like yingzhaosu A and arteflene, the peroxide function of compounds 9-13 is contained in a 2,3-dioxabicyclo[3.3.1]nonane system 6. Peroxides 9 and 10 (R(1) = OH) are readily available through a multicomponent, sequential, free-radical reaction involving thiol-monoterpenes co-oxygenation (a TOCO reaction). beta-Sulfenyl peroxides 9 and 10 (R(1) = OH) are converted into beta-sulfinyl and beta-sulfonyl peroxides of types 11-13 by controlled S-oxidation and manipulation of the tert-hydroxyl group through acylation, alkylation, or dehydration followed by selective hydrogenation. Ten enantiopure beta-sulfonyl peroxides of types 12 and 13 exhibit in vitro antimalarial activity comparable to that of artemisinin (IC(50) = 6-24 nM against Plasmodium falciparum NF54). In vivo testing of a few selected peroxides against Plasmodium berghei N indicates that the antimalarial efficacies of beta-sulfonyl peroxides 39a, 46a, 46b, and 50a are comparable to those of some of the best antimalarial drugs and are higher than artemisinin against chloroquine-resistant Plasmodium yoelii ssp. NS. In view of the nontoxicity of beta-sulfonyl peroxides 39a, 46a, and 46b in mice, at high dosing, these compounds are regarded as promising antimalarial drug candidates.

Potentiation of antimalarial activity of arteether in combination with Vetiver root extract.

Science.gov (United States)

Dhawan, Sangeeta; Gunjan, Sarika; Pal, Anirban; Tripathi, Renu

2016-05-01

In malaria, development of resistance towards artemisinin derivatives has urged the need for new drugs or new drug combinations to tackle the drug resistant malaria. We studied the fresh root extract of Vetiver zizanioides (Linn.) Nash (VET) with a CDRI-CIMAP antimalarial α/β arteether (ART) together for their antimalarial potential. Our results showed additive to synergistic antimalarial activity of VET and ART with sum fractional inhibitory concentrations Σ FICs 1.02 ± 0.24 and 1.12 ± 0.32 for chloroquine sensitive (CQS) and chloroquine resistant (CQR) strain of Plasmodium falciparum (William H. Welch), respectively. Further, these combinations were explored against multidrug resistant rodent malaria parasite i.e. P. yoelii nigeriensis. Analysis of in vivo interaction of ART and VET showed that 10 mg/kg x 5 days of ART with 1000 mg/kg of VET x 5 days cured 100% mice infected with MDR parasite, while the same dose of ART could produce only up to 30% cure and VET fraction was not curative at all. Synergism/additiveness, found between VET and ART is reported for the first time. The curative dose of ART in the combination was reduced to its one fourth, and thus limits the side effects, if any. Although antimalarial potential of ART was enhanced by VET, action mechanism of later needs to be elucidated in detail.

Stent Thrombosis in Drug-Eluting or Bare-Metal Stents in Patients Receiving Dual Antiplatelet Therapy.

Science.gov (United States)

Kereiakes, Dean J; Yeh, Robert W; Massaro, Joseph M; Driscoll-Shempp, Priscilla; Cutlip, Donald E; Steg, P Gabriel; Gershlick, Anthony H; Darius, Harald; Meredith, Ian T; Ormiston, John; Tanguay, Jean-François; Windecker, Stephan; Garratt, Kirk N; Kandzari, David E; Lee, David P; Simon, Daniel I; Iancu, Adrian Corneliu; Trebacz, Jaroslaw; Mauri, Laura

2015-10-01

This study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS. Despite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES. Prospective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months. Among 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference -1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference -1.8%, p = 0.053, noninferiority p stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

When is the Best Time for the Second Antiplatelet Agent in Non-St Elevation Acute Coronary Syndrome?

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Pedro Gabriel Melo de Barros e Silva

2016-03-01

Full Text Available Abstract Dual antiplatelet therapy is a well-established treatment in patients with non-ST elevation acute coronary syndrome (NSTE-ACS, with class I of recommendation (level of evidence A in current national and international guidelines. Nonetheless, these guidelines are not precise or consensual regarding the best time to start the second antiplatelet agent. The evidences are conflicting, and after more than a decade using clopidogrel in this scenario, benefits from the routine pretreatment, i.e. without knowing the coronary anatomy, with dual antiplatelet therapy remain uncertain. The recommendation for the upfront treatment with clopidogrel in NSTE-ACS is based on the reduction of non-fatal events in studies that used the conservative strategy with eventual invasive stratification, after many days of the acute event. This approach is different from the current management of these patients, considering the established benefits from the early invasive strategy, especially in moderate to high-risk patients. The only randomized study to date that specifically tested the pretreatment in NSTE-ACS in the context of early invasive strategy, used prasugrel, and it did not show any benefit in reducing ischemic events with pretreatment. On the contrary, its administration increased the risk of bleeding events. This study has brought the pretreatment again into discussion, and led to changes in recent guidelines of the American and European cardiology societies. In this paper, the authors review the main evidence of the pretreatment with dual antiplatelet therapy in NSTE-ACS.

Microbial burden of some herbal antimalarials marketed at Elele, Rivers State.

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Tatfeng, Y M; Olama, E H; Ojo, T O

2009-12-30

Herbal antimalarials still remain an alternative to our traditional communities who can not afford orthodox antimalarials. This study was aimed at investigating the microbial quality of six herbal antimalarials using standard microbiological methods. Of the six preparations analyzed, "schnapps", palm wine and water were the media of preparation; the water base preparations recorded higher microbial load. The mean microbial load was 159.5 × 10(5) cfu/ml and 217.4 × 10(2)cfu/ml in water and alcohol base preparations respectively. The microbial profile of the preparations showed that the schnapps base preparations were predominantly contaminated with Bacillus sp (Aerobic spore bearers) and Mucor spp. The palm wine preparation harboured Bacillus sp, yeasts and Mucor spp while the water base preparations had several isolates such as Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli 0157H7, Proteus mirabilis, Enterococcus feacalis, Serratia marcensces, Staph. aureus, Bacillus spp and Mucor spp. Conclusively, this study underlines the public health importance of these preparations given the high burden of such human pathogen as Ecoli O157H7, Ps aeruginosa, Stahp aureus, etc. in the preparations.

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.

Science.gov (United States)

Fielding, Alistair J; Lukinović, Valentina; Evans, Philip G; Alizadeh-Shekalgourabi, Said; Bisby, Roger H; Drew, Michael G B; Male, Verity; Del Casino, Alessio; Dunn, James F; Randle, Laura E; Dempster, Nicola M; Nahar, Lutfun; Sarker, Satyajit D; Cantú Reinhard, Fabián G; de Visser, Sam P; Dascombe, Mike J; Ismail, Fyaz M D

2017-05-17

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF 3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF 3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N 1 ,N 2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies

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J. O. Adebayo

2013-01-01

Full Text Available In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25–500 mg/kg body weight using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P>0.05 function indices of the liver and cardiovascular system at all doses administered but significantly increased (P<0.05 plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles.

Factors contributing to antimalarial drug resistance in Rachuonyo ...

African Journals Online (AJOL)

Qualitative and quantitative data were collected among 380 respondents including health care providers, people seeking malaria treatment and Community Own Resource (CORPs), from 47 registered health facilities. The study revealed that all health facilities were using general-purpose trucks to transport antimalarial ...

Antimalarial prescribing patterns in state hospitals and selected ...

African Journals Online (AJOL)

slowdown of progression to resistance could be achieved by improving prescribing practice, drug quality, and patient compliance. Objective: To determine the antimalarial prescribing pattern and to assess rational prescribing of chloroquine by prescribers in government hospitals and parastatals in Lagos State. Methods: ...

Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Science.gov (United States)

Shuldiner, Alan R; Palmer, Kathleen; Pakyz, Ruth E; Alestock, Tameka D; Maloney, Kristin A; O'Neill, Courtney; Bhatty, Shaun; Schub, Jamie; Overby, Casey Lynnette; Horenstein, Richard B; Pollin, Toni I; Kelemen, Mark D; Beitelshees, Amber L; Robinson, Shawn W; Blitzer, Miriam G; McArdle, Patrick F; Brown, Lawrence; Jeng, Linda Jo Bone; Zhao, Richard Y; Ambulos, Nicholas; Vesely, Mark R

2014-03-01

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.

Ameliorative antimalarial effects of the combination of rutin and swertiamarin on malarial parasites

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Divya Shitlani

2016-06-01

Full Text Available Objective: To ameliorate the antimalarial activity via the combination of rutin (flavonoid and swertiamarin (glycoside. Methods: The antimalarial effects were assessed by in vitro and in vivo methodology. In vitro antiplasmodial activity was assessed by using Plasmodium falciparum cultured media and determined the IC 50 value of individual drugs and their combinations. In in vivo methodology, antimalarial effects of rutin, swertiamarin (200–280 mg/kg/day, p.o. and their combination in 1:1, 1:2 and 2:1 ratios were investigated early and established malaria infections using Swiss albino mice infected with Plasmodium berghei. Chloroquine phosphate (5 mg/kg/day, p.o. was used as the standard drug. Results: IC 50 values of the rutin and swertiamarin via in vitro study revealed (9.50 ± 0.29 µg/ mL and (8.17 ± 0.17 µg/mL respectively. Whereas, the combination in 1:1 ratio [IC50 of (5.51 ± 0.18 µg/mL] showed better antiplasmodial activity against Plasmodium falciparum. In vivo results showed that rutin and swertiamarin had chemosuppressant effects in a dose-dependent manner, whereas, combination in 1:1 ratio possessed potential antimalarial activity similar to chloroquine phosphate. The drug interaction between rutin and swertiamarin revealed the synergistic effect on 1:1 ratio and additive effect on 1:2 and 2:1 ratios. Conclusions: The results of the in vitro and in vivo study clearly indicate that the combination (1:1 of rutin and swertiamarin showed potential antimalarial activity rather than an individual of each and their combinations 1:2 and 2:1.

Risk of bleeding in patients undergoing percutaneous endoscopic gastrotrostomy (PEG tube insertion under antiplatelet therapy: a systematic review with a meta-analysis

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Alfredo J. Lucendo

2015-03-01

Full Text Available Background and aim: Patients undergoing percutaneous endoscopic gastrostomy (PEG tube placement often are under antiplatelet therapy with a potential thromboembolic risk if these medications are discontinued. This systematic review aims to assess if maintaining aspirin and/or clopidogrel treatment increases the risk of bleeding following PEG placement. Methods: A systematic search of the MEDLINE, EMBASE, and SCOPUS databases was developed for studies investigating the risk of bleeding in patients on antiplatelet therapy undergoing PEG tube insertion. Summary estimates, including 95 % confidence intervals (CI, were calculated. A fixed or random effects model was used depending on heterogeneity (I². Publication bias risks were assessed by means of funnel plot analysis. Results: Eleven studies with a total of 6,233 patients (among whom 3,665 were undergoing antiplatelet treatment, met the inclusion criteria and were included in the quantitative summary. Any PEG tube placement-related bleeding was found in 2.67 % (95 % CI 1.66 %, 3.91 % of the entire population and in 2.7 % (95 % CI 1.5 %, 4.1 % of patients not receiving antiplatelet therapy. Pooled relative risk (RR for bleeding in patients under aspirin, when compared to controls, was 1.43 (95 % CI 0.89, 2.29; I² = 0 %; pooled RR for clopidogrel was 1.21 (95 % CI 0.48, 3.04; I² = 0 % and for dual antiplatelet therapy, 2.13; (95 % CI 0.77, 5.91; I² = 47 %. No significant publication bias was evident for the different medications analyzed. Conclusion: Antiplatelet therapy was safe among patients undergoing PEG tube insertion. Future prospective and randomized studies with larger sample sizes are required to confirm the results of this study.

Prospective observational study of the effect of dual antiplatelet therapy with tranexamic acid treatment on platelet function and bleeding after cardiac surgery.

Science.gov (United States)

Amour, J; Garnier, M; Szymezak, J; Le Manach, Y; Helley, D; Bertil, S; Ouattara, A; Riou, B; Gaussem, P

2016-12-01

The bleeding impact of dual antiplatelet therapy (DAPT), aspirin and clopidogrel, maintained until coronary artery bypass graft surgery (CABG), is still a matter of debate. The lack of preoperative antiplatelet activity measurement and heterogeneity of antifibrinolytic protocols in prior studies make the conclusions questionable. The aim of this prospective study was to determine, after preoperative antiplatelet activity measurement, if the maintenance of DAPT until CABG increases bleeding in patients treated with tranexamic acid (TA). This observational study included 150 consecutive patients, 89 treated with aspirin and 61 treated with DAPT, undergoing a first-time planned on-pump CABG with TA treatment. Antiplatelet activity was measured with platelet aggregation tests and quantification of VASP phosphorylation. Postoperative bleeding at 24 h was recorded and propensity score analysis was performed. Based on VASP assay, 54% of patients showed high on-clopidogrel platelet activity inhibition. Postoperative bleeding at 24 h increased by 22% in the DAPT group, compared with the aspirin group (680 [95% CI: 360-1670] vs 558 [95%CI: 267-1270] ml, P < 0.01), consistent with increased blood transfusion (21% vs 7%, P = 0.01); a higher incidence of mediastinitis did not reach statistical significance (15% vs 4%, P = 0.05). Bleeding correlated with the extent of clopidogrel antiplatelet effect, with the best correlation for the VASP assay. Maintenance of DAPT until the day of CABG in patients treated with TA, increased postoperative bleeding at 24 h in parallel with preoperative antiplatelet activity induced by clopidogrel. © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

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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.

Malaria and antimalarial plants in Roraima, Brazil.

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Milliken, W

1997-01-01

One of the numerous problems created by the gold rush which took place in northern Brazil (Roraima State) at the end of the 1980s was a severe epidemic of malaria amongst the indigenous peoples of the region. Worst hit were the Yanomami Indians, who had lived in almost total isolation prior to this event. The problem has been exacerbated by the development of chloroquine-resistant strains of Plasmodium falciparum. In an effort to identify viable alternatives to dependence on western medicine for malaria treatment, a survey was carried out on the local plant species (wild and cultivated) used for this purpose in Roraima. Fieldwork was carried out amongst seven indigenous peoples, as well as with the non-indigenous settlers. Over 90 species were collected, many of which have been cited as used for treatment of malaria and fevers elsewhere. Knowledge of antimalarial plants was found to vary greatly between the communities, and in some cases there was evidence of recent experimentation. Initial screening of plant extracts has shown a high incidence of significant antimalarial activity amongst the species collected.

The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.

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Helgren, Travis R; Sciotti, Richard J; Lee, Patricia; Duffy, Sandra; Avery, Vicky M; Igbinoba, Osayawemwen; Akoto, Matthew; Hagen, Timothy J

2015-01-15

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement. Copyright © 2014 Elqsevier Ltd. All rights reserved.

Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials▿

Science.gov (United States)

Creek, Darren J.; Charman, William N.; Chiu, Francis C. K.; Prankerd, Richard J.; Dong, Yuxiang; Vennerstrom, Jonathan L.; Charman, Susan A.

2008-01-01

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study. PMID:18268087

Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

OpenAIRE

Huthmacher, Carola; Hoppe, Andreas; Bulik, Sascha; Holzh?tter, Hermann-Georg

2010-01-01

Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicte...

[Neurosurgery in a patient on dual antiplatelet therapy. Case report and the review of the literature].

Science.gov (United States)

Lubnin, A Yu; Karnaukhov, V V; Moshkin, A V; Rylova, A V; Shimansky, V N

A neurosurgical intervention in a patient on dual antiplatelet therapy is a serious challenge for both the neurosurgeon and anesthesiologist.. The article describes a clinical case of a successful urgent neurosurgical intervention (ventriculoperitoneostomy for obstructive hydrocephalus caused by a large meningioma of the posterior surface of the petrous pyramid) in a patient on dual antiplatelet therapy (DAT) due to a recently placed coronary stent.. Given a high risk of coronary stent thrombosis, the surgery was performed in the presence of ongoing DAT. There were no intracranial hemorrhagic complications, but subcutaneous hemorrhagic complications developed. The article discusses the features of managing similar patients whose number is growing.

Mass anti-malarial administration in western Cambodia: a qualitative study of factors affecting coverage.

Science.gov (United States)

Pell, Christopher; Tripura, Rupam; Nguon, Chea; Cheah, Phaikyeong; Davoeung, Chan; Heng, Chhouen; Dara, Lim; Sareth, Ma; Dondorp, Arjen; von Seidlein, Lorenz; Peto, Thomas J

2017-05-19

Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region. Its effectiveness depends on high levels of coverage in the target population. This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia. Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities. Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo. Malaria was an important health concern and villagers reported a demand for malaria treatment. This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria. Participants generally understood the overall study aim and were familiar with study activities. Comprehension of the study rationale was however limited. After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as "side effects" contributed to a decrease of coverage in round two. Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings. This contributed to a subsequent increase in coverage. Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement. Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare.

In vivo antimalarial activity of a labdane diterpenoid from the leaves of Otostegia integrifolia Benth.

Science.gov (United States)

Endale, Abyot; Bisrat, Daniel; Animut, Abebe; Bucar, Franz; Asres, Kaleab

2013-12-01

In Ethiopian traditional medicine, the leaves of Otostegia integrifolia Benth. are used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the 80% methanol leaf extract O. integrifolia was tested for its in vivo antimalarial activity, in a 4-day suppressive assay against Plasmodium berghei. Activity-guided fractionation of this extract which showed potent antiplasmodial activity resulted in the isolation of a labdane diterpenoid identified as otostegindiol. Otostegindiol displayed a significant (P antimalarial activity at doses of 25, 50 and 100 mg/kg with chemosuppression values of 50.13, 65.58 and 73.16%, respectively. Acute toxicity studies revealed that the crude extract possesses no toxicity in mice up to a maximum dose of 5000 mg/kg suggesting the relative safety of the plant when administered orally. The results of the present study indicate that otostegindiol is among the antimalarial principles in this medicinal plant, and further support claims for the traditional medicinal use of the plant for the treatment of malaria. Copyright © 2013 John Wiley & Sons, Ltd.

Plant-Derived Antimalarial Agents: New Leads and Efficient Phytomedicines. Part II. Non-Alkaloidal Natural Products

Directory of Open Access Journals (Sweden)

Alaíde Braga de Oliveira

2009-08-01

Full Text Available Malaria is still the most destructive and dangerous parasitic infection in many tropical and subtropical countries. The burden of this disease is getting worse, mainly due to the increasing resistance of Plasmodium falciparum against the widely available antimalarial drugs. There is an urgent need for new, more affordable and accessible antimalarial agents possessing original modes of action. Natural products have played a dominant role in the discovery of leads for the development of drugs to treat human diseases, and this fact anticipates that new antimalarial leads may certainly emerge from tropical plant sources. This present review covers most of the recently-published non-alkaloidal natural compounds from plants with antiplasmodial and antimalarial properties, belonging to the classes of terpenes, limonoids, flavonoids, chromones, xanthones, anthraquinones, miscellaneous and related compounds, besides the majority of papers describing antiplasmodial crude extracts published in the last five years not reviewed before. In addition, some perspectives and remarks on the development of new drugs and phytomedicines for malaria are succinctly discussed.

Antimalarial activity of the terpene nerolidol.

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Saito, Alexandre Y; Marin Rodriguez, Adriana A; Menchaca Vega, Danielle S; Sussmann, Rodrigo A C; Kimura, Emília A; Katzin, Alejandro M

2016-12-01

Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent. In this study, the antimalarial activity of nerolidol was investigated in a mouse model of malaria. Mice were infected with Plasmodium berghei ANKA and were treated with 1000 mg/kg/dose nerolidol in two doses delivered by the oral or inhalation route. In mice treated with nerolidol, parasitaemia was inhibited by >99% (oral) and >80% (inhalation) until 14 days after infection (P  0.05). The toxicity of nerolidol administered by either route was not significant, whilst genotoxicity was observed only at the highest dose tested. These results indicate that combined use of nerolidol and other drugs targeting different points of the same isoprenoid pathway may be an effective treatment for malaria. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

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Plouffe, David; Brinker, Achim; McNamara, Case; Henson, Kerstin; Kato, Nobutaka; Kuhen, Kelli; Nagle, Advait; Adrián, Francisco; Matzen, Jason T.; Anderson, Paul; Nam, Tae-gyu; Gray, Nathanael S.; Chatterjee, Arnab; Janes, Jeff; Yan, S. Frank; Trager, Richard; Caldwell, Jeremy S.; Schultz, Peter G.; Zhou, Yingyao; Winzeler, Elizabeth A.

2008-01-01

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈1.7 million compounds, we identified a diverse collection of ≈6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities. PMID:18579783

Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake

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Carmen E Contreras

2004-03-01

Full Text Available The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

POTENCY OF THE INDONESIAN MEDICINAL PLANTS AS ANTIMALARIAL DRUGS

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Subeki Subeki

2012-12-01

Full Text Available The Indonesian traditional herbal medicine has been practiced for many centuries in Indonesia to treat malaria diseases. Although modern medicine is becoming increasingly important, herbal medicine is still very popular. In order to select raw material for preparation of safety herbal medicines, forty five medicinal plants have been tested for acute toxicity in mouse at a dose 715 mg/kg body weight. The extracts of Asclepias curassavica leave, Alstonia scholaris leave, Decospermum fruticosum leave, Elaocarpus petiolatus bark, Elaocarpus parvifolius bark, Eurycoma longifolia root, Garcinia rigida bark, Nephelium lappaceum bark, Pentaspodan motleyi leave, Picrasma javanica leave, Phyllanthus niruri whole, Quassia indica leave, Syzygium pycnanthum bark, Tetrasera scandens leave, Cratoxylum glaucum bark, Sandoricum emarginatum bark, Mallotus paniculatus leave, Microcos ovatolanceolata bark, Poikilospermum suaveolens leave, Fibraurea chloroleuea leave, Tetrasera scandens root, and Timonius billitonensis bark showed toxicity with mortality level of 20-100%. The remaining 32 plant extracts were not toxic at dose tested. The toxic plant species should be considered in the preparation of herbal medicines. Of the safety extracts were tested for their antimalarial activity against Plasmodium berghei in vivo at a dose 715 mg/kg body weight. Extract of Carica papaya leave was most active than other plant extracts with parasitemia 1.13%, while control showed 17.21%. More research is needed to scientifically prove efficacy and to identity antimalarial constituents in the plant extracts. Key words: Indonesian medicinal plant, jamu, toxicity, antimalarial activity, Plasmodium berghei.

Lead optimization of antimalarial propafenone analogues.

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Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin

2012-07-12

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

Safety and Tolerability Profile of Artemisinin-Based Antimalarial ...

African Journals Online (AJOL)

The WHO in 2001 advocated artemisinin- based antimalarial combination therapy (ACT), which was adopted by Nigeria in 2005. The objective of this study was to characterize the safety and tolerability profile of the ACTs in adult patients with uncomplicated malaria. A descriptive longitudinal study was conducted in the ...

Antimalarial natural products: a review

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Faraz Mojab

2012-03-01

Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

Bioguided investigation of the antimalarial activities of Trema orientalis

African Journals Online (AJOL)

Aghomotsegin

2015-10-28

Oct 28, 2015 ... Article Number: 3F00A6755934. ISSN 1684-5315 ... License 4.0 · International License ... extract was analyzed using thin layer chromatography (TLC) plates,. Merck .... makes it a viable candidate in the search for antimalarial.

Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity.

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Hwang, Jong Yeon; Kawasuji, Takashi; Lowes, David J; Clark, Julie A; Connelly, Michele C; Zhu, Fangyi; Guiguemde, W Armand; Sigal, Martina S; Wilson, Emily B; Derisi, Joseph L; Guy, R Kiplin

2011-10-27

We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.

Bioactive compounds fractionated from endophyte Streptomyces SUK 08 with promising ex-vivo antimalarial activity

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Noraziah Mohamad Zin

2017-12-01

Full Text Available Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract. Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry. Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/mL. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/mL. The IC50 of parasitemia at 5% and 30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs. Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations. Keywords: Butyl–propyl–ester, Cyclohexane, 2,3-Heptanedione, Endophyte, Streptomyces, Antimalarial

Duration of dual antiplatelet therapy in acute coronary syndrome.

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Wilson, Simon John; Newby, David E; Dawson, Dana; Irving, John; Berry, Colin

2017-04-01

Despite a large volume of evidence supporting the use of dual antiplatelet therapy in patients with acute coronary syndrome, there remains major uncertainty regarding the optimal duration of therapy. Clinical trials have varied markedly in the duration of therapy, both across and within trials. Recent systematic reviews and meta-analyses suggest that shorter durations of dual antiplatelet therapy are superior because the avoidance of atherothrombotic events is counterbalanced by the greater risks of excess major bleeding with apparent increases in all-cause mortality with longer durations. These findings did not show significant heterogeneity according to whether patients had stable or unstable coronary heart disease. Moreover, the potential hazards and benefits may differ when applied to the general broad population of patients encountered in everyday clinical practice who have markedly higher bleeding and atherothrombotic event rates. Clinicians lack definitive information regarding the duration of therapy in patients with acute coronary syndrome and risk scores do not appear to be sufficiently robust to address these concerns. We believe that there is a pressing need to undertake a broad inclusive safety trial of shorter durations of therapy in real world populations of patients with acute coronary syndrome. The clinical evidence would further inform future research into strategies for personalised medicine. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Antimalarial activity of Syzygium guineense during early and established Plasmodium infection in rodent models.

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Tadesse, Solomon Asmamaw; Wubneh, Zewdu Birhanu

2017-01-05

In Ethiopia, the leaves of Syzygium guineense have been found useful for the prevention and cure of malaria, and demonstrated antiplasmodial activity in vitro. Nevertheless, no scientific study has been conducted to confirm its antimalarial activity in vivo. Therefore, the objective of the study was to evaluate the antimalarial effect of Syzygium guineense leaf extract in mice. Inoculation of the study mice was carried out by using the malaria parasite, Plasmodium berghei. The plant extract was prepared at 200, 400 and 600 mg/kg. Chloroquine and distilled water was administered to the positive and negative control groups respectively. Parameters like parasitaemia, survival time and body weight were determined following standard tests (4-day suppressive, Rane's and repository tests). Syzygium guineense crude leaf extract displayed considerable (p activity in both the repository and curative tests. The extract also prevented body weight loss and prolonged survival date of mice significantly (P antimalarial activity in mice. The test substance was found to be safe with no observable signs of toxicity in the study mice. The results of the present work confirmed the in vitro antiplasmodial finding and traditional claims in vivo in mice. Therefore, Syzygium guineense could be regarded as a potential source to develop safe, effective and affordable antimalarial agent.

Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum

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Vaidya, Akhil B.; Morrisey, Joanne M.; Zhang, Zhongsheng; Das, Sudipta; Daly, Thomas M.; Otto, Thomas D.; Spillman, Natalie J.; Wyvratt, Matthew; Siegl, Peter; Marfurt, Jutta; Wirjanata, Grennady; Sebayang, Boni F.; Price, Ric N.; Chatterjee, Arnab; Nagle, Advait; Stasiak, Marcin; Charman, Susan A.; Angulo-Barturen, Iñigo; Ferrer, Santiago; Belén Jiménez-Díaz, María; Martínez, María Santos; Gamo, Francisco Javier; Avery, Vicky M.; Ruecker, Andrea; Delves, Michael; Kirk, Kiaran; Berriman, Matthew; Kortagere, Sandhya; Burrows, Jeremy; Fan, Erkang; Bergman, Lawrence W.

2014-01-01

The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na+ regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na+ homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na+ homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes. PMID:25422853

Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack

DEFF Research Database (Denmark)

Christensen, Hanne Krarup

2015-01-01

RATIONALE: The risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event. HYPOTHESIS: Because two antiplatelet agents are superior to one in patients with non-cardioembolic events, more intensive treatment might be even more effective. SAMPLE...... SIZE ESTIMATES: The sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance. METHODS AND DESIGN: Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing...... the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one-month. This international collaborative parallel-group prospective randomized open-label blinded-end-point phase III trial plans to recruit 4100 patients with acute...

In vitro antioxidant and antimalarial activities of leaves, pods and bark extracts of Acacia nilotica (L.) Del.

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Sadiq, Muhammad Bilal; Tharaphan, Pattamon; Chotivanich, Kesinee; Tarning, Joel; Anal, Anil Kumar

2017-07-18

The emergence of drug resistant malaria is threatening our ability to treat and control malaria in the Southeast Asian region. There is an urgent need to develop novel and chemically diverse antimalarial drugs. This study aimed at evaluating the antimalarial and antioxidant potentials of Acacia nilotica plant extracts. The antioxidant activities of leaves, pods and bark extracts were determined by standard antioxidant assays; reducing power capacity, % lipid peroxidation inhibition and ferric reducing antioxidant power assay. The antimalarial activities of plant extracts against Plasmodium falciparum parasites were determined by the 48 h schizont maturation inhibition assay. Further confirmation of schizonticide activity of extracts was made by extending the incubation period up to 96 h after removing the plant extract residues from parasites culture. Inhibition assays were analyzed by dose-response modelling. In all antioxidant assays, leaves of A. nilotica showed higher antioxidant activity than pods and bark. Antimalarial IC 50 values of leaves, pods and bark extracts were 1.29, 4.16 and 4.28 μg/ml respectively, in the 48 h maturation assay. The IC 50 values determined for leaves, pods and bark extracts were 3.72, 5.41 and 5.32 μg/ml respectively, after 96 h of incubation. All extracts inhibited the development of mature schizont, indicating schizonticide activity against P. falciparum. A. nilotica extracts showed promising antimalarial and antioxidant effects. However, further investigation is needed to isolate and identify the active components responsible for the antimalarial and antioxidant effects.

In-hospital mortality after pre-treatment with antiplatelet agents or oral anticoagulants and hematoma evacuation of intracerebral hematomas.

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Stein, Marco; Misselwitz, Björn; Hamann, Gerhard F; Kolodziej, Malgorzata; Reinges, Marcus H T; Uhl, Eberhard

2016-04-01

Pre-treatment with antiplatelet agents is described to be a risk factor for mortality after spontaneous intracerebral hemorrhage (ICH). However, the impact of antithrombotic agents on mortality in patients who undergo hematoma evacuation compared to conservatively treated patients with ICH remains controversial. This analysis is based on a prospective registry for quality assurance in stroke care in the State of Hesse, Germany. Patients' data were collected between January 2008 and December 2012. Only patients with the diagnosis of spontaneous ICH were included (International Classification of Diseases 10th Revision codes I61.0-I61.9). Predictors of in-hospital mortality were determined by univariate analysis. Predictors with Phematoma evacuation (odds ratio [OR]: 2.5; 95% confidence interval [CI]: 1.24-4.97; P=0.010) compared to patients without antiplatelet pre-treatment treatment (OR: 0.9; 95% CI: 0.79-1.09; P=0.376). In conclusion a higher rate of in-hospital mortality after pre-treatment with antiplatelet agents in combination with hematoma evacuation after spontaneous ICH was observed in the presented cohort. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anti-infective Discorhabdins from a Deep-Water Alaskan Sponge of the Genus Latrunculia†

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Na, MinKyun; Ding, Yuanqing; Wang, Bin; Tekwani, Babu L.; Schinazi, Raymond F.; Franzblau, Scott; Kelly, Michelle; Stone, Robert; Li, Xing-Cong; Ferreira, Daneel; Hamann, Mark T.

2016-01-01

Bioassay- and LC-MS-guided fractionation of a methanol extract from a new deep-water Alaskan sponge species of the genus Latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin B (1) and discorhabdin Y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins A (3), C (4), E (5), and L (6), dihydrodiscorhabdin C (7), and the benzene derivative 8. Compounds 3, 4, and 7 exhibited anti-HCV activity, antimalarial activity, and selective antimicrobial activity. Although compounds 3 and 7 displayed potent and selective in vitro antiprotozoal activity, Plasmodium berghei-infected mice did not respond to these metabolites due to their toxicity in vivo. PMID:20337497

Anti-infective discorhabdins from a deep-water alaskan sponge of the genus Latrunculia.

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Na, Minkyun; Ding, Yuanqing; Wang, Bin; Tekwani, Babu L; Schinazi, Raymond F; Franzblau, Scott; Kelly, Michelle; Stone, Robert; Li, Xing-Cong; Ferreira, Daneel; Hamann, Mark T

2010-03-26

Bioassay- and LC-MS-guided fractionation of a methanol extract from a new deep-water Alaskan sponge species of the genus Latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin B and discorhabdin Y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins A (3), C (4), E (5), and L (6), dihydrodiscorhabdin C (7), and the benzene derivative 8. Compounds 3, 4, and 7 exhibited anti-HCV activity, antimalarial activity, and selective antimicrobial activity. Although compounds 3 and 7 displayed potent and selective in vitro antiprotozoal activity, Plasmodium berghei-infected mice did not respond to these metabolites due to their toxicity in vivo.

Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis.

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Park, Jong-Ho; Saposnik, Gustavo; Ovbiagele, Bruce; Markovic, Daniela; Towfighi, Amytis

2016-02-01

Retrospective analyses of randomized controlled trials suggest that antiplatelet therapy may modify the potential cerebrovascular benefits of lowering homocysteine with B-vitamins among individuals with cardiovascular disease. We evaluated the effects of B-vitamin supplementation on risk of subsequent stroke among high cardiovascular risk individuals who are not taking antiplatelet medications. We systematically searched the Cochrane Central Register of controlled trials, PubMed, the Internet Stroke Center stroke trials, and the clinical trials.gov website from 1966 to April 2015. Inclusion criteria included: randomized controlled trials of homocysteine-lowering therapy with B-vitamins; high cardiovascular risk population and follow-up ≥1 year. We considered stroke as the primary outcome. Among 11 randomized controlled trials meeting inclusion criteria, three studies assessed stroke as an outcome and reported event rates according to whether or not individuals were taking antiplatelets: Vitamin Intervention for Stroke Prevention (VISP), VITAmins TO Prevent Stroke (VITATOPS), and Heart Outcomes Prevention Evaluation 2 (HOPE-2). A total of 4643 high vascular risk subjects not taking antiplatelets were evaluated. The overall effect size across studies was summarized using the fixed effects model after confirming there was no significant heterogeneity. Heterogeneity was assessed using the Cochran's Q and I(2) statistics. Compared with the control group, those taking B-vitamin supplementation had a lower risk of recurrent stroke (HR 0.86, 95% CI 0.62 to 1.19 for VISP; 0.65, 0.46 to 0.91 for VITATOPS; and 0.60, 0.39 to 0.92 for HOPE-2; overall HR 0.71, 0.58 to 0.88). Homocysteine lowering with B-vitamins among high vascular risk patients who are not taking antiplatelet therapy is related to a significant reduction (29%) in overall stroke risk. A clinical trial of B-vitamins in this group may be warranted. © 2016 World Stroke Organization.

Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

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González, Miguel A; Clark, Julie; Connelly, Michele; Rivas, Fatima

2014-11-15

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.

Science.gov (United States)

Faísca Phillips, Ana Maria; Nogueira, Fátima; Murtinheira, Fernanda; Barros, Maria Teresa

2015-01-01

The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anticoagulant and Antiplatelet Prescribing Patterns for Patients with Atrial Fibrillation after Percutaneous Coronary Intervention.

Science.gov (United States)

Woods, Erin A; Ackman, Margaret L; Graham, Michelle M; Koshman, Sheri L; Boswell, Rosaleen M; Barry, Arden R

2016-01-01

Current guidelines recommend triple antithrombotic therapy (TAT), defined as acetylsalicylic acid (ASA), clopidogrel, and warfarin, for patients with nonvalvular atrial fibrillation who have undergone percutaneous coronary intervention with stent implantation. The choice of anticoagulant/antiplatelet therapy in this population is ambiguous and complex, and prescribing patterns are not well documented. To characterize local prescribing patterns for anticoagulant/antiplatelet therapy after percutaneous coronary intervention in patients with nonvalvular atrial fibrillation. A chart review was conducted at a single quaternary cardiology centre. Patients with nonvalvular atrial fibrillation were identified via medical records, and those who underwent percutaneous coronary intervention were identified using a local clinical patient registry. Adult inpatients with nonvalvular atrial fibrillation and a CHADS2 score (based on congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) of 1 or higher who underwent percutaneous coronary intervention from 2011 to 2013 were included. Patients undergoing cardiovascular surgery or transcatheter aortic valve replacement, those with mechanical devices requiring anticoagulation, and those with an allergy to any component of TAT were excluded. Seventy patients were included. The median age was 75 years, and 52 (74%) were men. At discharge, 30 (43%) were receiving TAT and 27 (39%) were receiving dual antiplatelet therapy (clopidogrel and ASA). No patients received the combination of warfarin and clopidogrel. Among those who received TAT, 90% (19 of 21) who received a bare metal stent had a recommended duration of 1 month, and 75% (6 of 8) who received a drug-eluting stent had a recommended duration of 1 year. Direct-acting oral anticoagulants with 2 antiplatelet drugs were prescribed for 9% (6 of 70) of the patients, and 10% (7 of 70) received ticagrelor and ASA with or without warfarin. Overall, the

Identifying rapidly parasiticidal anti-malarial drugs using a simple and reliable in vitro parasite viability fast assay.

Science.gov (United States)

Linares, María; Viera, Sara; Crespo, Benigno; Franco, Virginia; Gómez-Lorenzo, María G; Jiménez-Díaz, María Belén; Angulo-Barturen, Íñigo; Sanz, Laura María; Gamo, Francisco-Javier

2015-11-05

The emergence of Plasmodium falciparum resistance to artemisinins threatens to undermine the effectiveness of artemisinin-based combination anti-malarial therapy. Developing suitable drugs to replace artemisinins requires the identification of new compounds that display rapid parasite killing kinetics. However, no current methods fully meet the requirements to screen large compound libraries for candidates with such properties. This study describes the development and validation of an in vitro parasite viability fast assay for identifying rapidly parasiticidal anti-malarial drugs. Parasite killing kinetics were determined by first culturing unlabelled erythrocytes with P. falciparum in the presence of anti-malarial drugs for 24 or 48 h. After removing the drug, samples were added to erythrocytes pre-labelled with intracellular dye to allow their subsequent identification. The ability of viable parasites to re-establish infection in labelled erythrocytes could then be detected by two-colour flow cytometry after tagging of parasite DNA. Thus, double-stained erythrocytes (with the pre-labelled intracellular dye and the parasite DNA dye) result only after establishment of new infections by surviving parasites. The capacity of the test anti-malarial drugs to eliminate viable parasites within 24 or 48 h could, therefore, be determined. The parasite viability fast assay could be completed within 48 h following drug treatment and distinguished between rapidly parasiticidal anti-malarial drugs versus those acting more slowly. The assay was validated against ten standard anti-malarial agents with known properties and results correlated well with established methods. An abbreviated assay, suitable for adaption to medium-high throughput screening, was validated and applied against a set of 20 compounds retrieved from the publically available Medicines for Malaria Venture 'Malaria Box'. The quantification of new infections to determine parasite viability offers important

Antioxidant and Antiplatelet Activities in Extracts from Green and Fully Ripe Tomato Fruits (Solanum lycopersicum and Pomace from Industrial Tomato Processing

Directory of Open Access Journals (Sweden)

Eduardo Fuentes

2013-01-01

Full Text Available The consumption of fruits and vegetables is accepted to be one of the strategies to reduce risk factors for these diseases. The aim of this study was to examine potential relationships between the antioxidant and the antiplatelet activities in green mature and fully ripe (red tomatoes and of lycopene-rich byproducts of tomato paste processing such as pomace. The total phenol content of tomato components was the highest in peels, pulp, and in the mucilaginous myxotesta covering the tomato seeds with values 36.9±0.8, 33.3±00.5, and 17.6±0.9 mg GAE/100 g, respectively (P<0.05. Tomato peels had the highest antioxidant activity, both, as measured by the FRAP (46.9±0.9 μmol Fe+2/g, P<0.05 and the DPPH assays (97.4±0.2%, 1000 μg/mL, P<0.05. Pomace extracts showed the highest antiplatelet activity induced by ADP, collagen, TRAP-6, and arachidonic acid. While the maturation stage of the tomato fruit affected the antioxidant effect, antiplatelet activity was independent of fruit ripeness. Finally, based on the present results, tomato and its byproducts may be considered as a valuable source of antioxidant and antiplatelet activities.

Antimalarials and the fight against malaria in Brazil.

Science.gov (United States)

Carmargo, Luiz Ma; de Oliveira, Saulo; Basano, Sergio; Garcia, Célia Rs

2009-08-01

Malaria, known as the "fevers," has been treated for over three thousand years in China with extracts of plants of the genus Artemisia (including Artemisia annua, A. opiacea, and A. lancea) from which the active compound is artemisin, a sesquiterpene that is highly effective in the treatment of the disease, especially against young forms of the parasite. South American Indians in the seventeenth century already used an extract of the bark of chinchona tree, commonly named "Jesuits' powder." Its active compound was isolated in 1820 and its use spread all over the world being used as a prophylactic drug during the construction of the Madeira-Mamoré railroad in the beginning of the twentieth century. During the 1920s to the 1940s, new antimalarial drugs were synthesized to increase the arsenal against this parasite. However, the parasite has presented systematic resistence to conventional antimalarial drugs, driving researchers to find new strategies to treat the disease. In the present review we discuss how Brazil treats Plasmodium-infected patients.

Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents.

Science.gov (United States)

Comer, Eamon; Beaudoin, Jennifer A; Kato, Nobutaka; Fitzgerald, Mark E; Heidebrecht, Richard W; Lee, Maurice duPont; Masi, Daniela; Mercier, Marion; Mulrooney, Carol; Muncipinto, Giovanni; Rowley, Ann; Crespo-Llado, Keila; Serrano, Adelfa E; Lukens, Amanda K; Wiegand, Roger C; Wirth, Dyann F; Palmer, Michelle A; Foley, Michael A; Munoz, Benito; Scherer, Christina A; Duvall, Jeremy R; Schreiber, Stuart L

2014-10-23

Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

[Randomised comparative study of early versus delayed surgery in hip-fracture patients on concomitant treatment with antiplatelet drugs. Determination of platelet aggregation, perioperative bleeding and a review of annual mortality].

Science.gov (United States)

Mas-Atance, J; Marzo-Alonso, C; Matute-Crespo, M; Trujillano-Cabello, J J; Català-Tello, N; de Miguel-Artal, M; Forcada-Calvet, P; Fernández-Martínez, J J

2013-01-01

A review of the perioperative management of patients with hip fractures and concomitant therapy with antiplatelet agents, and to analyse the differences in mortality and perioperative bleeding in early surgery (5 days). Platelet aggregation was measured on admission and immediately before surgery in all patients included in the study A total of 175 patients over 65 years old, with low energy hip fracture were randomised into 3 groups: Patients on antiplatelet therapy undergoing early surgery, patients on antiplatelet therapy undergoing delayed surgery, and patients not on antiplatelet therapy undergoing early surgery. The same clinical and laboratory data were collected prospectively up to 12 months for all the patients. The platelet aggregation was determined by a semi-quantitative computerised system based on impedance aggregometry in whole blood. Bleeding, transfusion requirements and analytical results showed no significant differences between groups. More than half (59.8%) of the patients not taking antiplatelet therapy had normal platelet aggregation on admission, while 13.5% of those taking antiplatelet agents did not. Multivariate analysis showed increased mortality at 12 months for the variables, low Barthel index before hip fracture (OR: 0.9-0.9) and number of transfusions (OR: 1.1-1.5). The average lenth of stay was 4.1 days greater in the delayed surgery group. Early surgery for patients receiving antiplatelet therapy has similar clinical outcomes to the delayed, but improves hospital efficiency by reducing the average length of stay. The antiplatelet drug reported by the patient showed low concordance with the determination of the platelet aggregation. Copyright © 2011 SECOT. Published by Elsevier Espana. All rights reserved.

Short synthesis and antimalarial activity of fagaronine

OpenAIRE

Rivaud, M.; Mendoza, A.; Sauvain, Michel; Valentin, A.; Jullian, Valérie

2012-01-01

Herein, we report a new synthesis of fagaronine 1, inspired by the synthesis reported by Luo for nornitidine. The in vitro biological activity of fagaronine against malaria on several chloroquine-sensitive and resistant Plasmodium falciparum strains was confirmed, and the selectivity index compared to mammalian cells was calculated. Fagaronine was found to have very good antimalarial activity in vivo, comparable to the activity of the reference compound chloroquine. Therefore, fagaronine appe...

Antimalarial Activity of Orally Administered Curcumin Incorporated in Eudragit®-Containing Liposomes

Directory of Open Access Journals (Sweden)

Elisabet Martí Coma-Cros

2018-05-01

Full Text Available Curcumin is an antimalarial compound easy to obtain and inexpensive, having shown little toxicity across a diverse population. However, the clinical use of this interesting polyphenol has been hampered by its poor oral absorption, extremely low aqueous solubility and rapid metabolism. In this study, we have used the anionic copolymer Eudragit® S100 to assemble liposomes incorporating curcumin and containing either hyaluronan (Eudragit-hyaluronan liposomes or the water-soluble dextrin Nutriose® FM06 (Eudragit-nutriosomes. Upon oral administration of the rehydrated freeze-dried nanosystems administered at 25/75 mg curcumin·kg−1·day−1, only Eudragit-nutriosomes improved the in vivo antimalarial activity of curcumin in a dose-dependent manner, by enhancing the survival of all Plasmodium yoelii-infected mice up to 11/11 days, as compared to 6/7 days upon administration of an equal dose of the free compound. On the other hand, animals treated with curcumin incorporated in Eudragit-hyaluronan liposomes did not live longer than the controls, a result consistent with the lower stability of this formulation after reconstitution. Polymer-lipid nanovesicles hold promise for their development into systems for the oral delivery of curcumin-based antimalarial therapies.

Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

OpenAIRE

Iwaniuk, Daniel P.; Whetmore, Eric D.; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C.; Roepe, Paul D.; Wolf, Christian

2009-01-01

We report the synthesis and in vitro antimalarial activity of several new 4-amino-and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of P. falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain st...

Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide.

Science.gov (United States)

Ugwu, D I; Okoro, U C; Ukoha, P O; Okafor, S; Ibezim, A; Kumar, N M

2017-07-28

Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC 50 value of 0.045 mM comparable with 0.34 mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Assessing the quality of anti-malarial drugs from Gabonese pharmacies using the MiniLab®: a field study

NARCIS (Netherlands)

Visser, Benjamin J.; Meerveld-Gerrits, Janneke; Kroon, Daniëlle; Mougoula, Judith; Vingerling, Rieke; Bache, Emmanuel; Boersma, Jimmy; van Vugt, Michèle; Agnandji, Selidji T.; Kaur, Harparkash; Grobusch, Martin P.

2015-01-01

Recent studies alluded to the alarming scale of poor anti-malarial drug quality in malaria-endemic countries, but also illustrated the major geographical gaps in data on anti-malarial drug quality from endemic countries. Data are particularly scarce from Central Africa, although it carries the

Muddled mechanisms: recent progress towards antimalarial target identification [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Rachel L. Edwards

2016-10-01

Full Text Available In the past decade, malaria rates have plummeted as a result of aggressive infection control measures and the adoption of artemisinin-based combination therapies (ACTs. However, a potential crisis looms ahead. Treatment failures to standard antimalarial regimens have been reported in Southeast Asia, and devastating consequences are expected if resistance spreads to the African continent. To prevent a potential public health emergency, the antimalarial arsenal must contain therapeutics with novel mechanisms of action (MOA. An impressive number of high-throughput screening (HTS campaigns have since been launched, identifying thousands of compounds with activity against one of the causative agents of malaria, Plasmodium falciparum. Now begins the difficult task of target identification, for which studies are often tedious, labor intensive, and difficult to interpret. In this review, we highlight approaches that have been instrumental in tackling the challenges of target assignment and elucidation of the MOA for hit compounds. Studies that apply these innovative techniques to antimalarial target identification are described, as well as the impact of the data in the field.

QSAR, docking and ADMET studies of artemisinin derivatives for antimalarial activity targeting plasmepsin II, a hemoglobin-degrading enzyme from P. falciparum.

Science.gov (United States)

Qidwai, Tabish; Yadav, Dharmendra K; Khan, Feroz; Dhawan, Sangeeta; Bhakuni, R S

2012-01-01

This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r(2)) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV(2)) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

New concepts in antimalarial use and mode of action in dermatology.

Science.gov (United States)

Kalia, Sunil; Dutz, Jan P

2007-01-01

Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed.

Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

Energy Technology Data Exchange (ETDEWEB)

Ei, Shun Lai; Mon, Hla Myat; Myint, Khin Htay

2008-06-15

In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively.

Detection of In Vitro Antimalarial Activity of Some Myanmar Medicinal Plants

International Nuclear Information System (INIS)

Shun Lai Ei; Hla Myat Mon; Khin Htay Myint

2008-06-01

In order to find out the novel effective antimalarials. six medicinal plants, namely Erythrina stricta Roxb. (Kathit), Luffa acutangula Roxb. (Thabut - Kja), Cordia rothii Roem. and Schult. (Thanet), Tribulus terrestris Linn. (Sule). Zizphus oenoplia Mill. (Paung - pe) and Mimusops elengi Roxb. (Khaye) were selected and tested for their antimalarial activity by using in vitro microdilution technique. According to the in vitro test results, Erythrina stricta Roxb. (Kathit) was found to possess significant suppressive effect on Plasmodium falciparum. With the serially diluted extract dosage concentrations ranging from 1.250 ng/ml to 40,000 ng/ml, the schizont suppressive percentage of Eryhrina stricta Roxb. (Kathi) was observed to be 19.57%, 35.44%, 55.18%, 96.04%,100% and 100% respectively

Synthesis and evaluation of antimalarial activity of curcumin derivatives; Sintese e avaliacao da atividade antimalarica de compostos derivados da curcumina

Energy Technology Data Exchange (ETDEWEB)

Gomes, Patricia Ramos; Miguel, Fabio Balbino; Almeida, Mauro Vieira de; Couri, Mara Rubia Costa [Universidade Federal de Juiz de Fora (UFSJ), MG (Brazil). Instituto de Ciencias Exatas. Departamento de Quimica; Oliveira, Michael Eder de; Ferreira, Vanessa Viana; Guimaraes, Daniel Silqueira Martins; Lima, Aline Brito de; Barbosa, Camila de Souza; Oliveira, Mariana Amorim de; Almeida, Mauro Vieira de; Viana, Gustavo Henrique Ribeiro; Varotti, Fernando de Pilla, E-mail: varotti@ufsj.edu.br [Universidade Federal de Sao Joao Del Rei (UFSJ), MG (Brazil). Centro de Ciencias da Saude; others, and

2014-05-15

ne of the main challenges in the development of new antimalarial drugs is to achieve a viable lead candidate with good pharmacokinetic properties. Curcumin has a broad range of biological activities, including antimalarial activity. Herein, we report the antimalarial activity of six curcumin derivatives (6-12) and an initial analysis of their pharmacokinetic properties. Five compounds have demonstrated potent activity against the P. falciparum in vitro (IC{sub 50} values ranging from 1.7 to 15.2 μg mL{sup -1}), with moderate or low cytotoxicity against the HeLa cell line. The substitution of the carbonyl group in 6 by a 2,4-dinitrophenylhydrazone group (to afford 11) increases the Selective Index. These preliminary results indicate curcumin derivatives as potential antimalarial compounds. (author)

Iliac artery mural thrombus formation. Effect of antiplatelet therapy on 111In-platelet deposition in baboons

International Nuclear Information System (INIS)

Hanson, S.R.; Paxton, L.D.; Harker, L.A.

1986-01-01

To measure the rate, extent, and time course of arterial mural thrombus formation in vivo and to assess the effects of antiplatelet therapy in that setting, we have studied autologous 111 In-platelet deposition induced by experimental iliac artery aneurysms in baboons. Scintillation camera imaging analyses were performed at 1, 24, 48, and 72 hours after implantation of the device. Correction for tissue attenuation was determined by using a small, comparably located 111 In source implanted at the time of surgery. In five animals, 111 In-platelet activity accumulated progressively after device implantation, reaching a maximum after the third day. Repeat image analysis carried out 2 weeks after the surgical procedure also showed progressive accumulation of 111 In-platelets over 3 days but at markedly reduced amounts as compared with the initial study. In five additional animals, treatment with a combination of aspirin and dipyridamole begun 1 hour after surgical implantation reduced 111 In-platelet deposition to negligible levels by the third day. Although platelet survival time was shortened and platelet turnover was reciprocally increased in all operated animals, platelet survival and turnover were not affected by antiplatelet therapy. We conclude that, in contrast to platelet survival and turnover measurements, 111 In-platelet imaging is a reliable and sensitive method for localizing and quantifying focal arterial thrombi and for assessing the effects of antiplatelet therapy

original article antimalarial use and the associated factors in rural

African Journals Online (AJOL)

boaz

This study was set out to find out the pattern of antimalarial drug use in a Nigerian rural community following the aggressive price subsidy ... facilities in South-East Nigeria also showed that only .... descriptive statistics in the analysis command,.

Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation.

Science.gov (United States)

Maetani, Micah; Zoller, Jochen; Melillo, Bruno; Verho, Oscar; Kato, Nobutaka; Pu, Jun; Comer, Eamon; Schreiber, Stuart L

2017-08-16

The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC 50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp 3 )-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

Science.gov (United States)

Palafox, Benjamin; Patouillard, Edith; Tougher, Sarah; Goodman, Catherine; Hanson, Kara; Kleinschmidt, Immo; Rueda, Sergio Torres; Kiefer, Sabine; O'Connell, Kathryn A; Zinsou, Cyprien; Phok, Sochea; Akulayi, Louis; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Chavasse, Desmond

2014-01-01

Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia). We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine) dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs) were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important antimalarial supply sources. The structure

Understanding private sector antimalarial distribution chains: a cross-sectional mixed methods study in six malaria-endemic countries.

Directory of Open Access Journals (Sweden)

Benjamin Palafox

Full Text Available Private for-profit outlets are important treatment sources for malaria in most endemic countries. However, these outlets constitute only the last link in a chain of businesses that includes manufacturers, importers and wholesalers, all of which influence the availability, price and quality of antimalarials patients can access. We present evidence on the composition, characteristics and operation of these distribution chains and of the businesses that comprise them in six endemic countries (Benin, Cambodia, Democratic Republic of Congo, Nigeria, Uganda and Zambia.We conducted nationally representative surveys of antimalarial wholesalers during 2009-2010 using an innovative sampling approach that captured registered and unregistered distribution channels, complemented by in-depth interviews with a range of stakeholders. Antimalarial distribution chains were pyramidal in shape, with antimalarials passing through a maximum of 4-6 steps between manufacturer and retailer; however, most likely pass through 2-3 steps. Less efficacious non-artemisinin therapies (e.g. chloroquine dominated weekly sales volumes among African wholesalers, while volumes for more efficacious artemisinin-based combination therapies (ACTs were many times smaller. ACT sales predominated only in Cambodia. In all countries, consumer demand was the principal consideration when selecting products to stock. Selling prices and reputation were key considerations regarding supplier choice. Business practices varied across countries, with large differences in the proportions of wholesalers offering credit and delivery services to customers, and the types of distribution models adopted by businesses. Regulatory compliance also varied across countries, particularly with respect to licensing. The proportion of wholesalers possessing any up-to-date licence from national regulators was lowest in Benin and Nigeria, where vendors in traditional markets are important antimalarial supply sources

Malaria healthcare policy change in Kenya: implications on sales and marketing of antimalarials.

Science.gov (United States)

Ngure, Peter K; Nyaoke, Lorraine; Minja, David

2012-03-01

Malaria healthcare policy change in Kenya aimed at improving the control of malaria but faced a number of challenges in implementation related to marketing of the drugs. This research investigated the effect of the change of the national malaria policy on drug sales and strategic marketing responses of antimalarial pharmaceutical companies in Kenya. A descriptive cross-sectional design was employed to describe the existing state of antimalarials market in Kenya after the change of the malaria healthcare policy. Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recorded a 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by all the companies. Further, SPs (which had been replaced as first-line therapy for malaria) registered good sales. In most cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs and generic antimalarial medicines exceeded that of Coartem® for most distributors. The most common change made to marketing strategies by distributors (62.5%) was to increase imports of antimalarials. A total of 40% of the manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the fact that continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence of malaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensure drugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the national guidelines.

In vivo Antimalarial Activity of Methanol and Water Extracts of ...

African Journals Online (AJOL)

review of the plants of the American continent with antimalarial ... dried at room temperature and ground into fine powder using a ball mill .... substance in a liquid is determined by ... In addition, ionic compounds are generally most soluble in ...

Antimalarial efficacy of nine medicinal plants traditionally used by the Karens of Andaman and Nicobar Islands, India

Directory of Open Access Journals (Sweden)

M. Punnam Chander

2016-03-01

Full Text Available The aim of this study was to assess the antimalarial activity of nine medicinal plants used by Karens of Andaman and Nicobar Islands, against Plasmodium falciparum chloroquine-sensitive MRC-2 isolate. The methanol extracts were obtained by cold percolation method and in vitro antimalarial activity was assessed using M-III method. The results indicated that out of nine plant species tested, four plants, viz., Z. spectabilis, S. wallichiana, C. pulcherrima and Amomum sp. demonstrated significant antimalarial activity (50% inhibitory concentration values were 5.5 ± 0.7, 12.0 ± 2.5, 14.6 ± 1.3 and 37.3 ± 2.5 μg/mL respectively with no toxicity effect on erythrocytes.

Lead Optimization of Anti-Malarial Propafenone Analogs

Science.gov (United States)

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V.; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W. Armand; Sigal, Martina; Clark, Julie A.; Wilson, Emily; Tang, Liang; Connelly, Michele C.; DeRisi, Joseph L.; Kyle, Dennis E.; Mirsalis, Jon; Guy, R. Kiplin

2015-01-01

Previously reported studies identified analogs of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are non-toxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID:22708838

Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda

OpenAIRE

Hubbard Alan E; Dorsey Grant; Gupta Vinay; Rosenthal Philip J; Greenhouse Bryan

2010-01-01

Abstract Background Molecular genotyping is performed in anti-malarial trials to determine whether recurrent parasitaemia after therapy represents a recrudescence (treatment failure) or new infection. The use of capillary instead of agarose gel electrophoresis for genotyping offers technical advantages, but it is unclear whether capillary electrophoresis will result in improved classification of anti-malarial treatment outcomes. Methods Samples were genotyped using both gel and capillary elec...

Practice points in gynecardiology: Abnormal uterine bleeding in premenopausal women taking oral anticoagulant or antiplatelet therapy.

Science.gov (United States)

Maas, Angela H E M; Euler, Mia von; Bongers, Marlies Y; Rolden, Herbert J A; Grutters, Janneke P C; Ulrich, Lian; Schenck-Gustafsson, Karin

2015-12-01

A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Thus using anticoagulants in premenopausal women demands specific expertise and close collaboration between cardiovascular physicians and gynecologists. In this article we summarize the scope of the problem and provide practical recommendations for the care for young women taking anticoagulants and/or (dual) antiplatelet therapy. We also recommend that more safety data on uterine bleeding with novel anticoagulants in premenopausal women should be obtained. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Development of a TaqMan Allelic Discrimination Assay for detection of Single Nucleotides Polymorphisms associated with anti-malarial drug resistance

Directory of Open Access Journals (Sweden)

Kamau Edwin

2012-01-01

Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in

Antimalarial and antiplasmodial activity of husk extract and fractions of Zea mays.

Science.gov (United States)

Okokon, Jude E; Antia, Bassey S; Mohanakrishnan, Dinesh; Sahal, Dinkar

2017-12-01

Zea mays L. (Poacae) husk decoctions are traditionally used in the treatment of malaria by various tribes in Nigeria. To assess the antimalarial and antiplasmodial potentials of the husk extract and fractions on malaria parasites using in vivo and in vitro models. The ethanol husk extract and fractions (187-748 mg/kg, p.o.) of Zea mays were investigated for antimalarial activity against Plasmodium berghei using rodent (mice) malaria models and in vitro activity against chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of Plasmodium falciparum using the SRBR green assay method. Median lethal dose and cytotoxic activities against HeLa and HEKS cells were also carried out. The GCMS analysis of the most active fraction was carried out. The husk extract (187-748 mg/kg, p.o.) with LD 50 of 1874.83 mg/kg was found to exert significant (p antimalarial activity against P. berghei infection in suppressive, prophylactive and curative tests. The crude extract and fractions also exerted prominent activity against both chloroquine sensitive (Pf 3D7) and resistant (Pf INDO) strains of P. falciparum with the ethyl acetate fraction exerting the highest activity with IC 50 values of 9.31 ± 0.46 μg/mL (Pf 3D7) and 3.69 ± 0.66 μg/mL (Pf INDO). The crude extract and fractions were not cytotoxic to the two cell lines tested with IC 50 values of >100 μg/mL against both HeLa and HEKS cell lines. These results suggest that the husk extract/fractions of Zea mays possesses antimalarial and antiplasmodial activities and these justify its use in ethnomedicine to treat malaria infections.

Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities.

Science.gov (United States)

Verlinden, Bianca K; Niemand, Jandeli; Snyman, Janette; Sharma, Shiv K; Beattie, Ross J; Woster, Patrick M; Birkholtz, Lyn-Marie

2011-10-13

A series of alkylated (bis)urea and (bis)thiourea polyamine analogues were synthesized and screened for antimalarial activity against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. All analogues showed growth inhibitory activity against P. falciparum at less than 3 μM, with the majority having effective IC(50) values in the 100-650 nM range. Analogues arrested parasitic growth within 24 h of exposure due to a block in nuclear division and therefore asexual development. Moreover, this effect appears to be cytotoxic and highly selective to malaria parasites (>7000-fold lower IC(50) against P. falciparum) and is not reversible by the exogenous addition of polyamines. With this first report of potent antimalarial activity of polyamine analogues containing 3-7-3 or 3-6-3 carbon backbones and substituted terminal urea- or thiourea moieties, we propose that these compounds represent a structurally novel class of antimalarial agents.

KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

NARCIS (Netherlands)

Kuhen, K.L.; Chatterjee, A.K.; Rottmann, M.; Gagaring, K.; Borboa, R.; Buenviaje, J.; Chen, Z.; Francek, C.; Wu, T.; Nagle, A.; Barnes, S.W.; Plouffe, D.; Lee, M.C.; Fidock, D.A.; Graumans, W.; Vegte, M.G. van de; Gemert, G.J.A. van; Wirjanata, G.; Sebayang, B.; Marfurt, J.; Russell, B.; Suwanarusk, R.; Price, R.N.; Nosten, F.; Tungtaeng, A.; Gettayacamin, M.; Sattabongkot, J.; Taylor, J.; Walker, J.R.; Tully, D.; Patra, K.P.; Flannery, E.L.; Vinetz, J.M.; Renia, L.; Sauerwein, R.W.; Winzeler, E.A.; Glynne, R.J.; Diagana, T.T.

2014-01-01

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have

CNS adverse events associated with antimalarial agents. Fact or fiction?

NARCIS (Netherlands)

Phillips-Howard, P. A.; ter Kuile, F. O.

1995-01-01

CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

Evaluation of bleeding following dental extraction in patients on long-term antiplatelet therapy: A clinical trial

Directory of Open Access Journals (Sweden)

K George Varghese

2015-01-01

Conclusion: Hence, we recommend routine single tooth extractions in patients on long-term antiplatelet medication, without interruption or alteration of their medication. Such patients do not have an increased risk of prolonged or excessive postoperative bleeding.

Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain.

Science.gov (United States)

Iwaniuk, Daniel P; Whetmore, Eric D; Rosa, Nicholas; Ekoue-Kovi, Kekeli; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

2009-09-15

We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11-15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites.

Science.gov (United States)

Ehrhardt, Katharina; Deregnaucourt, Christiane; Goetz, Alice-Anne; Tzanova, Tzvetomira; Gallo, Valentina; Arese, Paolo; Pradines, Bruno; Adjalley, Sophie H; Bagrel, Denyse; Blandin, Stephanie; Lanzer, Michael; Davioud-Charvet, Elisabeth

2016-09-01

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents.

Science.gov (United States)

Gayam, Venkatareddy; Ravi, Subban

2017-07-28

A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9-14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl 2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K 2 CO 3  as base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18-22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25-28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC 50 value of 44.06, 48.04 and 59.37 nM against chloroquine resistant K1 strain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Longitudinal assessment of thrombin generation potential in response to alteration of antiplatelet therapy after TIA or ischaemic stroke.

LENUS (Irish Health Repository)

Tobin, W O

2013-02-01

The impact of changing antiplatelet therapy on thrombin generation potential in patients with ischaemic cerebrovascular disease (CVD) is unclear. We assessed patients within 4 weeks of TIA or ischaemic stroke (baseline), and then 14 days (14d) and >90 days (90d) after altering antiplatelet therapy. Thrombin generation was assessed in platelet poor plasma. Ninety-one patients were recruited. Twenty-four were initially assessed on no antiplatelet therapy, and then after 14d (N = 23) and 90d (N = 8) on aspirin monotherapy; 52 were assessed on aspirin monotherapy, and after 14 and 90 days on aspirin and dipyridamole combination therapy; 21 patients were assessed on aspirin and after 14 days (N = 21) and 90 days (N = 19) on clopidogrel. Peak thrombin generation and endogenous thrombin potential were reduced at 14 and 90 days (p ≤ 0.04) in the overall cohort. We assessed the impact of individual antiplatelet regimens on thrombin generation parameters to investigate the cause of this effect. Lag time and time-to-peak thrombin generation were unchanged at 14 days, but reduced 90 days after commencing aspirin (p ≤ 0.009). Lag time, peak thrombin generation and endogenous thrombin potential were reduced at both 14 and 90 days after adding dipyridamole to aspirin (p ≤ 0.01). Lag time was reduced 14 days after changing from aspirin to clopidogrel (p = 0.045), but this effect was not maintained at 90 days (p = 0.2). This pilot study did not show any consistent effects of commencing aspirin, or of changing from aspirin to clopidogrel on thrombin generation potential during follow-up. The addition of dipyridamole to aspirin led to a persistent reduction in peak and total thrombin generation ex vivo, and illustrates the diverse, potentially beneficial, newly recognised \\'anti-coagulant\\' effects of dipyridamole in ischaemic CVD.

Virtual Screening Techniques to Probe the Antimalarial Activity of some Traditionally Used Phytochemicals.

Science.gov (United States)

Shibi, Indira G; Aswathy, Lilly; Jisha, Radhakrishnan S; Masand, Vijay H; Gajbhiye, Jayant M

2016-01-01

Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.

Risk of bleeding and stroke with oral anticoagulation and antiplatelet therapy in patients with atrial fibrillation in Taiwan: a nationwide cohort study.

Directory of Open Access Journals (Sweden)

Pei-Chun Chen

Full Text Available Data on the use of oral anticoagulation (OAC and antiplatelet therapy and the risk of bleeding and stroke amongst Asian patients with atrial fibrillation (AF are limited. We investigated the risks of bleeding and stroke with use of oral anticoagulation (OAC and antiplatelet therapy as mono- or combination therapy, in patients with AF from a Chinese nationwide cohort study.We studied a cohort of 10384 patients (57.2% men, age 67.8 ± 13.2 yrs between 1999 and 2010 from the National Health Insurance Research Database in Taiwan. Records of prescriptions were obtained during follow-up. The main outcome was a recurrent stroke during the follow-up period. Time-dependent Cox proportional hazards models were used for this analysis.We documented 1009 events for bleeding, as well as 224 hemorrhagic stroke and 1642 ischemic stroke events during a median 3.2 (interquartile range, 1.05-6.54 years' follow-up. Compared with warfarin users, patients with antiplatelet therapy had a lower risk of bleeding (adjusted relative risk [RR], 0.59, 95% confidence interval [CI], 0.49-0.71, p<0.001 whilst combination therapy had a non-statistically significant higher bleeding risk (RR, 1.33, 95%, 0.91-1.94, p = 0.20. Patients on antiplatelet monotherapy had a similar risk for ischemic stroke compared with OAC (RR 1.05, 95% CI, 0.89-1.25, p = 0.50, whilst those on combination therapy had a significantly higher risk (RR 1.90, 95% CI, 1.34-2.70, p<0.001.In a national representative cohort, antiplatelet therapy had no significant difference in ischemic stroke risk to warfarin. For bleeding, aspirin had a lower risk compared to warfarin. This may reflect poor anticoagulation control, highlighting important missed opportunities for improved stroke prevention, especially in countries where anticoagulation management is suboptimal.

Antiplatelet Agents and the Prevention of Spontaneous Preterm Birth A Systematic Review and Meta-analysis

NARCIS (Netherlands)

van Vliet, Elvira O. G.; Askie, Lisa A.; Mol, Ben W. J.; Oudijk, Martijn A.

2017-01-01

OBJECTIVE: Spontaneous preterm birth is an important cause of neonatal mortality and morbidity. An increasing body of evidence suggests that uteroplacental ischemia plays an important role in the etiology of spontaneous preterm birth. We aimed to study whether antiplatelet agents reduce the risk of

In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica.

Science.gov (United States)

Chinchilla, Misael; Valerio, Idalia; Sánchez, Ronald; Mora, Víctor; Bagnarello, Vanessa; Martínez, Laura; Gonzalez, Antonieta; Vanegas, Juan Carlos; Apestegui, Alvaro

2012-06-01

Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biol6gica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9 microg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

Dual or Single Antiplatelet Therapy After Transcatheter Aortic Valve Implantation? A Systematic Review and Meta-Analysis.

Science.gov (United States)

Vavuranakis, Manolis; Siasos, Gerasimos; Zografos, Theodoros; Oikonomou, Evangelos; Vrachatis, Dimitris; Kalogeras, Konstantinos; Papaioannou, Theodoros; Kolokathis, Michail-Aggelos; Moldovan, Carmen; Tousoulis, Dimitrios

2016-01-01

Transcatheter aortic valve implantation (TAVI) has undeniably earned a prestigious post in the quiver of interventional cardiologists against symptomatic severe aortic stenosis. Cerebrovascular events are listed within the most frequent complications. We performed a systematic search of EMBASE, MEDLINE, and the Cochrane library from inception to March 2016 for the following search terms (transcatheter AND antiplatelet) OR (transcatheter AND antithrombotic) to retrieve studies of dual antiplatelet treatment (DAPT) and single antiplatelet treatment (SAPT) in patients after TAVI to study thrombotic, hemorrhagic and cardiovascular events at 30 days post procedure. From a total of 208 records 4 studies met inclusion criteria. In the included studies, 286 patients were enrolled in the DAPT group and 354 patients in the SAPT group. There was no difference in all-cause mortality, cardiovascular mortality, stroke, and myocardial infraction 30 days post TAVI between DAPT and SAPT. However, patients in the DAPT group had a significantly increased incidence of lethal and major bleeding at 30 days of follow-up and the incidence of the combined end-point of stroke, spontaneous MI, all-cause mortality and major bleeding was significantly higher in the DAPT group in comparison to the SAPT group. DAPT compared to SAPT in patients after TAVI increases incidence of hemorrhagic events with no benefits in terms of thrombotic events and cardiovascular mortality. However, these data must be interpreted cautiously and the choice of DAPT over SAPT must be based on an individual patient characteristic according to medical practice criteria.

Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.

Science.gov (United States)

Shiraki, Hiroaki; Kozar, Michael P; Melendez, Victor; Hudson, Thomas H; Ohrt, Colin; Magill, Alan J; Lin, Ai J

2011-01-13

In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.

Heme-binding activity of methoxyflavones from Pentzia monodiana Maire (Asteraceae).

Science.gov (United States)

Ortiz, Sergio; Dali-Yahia, Kamel; Vasquez-Ocmin, Pedro; Grougnet, Raphaël; Grellier, Philippe; Michel, Sylvie; Maciuk, Alexandre; Boutefnouchet, Sabrina

2017-04-01

A heme-binding assay based on mass spectrometry was performed on P. monodiana Maire (Asteraceae) extracts to identify metabolites able to form adducts with heminic part of haemoglobin, as potential antimalarial drugs. Main adducts were characterized and their stability was measured. Isolation of main constituents of P. monodiana Maire lead to identification of the two methoxyflavones 3'-O-methyleupatorin (7) and artemetin (8) involved in the adducts formation. Four seco-tanapartholides (1-4), a guaianolide (5), a germacranolide (6) and two other methoxyflavones (9, 10) were also characterized. Evaluation of isolated compounds on P. falciparum and T. brucei brucei showed a moderate antiprotozoal activity of the two methoxyflavones. Copyright © 2017. Published by Elsevier B.V.

Synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants.

Science.gov (United States)

Tang, Ling; Bei, Zhuchun; Song, Yabin; Xu, Likun; Wang, Hong; Zhang, Dongna; Dou, Yuanyuan; Lv, Kai; Wang, Hongquan

2017-07-01

Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used. We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice. Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED 50 ], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED 50 : 0.48 mg/kg). The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.

A novel multiple-stage antimalarial agent that inhibits protein synthesis

Science.gov (United States)

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus C. S.; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana J.; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick; Stojanovski, Laste; Osuna-Cabello, Maria; Brock, Paddy M.; Churcher, Tom S.; Sala, Katarzyna A.; Zakutansky, Sara E.; Jiménez-Díaz, María Belén; Sanz, Laura Maria; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Iñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, Peter; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon; Fairlamb, Alan H.; Willis, Paul A.; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

2015-06-01

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.

Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial.

Science.gov (United States)

Hankey, Graeme J; Eikelboom, John W; Yi, Qilong; Lees, Kennedy R; Chen, Christopher; Xavier, Denis; Navarro, Jose C; Ranawaka, Udaya K; Uddin, Wasim; Ricci, Stefano; Gommans, John; Schmidt, Reinhold

2012-06-01

Previous studies have suggested that any benefits of folic acid-based therapy to lower serum homocysteine in prevention of cardiovascular events might be offset by concomitant use of antiplatelet therapy. We aimed to establish whether there is an interaction between antiplatelet therapy and the effects of folic acid-based homocysteine-lowering therapy on major vascular events in patients with stroke or transient ischaemic attack enrolled in the vitamins to prevent stroke (VITATOPS) trial. In the VITATOPS trial, 8164 patients with recent stroke or transient ischaemic attack were randomly allocated to double-blind treatment with one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), and 500 μg vitamin B(12)) and followed up for a median 3·4 years (IQR 2·0-5·5) for the primary composite outcome of stroke, myocardial infarction, or death from vascular causes. In our post-hoc analysis of the interaction between antiplatelet therapy and the effects of treatment with B vitamins on the primary outcome, we used Cox proportional hazards regression before and after adjusting for imbalances in baseline prognostic factors in participants who were and were not taking antiplatelet drugs at baseline and in participants assigned to receive B vitamins or placebo. We also assessed the interaction in different subgroups of patients and different secondary outcomes. The VITATOPS trial is registered with ClinicalTrials.gov, number NCT00097669, and Current Controlled Trials, number ISRCTN74743444. At baseline, 6609 patients were taking antiplatelet therapy and 1463 were not. Patients not receiving antiplatelet therapy were more likely to be younger, east Asian, and disabled, to have a haemorrhagic stroke or cardioembolic ischaemic stroke, and to have a history of hypertension or atrial fibrillation. They were less likely to be smokers and to have a history of peripheral artery disease, hypercholesterolaemia, diabetes, ischaemic heart disease, and a

Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications.

Science.gov (United States)

Bordeaux, Jeremy S; Martires, Kathryn J; Goldberg, Dori; Pattee, Sean F; Fu, Pingfu; Maloney, Mary E

2011-09-01

Few prospective studies have evaluated the safety of dermatologic surgery. We sought to determine rates of bleeding, infection, flap and graft necrosis, and dehiscence in outpatient dermatologic surgery, and to examine their relationship to type of repair, anatomic location of repair, antibiotic use, antiplatelet use, or anticoagulant use. Patients presenting to University of Massachusetts Medical School Dermatology Clinic for surgery during a 15-month period were prospectively entered. Medications, procedures, and complications were recorded. Of the 1911 patients, 38% were on one anticoagulant or antiplatelet medication, and 8.0% were on two or more. Risk of hemorrhage was 0.89%. Complex repair (odds ratio [OR] = 5.80), graft repair (OR = 7.58), flap repair (OR = 11.93), and partial repair (OR = 43.13) were more likely to result in bleeding than intermediate repair. Patients on both clopidogrel and warfarin were 40 times more likely to have bleeding complications than all others (P = .03). Risk of infection was 1.3%, but was greater than 3% on the genitalia, scalp, back, and leg. Partial flap necrosis occurred in 1.7% of flaps, and partial graft necrosis occurred in 8.6% of grafts. Partial graft necrosis occurred in 20% of grafts on the scalp and 10% of grafts on the nose. All complications resolved without sequelae. The study was limited to one academic dermatology practice. The rate of complications in dermatologic surgery is low, even when multiple oral anticoagulant and antiplatelet medications are continued, and prophylactic antibiotics are not used. Closure type and use of warfarin or clopidogrel increase bleeding risk. However, these medications should be continued to avoid adverse thrombotic events. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Practice points in gynecardiology: Abnormal uterine bleeding in premenopausal women taking oral anticoagulant or antiplatelet therapy

NARCIS (Netherlands)

Maas, A.H.E.M.; Euler, M.; Bongers, M.Y.; Rolden, H.J.A.; Grutters, J.P.C.; Ulrich, L.; Schenck-Gustafsson, K.

2015-01-01

A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual

Antimalarial Activity of Ultra-Short Peptides

Directory of Open Access Journals (Sweden)

María Yolanda Rios

2009-12-01

Full Text Available Ultra-short peptides 1-9 were designed and synthesized with phenylalanine, ornithine and proline amino acid residues and their effect on antimalarial activity was analyzed. On the basis of the IC50 data for these compounds, the effects of nature, polarity, and amino acid sequence on Plasmodium berghei schizont cultures were analyzed too. Tetrapeptides Phe-Orn-Phe-Orn (4 and Lys-Phe-Phe-Orn (5 showed a very important activity with IC50 values of 3.31 and 2.57 μM, respectively. These two tetrapeptides are candidates for subsequent in vivo assays and SARS investigations.

Evaluation of In-vivo Antimalarial Activity of Methanol Leaf Extract of ...

African Journals Online (AJOL)

Abstract. Purpose: To evaluate the in-vivo antimalarial activity of the methanol extract of the leaves of Glyphaea brevis in ... alternative malarial drugs, with novel modes of action [4]. ... The mean lethal dose of the three fractions. (ethylacetate ...

Efforts Aimed To Reduce Attrition in Antimalarial Drug Discovery: A Systematic Evaluation of the Current Antimalarial Targets Portfolio.

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Chaparro, María Jesús; Calderón, Félix; Castañeda, Pablo; Fernández-Alvaro, Elena; Gabarró, Raquel; Gamo, Francisco Javier; Gómez-Lorenzo, María G; Martín, Julio; Fernández, Esther

2018-04-13

Malaria remains a major global health problem. In 2015 alone, more than 200 million cases of malaria were reported, and more than 400,000 deaths occurred. Since 2010, emerging resistance to current front-line ACTs (artemisinin combination therapies) has been detected in endemic countries. Therefore, there is an urgency for new therapies based on novel modes of action, able to relieve symptoms as fast as the artemisinins and/or block malaria transmission. During the past few years, the antimalarial community has focused their efforts on phenotypic screening as a pragmatic approach to identify new hits. Optimization efforts on several chemical series have been successful, and clinical candidates have been identified. In addition, recent advances in genetics and proteomics have led to the target deconvolution of phenotypic clinical candidates. New mechanisms of action will also be critical to overcome resistance and reduce attrition. Therefore, a complementary strategy focused on identifying well-validated targets to start hit identification programs is essential to reinforce the clinical pipeline. Leveraging published data, we have assessed the status quo of the current antimalarial target portfolio with a focus on the blood stage clinical disease. From an extensive list of reported Plasmodium targets, we have defined triage criteria. These criteria consider genetic, pharmacological, and chemical validation, as well as tractability/doability, and safety implications. These criteria have provided a quantitative score that has led us to prioritize those targets with the highest probability to deliver successful and differentiated new drugs.

Concomitant nitrates enhance clopidogrel response during dual anti-platelet therapy.

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Lee, Dong Hyun; Kim, Moo Hyun; Guo, Long Zhe; De Jin, Cai; Cho, Young Rak; Park, Kyungil; Park, Jong Sung; Park, Tae-Ho; Serebruany, Victor

2016-01-15

Despite advances in modern anti-platelet strategies, clopidogrel still remains the cornerstone of dual anti-platelet therapy (DAPT) in patients undergoing percutaneous coronary interventions (PCI). There is some inconclusive evidence that response after clopidogrel may be impacted by concomitant medications, potentially affecting clinical outcomes. Sustained released nitrates (SRN) are commonly used together with clopidogrel in post-PCI setting for mild vasodilatation and nitric oxide-induced platelet inhibition. We prospectively enrolled 458 patients (64.5 ± 9.6 years old, and 73.4% males) following PCI undergoing DAPT with clopidogrel and aspirin. Platelet reactivity was assessed by the VerifyNow™ P2Y12 assay at the maintenance outpatient setting. Concomitant SRN (n=266) significantly (p=0.008) enhanced platelet inhibition after DAPT (251.6 ± 80.9PRU) when compared (232.1 ± 73.5PRU) to the SRN-free (n=192) patients. Multivariate logistic regression analysis with the cut-off value of 253 PRU for defining heightened platelet reactivity confirmed independent correlation of more potent platelet inhibition during DAPT and use of SRN (Relative risk=1.675; Odds ratio [1.059-2.648]; p=0.027). In contrast, statins, calcium-channel blockers, beta blockers, angiotensin receptor blockers, ACE-inhibitors, diuretics, and anti-diabetic agents did not significantly impact platelet inhibition following DAPT. The synergic ability of SRN to enhance response during DAPT may have important clinical implications with regard to better cardiovascular protection, but extra bleeding risks, requiring further confirmation in a large randomized study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Characterization of primaquine imidazolidin-4-ones with antimalarial activity by electrospray ionization-ion trap mass spectrometry

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Vale, Nuno; Moreira, Rui; Gomes, Paula

2008-02-01

The extensive characterization by electrospray ionization-ion trap mass spectrometry (ESI-MSn) of 20 imidazolidin-4-ones derived from the antimalarial primaquine was well obtained. These compounds are being under investigation as potential antimalarials, as they have been previously found to be active against rodent P. berghei malaria and to be highly stable under physiological conditions. Experiments by collision-induced dissociation (CID) in the nozzle-skimmer region or by tandem-MS have shown the title compounds to be remarkably stable. Mechanisms are proposed to explain the major fragmentations observed in ESI-MSn experiments. Overall, this work represents an unprecedented contribution to a deeper insight into imidazolidin-4-one antimalarials based on a classic 8-aminoquinolinic scaffold. Data herein reported and discussed may be an useful guide for future studies on therapeutically relevant molecules possessing either the 8-aminoquinoline or the imidazolidin-4-one motifs.

In vitro antimalarial activity of extracts of some plants from a biological reserve in Costa Rica

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Misael Chinchilla

2012-06-01

Full Text Available Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB, were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae; Xanthosoma undipes (Araceae; Iriartea deltoidea (Arecaceae; Neurolaena lobata (Asteraceae; Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae; Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae; Hampea appendiculata (Malvaceae; Ruagea glabra, Guarea glabra (Meliaceae; Psidium guajava (Myrtaceae; Bocconia frutescens (Papaveraceae; Piper friedrichsthalii (Piperaceae; Clematis dioica (Ranunculaceae; Prunus annularis (Rosaceae; Siparuna thecaphora (Siparunaceae; Solanum arboreum, Witheringia solanácea (Solanaceae; Ticodendrum incognitum (Ticodendraceae; Heliocarpus appendiculatus (Tiliaceae and Myriocarpa longipes (Urticaceae. We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity.

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Vanaerschot, Manu; Lucantoni, Leonardo; Li, Tao; Combrinck, Jill M; Ruecker, Andrea; Kumar, T R Santha; Rubiano, Kelly; Ferreira, Pedro E; Siciliano, Giulia; Gulati, Sonia; Henrich, Philipp P; Ng, Caroline L; Murithi, James M; Corey, Victoria C; Duffy, Sandra; Lieberman, Ori J; Veiga, M Isabel; Sinden, Robert E; Alano, Pietro; Delves, Michael J; Lee Sim, Kim; Winzeler, Elizabeth A; Egan, Timothy J; Hoffman, Stephen L; Avery, Vicky M; Fidock, David A

2017-10-01

Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

Hexahydroquinolines are Antimalarial Candidates with Potent Blood Stage and Transmission-Blocking Activity

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Vanaerschot, Manu; Lucantoni, Leonardo; Li, Tao; Combrinck, Jill M.; Ruecker, Andrea; Kumar, T.R. Santha; Rubiano, Kelly; Ferreira, Pedro E.; Siciliano, Giulia; Gulati, Sonia; Henrich, Philipp P.; Ng, Caroline L.; Murithi, James M.; Corey, Victoria C.; Duffy, Sandra; Lieberman, Ori J.; Veiga, M. Isabel; Sinden, Robert E.; Alano, Pietro; Delves, Michael J.; Sim, Kim Lee; Winzeler, Elizabeth A.; Egan, Timothy J.; Hoffman, Stephen L.; Avery, Vicky M.; Fidock, David A.

2017-01-01

Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress P. berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR/Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 as a determinant of parasite resistance to HHQs. Hemoglobin and heme fractionation assays suggest a mode of action that results in reduced hemozoin levels and might involve inhibition of host hemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs including lumefantrine, confirming that HHQs have a different mode of action than other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria. PMID:28808258

Antiplatelet activity of white and pink Nelumbo nucifera Gaertn flowers

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Brindha Durairaj

2010-09-01

Full Text Available Nelumbo nucifera Gaertn (Nelumbonaceae a plant used in Ayurvedic medicine (common name: lotus, is a perennial, large and rhizomatous aquatic herb most prevalent in South India. Preliminary phytochemical screening of both white and pink Nelumbo nucifera flowers revealed the presence of phytochemical constituents (flavonoids, alkaloids, phenols etc,. Hence, an attempt has been made to screen the effect of Nelumbo nucifera flowers (both types on platelet aggregation. The antiplatelet activity of hydroethanolic extract of both types of flowers was studied using platelet-rich plasma in different concentrations (100-500µg/ml. Both white and pink Nelumbo nucifera flower extracts showed dose-dependent effective antiplatelet activity with maximum activity at 500µg/ml concentration; prevention of platelet aggregation was 50% of that achieved with standard aspirin. Furthermore, the antiplatelet activity of white flowers was relatively high (pNelumbo nucifera Gaertn (Nelumbonaceae, planta utilizada na medicina Ayurvédica, é erva aquática rizomatosa grande, predominante no sul da Índia. A triagem fitoquímica preliminar das flores brancas e cor-de-rosa de Nelumbo nucifera revelou a presença de constituintes fitoquímicos (flavonoides, alcaloides, fenóis etc. Assim, tentou-se a triagem do efeito das flores de Nelumbo nucifera de ambos os tipos na agregação plaquetária. A atividade antiplaquetária dos extratos hidroetanólico de ambos os tipos de flores foi estudada, utilizando-se plasma rico em plaquetas em duas diferentes concentrações (100 - 500 µg/mL. Tanto os extratos das flores brancas quanto daquelas de cor-de-rosa mostraram atividade antiplaquetária dose-dependente, com o máximo na concentração de 500 µg/mL. A prevenção da agregação plaquetária foi 50% daquela alcançada com o padrão de ácido acetilsalicílico. Além disso, a atividade antiplaquetária das flores brancas foi, relativamente, alta (p<0,05; ANOVA

Antiplatelet and anticoagulation regimen in patients with mechanical valve undergoing PCI - State-of-the-art review.

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Gajanana, Deepakraj; Rogers, Toby; Iantorno, Micaela; Buchanan, Kyle D; Ben-Dor, Itsik; Pichard, Augusto D; Satler, Lowell F; Torguson, Rebecca; Okubagzi, Petros G; Waksman, Ron

2018-04-02

A common clinical dilemma regarding treatment of patients with a mechanical valve is the need for concomitant antiplatelet therapy for a variety of reasons, referred to as triple therapy. Triple therapy is when a patient is prescribed aspirin, a P2Y12 antagonist, and an oral anticoagulant. Based on the totality of the available evidence, best practice in 2017 for patients with mechanical valves undergoing percutaneous coronary intervention (PCI) is unclear. Furthermore, the optimal duration of dual antiplatelet therapy after PCI is evolving. With better valve designs that are less thrombogenic, the thromboembolic risks can be reduced at a lower international normalized ratio target, thus decreasing the bleeding risk. This review will offer an in-depth survey of current guidelines, current evidence, suggested approach for PCI in this cohort, and future studies regarding mechanical valve patients undergoing PCI. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel multiple-stage antimalarial agent that inhibits protein synthesis

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Baragana, B.; Hallyburton, I.; Lee, M.C.; Norcross, N.R.; Grimaldi, R.; Otto, T.D.; Proto, W.R.; Blagborough, A.M.; Meister, S.; Wirjanata, G.; Ruecker, A.; Upton, L.M.; Abraham, T.S.; Almeida, M.J.; Pradhan, A.; Porzelle, A.; Martinez, M.S.; Bolscher, J.M.; Woodland, A.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.; Stojanovski, L.; Osuna-Cabello, M.; Brock, P.M.; Churcher, T.S.; Sala, K.A.; Zakutansky, S.E.; Jimenez-Diaz, M.B.; Sanz, L.M.; Riley, J.; Basak, R.; Campbell, M.; Avery, V.M.; Sauerwein, R.W.; Dechering, K.J.; Noviyanti, R.; Campo, B.; Frearson, J.A.; Angulo-Barturen, I.; Ferrer-Bazaga, S.; Gamo, F.J.; Wyatt, P.G.; Leroy, D.; Siegl, P.; Delves, M.J.; Kyle, D.E.; Wittlin, S.; Marfurt, J.; Price, R.N.; Sinden, R.E.; Winzeler, E.A.; Charman, S.A.; Bebrevska, L.; Gray, D.W.; Campbell, S.; Fairlamb, A.H.; Willis, P.A.; Rayner, J.C.; Fidock, D.A.; Read, K.D.; Gilbert, I.H.

2015-01-01

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial

Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65.

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Awang, Normah; Jumat, Hafizah; Ishak, Shafariatul Akmar; Kamaludin, Nurul Farahana

2014-06-01

Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4-n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094±0.011 and 0.892±0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001±0.00009 and 0.0009±0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001±0.00005 and 0.00009±0.00003 μg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents.

Comparison of antiplatelet regimens in secondary stroke prevention

DEFF Research Database (Denmark)

Christiansen, Christine Benn; Pallisgaard, Jannik; Gerds, Thomas Alexander

2015-01-01

BACKGROUND: In patients with ischemic stroke of non-cardioembolic origin, acetylsalicylic acid, clopidogrel, or a combination of acetylsalicylic acid and dipyridamole are recommended for the prevention of a recurrent stroke. The purpose of this study was to examine the risk of bleeding or recurrent...... stroke associated with these three treatments. METHODS: Patients who were discharged with first-time ischemic stroke from 2007-2010, with no history of atrial fibrillation were identified from Danish nationwide registries. Hazard ratios (HRs) and 1-year risks of recurrent ischemic stroke and bleeding...... were calculated for each antiplatelet regimen. RESULTS: Among patients discharged after first-time ischemic stroke, 3043 patients were treated with acetylsalicylic acid, 12,295 with a combination of acetylsalicylic acid and dipyridamole, and 3885 with clopidogrel. Adjusted HRs for clopidogrel versus...

Evaluation of in vivo antimalarial activity of the ethanolic leaf extracts ...

African Journals Online (AJOL)

Prof. Ogunji

Plasmodium berghei berghei in mice was evaluated. ... indicated in the consistent increase in weight and slight increase in the PCV ... Key words: Chromolaena odorata, Cymbopogon citratus, anti-malarial .... This was prepared by determining both the percentage parasitaemia and the ..... Malaria vaccine: Multiple targets.

Screening of the antimalarial activity of plants of the Cucurbitaceae family

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Cláudia Zuany Amorim

1991-01-01

Full Text Available Crude ethanolic extracts (CEEs from two species of Cucurbitaceae, Cucurbita maxima and Momordica charantia (commonly called "abóbora moranga" and melão de São Caetano", respectively were assayed for antimalarial activity by the 4-d suppressive test. The CEE of dry C. maxima seeds showed strong antimalarial activity following oral administration (259 and 500 mg/kg, reducing by 50% the levels of parasistemia in Plasmodium berghey-infected mice. Treatment of normal animals with 500 mg/Kg of the extract three days before intravenous injection of P. berghei caused a significant 30% reduction in parasitemic levels. No effect was observed when the animals were treated with the CEE only on the day of inoculation. Oral administration of the CEE of dry M. charantia leaves adminstered orally was ineffective up to 500 mg/Kg in lowering the parasitemic levels of malarious mice.

Isolation and chemical identification of lipid derivatives from avocado (Persea americana) pulp with antiplatelet and antithrombotic activities.

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Rodriguez-Sanchez, Dariana Graciela; Flores-García, Mirthala; Silva-Platas, Christian; Rizzo, Sheryl; Torre-Amione, Guillermo; De la Peña-Diaz, Aurora; Hernández-Brenes, Carmen; García-Rivas, Gerardo

2015-01-01

Platelets play a pivotal role in physiological hemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute ischemic events. Avocado pulp (Persea americana) is a good source of bioactive compounds, and its inclusion in the diet as a source of fatty acid has been related to reduced platelet aggregability. Nevertheless, constituents of avocado pulp with antiplatelet activity remain unknown. The present study aims to characterize the chemical nature of avocado constituents with inhibitory effects on platelet aggregation. Centrifugal partition chromatography (CPC) was used as a fractionation and purification tool, guided by an in vitro adenosine diphosphate (ADP), arachidonic acid or collagen-platelet aggregation assay. Antiplatelet activity was initially linked to seven acetogenins that were further purified, and their dose-dependent effects in the presence of various agonists were contrasted. This process led to the identification of Persenone-C (3) as the most potent antiplatelet acetogenin (IC₅₀=3.4 mM) among the evaluated compounds. In vivo evaluations with Persenone A (4) demonstrated potential protective effects against arterial thrombosis (25 mg kg⁻¹ of body weight), as coagulation times increased (2-fold with respect to the vehicle) and thrombus formation was attenuated (71% versus vehicle). From these results, avocado may be referred to as a functional food containing acetogenin compounds that inhibit platelet aggregation with a potential preventive effect on thrombus formation, such as those that occur in ischaemic diseases.

QUANTITATIVE ELECTRONIC STRUCTURE - ACTIVITY RELATIONSHIP OF ANTIMALARIAL COMPOUND OF ARTEMISININ DERIVATIVES USING PRINCIPAL COMPONENT REGRESSION APPROACH

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Paul Robert Martin Werfette

2010-06-01

Full Text Available Analysis of quantitative structure - activity relationship (QSAR for a series of antimalarial compound artemisinin derivatives has been done using principal component regression. The descriptors for QSAR study were representation of electronic structure i.e. atomic net charges of the artemisinin skeleton calculated by AM1 semi-empirical method. The antimalarial activity of the compound was expressed in log 1/IC50 which is an experimental data. The main purpose of the principal component analysis approach is to transform a large data set of atomic net charges to simplify into a data set which known as latent variables. The best QSAR equation to analyze of log 1/IC50 can be obtained from the regression method as a linear function of several latent variables i.e. x1, x2, x3, x4 and x5. The best QSAR model is expressed in the following equation,  (;;   Keywords: QSAR, antimalarial, artemisinin, principal component regression

A herbicide structure-activity analysis of the antimalarial lead compound MMV007978 against Arabidopsis thaliana.

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Corral, Maxime G; Leroux, Julie; Tresch, Stefan; Newton, Trevor; Stubbs, Keith A; Mylne, Joshua S

2018-07-01

To fight herbicide-resistant weeds, new herbicides are needed; particularly ones with new modes of action. Building on the revelation that many antimalarial drugs are herbicidal, here we focus on the Medicines for Malaria Venture antimalarial lead compound MMV007978 that has herbicidal activity against the model plant Arabidopsis thaliana. Twenty-two variations of the lead compound thiophenyl motif revealed that change was tolerated provided ring size and charge were retained. MMV007978 was active against select monocot and dicot weeds, and physiological profiling indicated that its mode of action is related to germination and cell division. Of interest is the fact that the compound has a profile that is currently not found among known herbicides. We demonstrate that the antimalarial compound MMV007978 is also herbicidal and that exploiting lead compounds that are often understudied could lead to the identification of interesting herbicidal scaffolds. Further structural investigation of MMV007978 could provide improved herbicidal chemistries with a potential new mode of action. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial

NARCIS (Netherlands)

Hess, C.N.; James, S.; Lopes, R.D.; Wojdyla, D.M.; Neely, M.L.; Liaw, D.; Hagstrom, E.; Bhatt, D.L.; Husted, S.; Goodman, S.G.; Lewis, B.S.; Verheugt, F.W.A.; Caterina, R. De; Ogawa, H.; Wallentin, L.; Alexander, J.H.

2015-01-01

BACKGROUND: Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS). OBJECTIVES: We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS. METHODS: This study examined high-risk ACS patients who were treated with

The effect of pre-injury anti-platelet therapy on the development of complications in isolated blunt chest wall trauma: a retrospective study.

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Ceri Battle

Full Text Available INTRODUCTION: The difficulties in the management of the blunt chest wall trauma patient in the Emergency Department due to the development of late complications are well recognised in the literature. Pre-injury anti-platelet therapy has been previously investigated as a risk factor for poor outcomes following traumatic head injury, but not in the blunt chest wall trauma patient cohort. The aim of this study was to investigate pre-injury anti-platelet therapy as a risk factor for the development of complications in the recovery phase following blunt chest wall trauma. METHODS: A retrospective study was completed in which the medical notes were analysed of all blunt chest wall trauma patients presenting to a large trauma centre in Wales in 2012 and 2013. Using univariate and multivariable logistic regression analysis, pre-injury platelet therapy was investigated as a risk factor for the development of complications following blunt chest wall trauma. Previously identified risk factors were included in the analysis to address the influence of confounding. RESULTS: A total of 1303 isolated blunt chest wall trauma patients presented to the ED in Morriston Hospital in 2012 and 2013 with complications recorded in 144 patients (11%. On multi-variable analysis, pre-injury anti-platelet therapy was found to be a significant risk factor for the development of complications following isolated blunt chest wall trauma (odds ratio: 16.9; 95% confidence intervals: 8.2-35.2. As in previous studies patient age, number of rib fractures, chronic lung disease and pre-injury anti-coagulant use were also found to be significant risk factors. CONCLUSIONS: Pre-injury anti-platelet therapy is being increasingly used as a first line treatment for a number of conditions and there is a concurrent increase in trauma in the elderly population. Pre-injury anti-platelet therapy should be considered as a risk factor for the development of complications by clinicians managing

Gracilioethers A-C, Antimalarial Metabolites from the Marine Sponge Agelas gracilis

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Ueoka, R.; Nakao, Y.; Kawatsu, S.; Yaegashi, J.; Matsumoto, Y.; Matsunaga, S.; Furihata, K; van Soest, R.W.M.; Fusetani, N.

2009-01-01

Three new antiprotozoan compounds, gracilioethers A−C (1−3), have been isolated from the marine sponge Agelas gracilis. Their structures were elucidated on the basis of spectroscopic and chemical methods. Gracilioethers A−C showed antimalarial activity against Plasmodium falciparum with IC50 values

A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

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Jason P Wendler

Full Text Available Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

The relationship between cerebrovascular complications and previously established use of antiplatelet therapy in left-sided infective endocarditis

DEFF Research Database (Denmark)

Snygg-Martin, Ulrika; Rasmussen, Rasmus Vedby; Hassager, Christian

2011-01-01

Cerebrovascular complications (CVC) in infective endocarditis (IE) are common. The only established treatments to reduce the incidence of CVC in IE are antibiotics and in selected cases early cardiac surgery. Potential effects of previously established antiplatelet therapy are under debate....

Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action.

Science.gov (United States)

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 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.

Antimicrobial peptides: a new class of antimalarial drugs?

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Nuno eVale

2014-12-01

Full Text Available A range of antimicrobial peptides (AMP exhibit activity on malaria parasites, Plasmodium spp, in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs.

A single LC-tandem mass spectrometry method for the simultaneous determination of 14 antimalarial drugs and their metabolites in human plasma.

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Hodel, E M; Zanolari, B; Mercier, T; Biollaz, J; Keiser, J; Olliaro, P; Genton, B; Decosterd, L A

2009-04-01

Among the various determinants of treatment response, the achievement of sufficient blood levels is essential for curing malaria. For helping us at improving our current understanding of antimalarial drugs pharmacokinetics, efficacy and toxicity, we have developed a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) requiring 200mul of plasma for the simultaneous determination of 14 antimalarial drugs and their metabolites which are the components of the current first-line combination treatments for malaria (artemether, artesunate, dihydroartemisinin, amodiaquine, N-desethyl-amodiaquine, lumefantrine, desbutyl-lumefantrine, piperaquine, pyronaridine, mefloquine, chloroquine, quinine, pyrimethamine and sulfadoxine). Plasma is purified by a combination of protein precipitation, evaporation and reconstitution in methanol/ammonium formate 20mM (pH 4.0) 1:1. Reverse-phase chromatographic separation of antimalarial drugs is obtained using a gradient elution of 20mM ammonium formate and acetonitrile both containing 0.5% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 21min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effect variability, overall process efficiency, standard addition experiments as well as antimalarials short- and long-term stability in plasma. The reactivity of endoperoxide-containing antimalarials in the presence of hemolysis was tested both in vitro and on malaria patients samples. With this method, signal intensity of artemisinin decreased by about 20% in the presence of 0.2% hemolysed red-blood cells in plasma, whereas its derivatives were essentially not affected. The method is precise (inter-day CV%: 3.1-12.6%) and sensitive

Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies.

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Pingaew, Ratchanok; Prachayasittikul, Veda; Worachartcheewan, Apilak; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2015-10-20

A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

In vitro toxicity, antiplatelet and acetylcholinesterase inhibition of Buddleja thyrsoides Lam. leaves.

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Mahlke, Janaína Dorneles; Boligon, Aline Augusti; Machado, Michel Mansur; Athayde, Margareth Linde

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder resulting in impaired memory and behaviour of remarkable socio-economic impact. A decrease in cholinergic activity is a key event in the biochemical of AD. Buddleja thyrsoides is a plant widely distributed in Southern parts of South America. In Brazilian traditional medicine, the infusion of its leaves and flowers is used for the treatment of bronchitis and cough. Crude ethanolic (70%) extract and fractions (dichloromethane, ethyl acetate and n-butanolic) were investigated regarding their toxicities in vitro and antiplatelet action. The enzyme acetylcholinesterase inhibition was evaluated to study the crude extract. The crude extract and fractions were evaluated by means of Brine Shrimp Lethality test and they showed low activities with LC(50) values 1698, 2818, 2187 and 3672 µg mL(-1) for dichloromethane, ethyl acetate, n-butanolic fractions and crude extract, respectively. Buddleja thyrsoides presented great antiplatelet action. The IC(50) values obtained for crude extract and dichloromethane, ethyl acetate and n-butanolic fractions were 361.29, 354.23, 368.75 and 344.30, respectively, while the IC(50) for the standard AAS was 257.01 µg mL(-1). The crude extract showed an inhibition of 22.8% of the acetylcholinesterase enzyme in 24 h.

Machine learning prioritizes synthesis of primaquine ureidoamides with high antimalarial activity and attenuated cytotoxicity.

Science.gov (United States)

Levatić, Jurica; Pavić, Kristina; Perković, Ivana; Uzelac, Lidija; Ester, Katja; Kralj, Marijeta; Kaiser, Marcel; Rottmann, Matthias; Supek, Fran; Zorc, Branka

2018-02-25

Primaquine (PQ) is a commonly used drug that can prevent the transmission of Plasmodium falciparum malaria, however toxicity limits its use. We prepared five groups of PQ derivatives: amides 1a-k, ureas 2a-k, semicarbazides 3a,b, acylsemicarbazides 4a-k and bis-ureas 5a-v, and evaluated them for antimalarial activity in vitro against the erythrocytic stage of P. falciparum NF54. Particular substituents, such as trityl (in 2j and 5r) and methoxybenzhydryl (in 3b and 5v) were associated with a favorable cytotoxicity-to-activity ratio. To systematically link structural features of PQ derivatives to antiplasmodial activity, we performed a quantitative structure-activity relationship (QSAR) study using the Support Vector Machines machine learning method. This yielded a highly accurate statistical model (R 2  = 0.776 in cross-validation), which was used to prioritize novel candidate compounds. Seven novel PQ-ureidoamides 10a-g were synthesized and evaluated for activity, highlighting the benzhydryl ureidoamides 10e and 10f derived from p-chlorophenylglycine. Further experiments on human cell lines revealed that 10e and 10f are an order of magnitude less toxic than PQ in vitro while having antimalarial activity indistinguishable from PQ. The toxicity profile of novel compounds 10 toward human cells was particularly favorable when the glucose-6-phosphate dehydrogenase (G6PD) was inhibited, while toxicity of PQ was exacerbated by G6PD inhibition. Our work therefore highlights promising lead compounds for the development of effective antimalarial drugs that may also be safer for G6PD-deficient patients. In addition, we provide computational inferences of antimalarial activity and cytotoxicity for thousands of PQ-like molecular structures. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639

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Gasparovic Hrvoje

2012-08-01

Full Text Available Abstract Background Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive. The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. Methods Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology as well as bleeding events will be recorded. Discussion This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management. This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639.

Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides

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Soo Hyun Lee

2016-05-01

Full Text Available Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1–13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT and prothrombin time (PT in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (1, 33.2 ± 0.7 s and N-(4′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (2, 43.5 ± 0.6 s were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2 ± 0.7 s and 2 (43.5 ± 0.6 s were compared with heparin (62.5 ± 0.8 s in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo and on tail bleeding time (in vivo on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs. Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.

Mutations in the P-Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials

Science.gov (United States)

2015-01-01

Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target. PMID:25322084

Search for Antiprotozoal Activity in Herbal Medicinal Preparations; New Natural Leads against Neglected Tropical Diseases

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Núria Llurba Montesino

2015-08-01

Full Text Available Sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are infectious diseases caused by unicellular eukaryotic parasites (“protozoans”. The three first mentioned are classified as Neglected Tropical Diseases (NTDs by the World Health Organization and together threaten more than one billion lives worldwide. Due to the lack of research interest and the high increase of resistance against the existing treatments, the search for effective and safe new therapies is urgently required. In view of the large tradition of natural products as sources against infectious diseases [1,2], the aim of the present study is to investigate the potential of legally approved and marketed herbal medicinal products (HMPs as antiprotozoal agents. Fifty-eight extracts from 53 HMPs on the German market were tested by a Multiple-Target-Screening (MTS against parasites of the genera Leishmania, Trypanosoma, and Plasmodium. Sixteen HMPs showed in vitro activity against at least one of the pathogens (IC50 < 10 µg/mL. Six extracts from preparations of Salvia, Valeriana, Hypericum, Silybum, Arnica, and Curcuma exhibited high activity (IC50 < 2.5 µg/mL. They were analytically characterized by UHPLC/ESI-QqTOF-MSMS and the activity-guided fractionation of the extracts with the aim to isolate and identify the active compounds is in progress.

Effects of the anti-malarial compound cryptolepine and its analogues in human lymphocytes and sperm in the Comet assay.

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Gopalan, Rajendran C; Emerce, Esra; Wright, Colin W; Karahalil, Bensu; Karakaya, Ali E; Anderson, Diana

2011-12-15

Malaria is a mosquito-borne infectious disease caused by the genus Plasmodium. It causes one million deaths per year in African children under the age of 5 years. There is an increasing development of resistance of malarial parasites to chloroquine and other currently used anti-malarial drugs. Some plant products such as the indoloquinoline alkaloid cryptolepine have been shown to have potent activity against P. falciparum in vitro. On account of its toxicity, cryptolepine is not suitable for use as an antimalarial drug but a number of analogues of cryptolepine have been synthesised in an attempt to find compounds that have reduced cytotoxicity and these have been investigated in the present study in human sperm and lymphocytes using the Comet assay. The results suggest that cryptolepine and the analogues cause DNA damage in lymphocytes, but appear to have no effect on human sperm at the assessed doses. In the context of antimalarial drug development, the data suggest that all cryptolepine compounds and in particular 2,7-dibromocryptolepine cause DNA damage and therefore may not be suitable for pre clinical development as antimalarial agents. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Identification of β-Amino alcohol grafted 1,4,5 trisubstituted 1,2,3-triazoles as potent antimalarial agents.

Science.gov (United States)

Devender, Nalmala; Gunjan, Sarika; Chhabra, Stuti; Singh, Kartikey; Pasam, Venkata Reddy; Shukla, Sanjeev K; Sharma, Abhisheak; Jaiswal, Swati; Singh, Sunil Kumar; Kumar, Yogesh; Lal, Jawahar; Trivedi, Arun Kumar; Tripathi, Renu; Tripathi, Rama Pati

2016-02-15

In a quest to discover new drugs, we have synthesized a series of novel β-amino alcohol grafted 1,2,3-triazoles and screened them for their in vitro antiplasmodial and in vivo antimalarial activity. Among them, compounds 16 and 25 showed potent activity against chloroquine-sensitive (Pf3D7) strain with IC50 of 0.87 and 0.3 μM respectively, while compounds 7 and 13 exhibited better activity in vitro than the reference drug against chloroquine-resistance strain (PfK1) with IC50 of 0.5 μM each. Compound 25 showed 86.8% in vivo antimalarial efficacy with favorable pharmacokinetic parameters. Mechanistic studies divulged that potent compounds significantly boosted p53 protein levels to exhibit the antimalarial activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Trends in pregnancy outcomes in Malawian adolescents receiving antimalarial and hematinic supplements

NARCIS (Netherlands)

Msyamboza, Kelias; Savage, Emma; Kalanda, Gertrude; Kazembe, Peter; Gies, Sabine; d'Alessandro, Umberto; Brabin, Bernard J.

2010-01-01

Objective. To describe pregnancy outcomes of adolescent and adult primigravidae receiving antimalarials and hematinic supplementation and compare findings with a survey in this area a decade earlier. Design. Cross-sectional surveys in intervention and control sites. Setting. Community, antenatal and

In vitro antimalarial drug susceptibility in Thai border areas from 1998–2003

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Mungthin Mathirut

2005-08-01

Full Text Available Abstract Background The Thai-Myanmar and Thai-Cambodia borders have been historically linked with the emergence and spread of Plasmodium falciparum parasites resistant to antimalarial drugs. Indeed, the areas are often described as harbouring multi-drug resistant parasites. These areas of Thailand have experienced significant changes in antimalarial drug exposure patterns over the past decade. This study describes the in vitro antimalarial susceptibility patterns of 95 laboratory-adapted P. falciparum isolates, collected between 1998 and 2003,. Methods Ninety five P. falciparum isolates were collected from five sites in Thailand between 1998 and 2003. After laboratory adaptation to in vitro culture, the susceptibility of these parasites to a range of established antimalarial drugs (chloroquine [CQ], mefloquine [MQ], quinine [QN] and dihydroartemisinin [DHA] was determined by the isotopic microtest. Results Mefloquine (MQ sensitivity remained poorest in areas previously described as MQ-resistant areas. Sensitivity to MQ of parasites from this area was significantly lower than those from areas reported to harbour moderate (p = 0.002 of low level MQ resistance (p = 000001. Importantly for all drugs tested, there was a considerable range in absolute parasite sensitivities. There was a weak, but statistically positive correlation between parasite sensitivity to CQ and sensitivity to both QN and MQ and a positive correlation between MQ and QN. In terms of geographical distribution, parasites from the Thai-Cambodia were tended to be less sensitive to all drugs tested compared to the Thai-Myanmar border. Parasite sensitivity to all drugs was stable over the 6-year collection period with the exception of QN. Conclusion This study highlights the high degree of variability in parasite drug sensitivity in Thailand. There were geographical differences in the pattern of resistance which might reflect differences in drug usage in each area. In contrast to many

Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review

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Shweta Sinha

2017-10-01

Full Text Available The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000–2,000,000 compounds per screening campaign, before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug–drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells.

Antimalarial activity of 4-(5-trifluoromethyl-1H-pyrazol-1-yl)-chloroquine analogues.

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Cunico, Wilson; Cechinel, Cleber A; Bonacorso, Helio G; Martins, Marcos A P; Zanatta, Nilo; de Souza, Marcus V N; Freitas, Isabela O; Soares, Rodrigo P P; Krettli, Antoniana U

2006-02-01

The antimalarial activity of chloroquine-pyrazole analogues, synthesized from the reaction of 1,1,1-trifluoro-4-methoxy-3-alken-2-ones with 4-hydrazino-7-chloroquinoline, has been evaluated in vitro against a chloroquine resistant Plasmodium falciparum clone. Parasite growth in the presence of the test drugs was measured by incorporation of [(3)H]hypoxanthine in comparison to controls with no drugs. All but one of the eight (4,5-dihydropyrazol-1-yl) chloroquine 2 derivatives tested showed a significant activity in vitro, thus, are a promising new class of antimalarials. The three most active ones were also tested in vivo against Plasmodium berghei in mice. However, the (pyrazol-1-yl) chloroquine 3 derivatives were mostly inactive, suggesting that the aromatic functionality of the pyrazole ring was critical.

Biological Activities of Hydrazone Derivatives

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S. Güniz Küçükgüzel

2007-08-01

Full Text Available There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, antiinflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumoral, vasodilator, antiviral and antischistosomiasis activities. Hydrazones possessing an azometine -NHN=CH- proton constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations have been guiding for the development of new hydrazones that possess varied biological activities.

A review exploring biological activities of hydrazones

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Garima Verma

2014-01-01

Full Text Available The development of novel compounds, hydrazones has shown that they possess a wide variety of biological activities viz. antimicrobial, anticonvulsant, antidepressant, anti-inflammatory, analgesic, antiplatelet, antimalarial, anticancer, antifungal, antitubercular, antiviral, cardio protective etc., Hydrazones/azomethines/imines possess-NHN = CH- and constitute an important class of compounds for new drug development. A number of researchers have synthesized and evaluated the biological activities of hydrazones. This review aims at highlighting the diverse biological activities of hydrazones.

Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives.

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Bhat, Hans Raj; Singh, Udaya Pratap; Thakur, Anjali; Kumar Ghosh, Surajit; Gogoi, Kabita; Prakash, Anil; Singh, Ramendra K

2015-10-01

A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS). Copyright © 2015 Elsevier Inc. All rights reserved.

4-Aminoquinoline-pyrimidine hybrids: synthesis, antimalarial activity, heme binding and docking studies.

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Kumar, Deepak; Khan, Shabana I; Tekwani, Babu L; Ponnan, Prija; Rawat, Diwan S

2015-01-07

A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Antimalarial efficacy of Pongamia pinnata (L) Pierre against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA).

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Satish, P V V; Sunita, K

2017-09-11

The objective of the current study was to assess the in vitro antiplasmodial activities of leaf, bark, flower, and the root of Pongamia pinnata against chloroquine-sensitive Plasmodium falciparum (3D7 strain), cytotoxicity against Brine shrimp larvae and THP-1 cell line. For in vivo study, the plant extract which has shown potent in vitro antimalarial activity was tested against Plasmodium berghei (ANKA strain). The plant Pongamia pinnata was collected from the herbal garden of Acharya Nagarjuna University of Guntur district, Andhra Pradesh, India. Sequentially crude extracts of methanol (polar), chloroform (non-polar), hexane (non-polar), ethyl acetate (non-polar) and aqueous (polar) of dried leaves, bark, flowers and roots of Pongamia pinnata were prepared using Soxhlet apparatus. The extracts were screened for in vitro antimalarial activity against P. falciparum 3D7 strain. The cytotoxicity studies of crude extracts were conducted against Brine shrimp larvae and THP-1 cell line. Phytochemical analysis of the plant extracts was carried out by following the standard methods. The chemical injury to erythrocytes due to the plant extracts was checked. The in vivo study was conducted on P. berghei (ANKA) infected BALB/c albino mice by following 4-Day Suppressive, Repository, and Curative tests. Out of all the tested extracts, the methanol extract of the bark of Pongamia pinnata had shown an IC 50 value of 11.67 μg/mL with potent in vitro antimalarial activity and cytotoxicity evaluation revealed that this extract was not toxic against Brine shrimp and THP-1 cells. The injury to erythrocytes analysis had not shown any morphological alterations and damage to the erythrocytes after 48 h of incubation. Because methanolic bark extract of Pongamia pinnata has shown good antimalarial activity in vitro, it was also tested in vivo. So the extract had exhibited an excellent activity against P. berghei malaria parasite while decrement of parasite counts was moderately low and

Cyquant cell proliferation assay as a fluorescence-based method for in vitro screening of antimalarial activity.

Science.gov (United States)

Sriwilaijaroen, Nongluk; Kelly, Jane Xu; Riscoe, Michael; Wilairat, Prapon

2004-12-01

The appearance of drug resistant parasites and the absence of an effective vaccine have resulted in the need for new effective antimalarial drugs. Consequently, a convenient method for in vitro screening of large numbers of antimalarial drug candidates has become apparent. The CyQUANT cell proliferation assay is a highly sensitive fluorescence-based method for quantitation of cell number by measuring the strong fluorescence produced when green GR dye binds to nucleic acids. We have applied the CyQUANT assay method to evaluate the growth of Plasmodium falciparum D6 strain in culture. The GR-nucleic acid fluorescence linearly correlated with percent parasitemia at both 0.75 or 1 percent hematocrit with the same correlation coefficient of r2 = 0.99. The sensitivity of P. falciparum D6 strain to chloroquine and to 3,6-bis-omega-diethylaminoamyloxyxanthone, a novel antimalarial, determined by the CyQUANT assay were comparable to those obtained by the traditional [3H]-ethanolamine assay: IC50 value of chloroquine was 54 nM and 51 nM by the CyQUANT and [3H]-ethanolamine assay, respectively; IC50 value for 3,6-bis-omega-diethylaminoamyloxyxanthone was 254 nM and 223 nM by the CyQUANT and [3H]-ethanolamine assay, respectively. This procedure requires no radioisotope, uses simple equipment, and is an easy and convenient procedure, with no washing and harvesting steps. Moreover, all procedures can be set up continuously and thus, the CyQUANT assay is suitable in automatic high through-put drug screening of antimalarial drugs.

Tympanic membrane bleeding complications during hyperbaric oxygen treatment in patients with or without antiplatelet and anticoagulant drug treatment

NARCIS (Netherlands)

Fijen, Valerie A.; Westerweel, Peter E.; van Ooij, Pieter Jan A. M.; van Hulst, Rob A.

2016-01-01

Middle ear barotrauma (MEBt) is a frequently occurring complication of hyperbaric oxygen treatment (HBOT). High-grade MEBt may involve tympanic membrane (TM) haemorrhaging. Although many patients undergoing HBOT use antiplatelet or anticoagulant drugs, it is unknown whether these drugs increase the

Stevens-Johnson syndrome associated with Malarone antimalarial prophylaxis.

Science.gov (United States)

Emberger, Michael; Lechner, Arno Michael; Zelger, Bernhard

2003-07-01

To the best of our knowledge, Stevens-Johnson syndrome (SJS) has not been reported previously as an adverse reaction to Malarone, which is a combination of atovaquone and proguanil hydrochloride used for antimalarial prophylaxis and therapy. We describe a 65-year-old patient who had SJS with typical clinical and histopathological findings associated with the use of Malarone prophylaxis for malaria. This report should alert physicians to this severe cutaneous reaction, and Malarone should be added to the list of drugs that can potentially cause SJS.

Antiplatelet therapy: aspirin resistance and all that jazz!

Science.gov (United States)

Divani, Afshin A; Zantek, Nicole D; Borhani-Haghighi, Afshin; Rao, Gundu H R

2013-01-01

Platelets play a crucial role in the pathogenesis of atherosclerosis, thrombosis, and stroke. Aspirin used alone or in combination with other antiplatelet drugs has been shown to offer significant benefit to patients at high risk of vascular events. Resistance to the action of aspirin may decrease this benefit. Aspirin resistance has been defined by clinical and/or laboratory criteria; however, detection by laboratory methods prior to experiencing a clinical event will likely provide the greatest opportunity for intervention. Numerous laboratory methods with different cutoff points have been used to evaluate the resistance. Noncompliance with aspirin treatment has also confounded studies. A single assay is currently insufficient to establish resistance. Combinations of results to confirm compliance and platelet inhibition may identify "at-risk" individuals who truly have aspirin resistance. The most effective strategy for managing patients with aspirin resistance is unknown; however, studies are currently underway to address this issue.

New anti-HIV-1, antimalarial, and antifungal compounds from Terminalia bellerica

DEFF Research Database (Denmark)

Valsaraj, R; Pushpangadan, P; Smitt, U W

1997-01-01

A bioactivity-guided fractionation of an extract of Terminalia bellerica fruit rind led to the isolation of two new lignans named termilignan (1) and thannilignan (2), together with 7-hydroxy-3',4'-(methylenedioxy)flavan (3) and anolignan B (4). All four compounds possessed demonstrable anti-HIV-......, antimalarial, and antifungal activity in vitro....

Role of Quinone Reductase 2 in the Antimalarial Properties of Indolone-Type Derivatives

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Laure-Estelle Cassagnes

2017-01-01

Full Text Available Indolone-N-oxides have antiplasmodial properties against Plasmodium falciparum at the erythrocytic stage, with IC50 values in the nanomolar range. The mechanism of action of indolone derivatives involves the production of free radicals, which follows their bioreduction by an unknown mechanism. In this study, we hypothesized that human quinone reductase 2 (hQR2, known to act as a flavin redox switch upon binding to the broadly used antimalarial chloroquine, could be involved in the activity of the redox-active indolone derivatives. Therefore, we investigated the role of hQR2 in the reduction of indolone derivatives. We analyzed the interaction between hQR2 and several indolone-type derivatives by examining enzymatic kinetics, the substrate/protein complex structure with X-ray diffraction analysis, and the production of free radicals with electron paramagnetic resonance. The reduction of each compound in cells overexpressing hQR2 was compared to its reduction in naïve cells. This process could be inhibited by the specific hQR2 inhibitor, S29434. These results confirmed that the anti-malarial activity of indolone-type derivatives was linked to their ability to serve as hQR2 substrates and not as hQR2 inhibitors as reported for chloroquine, leading to the possibility that substrate of hQR2 could be considered as a new avenue for the design of new antimalarial compounds.

Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study

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Swai Ndeniria

2011-04-01

Full Text Available Abstract Background Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment. The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs on prescription of anti-malarials in urban Tanzania. Methods The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF in Dar es Salaam, Tanzania. The participants were all clinicians and their patients in the above health facilities. The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF. Three HF without mRDTs were selected as matched controls. The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age. The main outcome measures were: (1 anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2 anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation. Results Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80 in intervention and 32% (9-54 in control HF. For quinine vials, the reduction was 63% (54-72 in intervention and an increase of 2.49 times (1.62-3.35 in control HF. Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26. The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22% and control HF (60% (Risk ratio 0.30, 95%CI 0.14-0.70. Adherence to test result was excellent since only 7% of negative patients received an anti-malarial. However, antibiotic

Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.

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Venerito, M; Schneider, C; Costanzo, R; Breja, R; Röhl, F-W; Malfertheiner, P

2018-06-01

Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding. To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs. Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis. Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users. Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non

The Emerging Role of miR-223 in Platelet Reactivity: Implications in Antiplatelet Therapy

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Shi, Rui; Zhou, Xin; Ji, Wen-Jie; Zhang, Ying-Ying; Ma, Yong-Qiang; Zhang, Jian-Qi

2015-01-01

Platelets are anuclear cells and are devoid of genomic DNA, but they are capable of de novo protein synthesis from mRNA derived from their progenitor cells, megakaryocytes. There is mounting evidence that microRNA (miRNA) plays an important role in regulating gene expression in platelets. miR-223 is the most abundant miRNAs in megakaryocytes and platelets. One of the miR-223-regulated genes is ADP P2Y12, a key target for current antiplatelet drug therapy. Recent studies showed that a blunted response to P2Y12 antagonist, that is, high on-treatment platelet reactivity (HTPR), is a strong predictor of major cardiovascular events (MACEs) in coronary heart disease (CHD) patients receiving antiplatelet treatment. Recent clinical cohort study showed that the level of circulating miR-223 is inversely associated with MACE in CHD patients. In addition, our recent data demonstrated that the level of both intraplatelet and circulating miR-223 is an independent predictor for HTPR, thus providing a link between miR-223 and MACE. These lines of evidence indicate that miR-223 may serve as a potential regulatory target for HTPR, as well as a diagnostic tool for identification of HTPR in clinical settings. PMID:26221610

Antimycobacterial and antimalarial activities of endophytic fungi associated with the ancient and narrowly endemic neotropical plant Vellozia gigantea from Brazil.

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Ferreira, Mariana C; Cantrell, Charles L; Wedge, David E; Gonçalves, Vívian N; Jacob, Melissa R; Khan, Shabana; Rosa, Carlos A; Rosa, Luiz H

2017-10-01

Endophytic fungi, present mainly in the Ascomycota and Basidiomycota phyla, are associated with different plants and represent important producers of bioactive natural products. Brazil has a rich biodiversity of plant species, including those reported as being endemic. Among the endemic Brazilian plant species, Vellozia gigantea (Velloziaceae) is threatened by extinction and is a promising target to recover endophytic fungi. The present study focused on bioprospecting of bioactive compounds of the endophytic fungi associated with V. gigantea, an endemic, ancient, and endangered plant species that occurs only in the rupestrian grasslands of Brazil. The capability of 285 fungal isolates to produce antimicrobial and antimalarial activities was examined. Fungi were grown at solid-state fermentation to recover their crude extracts in dichloromethane. Bioactive extracts were analysed by chromatographic fractionation and NMR and displayed compounds with antimicrobial, antimycobacterial, and antimalarial activities. Five fungi produced antimicrobial and antimalarial compounds. Extracts of Diaporthe miriciae showed antifungal, antibacterial, and antimalarial activities; Trichoderma effusum displayed selective antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare; and three Penicillium species showed antibacterial activity. D. miriciae extract contained highly functionalised secondary metabolites, yielding the compound epoxycytochalasin H with high antimalarial activity against the chloroquine-resistant strain of Plasmodium falciparum, with an IC50 approximately 3.5-fold lower than that with chloroquine. Our results indicate that V. gigantea may represent a microhabitat repository hotspot of potential fungi producers of bioactive compounds and suggest that endophytic fungal communities might be an important biological component contributing to the fitness of the plants living in the rupestrian grassland.

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia.

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Audia, Sylvain; Rossato, Marzia; Santegoets, Kim; Spijkers, Sanne; Wichers, Catharina; Bekker, Cornelis; Bloem, Andries; Boon, Louis; Flinsenberg, Thijs; Compeer, Ewoud; van den Broek, Theo; Facy, Olivier; Ortega-Deballon, Pablo; Berthier, Sabine; Leguy-Seguin, Vanessa; Martin, Laurent; Ciudad, Marion; Samson, Maxime; Trad, Malika; Lorcerie, Bernard; Janikashvili, Nona; Saas, Philippe; Bonnotte, Bernard; Radstake, Timothy R D J

2014-10-30

Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP. © 2014 by The American Society of Hematology.

Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis.

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Jackson, Joseph W; Singh, Meera V; Singh, Vir B; Jones, Letitia D; Davidson, Gregory A; Ture, Sara; Morrell, Craig N; Schifitto, Giovanni; Maggirwar, Sanjay B

2016-01-01

Platelets play an essential role in hemostasis and wound healing by facilitating thrombus formation at sites of injury. Platelets also mediate inflammation and contain several pro-inflammatory molecules including cytokines and chemokines that mediate leukocyte recruitment and activation. Not surprisingly, platelet dysfunction is known to contribute to several inflammatory disorders. Antiplatelet therapies, such as aspirin, adenosine diphosphate (ADP) antagonists, glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, and anticoagulants such as warfarin, dampen platelet activity at the risk of unwarranted bleeding. Thus, the development of drugs that reduce platelet-mediated inflammation without interfering with thrombus formation is of importance to combat platelet-associated disorders. We have shown here for the first time that the tetracycline antibiotic, minocycline, administered to HIV-infected individuals reduces plasma levels of soluble CD40L and platelet factor 4 levels, host molecules predominately released by platelets. Minocycline reduced the activation of isolated platelets in the presence of the potent platelet activator, thrombin, as measured by ELISA and flow cytometry. Platelet degranulation was reduced upon exposure to minocycline as shown by mepacrine retention and flow cytometry. However, minocycline had no effect on spreading, aggregation, GPIIb/IIIa activation, or in vivo thrombus formation. Lastly, immunoblot analysis suggests that the antiplatelet activity of minocycline is likely mediated by inhibition of mixed lineage kinase 3 (MLK3)-p38 MAPK signaling axis and loss of p38 activity. Our findings provide a better understanding of platelet biology and a novel repurposing of an established antibiotic, minocycline, to specifically reduce platelet granule release without affecting thrombosis, which may yield insights in generating novel, specific antiplatelet therapies.

Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

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Swain Bijay K

2009-02-01

Full Text Available Abstract Background Herbal extracts of Andrographis paniculata (AP and Hedyotis corymbosa (HC are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20 and resistant (MRC-pf-303 strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50 of AP (7.2 μg/ml was found better than HC (10.8 μg/ml. Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC and their individual synergism with curcumin (AP+CUR, HC+CUR were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs.

Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin

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Mishra, Kirti; Dash, Aditya P; Swain, Bijay K; Dey, Nrisingha

2009-01-01

Background Herbal extracts of Andrographis paniculata (AP) and Hedyotis corymbosa (HC) are known as hepato-protective and fever-reducing drugs since ancient time and they have been used regularly by the people in the south Asian sub-continent. Methanolic extracts of these two plants were tested in vitro on choloroquine sensitive (MRC-pf-20) and resistant (MRC-pf-303) strains of Plasmodium falciparum for their anti-malarial activity. Methods Growth inhibition was determined using different concentrations of these plant extracts on synchronized P. falciparum cultures at the ring stage. The interactions between these two plant extracts and individually with curcumin were studied in vitro. The performance of these two herbal extracts in isolation and combination were further evaluated in vivo on Balb/c mice infected with Plasmodium berghei ANKA and their efficacy was compared with that of curcumin. The in vivo toxicity of the plant derived compounds as well as their parasite stage-specificity was studied. Results The 50% inhibitory concentration (IC50) of AP (7.2 μg/ml) was found better than HC (10.8 μg/ml). Combination of these two herbal drugs showed substantial enhancement in their anti-malarial activity. Combinatorial effect of each of these with curcumin also revealed anti-malarial effect. Additive interaction between the plant extracts (AP + HC) and their individual synergism with curcumin (AP+CUR, HC+CUR) were evident from this study. Increased in vivo potency was also observed with the combination of plant extracts over the individual extracts and curcumin. Both the plant extracts were found to inhibit the ring stage of the parasite and did not show any in vivo toxicity, whether used in isolation or in combination. Conclusion Both these two plant extracts in combination with curcumin could be an effective, alternative source of herbal anti-malarial drugs. PMID:19216765

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

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Paquet, T.; Manach, C.; Cabrera, D.G.; Younis, Y.; Henrich, P.P.; Abraham, T.S.; Lee, M.C.; Basak, R.; Ghidelli-Disse, S.; Lafuente-Monasterio, M.J.; Bantscheff, M.; Ruecker, A.; Blagborough, A.M.; Zakutansky, S.E.; Zeeman, A.M.; White, K.L.; Shackleford, D.M.; Mannila, J.; Morizzi, J.; Scheurer, C.; Angulo-Barturen, I.; Martinez, M.S.; Ferrer, S.; Sanz, L.M.; Gamo, F.J.; Reader, J.; Botha, M.; Dechering, K.J.; Sauerwein, R.W.; Tungtaeng, A.; Vanachayangkul, P.; Lim, C.S.; Burrows, J.; Witty, M.J.; Marsh, K.C.; Bodenreider, C.; Rochford, R.; Solapure, S.M.; Jimenez-Diaz, M.B.; Wittlin, S.; Charman, S.A.; Donini, C.; Campo, B.; Birkholtz, L.M.; Hanson, K.K.; Drewes, G.; Kocken, C.H.; Delves, M.J.; Leroy, D.; Fidock, D.A.; Waterson, D.; Street, L.J.; Chibale, K

2017-01-01

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with

Antimalarial peroxides: the first intramolecular 1,2,4,5-tetraoxane

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BOGDAN A. SOLAJA

2002-07-01

Full Text Available An intramolecular steroidal 1,2,4,5-tetraoxane has been synthesised in six steps starting from methyl 3-oxo-7a,12a-diacetoxy-5b-cholan-24-oate. The synthesised 1,2,4,5-tetraoxane has moderate in vitro antimalarial activity against P. falciparum strains (IC50 (D6 = 0.35 mg/mL; IC50 (W2 = 0.29 mg/mL.

Peculiarities in cases of spina bifida cystica managed recently in south-east Nigeria: could antimalarial drugs be a major but unrecognized etiologic factor?

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Emejulu, Jude-Kennedy C; Okwaraoha, Blaise Ogedi

2011-01-01

Spina bifida is a long-known disease arising from the incomplete fusion of the caudal neuropore in the first month of intrauterine life. It is thought to have a multifactorial etiology, the most important of which is folic acid deficiency. In evaluating its etiology, the role of antifolate agents like antimalarial drugs is rarely given a strong mention. This is a 44-month prospective study of consecutive cases of spina bifida cystica presenting to the Neurosurgery Unit of Nnamdi Azikiwe University Teaching Hospital, Nnewi, South-East Nigeria. Data collection was with a structured proforma from presentation, and collation done with Microsoft Excel broadsheet and data analysis with SPSS and χ2 test. A total of 41 cases of spina bifida were attended to within the period, with 92.7% cases of spina bifida cystica. Most presented by >12-24 months, with a consistent history of maternal ingestion of antimalarial drugs during the first trimester of pregnancy. Spina bifida cystica was diagnosed mostly in children whose mothers ingested antimalarial drugs during the first trimester of gestation. There may be a need to critically evaluate the contribution of antimalarial drugs to the etiopathogenesis of this malformation and develop safer antimalarial treatment in pregnancy. Copyright © 2012 S. Karger AG, Basel.

Phytochemical screening and antimalarial activity of some plants traditionally used in Indonesia

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Syamsudin Abdillah

2015-06-01

Full Text Available Objective: To evaluate ethanolic extracts of phytochemical screening, in vitro and in vivo antiplasmodial activities of 15 plants used as antimalarial in Sei Kepayang, North Sumatra. Methods: Extraction was done through maceration with 70% ethanol and screened against chemical content, in vitro test anti-plasmodium against Plasmodium falciparum 3D7 strain and in vivo test in mice infected Plasmodium berghei. Results: The results showed that the plant extract contained a group of saponins, flavonoids, alkaloids, quinone, sterols, triterpene, tannins and cumarine. However, extract of Momordica charantia, Carica papaya, Garcinia atroviridis, Alstonia scholaris, Smallanthus sonchifolia and Cassia siamea had strong anti-plasmodium activity both in vitro and in vivo. Conclusions: In vitro and in vivo antiplasmodial activities of 15 plants are used as antimalarial in Sei Kepayang, North Sumatra. All the plants have in vitro and in vivo anti-plasmodium activity except Orthosiphon stamineus and Luffa cylindrica (ED50 > 1 000 mg/kg body weight and IC50 > 100 μg/mL, respectively.

Antimalarial Activity of KAF156 in Falciparum and Vivax Malaria.

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White, Nicholas J; Duong, Tran T; Uthaisin, Chirapong; Nosten, François; Phyo, Aung P; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon; Jittamala, Podjanee; Chuthasmit, Kittiphum; Cheung, Ming S; Feng, Yiyan; Li, Ruobing; Magnusson, Baldur; Sultan, Marc; Wieser, Daniela; Xun, Xiaolei; Zhao, Rong; Diagana, Thierry T; Pertel, Peter; Leong, F Joel

2016-09-22

KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean (±SD) KAF156 terminal elimination half-life was 44.1±8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and

Comparison on Anticoagulation and Antiplatelet Aggregation Effects of Puerarin with Heparin Sodium and Tirofiban Hydrochloride: An In Vitro Study.

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Li, Si-Wei; Feng, Xue; Xu, Hao; Chen, Ke-Ji

2018-02-01

To detect the anticoagulation and antiplatelet effects of different concentrations of puerarin, heparin sodium and tirofiban hydrochloride on the blood samples of healthy volunteers by Sonoclot coagulation and platelet function analyzer. Peripheral blood samples were extracted from 20 healthy volunteers, followed by adding different concentrations of puerarin, heparin sodium and tirofiban hydrochloride. Samples were detected for activated clotting time (ACT), clot rate (CR) and platelet function (PF) by Sonoclot coagulation and platelet function analyzer instrument. For puerarin and heparin sodium, the values of ACT gradually increased, and the values of CR and PF gradually decreased with increasing in drug concentration. There was a linear (or log linear) relationship between ACT, CR, PF value and drug concentration (Phydrochloride, the values of ACT and CR had no significant changes, while PF values gradually decreased with concentration increasing. There was also a linear relationship between PF values and concentrations of tirofiban hydrochloride (Psodium. For high concentrations of puerarin (e.g. 3.8 mg/600 μL) and tirofiban hydrochloride (e.g. 0.8 μg/600 μL), PF values had no significant difference. However, PF values for high puerarin concentration had a larger variance. Puerarin has similar anticoagulant and antiplatelet effects with the heparin sodium, and may have a lower hemorrhage risk than heparin sodium when obtained the same anticoagulation effect in the concentration range of this experiment. In addition, for high concentration, puerarin had the same antiplatelet function as tirofiban hydrochloride but with a larger individual variability.

Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis

NARCIS (Netherlands)

Gouya, G.; Arrich, J.; Wolzt, M.; Huber, K.; Verheugt, F.W.A.; Gurbel, P.A.; Pirker-Kees, A.; Siller-Matula, J.M.

2014-01-01

BACKGROUND AND PURPOSE: The efficacy and safety of different antiplatelet regimes for prevention of stroke in patients at high risk were investigated in a systematic review and meta-analysis. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Web of Science.

The Antimalarial Effect of Curcumin Is Mediated by the Inhibition of Glycogen Synthase Kinase-3β.

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Ali, Amatul Hamizah; Sudi, Suhaini; Basir, Rusliza; Embi, Noor; Sidek, Hasidah Mohd

2017-02-01

Curcumin, a bioactive compound in Curcuma longa, exhibits various pharmacological activities, including antimalarial effects. In silico docking simulation studies suggest that curcumin possesses glycogen synthase kinase-3β (GSK3β)-inhibitory properties. The involvement of GSK3 in the antimalarial effects in vivo is yet to be demonstrated. In this study, we aimed to evaluate whether the antimalarial effects of curcumin involve phosphorylation of host GSK3β. Intraperitoneal administration of curcumin into Plasmodium berghei NK65-infected mice resulted in dose-dependent chemosuppression of parasitemia development. At the highest dose tested (30 mg/kg body weight), both therapeutic and prophylactic administrations of curcumin resulted in suppression exceeding 50% and improved median survival time of infected mice compared to control. Western analysis revealed a 5.5-fold (therapeutic group) and 1.8-fold (prophylactic group) increase in phosphorylation of Ser 9 GSK3β and 1.6-fold (therapeutic group) and 1.7-fold (prophylactic group) increase in Ser 473 Akt in liver of curcumin-treated infected animals. Following P. berghei infection, levels of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, and IL-4 were elevated by 7.5-, 35.0-, 33.0-, and 2.2-fold, respectively. Curcumin treatment (therapeutic) caused a significant decrease (by 6.0- and 2.0-fold, respectively) in serum TNF-α and IFN-γ level, while IL-10 and IL-4 were elevated (by 1.4- and 1.8-fold). Findings from the present study demonstrate for the first time that the antimalarial action of curcumin involved inhibition of GSK3β.

Antimalarial Activity of the Chemical Constituents of the Leaf Latex of Aloe pulcherrima Gilbert and Sebsebe.

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Teka, Tekleab; Bisrat, Daniel; Yeshak, Mariamawit Yonathan; Asres, Kaleab

2016-10-28

Malaria is one of the three major global public health threats due to a wide spread resistance of the parasites to the standard antimalarial drugs. Considering this growing problem, the ethnomedicinal approach in the search for new antimalarial drugs from plant sources has proven to be more effective and inexpensive. The leaves of Aloe pulcherrima Gilbert and Sebsebe, an endemic Ethiopian plant, are locally used for the treatment of malaria and other infectious diseases. Application of the leaf latex of A. pulcherrima on preparative silica gel TLC led to the isolation of two C -glycosylated anthrones, identified as nataloin ( 1 ) and 7-hydroxyaloin ( 2 ) by spectroscopic techniques (UV, IR, ¹H- and 13 C-NMR, HR-ESIMS). Both the latex and isolated compounds displayed antimalarial activity in a dose-independent manner using a four-day suppressive test, with the highest percent suppression of 56.2% achieved at 200 mg/kg/day for 2 . The results indicate that both the leaf latex of A. pulcherrima and its two major constituents are endowed with antiplasmodial activities, which support the traditional use of the leaves of the plant for the treatment of malaria.

Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

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Daria Van Tyne

2011-04-01

Full Text Available The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb, and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS, searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

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Adeleke Clement Adebajo

2014-08-01

Full Text Available Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED50 values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED50 value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED50 of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED50 = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05 more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity.

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial: study protocol for a randomized controlled trial

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Park Kyung

2012-03-01

Full Text Available Abstract Background Second-generation drug-eluting stents (DES have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES. In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI. A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES and antiplatelet regimen (TAT vs DDAT. The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734.

Antiprotozoal and antimicrobial compounds from the plant pathogen Septoria pistaciarum.

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Kumarihamy, Mallika; Khan, Shabana I; Jacob, Melissa; Tekwani, Babu L; Duke, Stephen O; Ferreira, Daneel; Nanayakkara, N P Dhammika

2012-05-25

Four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids, 17-hydroxy-N-(O-methyl)septoriamycin A (1), 17-acetoxy-N-(O-methyl)septoriamycin A (2), 13-(S)-hydroxy-N-(O-methyl)septoriamycin A (3), and 13-(R)-hydroxy-N-(O-methyl)septoriamycin A (4), together with the known compounds (+)-cercosporin (5), (+)-14-O-acetylcercosporin (6), (+)-di-O-acetylcercosporin (7), lumichrome, and brassicasterol, were isolated from an ethyl acetate extract of a culture medium of Septoria pistaciarum. Methylation of septoriamycin A (8) with diazomethane yielded three di-O-methyl analogues, two of which existed as mixtures of rotamers. We previously reported antimalarial activity of septoriamycin A. This compound also exhibited significant activity against Leishmania donovani promastigotes. Compounds 5-7 showed moderate in vitro activity against L. donovani promastigotes and chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum, whereas compound 5 was fairly active against methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus. Compounds 5-7 also displayed moderate phytotoxic activity against both a dicot (lettuce, Lactuca sativa) and a monocot (bentgrass, Agrostis stolonifera) and cytotoxicity against a panel of cell lines.

Endoperoxide polyketides from a Chinese Plakortis simplex: further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes.

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Chianese, Giuseppina; Persico, Marco; Yang, Fan; Lin, Hou-Wen; Guo, Yue-Wei; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Taglialatela-Scafati, Orazio; Fattorusso, Caterina

2014-09-01

Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4-7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure-activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

Institute of Scientific and Technical Information of China (English)

Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

2014-01-01

Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.（G.mangostana）（pericarp）in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry（LC/MS/MS）.Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.（pericarp）at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control（non-exposed）,while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.（pericarp）.

Continuing versus discontinuing antiplatelet drugs, vasodilators, and/or cerebral ameliorators on perioperative total blood loss in total knee arthroplasty without pneumatic tourniquet

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Sachiyuki Tsukada, MD

2018-03-01

Full Text Available Background: Although studies have supported the utility of perioperative continuation of antiplatelet drugs, vasodilators, and cerebral ameliorators in most procedures, no study compared total volume of blood loss after total knee arthroplasty (TKA in patients continuing and discontinuing these drugs. Methods: We retrospectively reviewed 266 consecutive patients undergoing TKA, and included 67 patients (25.2% taking antiplatelet drugs, vasodilators, or cerebral ameliorators in this study. All TKAs were performed without a pneumatic tourniquet. The primary outcome was perioperative total blood loss calculated from blood volume and change in hemoglobin. As subgroup analysis, we compared perioperative total blood loss in patients taking antiplatelet drugs. Results: There was no significant difference between the continuing group (n = 38 and discontinuing group (n = 29 in terms of the perioperative total blood loss (1025 ± 364 vs 1151 ± 327 mL, respectively; mean difference 126 mL; 95% confidence interval −45 to 298 mL; P = .15. No major bleeding or thrombotic events occurred in either group until postoperative 3-month follow-up. In patients taking antiplatelet drugs (n = 51, no significant difference was observed in the total blood loss between the continuing group (n = 30 and discontinuing group (n = 21 (1056 ± 287 vs 1151 ± 305 mL, respectively; mean difference 95 mL; 95% confidence interval −75 to 264 mL; P = .27. Conclusions: No significant differences in terms of perioperative total blood loss were observed between patients continuing and discontinuing study drugs. Continuing these drugs may be preferable in the perioperative period of TKA. Keywords: Knee, Primary arthroplasty, Bleeding events, Thrombotic events, Noncardiac surgery

Antimalarial Bioavailability and Disposition of Artesunate in Acute Falciparum Malaria

OpenAIRE

Newton, Paul; Suputtamongkol, Yupin; Teja-Isavadharm, Paktiya; Pukrittayakamee, Sasithon; Navaratnam, V; Bates, Imelda; White, Nicholas

2000-01-01

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimal...

Lumbar puncture in patients using anticoagulants and antiplatelet agents

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Renan Domingues

2016-08-01

Full Text Available ABSTRACT The use of anticoagulants and antiplatelet agents has largely increased. Diagnostic lumbar puncture in patients taking these drugs represents a challenge considering the opposing risks of bleeding and thrombotic complications. To date there are no controlled trials, specific guidelines, nor clear recommendations in this area. In the present review we make some recommendations about lumbar puncture in patients using these drugs. Our recommendations take into consideration the pharmacology of these drugs, the thrombotic risk according to the underlying disease, and the urgency in cerebrospinal fluid analysis. Evaluating such information and a rigorous monitoring of neurological symptoms after lumbar puncture are crucial to minimize the risk of hemorrhage associated neurological deficits. An individualized patient decision-making and an effective communication between the assistant physician and the responsible for conducting the lumbar puncture are essential to minimize potential risks.

Assessment of the in Vitro Antiprotozoal and Cytotoxic Potential of 20 Selected Medicinal Plants from the Island of Soqotra

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Louis Maes

2012-12-01

Full Text Available Malaria, leishmaniasis and human African trypanosomiasis continue to be major public health problems in need of new and more effective drugs. The aim of this study was to evaluate in vitro antiprotozoal activity of twenty endemic medicinal plants collected from the island of Soqotra in the Indian Ocean. The plant materials were extracted with methanol and tested for antiplasmodial activity against erythrocytic schizonts of Plasmodium falciparum, for antileishmanial activity against intracellular amastigotes of Leishmania infantum and for antitrypanosomal activity against intracellular amastigotes of Trypanosoma cruzi and free trypomastigotes of T. brucei. To assess selectivity, cytotoxicity was determined against MRC-5 fibroblasts. Selective activity was obtained for Punica protopunica against Plasmodium (IC50 2.2 µg/mL while Eureiandra balfourii and Hypoestes pubescens displayed activity against the three kinetoplastid parasites (IC50 < 10 µg/mL. Acridocarpus socotranus showed activity against T. brucei and T. cruzi (IC50 3.5 and 8.4 µg/mL. Ballochia atrovirgata, Dendrosicycos socotrana, Dracaena cinnabari and Euphorbia socotrana displayed non-specific inhibition of the parasites related to high cytotoxicity.

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

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Valter F de Andrade-Neto

2007-06-01

Full Text Available 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.

Patent foramen ovale closure with GORE HELEX or CARDIOFORM Septal Occluder vs. antiplatelet therapy for reduction of recurrent stroke or new brain infarct in patients with prior cryptogenic stroke

DEFF Research Database (Denmark)

Kasner, Scott E; Thomassen, Lars; Søndergaard, Lars

2017-01-01

Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale...... with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent...... closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects...

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro.

Science.gov (United States)

Kedzierska, Ewa; Orzelska, Jolanta; Perković, Ivana; Knežević, Danijel; Fidecka, Sylwia; Kaiser, Marcel; Zorc, Branka

2016-02-01

New primaquine (PQ) urea and semicarbazide derivatives 1-4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L-6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited 'head-twitch' responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8-aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine-induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the 'writhing' test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Antimalarial activity of 80 % methanolic extract of Brassica nigra (L.) Koch. (Brassicaceae) seeds against Plasmodium berghei infection in mice.

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Muluye, Abrham Belachew; Melese, Eshetie; Adinew, Getnet Mequanint

2015-10-15

Resistances to currently available drugs and insecticides, significant drug toxicities and costs and lack of vaccines currently complicated the treatment of malaria. A continued search for safe, effective and affordable plant-based antimalarial agents thus becomes crucial and vital in the face of these difficulties. The aim of the study was to evaluate the antimalarial activity of 80 % methanolic extract of the seeds of Brassica nigra against Plasmodium berghei infection in mice. Chloroquine sensitive Plasmodium berghei (ANKA strain) was used to test the antimalarial activity of the extract. In suppressive and prophylactic models, Swiss albino male mice were randomly grouped into five groups of five mice each. Group I mice were treated with the vehicle, group II, III and IV were treated with 100, 200, and 400 mg/kg of the extract, respectively and the last group (V) mice were treated with chloroquine (10 mg/kg). The level of parasitemia, survival time and variation in weight of mice were used to determine the antimalarial activity of the extract. Chemosuppressive activities produced by the extract of the seeds of Brassica nigra were 21.88, 50.00 (P activities were 17.42, 21.21 and 53.79 % (P activities and the plant may contain biologically active principles which are relevant in the treatment and prophylaxis of malaria, thus supporting further studies of the plant for its active components.

A medicinal chemistry perspective on 4-aminoquinoline antimalarial drugs.

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O'Neill, Paul M; Ward, Stephen A; Berry, Neil G; Jeyadevan, J Prince; Biagini, Giancarlo A; Asadollaly, Egbaleh; Park, B Kevin; Bray, Patrick G

2006-01-01

A broad overview is presented describing the current knowledge and the ongoing research concerning the 4-aminoquinolines (4AQ) as chemotherapeutic antimalarial agents. Included are discussions of mechanism of action, structure activity relationships (SAR), chemistry, metabolism and toxicity and parasite resistance mechanisms. In discussions of SAR, particular emphasis has been given to activity versus chloroquine resistant strains of Plasmodium falciparum. Promising new lead compounds undergoing development are described and an overview of physicochemical properties of chloroquine and amodiaquine analogues is also included.

Preventive Aspirin and Other Antiplatelet Medication Use Among U.S. Adults Aged ≥40 Years: Data from the National Health and Nutrition Examination Survey, 2011–2012

Science.gov (United States)

Dillon, Charles F.; Eberhardt, Mark S.; Wright, Jacqueline D.; Burt, Vicki L.

2015-01-01

Objective We estimated the prevalence of preventive aspirin and/or other antiplatelet medication use and the dosage of aspirin use in the U.S. adult population. Methods We conducted cross-sectional analyses of a representative sample (n=3,599) of U.S. adults aged ≥40 years from the National Health and Nutrition Examination Survey, 2011–2012. Results In 2011–2012, one-third of U.S. adults aged ≥40 years reported taking preventive aspirin and/or other antiplatelet medications, 97% of whom indicated preventive aspirin use. Preventive aspirin use increased with age (from 11% of those aged 40–49 years to 54% of those ≥80 years of age, paspirin than non-Hispanic Asian (20%, paspirin. Among those with cardiovascular disease, 76% reported taking preventive aspirin and/or other antiplatelet medications, of whom 91% were taking preventive aspirin. Among adults without cardiovascular disease, 28% reported taking preventive aspirin. Adherence rates to medically recommended aspirin use were 82% overall, 91% for secondary prevention, and 79% for primary prevention. Among current preventive aspirin users, 70% were taking 81 milligrams (mg) of aspirin daily and 13% were taking 325 mg of aspirin daily. Conclusion The vast majority of antiplatelet therapy is preventive aspirin use. A health-care provider's recommendation to take preventive aspirin is an important determinant of current preventive aspirin use. PMID:26556936

Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus

DEFF Research Database (Denmark)

Kuhn, A; Sigges, J; Biazar, C

2014-01-01

. Smoking behaviour was assessed by the EUSCLE Core Set Questionnaire in 838 patients and statistically analysed using an SPSS database. The results were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the efficacy of antimalarial treatment. RESULTS: A high...

How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs.

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Katia Bruxvoort

Full Text Available BACKGROUND: High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic. OBJECTIVE: We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment. RESULTS: The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90-100% and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained. CONCLUSION: Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report.

How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs.

Science.gov (United States)

Bruxvoort, Katia; Goodman, Catherine; Kachur, S Patrick; Schellenberg, David

2014-01-01

High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs) in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic. We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment. The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90-100%) and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained. Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report.

Ligand-based virtual screening and in silico design of new antimalarial compounds using nonstochastic and stochastic total and atom-type quadratic maps.

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Marrero-Ponce, Yovani; Iyarreta-Veitía, Maité; Montero-Torres, Alina; Romero-Zaldivar, Carlos; Brandt, Carlos A; Avila, Priscilla E; Kirchgatter, Karin; Machado, Yanetsy

2005-01-01

Malaria has been one of the most significant public health problems for centuries. It affects many tropical and subtropical regions of the world. The increasing resistance of Plasmodium spp. to existing therapies has heightened alarms about malaria in the international health community. Nowadays, there is a pressing need for identifying and developing new drug-based antimalarial therapies. In an effort to overcome this problem, the main purpose of this study is to develop simple linear discriminant-based quantitative structure-activity relationship (QSAR) models for the classification and prediction of antimalarial activity using some of the TOMOCOMD-CARDD (TOpological MOlecular COMputer Design-Computer Aided "Rational" Drug Design) fingerprints, so as to enable computational screening from virtual combinatorial datasets. In this sense, a database of 1562 organic chemicals having great structural variability, 597 of them antimalarial agents and 965 compounds having other clinical uses, was analyzed and presented as a helpful tool, not only for theoretical chemists but also for other researchers in this area. This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. Afterward, two linear classification functions were derived in order to discriminate between antimalarial and nonantimalarial compounds. The models (including nonstochastic and stochastic indices) correctly classify more than 93% of the compound set, in both training and external prediction datasets. They showed high Matthews' correlation coefficients, 0.889 and 0.866 for the training set and 0.855 and 0.857 for the test one. The models' predictivity was also assessed and validated by the random removal of 10% of the compounds to form a new test set, for which predictions were made using the models. The overall means of the correct classification for this process (leave group 10% full-out cross validation) using the equations with nonstochastic

Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

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Dea Shahinas

2013-02-01

Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

Deconstructing Quinoline-Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta-Hematin Crystal Growth Inhibitors.

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Olafson, Katy N; Nguyen, Tam Q; Vekilov, Peter G; Rimer, Jeffrey D

2017-10-04

A versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces and alter their growth rates. Elucidating a modifier's binding specificity to anisotropic crystal surfaces is a ubiquitous challenge that is critical to their design. In this study, we select hematin, a byproduct of malaria parasites, as a model system to examine the complementarity of modifiers (i.e., antimalarial drugs) to β-hematin crystal surfaces. We divide two antimalarials, chloroquine and amodiaquine, into segments consisting of a quinoline base, common to both drugs, and side chains that differentiate their modes of action. Using a combination of scanning probe microscopy, bulk crystallization, and analytical techniques, we show that the base and side chain work synergistically to reduce the rate of hematin crystallization. In contrast to general observations that modifiers retain their function upon segmentation, we show that the constituents do not act as modifiers. A systematic study of quinoline isomers and analogues shows how subtle rearrangement and removal of functional moieties can create effective constituents from previously ineffective modifiers, along with tuning their inhibitory modes of action. These findings highlight the importance of specific functional moieties in drug compounds, leading to an improved understanding of modifier-crystal interactions that could prove to be applicable to the design of new antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Heme polymerization inhibition activity (HPIA) assay of synthesized xanthone derivative as antimalarial compound

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Fitriastuti, Dhina; Jumina, Priatmoko

2017-03-01

Xanthone is a phenolic secondary metabolite of Garcinia and Calophyllum herbs which has been clinically proven to display anti malaria activity. In the present paper, 2,3,4-trihydroxy-5-methyl xanthone which has been synthesized from gallic acid and o-cresol in Eaton's reagent was tested for its activity as antimalarial. Thus, HPIA assay of the synthesized xanthones was successfully conducted. The HPIA assay was carried out towards the xanthone, chloroquine diphosphate as positive control and distilled water as negative control in various concentration. The samples were reacted with hematin (ferriprotoporphyrin IX hydroxide) and the absorbance of the precipitate was observed by using Elisa reader. The results of HPIA assay showed that 2,3,4-trihydroxy-5-methyl xanthone and chloroquine have IC50 values of 0.755 and 1.462 mg/mL or 2.92 and 4.57 mM, respectively. 2,3,4-Trihydroxy-5-methyl xanthone displayed better antimalarial activity than chloroquine.

Synthesis, in vitro and in silico antimalarial activity of 7-chloroquinoline and 4H-chromene conjugates.

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Parthiban, A; Muthukumaran, J; Manhas, Ashan; Srivastava, Kumkum; Krishna, R; Rao, H Surya Prakash

2015-10-15

A new series of chloroquinoline-4H-chromene conjugates incorporating piperizine or azipane tethers were synthesized and their anti-malarial activity were evaluated against two Plasmodium falciparum strains namely 3D7 chloroquine sensitive (CQS) and K1 chloroquine resistant (CQR). Chloroquine was used as the standard and also reference for comparison. The conjugates exhibit intense UV absorption with λmax located at 342 nm (log ε=4.0), 254 nm (log ε=4.2), 223 nm (log ε=4.4) which can be used to spectrometrically track the molecules even in trace amounts. Among all the synthetic compounds, two molecules namely 6-nitro and N-piperazine groups incorporated 7d and 6-chloro and N-azapane incorporated 15b chloroquinoline-4H-chromene conjugates showed significant anti-malarial activity against two strains (3D7 and K1) of P. falciparum. These values are lesser than the values of standard antimalarial compound. Molecular docking results suggested that these two compounds showing strong binding affinity with P. falciparum lactate dehydrogenase (PfLDH) and also they occupy the co-factor position which indicated that they could be the potent inhibitors for dreadful disease malaria and specifically attack the glycolytic pathway in parasite for energy production. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antiplatelet therapy at the time of coronary artery bypass grafting

DEFF Research Database (Denmark)

Kremke, Michael; Jensen, Mariann Tang; Bak, Mikkel

2013-01-01

OBJECTIVES: The purpose of this multicentre cohort study was to examine the relationship between antiplatelet therapy (APT) at the time of coronary artery bypass grafting (CABG) and postoperative bleeding complications, transfusion requirements and adverse cardiovascular events. METHODS: A matched...... Denmark Heart Registry. RESULTS: Of the 6350 patients enrolled, 1846 (29%) had been exposed to aspirin or clopidogrel within 5 days prior to CABG (the APT group). Matching with the remaining 4504 (71%) patients of the control group resulted in 1132 pairs of patients. Patients in the APT group had greater...... postoperative bleeding (OR: 2.08, 95% CI: 1.55-2.80). Overall, preoperative APT had no significant effect on postoperative 30-day mortality, incidence of myocardial infarction, stroke or need for dialysis. CONCLUSIONS: Preoperative APT is associated with increased bleeding and greater transfusion requirements...

Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry

NARCIS (Netherlands)

Verheugt, F.W.A.; Gao, H.; Mahmeed, W. Al; Ambrosio, G.; Angchaisuksiri, P.; Atar, D.; Bassand, J.P.; Camm, A.J.; Cools, F.; Eikelboom, J.; Kayani, G.; Lim, T.W.; Misselwitz, F.; Pieper, K.S.; Eickels, M. van; Kakkar, A.K.

2018-01-01

Aims: Current atrial fibrillation (AF) guidelines discourage antiplatelet (AP) monotherapy as alternative to anticoagulants (ACs). Why AP only is still used is largely unknown. Methods and results: Factors associated with AP monotherapy prescription were analysed in GARFIELD-AF, a registry of

Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

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Kaludov Nikola

2011-09-01

Full Text Available Abstract Background Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds. Methods A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design. Results Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM, with six being very effective (IC50 ≤ 1 μM, and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a

Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas.

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Ekoue-Kovi, Kekeli; Yearick, Kimberly; Iwaniuk, Daniel P; Natarajan, Jayakumar K; Alumasa, John; de Dios, Angel C; Roepe, Paul D; Wolf, Christian

2009-01-01

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3-8 and 11-26, ureas 19-22, thioureas 23-26, and amides 27-54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC(50)s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

Synthesis and antimalarial activity evaluation of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one derivatives

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Mukesh Kumar Kumawat

2016-09-01

Full Text Available Some novel derivatives of 3-(3-(7-chloroquinolin-4-ylaminopropyl-1,3-thiazinan-4-one were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro antimalarial activity against chloroquine sensitive strain of Plasmodium falciparum (RKL-2 employing chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities towards the parasite in comparison to the standard. It was found that antimalarial activity of 3-(3-(7-chloroquinolin-4-ylaminopropyl-2-(4-bromophenyl-1,3-thiazinan-4-one was marginally superior than all the compounds evaluated.

Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial

NARCIS (Netherlands)

Kopin, D.; Jones, W.S.; Sherwood, M.W.; Wojdyla, D.M.; Wallentin, L.; Lewis, B.S.; Verheugt, F.W.A.; Vinereanu, D.; Bahit, M.C.; Halvorsen, S.; Huber, K.; Parkhomenko, A.; Granger, C.B.; Lopes, R.D.; Alexander, J.H.

2018-01-01

BACKGROUND: We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. METHODS: Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are

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

Science.gov (United States)

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

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

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Mwafongo Winfred

2010-10-01

Full Text Available Abstract 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

Frequency of "Pocket" Hematoma in Patients Receiving Vitamin K Antagonist and Antiplatelet Therapy at the Time of Pacemaker or Cardioverter Defibrillator Implantation (from the POCKET Study).

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Malagù, Michele; Trevisan, Filippo; Scalone, Antonella; Marcantoni, Lina; Sammarco, Giuseppe; Bertini, Matteo

2017-04-01

In patients undergoing cardiac device implantation, anticoagulant and antiplatelet therapy are associated with an increased risk of pocket hematoma. In case of vitamin K antagonist therapy, a strategy of continued warfarin with no heparin bridge showed a reduction of pocket hematoma. Evidence regarding antiplatelet therapy management is limited. This is a single-center observational study which reflects our systematic approach to the problem. In 2012, we proposed an improved management protocol for anticoagulant and antiplatelet therapy (no-bridge protocol) based on individual thromboembolic risk stratification, noninterruption of oral anticoagulation, no bridge with heparin and elastic adherence compression bandage. The primary end point was the incidence of clinically significant pocket hematoma in the first 30 days after implantation. A total of 1,035 patients were enrolled, of whom 522 received the standard management and 513 the new protocol. The primary end point occurred in 34 patients of the standard management group and 8 patients of the no-bridge protocol group (6.5% vs 1.6%, p hematoma (relative risk [RR] 3.48, 95% confidence interval [CI] 1.55 to 7.83 and RR 2.43, 95% CI 1.25 to 4.76, respectively), whereas the no-bridge protocol was associated with a reduction of pocket hematoma (RR 0.33, 95% CI 0.14 to 0.76). New anticoagulant and antiplatelet therapy management protocol was associated with a reduced incidence of clinically significant pocket hematomas, thromboembolic events, pocket infections, and lead dislodgements. Copyright © 2017 Elsevier Inc. All rights reserved.

Plants of the Annonaceae traditionally used as antimalarials: a review

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Gina Frausin

2014-01-01

Full Text Available Species of the Annonaceae family are used all over the tropics in traditional medicine in tropical regions for the treatment of malaria and other illnesses. Phytochemical studies of this family have revealed chemical components which could offer new alternatives for the treatment and control of malaria. Searches in scientific reference sites (SciFinder Scholar, Scielo, PubMed, ScienceDirect and ISI Web of Science and a bibliographic literature search for species of Annonaceae used traditionally to treat malaria and fever were carried out. This family contains 2,100 species in 123 genera. We encountered 113 articles reporting medicinal use of one or more species of this family including 63 species in 27 genera with uses as antimalarials and febrifuges. Even though the same species of Annonaceae are used by diverse ethnic groups, different plant parts are often chosen for applications, and diverse methods of preparation and treatment are used. The ethanol extracts of Polyalthia debilis and Xylopia aromatica proved to be quite active against Plasmodium falciparum in vitro (median inhibition concentration, IC50 < 1.5 µg/mL. Intraperitoneal injection of Annickia chlorantha aqueous extracts (cited as Enantia chlorantha cleared chloroquine-resistant Plasmodium yoelii nigeriensis from the blood of mice in a dose-dependant manner. More phytochemical profiles of Annonaceous species are required; especially information on the more commonly distributed antimalarial compounds in this family.

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS)

DEFF Research Database (Denmark)

Bath, Philip M; Woodhouse, Lisa J; Appleton, Jason P

2018-01-01

, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using...... was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using...... therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did...

Evolutionary ARMS Race: Antimalarial Resistance Molecular Surveillance.

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Prosser, Christiane; Meyer, Wieland; Ellis, John; Lee, Rogan

2018-04-01

Molecular surveillance of antimalarial drug resistance markers has become an important part of resistance detection and containment. In the current climate of multidrug resistance, including resistance to the global front-line drug artemisinin, there is a consensus to upscale molecular surveillance. The most salient limitation to current surveillance efforts is that skill and infrastructure requirements preclude many regions. This includes sub-Saharan Africa, where Plasmodium falciparum is responsible for most of the global malaria disease burden. New molecular and data technologies have emerged with an emphasis on accessibility. These may allow surveillance to be conducted in broad settings where it is most needed, including at the primary healthcare level in endemic countries, and extending to the village health worker. Copyright © 2018 Elsevier Ltd. All rights reserved.

Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study.

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Rowcliffe, M; Nezami, B; Westphal, E S; Rainka, M; Janda, M; Bates, V; Gengo, F

2016-04-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) adversely interact with aspirin, diminishing its antiplatelet effect and potentially placing patients at an increased risk for recurrent thrombotic events. This crossover study aimed to determine whether the topical NSAID diclofenac epolamine 1.3% patch or oral diclofenac 50 mg interfered with the antiplatelet effects of aspirin 325 mg. Twelve healthy men and women aged 18-50 were included. Participants were randomized into 5 treatment arms: aspirin, diclofenac potassium 50 mg, diclofenac patch, diclofenac potassium plus ASA 325 mg, and diclofenac patch plus aspirin. Platelet responsiveness was determined using whole-blood impedance aggregation (WBA) to collagen 1 μg/mL and arachidonic acid (AA) 0.5 mM and was sampled every 2 hours. No significant difference in platelet function was observed following the diclofenac patch and aspirin vs aspirin alone. Oral diclofenac produced a mixed effect with significant reduction in platelet inhibition at hour 2 and hour 8 following aspirin administration. Topical diclofenac does not significantly interfere with the antiplatelet effects of aspirin and may be a safer alternative to the oral formulation. © 2015, The American College of Clinical Pharmacology.

Novel direct factor Xa inhibitory compounds from Tenebrio molitor with anti-platelet aggregation activity.

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Lee, Wonhwa; Kim, Mi-Ae; Park, InWha; Hwang, Jae Sam; Na, MinKyun; Bae, Jong-Sup

2017-11-01

Tenebrio molitor is an edible insect that has antimicrobial, anticancer, and antihypertensive effects. The aim of this study was to identify the unreported bioactive compounds from T. molitor larvae with inhibitory activities against factor Xa (FXa) and platelet aggregation. Isolated compounds were evaluated for their anti-FXa and anti-platelet aggregation properties by monitoring clotting time, platelet aggregation, FXa activity, and thrombus formation. A diketopiperazine (1, cyclo( L -Pro- L -Tyr)) and a phenylethanoid (2, N-acetyltyramine) were isolated and inhibited the catalytic activity of FXa in a mixed inhibition model and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and U46619. They inhibited ADP- and U46619-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) and the expression of P-selectin and PAC-1 in platelets. They also improved the production of nitric oxide and inhibited the oversecretion of endothelin-1 compared to that of the ADP- or U46619-treated group. In an animal model of arterial and pulmonary thrombosis, the isolated compounds showed enhanced antithrombotic effects. They also elicited anticoagulant effects in mice. Compounds 1-2 inhibited ADP-, collagen-, or U46619-induced platelet aggregation and showed similar anti-thrombotic efficacy to rivaroxaban, a positive control. Therefore, 1-2 could serve as candidates and provide scaffolds for the development of new anti-FXa and anti-platelet drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

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Egan, J.A.Judith A.; Laseter, Anne G; Filer, C.N.Crist N. E-mail: crist.filer@perkinelmer.com

2002-09-01

To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3-{sup 3}H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl-{sup 3}H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [{sup 3}H] ethyl iodide.

Tritium labelling and characterization of the antimalarial drug (+/-)-chloroquine by several methods

International Nuclear Information System (INIS)

Egan, J.A.Judith A.; Laseter, Anne G.; Filer, C.N.Crist N.

2002-01-01

To study its mechanism of antimalarial action, a tritium labelled analogue of (+/-)-chloroquine was required at high specific activity. Two synthetic methods were successfully employed. [3- 3 H] (+/-)-Chloroquine 2 was prepared by the catalytic tritium dehalogenation of an iodo precursor and [N-ethyl- 3 H] (+/-)-chloroquine 4 was synthesized by the alkylation of (+/-)-desethylchloroquine with [ 3 H] ethyl iodide

High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery

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Cervantes Serena

2009-06-01

Full Text Available Abstract Background Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. Results After screening a library of newly synthesized stryrl dyes, we discovered three RNA binding dyes that provide morphological details of live parasites. Utilizing an inverted confocal imaging platform, live cell imaging of parasites increases parasite detection, improves the spatial and temporal resolution of the parasite under drug treatments, and can resolve morphological changes in individual cells. Conclusion This simple one-step technique is suitable for automation in a microplate format for novel antimalarial compound HTS. We have developed a new P. falciparum RNA high-content imaging growth inhibition assay that is robust with time and energy efficiency.

4-Nitro styrylquinoline is an antimalarial inhibiting multiple stages of Plasmodium falciparum asexual life cycle.

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Roberts, Bracken F; Zheng, Yongsheng; Cleaveleand, Jacob; Lee, Sukjun; Lee, Eunyoung; Ayong, Lawrence; Yuan, Yu; Chakrabarti, Debopam

2017-04-01

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Management of antiplatelet therapy in patients undergoing elective invasive procedures. Proposals from the French Working Group on perioperative haemostasis (GIHP) and the French Study Group on thrombosis and haemostasis (GFHT). In collaboration with the French Society for Anaesthesia and Intensive Care Medicine (SFAR).

Science.gov (United States)

Godier, Anne; Fontana, Pierre; Motte, Serge; Steib, Annick; Bonhomme, Fanny; Schlumberger, Sylvie; Lecompte, Thomas; Rosencher, Nadia; Susen, Sophie; Vincentelli, André; Gruel, Yves; Albaladejo, Pierre; Collet, Jean-Philippe

2018-01-05

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT) in collaboration with the French Society for Anaesthesia and Intensive Care Medicine (SFAR) drafted up-to-date proposals for the management of antiplatelet therapy in patients undergoing elective invasive procedures. The proposals were discussed and validated by a vote; all proposals but one could be assigned with a high strength. The management of antiplatelet therapy is based on their indication and the procedure. The risk of bleeding related to the procedure can be divided into high, moderate and low categories depending on the possibility of performing the procedure in patients receiving antiplatelet agents (none, monotherapy and dual antiplatelet therapy respectively). If discontinuation of antiplatelet therapy is indicated before the procedure, a last intake of aspirin, clopidogrel, ticagrelor and prasugrel 3, 5, 5 and 7 days before surgery respectively is proposed. The thrombotic risk associated with discontinuation should be assessed according to each specific indication of antiplatelet therapy and is higher for patients receiving dual therapy for coronary artery disease (with further refinements based on a few well-accepted items) than for those receiving monotherapy for cardiovascular prevention, for secondary stroke prevention or for lower extremity arterial disease. These proposals also address the issue of the potential role of platelet functional tests and consider management of antiplatelet therapy for regional anaesthesia, including central neuraxial anaesthesia and peripheral nerve blocks, and for coronary artery surgery. Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Saleability of anti-malarials in private drug shops in Muheza, Tanzania: a baseline study in an era of assumed artemisinin combination therapy (ACT

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Ringsted Frank M

2011-08-01

Full Text Available Abstract Background Artemether-lumefantrine (ALu replaced sulphadoxine-pymimethamine (SP as the official first-line anti-malarial in Tanzania in November 2006. So far, artemisinin combination therapy (ACT is contra-indicated during pregnancy by the national malaria treatment guidelines, and pregnant women depend on SP for Intermittent Preventive Treatment (IPTp during pregnancy. SP is still being dispensed by private drug stores, but it is unknown to which extent. If significant, it may undermine its official use for IPTp through induction of resistance. The main study objective was to perform a baseline study of the private market for anti-malarials in Muheza town, an area with widespread anti-malarial drug resistance, prior to the implementation of a provider training and accreditation programme that will allow accredited drug shops to sell subsidized ALu. Methods All drug shops selling prescription-only anti-malarials, in Muheza town, Tanga Region voluntarily participated from July to December 2009. Qualitative in-depth interviews were conducted with owners or shopkeepers on saleability of anti-malarials, and structured questionnaires provided quantitative data on drugs sales volume. Results All surveyed drug shops illicitly sold SP and quinine (QN, and legally amodiaquine (AQ. Calculated monthly sale was 4,041 doses, in a town with a population of 15,000 people. Local brands of SP accounted for 74% of sales volume, compared to AQ (13%, QN (11% and ACT (2%. Conclusions In community practice, the saleability of ACT was negligible. SP was best-selling, and use was not reserved for IPTp, as stipulated in the national anti-malarial policy. It is a major reason for concern that such drug-pressure in the community equals de facto intermittent presumptive treatment. In an area where SP drug resistance remains high, unregulated SP dispensing to people other than pregnant women runs the risk of eventually jeopardizing the effectiveness of the IPTp

QSAR studies of some side chain modified 7-chloro-4-aminoquinolines as antimalarial agents

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Nitendra K. Sahu

2014-11-01

Full Text Available The quantitative structure–activity relationship (QSAR analyses were carried out for a series of new side chain modified 4-amino-7-chloroquinolines to find out the structural requirements of their antimalarial activities against both chloroquine sensitive (HB3 and resistant (Dd2 Plasmodium falciparum strain. The statistically significant best 2D QSAR models for Dd2, having correlation coefficient (r2 = 0.9188 and cross validated squared correlation coefficient (q2 = 0.8349 with external predictive ability (pred_r2 = 0.7258 and for HB3, having r2 = 0.9024, q2 = 0.8089 and pred_r2 = 0.7463 were developed by multiple linear regression coupled with genetic algorithm (GA–MLR and stepwise (SW–MLR forward algorithm, respectively. The results of the present study may be useful on the designing of more potent analogues as antimalarial agents.

A characterization of the antimalarial activity of the bark of Cylicodiscus gabunensis Harms.

Science.gov (United States)

Aldulaimi, Omar; Uche, Fidelia I; Hameed, Hamza; Mbye, Haddijatou; Ullah, Imran; Drijfhout, Falko; Claridge, Timothy D W; Horrocks, Paul; Li, Wen-Wu

2017-02-23

A decoction of the bark of Cylicodiscus gabunensis Harms is used as a traditional medicine in the treatment of malaria in Nigeria. This study aims to validate the antimalarial potency of this decoction in vitro against Plasmodium falciparum and define potential bioactive constituents within the C. gabunensis bark. A bioassay-guided separation and fractionation protocol was applied to C. gabunensis extracts, exploiting the use of a Malaria Sybr Green I Fluorescence assay method to monitor antiproliferative effects on parasites as well as define 50% inhibition concentrations. Spectroscopic techniques, including GC-MS, TOF LC-MS and 1 H NMR were used to identify phytochemicals present in bioactive fractions. Analogues of gallic acid were synthesized de novo to support the demonstration of the antimalarial action of phenolic acids identified in C. gabunensis bark. In vitro cytotoxicity of plant extracts, fractions and gallate analogues was evaluated against the HepG2 cell line. The antimalarial activity of ethanolic extracts of C. gabunensis bark was confirmed in vitro, with evidence for phenolic acids, primarily gallic acid and close analogues such as ethyl gallate, likely providing this effect. Further fractionation produced the most potent fraction with a 50% inhibitory concentration of 4.7µg/ml. Spectroscopic analysis, including 1 H NMR, LC-MS and GC-MS analysis of this fraction and its acid hydrolyzed products, indicated the presence of conjugates of gallic acid with oligosaccharides. The extracts/fractions and synthetic alkyl and alkenyl gallates showed moderate selectivity against P. falciparum. These results support the use of the bark of C. gabunensis as a traditional medicine in the treatment of human malaria, with phenolic acid oligosaccharide complexes evident in the most bioactive fractions. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues.

Science.gov (United States)

Bharate, Sandip B; Bhutani, Kamlesh K; Khan, Shabana I; Tekwani, Babu L; Jacob, Melissa R; Khan, Ikhlas A; Singh, Inder Pal

2006-03-15

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.

Antiplatelet Activity of Morus alba Leaves Extract, Mediated via Inhibiting Granule Secretion and Blocking the Phosphorylation of Extracellular-Signal-Regulated Kinase and Akt

Science.gov (United States)

Rhee, Man Hee; Sung, Yoon-Young; Yang, Won-Kyung; Kim, Seung Hyung; Kim, Ho-Kyoung

2014-01-01

Ethnopharmacological Relevance. Morus alba L. leaves (MAE) have been used in fork medicine for the treatment of beriberi, edema, diabetes, hypertension, and atherosclerosis. However, underlying mechanism of MAE on cardiovascular protection remains to be elucidated. Therefore, we investigated whether MAE affect platelet aggregation and thrombosis. Materials and Methods. The anti-platelet activity of MAE was studied using rat platelets. The extent of anti-platelet activity of MAE was assayed in collagen-induced platelet aggregation. ATP and serotonin release was carried out. The activation of integrin α IIb β 3 and phosphorylation of signaling molecules, including MAPK and Akt, were investigated with cytofluorometer and immunoblotting, respectively. The thrombus formation in vivo was also evaluated in arteriovenous shunt model of rats. Results. HPLC chromatographic analysis revealed that MAE contained rutin and isoquercetin. MAE dose-dependently inhibited collagen-induced platelet aggregation. MAE also attenuated serotonin secretion and thromboxane A2 formation. In addition, the extract in vivo activity showed that MAE at 100, 200, and 400 mg/kg significantly and dose-dependently attenuated thrombus formation in rat arterio-venous shunt model by 52.3% (P < 0.001), 28.3% (P < 0.01), and 19.1% (P < 0.05), respectively. Conclusions. MAE inhibit platelet activation, TXB2 formation, serotonin secretion, aggregation, and thrombus formation. The plant extract could be considered as a candidate to anti-platelet and antithrombotic agent. PMID:24701244

Net clinical benefit of combination anticoagulant and antiplatelet therapy versus anticoagulation alone in atrial fibrillation patients: Results from the amadeus trial

NARCIS (Netherlands)

Lane, Deirdre; Kamphuisen, Pieter; Minini, Pascal; De Peuter, Olaf R.; Buller, Harry R.; Lip, Gregory Y. H.

2010-01-01

Background: To compare the effect of combination anticoagulant and antiplatelet (AP) therapy with anticoagulation alone on stroke and bleeding risk in atrial fibrillation (AF) patients and examine predictors of clinically relevant bleeding. Methods: Post-hoc analysis of 4576 AF patients [mean (SD)

Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname

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Evans Lawrence

2012-06-01

Full Text Available Abstract Background Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector and unlicensed facilities (informal sector is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. Methods To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Results Quality issues were observed in 45 of 77 (58% anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30 and 11% (5/47 respectively. A higher proportion of medicines sampled from the private sector 34% (11/32 failed quality control tests versus 16% (7/45 in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86% were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. Conclusions The findings of the studies in both countries point to

Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname.

Science.gov (United States)

Evans, Lawrence; Coignez, Veerle; Barojas, Adrian; Bempong, Daniel; Bradby, Sanford; Dijiba, Yanga; James, Makeida; Bretas, Gustavo; Adhin, Malti; Ceron, Nicolas; Hinds-Semple, Alison; Chibwe, Kennedy; Lukulay, Patrick; Pribluda, Victor

2012-06-15

Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non-recommended treatments and/or poor quality products. To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom®, the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines

High content live cell imaging for the discovery of new antimalarial marine natural products

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Cervantes Serena

2012-01-01

Full Text Available Abstract Background The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. Methods A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Results Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Conclusion Collectively, our results show that high-content live cell-imaging (HCLCI can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.

High content live cell imaging for the discovery of new antimalarial marine natural products.

Science.gov (United States)

Cervantes, Serena; Stout, Paige E; Prudhomme, Jacques; Engel, Sebastian; Bruton, Matthew; Cervantes, Michael; Carter, David; Tae-Chang, Young; Hay, Mark E; Aalbersberg, William; Kubanek, Julia; Le Roch, Karine G

2012-01-03

The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum. A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope. Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts. Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials. © 2011 Cervantes et al; licensee BioMed Central Ltd.

ent-Pimarane and ent-Kaurane Diterpenes from Aldama discolor (Asteraceae and Their Antiprotozoal Activity

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Mauro S. Nogueira

2016-09-01

Full Text Available Aldama discolor (syn.Viguiera discolor is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1, as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2, ent-2S,4S-2-19-epoxy-pimara-8(3,15-diene-7β-ol (3 and ent-7-oxo-pimara-8,15-diene-3β-ol (4, were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line. The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC 50 = 3.5 μ M and L. donovani (IC 50 = 2.5 μ M and ent-pimarane 2 against P. falciparum (IC 50 = 3.8 μ M. Both compounds returned high selectivity indices (SI >10 in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5, which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2 μ g/mL.

ent-Pimarane and ent-Kaurane Diterpenes from Aldama discolor (Asteraceae) and Their Antiprotozoal Activity.

Science.gov (United States)

Nogueira, Mauro S; Da Costa, Fernando B; Brun, Reto; Kaiser, Marcel; Schmidt, Thomas J

2016-09-15

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian "Cerrado", which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2), ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7β-ol (3) and ent-7-oxo-pimara-8,15-diene-3β-ol (4), were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line). The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC 50 = 3.5 μ M) and L. donovani (IC 50 = 2.5 μ M) and ent-pimarane 2 against P. falciparum (IC 50 = 3.8 μ M). Both compounds returned high selectivity indices (SI >10) in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5), which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2 μ g/mL).

2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy.

Science.gov (United States)

Mehta, Shamir R; Bainey, Kevin R; Cantor, Warren J; Lordkipanidzé, Marie; Marquis-Gravel, Guillaume; Robinson, Simon D; Sibbald, Matthew; So, Derek Y; Wong, Graham C; Abunassar, Joseph G; Ackman, Margaret L; Bell, Alan D; Cartier, Raymond; Douketis, James D; Lawler, Patrick R; McMurtry, Michael S; Udell, Jacob A; van Diepen, Sean; Verma, Subodh; Mancini, G B John; Cairns, John A; Tanguay, Jean-François

2018-03-01

Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence. The present update to the 2011 and 2013 Canadian Cardiovascular Society APT guidelines incorporates new evidence on how to optimize APT use, particularly in situations in which few to no data were previously available. The recommendations update focuses on the following primary topics: (1) the duration of dual APT (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome and non-acute coronary syndrome indications; (2) management of DAPT in patients who undergo noncardiac surgery; (3) management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery; (4) when and how to switch between different oral antiplatelet therapies; and (5) management of antiplatelet and anticoagulant therapy in patients who undergo PCI. For PCI patients, we specifically analyze the particular considerations in patients with atrial fibrillation, mechanical or bioprosthetic valves (including transcatheter aortic valve replacement), venous thromboembolic disease, and established left ventricular thrombus or possible left ventricular thrombus with reduced ejection fraction after ST-segment elevation myocardial infarction. In addition to specific recommendations, we provide values and preferences and practical tips to aid the practicing clinician in the day to day use of these important agents. Copyright © 2018. Published by Elsevier Inc.

Comparison of antiplatelet activity of garlic tablets with cardio-protective dose of aspirin in healthy volunteers: a randomized clinical trial

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Mojtaba Shafiekhani

2016-08-01

Full Text Available Objective: Some of the adverse effects of aspirin including peptic ulcers, gastrointestinal bleeding and aspirin resistance compelled researchers to find a suitable alternative with fewer adverse effects. In this clinical trial, we aimed to find the effective antiplatelet dose of garlic. Materials and Methods: This randomized controlled clinical trial (RCT was conducted on 62 healthy volunteers of 20-50 years old. All volunteers used 80 mg aspirin per day for 1 week and at the end of this time, platelet aggregation (PA induced by 4 agonists acting in aggregation pathway including adenosinediphosphate (20 μmol/l, epinephrine (20 μmol/l, collagen(0.19 mg/ ml and arachidonic acid (0.5mg/ ml was measured by Light Transmittance Aggregometry (LTA in all participants. After one month washout period, volunteers were randomized into 3 groups and each received 1, 2 or 3 garlic tablets (1250 mg a day for 1 month. After one month, PA was examined in all groups. Results: The mean ±SD of the age of all volunteers was 28.60 ± 9.00 years. In addition, 52.00 % of our volunteers were male and 48.00% of them were female. Garlic tablet didnot have significant effect on PA at any dose. However, 30% of volunteers in the group that used 3 garlic tablets/day reported adverse effect (i.e. bleeding. No significant association between sex, age and PA was observed. Conclusion:  In this study, we were unable to determine the effective anti-platelet dose of garlic which that could be equal to that of aspirin anti-platelet activity, as assessed LTA method.

Spray-dried Eudragit® L100 microparticles containing ferulic acid: Formulation, in vitro cytoprotection and in vivo anti-platelet effect

International Nuclear Information System (INIS)

Nadal, Jessica Mendes; Gomes, Mona Lisa Simionatto; Borsato, Débora Maria; Almeida, Martinha Antunes; Barboza, Fernanda Malaquias; Zawadzki, Sônia Faria; Kanunfre, Carla Cristine; Farago, Paulo Vitor; Zanin, Sandra Maria Warumby

2016-01-01

This paper aimed to obtain new spray-dried microparticles containing ferulic acid (FA) prepared by using a methacrylic polymer (Eudragit® L100). Microparticles were intended for oral use in order to provide a controlled release, and improved in vitro and in vivo biological effects. FA-loaded Eudragit® L100 microparticles were obtained by spray-drying. Physicochemical properties, in vitro cell-based effects, and in vivo platelet aggregation were investigated. FA-loaded Eudragit® L100 microparticles were successfully prepared by spray-drying. Formulations showed suitable encapsulation efficiency, i.e. close to 100%. Microparticles were of spherical and almost-spherical shape with a smooth surface and a mean diameter between 2 and 3 μm. Fourier-transformed infrared spectra demonstrated no chemical bond between FA and polymer. X-ray diffraction and differential scanning calorimetry analyses indicated that microencapsulation led to drug amorphization. FA-loaded microparticles showed a slower dissolution rate than pure drug. The chosen formulation demonstrated higher in vitro cytoprotection, anti-inflammatory and immunomodulatory potential and also improved in vivo anti-platelet effect. These results support an experimental basis for the use of FA spray-dried microparticles as a feasible oral drug delivery carrier for the controlled release of FA and improved cytoprotective and anti-platelet effects. - Highlights: • Ferulic acid-loaded Eudragit® L100 microparticles with high drug-loading were obtained. • Spray-dried Eudragit® L100 microparticles containing ferulic acid showed improved in vitro cytoprotective effect. • Ferulic acid spray-dried microparticles had potential as in vitro anti-inflammatory and immunomodulatory. • In vivo studies demonstrated an enhanced antiplatelet effect for ferulic acid-loaded Eudragit® L100 microparticles.

Spray-dried Eudragit® L100 microparticles containing ferulic acid: Formulation, in vitro cytoprotection and in vivo anti-platelet effect

Energy Technology Data Exchange (ETDEWEB)

Nadal, Jessica Mendes; Gomes, Mona Lisa Simionatto [Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacy, Federal University of Paraná (Brazil); Borsato, Débora Maria [Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, State University of Ponta Grossa (Brazil); Almeida, Martinha Antunes [Postgraduate Program in Chemistry, Department of Chemistry, Federal University of Paraná (Brazil); Barboza, Fernanda Malaquias [Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, State University of Ponta Grossa (Brazil); Zawadzki, Sônia Faria [Postgraduate Program in Chemistry, Department of Chemistry, Federal University of Paraná (Brazil); Kanunfre, Carla Cristine [Postgraduate Program in Biomedical Science, Department of General Biology, State University of Ponta Grossa (Brazil); Farago, Paulo Vitor, E-mail: pvfarago@gmail.com [Postgraduate Program in Pharmaceutical Sciences, Department of Pharmaceutical Sciences, State University of Ponta Grossa (Brazil); Zanin, Sandra Maria Warumby [Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacy, Federal University of Paraná (Brazil)

2016-07-01

This paper aimed to obtain new spray-dried microparticles containing ferulic acid (FA) prepared by using a methacrylic polymer (Eudragit® L100). Microparticles were intended for oral use in order to provide a controlled release, and improved in vitro and in vivo biological effects. FA-loaded Eudragit® L100 microparticles were obtained by spray-drying. Physicochemical properties, in vitro cell-based effects, and in vivo platelet aggregation were investigated. FA-loaded Eudragit® L100 microparticles were successfully prepared by spray-drying. Formulations showed suitable encapsulation efficiency, i.e. close to 100%. Microparticles were of spherical and almost-spherical shape with a smooth surface and a mean diameter between 2 and 3 μm. Fourier-transformed infrared spectra demonstrated no chemical bond between FA and polymer. X-ray diffraction and differential scanning calorimetry analyses indicated that microencapsulation led to drug amorphization. FA-loaded microparticles showed a slower dissolution rate than pure drug. The chosen formulation demonstrated higher in vitro cytoprotection, anti-inflammatory and immunomodulatory potential and also improved in vivo anti-platelet effect. These results support an experimental basis for the use of FA spray-dried microparticles as a feasible oral drug delivery carrier for the controlled release of FA and improved cytoprotective and anti-platelet effects. - Highlights: • Ferulic acid-loaded Eudragit® L100 microparticles with high drug-loading were obtained. • Spray-dried Eudragit® L100 microparticles containing ferulic acid showed improved in vitro cytoprotective effect. • Ferulic acid spray-dried microparticles had potential as in vitro anti-inflammatory and immunomodulatory. • In vivo studies demonstrated an enhanced antiplatelet effect for ferulic acid-loaded Eudragit® L100 microparticles.

Significant Risk Factors for Postoperative Enlargement of Basal Ganglia Hematoma after Frameless Stereotactic Aspiration: Antiplatelet Medication and Concomitant IVH.

Science.gov (United States)

Son, Wonsoo; Park, Jaechan

2017-09-01

Frameless stereotactic aspiration of a hematoma can be the one of the treatment options for spontaneous intracerebral hemorrhage in the basal ganglia. Postoperative hematoma enlargement, however, can be a serious complication of intracranial surgery that frequently results in severe neurological deficit and even death. Therefore, it is important to identify the risk factors of postoperative hematoma growth. During a 13-year period, 101 patients underwent minimally invasive frameless stereotactic aspiration for basal ganglia hematoma. Patients were classified into two groups according to whether or not they had postoperative hematoma enlargement in a computed tomography scan. Baseline demographic data and several risk factors, such as hypertension, preoperative hematoma growth, antiplatelet medication, presence of concomitant intraventricular hemorrhage (IVH), were analysed via a univariate statistical study. Nine of 101 patients (8.9%) showed hematoma enlargement after frameless stereotactic aspiration. Among the various risk factors, concomitant IVH and antiplatelet medication were found to be significantly associated with postoperative enlargement of hematomas. In conclusion, our study revealed that aspirin use and concomitant IVH are factors associated with hematoma enlargement subsequent to frameless stereotactic aspiration for basal ganglia hematoma.

New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

Science.gov (United States)

Soares, Roberta Reis; da Silva, José Marcio Fernandes; Carlos, Bianca Cecheto; da Fonseca, Camila Campos; de Souza, Laila Salomé Araújo; Lopes, Fernanda Valério; de Paula Dias, Rafael Mafra; Moreira, Paulo Otávio Lourenço; Abramo, Clarice; Viana, Gustavo Henrique Ribeiro; de Pila Varotti, Fernando; da Silva, Adilson David; Scopel, Kézia Katiani Gorza

2015-06-01

Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries

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O'Connell Kathryn A

2011-10-01

Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC, Madagascar, Nigeria, Uganda and Zambia. Methods Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. Results 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets as compared to first-line quality-assured ACT ( Conclusions These standardized, nationally representative results demonstrate the typically low availability, low market share and high prices of ACT, in the private sector where most anti-malarials are accessed, with some exceptions. The results confirm that there is substantial room to improve availability and affordability of ACT treatment in the surveyed countries. The data will also be useful for monitoring the impact of interventions such as the Affordable Medicines Facility for malaria.

The Intracranial-B2LEED3S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment

NARCIS (Netherlands)

Amarenco, Pierre; Sissani, Leila; Labreuche, Julien; Vicaut, Eric; Bousser, Marie Germaine; Chamorro, Angel; Fisher, Marc; Ford, Ian; Fox, Kim M; Hennerici, Michael G; Mattle, Heinrich; Rothwell, Peter M; Steg, Philippe Gabriel; Diener, Hans-Christoph; Sacco, Ralph L; Greving, Jacoba P; Algra, Ale

2017-01-01

BACKGROUND: Chronic antiplatelet therapy in the post-acute phase of non-cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications. METHODS: We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a

Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

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Mullié Catherine

2012-03-01

Full Text Available Abstract Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ (+- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R -enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S and (R-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

OpenAIRE

Arezoo Rafiee Parhizgar; Azar Tahghighi

2017-01-01

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the othe...

Assessment of anti-protozoal activity of plants traditionally used in Ecuador in the treatment of leishmaniasis.

Science.gov (United States)

Gachet, María Salomé; Lecaro, Javier Salazar; Kaiser, Marcel; Brun, Reto; Navarrete, Hugo; Muñoz, Ricardo A; Bauer, Rudolf; Schühly, Wolfgang

2010-03-02

For the assessment of the in vitro anti-protozoal potential of plants traditionally used in Ecuador in the treatment of leishmaniasis, a combined approach based on interviews with healers as well as a literature search was carried out. From three regions of Ecuador, 256 local healers called "Agents of Traditional Medicine" (ATMs) were interviewed about their knowledge of the use of plants to treat and heal the illness recognized by the ATMs as leishmaniasis. From literature sources, 14 plants were identified as being used in the treatment of leishmaniasis. Subsequently, plant material was collected from a representative selection of 39 species. A total of 140 extracts were screened in vitro against Leishmania donovani, Plasmodium falciparum, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. Additionally, these extracts were evaluated for their anti-microbial activities using five gram-positive and -negative bacteria as well as Candida albicans. The survey resulted in 431 use-records for 145 plant-taxa used for the treatment of leishmaniasis. The 10 most frequently reported taxa accounted for 37.7% of all records. In the case of leishmaniasis, activity was observed for Elephantopus mollis, Minquartia guianensis, Bocconia integrifolia, Gouania lupuloides, Scoparia dulcis, an as-yet-unidentified species of Piper and Brugmansia. For the leaves of M. guianensis and the twigs and bark of G. lupuloides a good selectivity index (SI) was found. IC(50) values and the SI of active plant extracts are presented. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

International Nuclear Information System (INIS)

Ofulla, A.V.O.

1995-01-01

The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro 3 H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC 50 s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC 50 of 5.98 ± 2.9 SD, n=6), followed by A. mossambicensis (mean IC 50 73.36 ± 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 (± 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs

High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death.

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Wein, Sharon; Taudon, Nicolas; Maynadier, Marjorie; Tran Van Ba, Christophe; Margout, Delphine; Bordat, Yann; Fraisse, Laurent; Wengelnik, Kai; Cerdan, Rachel; Bressolle-Gomeni, Françoise; Vial, Henri J

2017-08-01

Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei -infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei -infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs. Copyright © 2017 American Society for Microbiology.

Effect of Antimalarial Drugs on Plasmodia Cell-Free Protein Synthesis

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Ana Ferreras

2002-04-01

Full Text Available A cell-free system from Plasmodium falciparum able to translate endogenous mRNA was used to determine the effect of artemisinin, chloroquine and primaquine on the protein synthesis mechanism of the parasite. The antimalarial drugs did not inhibit the incorporation of [³H] methionine into parasite proteins even at concentrations higher than the ones found to strongly inhibit the parasite growth. Results clearly indicate that these compounds do not have a direct effect on protein synthesis activity of P. falciparum coded by endogenous mRNA.

Photoreactivity of biologically active compounds. VII. Interaction of antimalarial drugs with melanin in vitro as part of phototoxicity screening.

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Kristensen, S; Orsteen, A L; Sande, S A; Tønnesen, H H

1994-10-01

The drugs commonly used in the treatment of malaria are photochemically unstable. Several of these compounds accumulate in melanin-rich tissues and cause toxic reactions which may be light induced. As part of the screening of the photochemical properties and phototoxic capabilities of antimalarials, the in vitro interaction of eight antimalarials with melanin was studied. The dissociation constant for the drug-melanin complex and the relative number of binding sites on melanin were estimated for six of the drugs using a curve-fitting program. The reaction rate for the formation of the melanin-drug complex was determined, and the complexes were further characterized by zeta potential measurements.

Isolation and Purification of C-phycocyanin from Nostoc muscorum (Cyanophyceae and Cyanobacteria Exhibits Antimalarial Activity In vitro

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Sukla Biswas

2010-10-01

Full Text Available The Phycobilin pigments are intensively fluorescent and water soluble. They are categorized into three types, such as pigments containing high, intermediate and low energies are Phycoerythrins (Phycoerythrocyanins, Phycocyanins and Allophycocyanins, respectively. Besides light harvesting, the Phycobiliproteins have shown industrial and biomedical importance. Among them, C-phycocyanin (C-PC has been considered to be the most preferred one. The present study was undertaken to evaluate the antimalarial activity of C-PC isolated from a Nitrogen-fixing Cyanobacterium and Nostoc muscorum. C- PC was extracted and purified by acetone extraction and ammonium sulfate precipitation and dialysis followed by amicon filtration. It was isolated as a~124 kDa water soluble protein molecule. It showed antimalarial activity in vitro against Chloroquine sensitive and resistant Plasmodium falciparum strains. Inhibitory concentrations at 50%, 90% and 95% were determined as 10.27±2.79, 53.53±6.26 and 73.78±6.92 µg/ml against the Chloroquine-sensitive strains; 10.37±1.43, 56.99±11.07 and 72.79±8.59 µg/ml against Chloroquine resistant of Plasmodium falciparum strains. C-PC was found to have antimalarial activity even at a concentration of 3.0 µg/ml. The possible mechanism might be relied on the destruction of polymerization of Haemozoin by binding of C-PC with Ferriprotoporphyrin-IX at the water surface of the plasma membrane.

7-Chloroquinolinotriazoles: synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies.

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Pereira, Guilherme R; Brandão, Geraldo Célio; Arantes, Lucas M; de Oliveira, Háliton A; de Paula, Renata Cristina; do Nascimento, Maria Fernanda A; dos Santos, Fábio M; da Rocha, Ramon K; Lopes, Júlio César D; de Oliveira, Alaíde Braga

2014-02-12

Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

A Novel Role of Eruca sativa Mill. (Rocket Extract: Antiplatelet (NF-κB Inhibition and Antithrombotic Activities

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Eduardo Fuentes

2014-12-01

Full Text Available Background: Epidemiological studies have shown the prevention of cardiovascular diseases through the regular consumption of vegetables. Eruca sativa Mill., commonly known as rocket, is a leafy vegetable that has anti-inflammatory activity. However, its antiplatelet and antithrombotic activities have not been described. Methods: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL, was evaluated on human platelets: (i P-selectin expression by flow cytometry; (ii platelet aggregation induced by ADP, collagen and arachidonic acid; (iii IL-1β, TGF-β1, CCL5 and thromboxane B2 release; and (iv activation of NF-κB and PKA by western blot. Furthermore, (v antithrombotic activity (200 mg/kg and (vi bleeding time in murine models were evaluated. Results: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL inhibited P-selectin expression and platelet aggregation induced by ADP. The release of platelet inflammatory mediators (IL-1β, TGF-β1, CCL5 and thromboxane B2 induced by ADP was inhibited by Eruca sativa Mill. aqueous extract. Furthermore, Eruca sativa Mill. aqueous extract inhibited NF-κB activation. Finally, in murine models, Eruca sativa Mill. aqueous extract showed significant antithrombotic activity and a slight effect on bleeding time. Conclusion: Eruca sativa Mill. presents antiplatelet and antithrombotic activity.

Phytochemical Analysis and Antimalarial Activity Aqueous Extract of Lecaniodiscus cupanioides Root

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Mikhail Olugbemiro Nafiu

2013-01-01

Full Text Available Root aqueous extract of Lecaniodiscus cupanioides was evaluated for antimalarial activity and analyzed for its phytochemical constituents. Twenty-four (24 albino mice were infected by intraperitoneal injection of standard inoculum of chloroquine sensitive Plasmodium berghei (NK 65. The animals were randomly divided into 6 groups of 3 mice each. Group 1 served as the control while groups II–IV were orally administered 50, 150, and 250 mg/kg body weights of extract. Groups 5 and 6 received 1.75 and 5 mg/kg of artesunate and chloroquine, respectively. The results of the phytochemical analysis showed the presence of alkaloids (2.37%, saponin (0.336, tannin (0.012 per cent, phenol (0.008 per cent, and anthraquinone (0.002 per cent. There was 100 per cent parasite inhibition in the chloroquine group and 70 per cent in the 50 mg/kg body weight on day 12, respectively. The mean survival time (MST, for the control group was 14 days, artesunate 16 days, and chloroquine 30 days, while the groups that received 50 and 250 mg/kg body weight recorded similar MST of 17 days and the 150 mg/kg body weight group recorded 19 days. The results obtained indicated that the aqueous extract of Lecaniodiscus cupanioides may provide an alternative antimalarial.

Management of patients taking antiplatelet or anticoagulant medication requiring invasive breast procedures: United Kingdom survey of radiologists' and surgeons' current practice

International Nuclear Information System (INIS)

Pritchard, M.G.; Townend, J.N.; Lester, W.A.; England, D.W.; Kearins, O.; Bradley, S.A.

2008-01-01

Aim: To determine the current practice in the UK National Health Service Breast Screening Programme for invasive diagnostic procedures and surgery in patients taking anticoagulant and antiplatelet medication. Materials and methods: Lead radiologists and surgeons at each breast screening service were surveyed to determine current practice. One hundred and five respondents provided information regarding their services, protocols, and willingness to proceed with combinations of procedures and anti-haemostatic medications. Results: Between units there was wide variation in practice. Within 21 services providing more than one response, 10 (48%) disagreed on whether protocols existed. Decisions to perform biopsies were unrelated to professional group. The taking of a drug history was variable. Surgeons reported more adverse effects than radiologists [21 (48%) versus 12 (26%)], but no difference in self-assessment of knowledge. Conclusion: Both radiologists and surgeons have expressed uncertainty about their understanding of anticoagulant and antiplatelet treatment. This is reflected in a wide range of practice. Guidance regarding the management of these patients is suggested

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.

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Hindley, Stephen; Ward, Stephen A; Storr, Richard C; Searle, Natalie L; Bray, Patrick G; Park, B Kevin; Davies, Jill; O'Neill, Paul M

2002-02-28

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot

Early home treatment of childhood fevers with ineffective antimalarials is deleterious in the outcome of severe malaria

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Olumese Peter E

2008-07-01

Full Text Available Abstract Background Early diagnosis and prompt treatment including appropriate home-based treatment of malaria is a major strategy for malaria control. A major determinant of clinical outcome in case management is compliance and adherence to effective antimalarial regimen. Home-based malaria treatment with inappropriate medicines is ineffective and there is insufficient evidence on how this contributes to the outcome of severe malaria. This study evaluated the effects of pre-hospital antimalarial drugs use on the presentation and outcome of severe malaria in children in Ibadan, Nigeria. Methods Two hundred and sixty-eight children with a median age of 30 months comprising 114 children with cerebral malaria and 154 with severe malarial anaemia (as defined by WHO were prospectively enrolled. Data on socio-demographic data, treatments given at home, clinical course and outcome of admission were collected and analysed. Results A total of 168 children had treatment with an antimalarial treatment at home before presenting at the hospital when there was no improvement. There were no significant differences in the haematocrit levels, parasite counts and nutritional status of the pre-hospital treated and untreated groups. The most commonly used antimalarial medicine was chloroquine. Treatment policy was revised to Artemesinin-based Combination Therapy (ACT in 2005 as a response to unacceptable levels of therapeutic failures with chloroquine, however chloroquine use remains high. The risk of presenting as cerebral malaria was 1.63 times higher with pre-hospital use of chloroquine for treatment of malaria, with a four-fold increase in the risk of mortality. Controlling for other confounding factors including age and clinical severity, pre-hospital treatment with chloroquine was an independent predictor of mortality. Conclusion This study showed that, home treatment with chloroquine significantly impacts on the outcome of severe malaria. This finding

Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.

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Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stephane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie-Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gael; Le Bihan, Amelie; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio

2016-09-20

More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Platelet factor 4 activity against P. falciparum and its translation to nonpeptidic mimics as antimalarials.

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Love, Melissa S; Millholland, Melanie G; Mishra, Satish; Kulkarni, Swapnil; Freeman, Katie B; Pan, Wenxi; Kavash, Robert W; Costanzo, Michael J; Jo, Hyunil; Daly, Thomas M; Williams, Dewight R; Kowalska, M Anna; Bergman, Lawrence W; Poncz, Mortimer; DeGrado, William F; Sinnis, Photini; Scott, Richard W; Greenbaum, Doron C

2012-12-13

Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential. Copyright © 2012 Elsevier Inc. All rights reserved.

Synthesis of gallinamide A analogues as potent falcipain inhibitors and antimalarials.

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Conroy, Trent; Guo, Jin T; Elias, Nabiha; Cergol, Katie M; Gut, Jiri; Legac, Jennifer; Khatoon, Lubna; Liu, Yang; McGowan, Sheena; Rosenthal, Philip J; Hunt, Nicholas H; Payne, Richard J

2014-12-26

Analogues of the natural product gallinamide A were prepared to elucidate novel inhibitors of the falcipain cysteine proteases. Analogues exhibited potent inhibition of falcipain-2 (FP-2) and falcipain-3 (FP-3) and of the development of Plasmodium falciparum in vitro. Several compounds were equipotent to chloroquine as inhibitors of the 3D7 strain of P. falciparum and maintained potent activity against the chloroquine-resistant Dd2 parasite. These compounds serve as promising leads for the development of novel antimalarial agents.

Screening of Kenyan medicinal plants for antimalarial effects on Plasmodium falciparum in vitror. Final report for the period 15 December 1993 - 31 December 1994

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Ofulla, A V.O.

1995-01-01

The antimalarial activities of extracts of Albizia gummifera and Aspilia mossambicensis against culture adapted isolates of Plasmodium falciparum were evaluated using an in citro {sup 3}H-hypoxanthine uptake technique. Chloroquine was used as a standard antimalarial drug for comparison with the plant extracts. The plant extracts showed various levels of activities (expressed as 50% inhibitory concentration (IC{sub 50}s) in ug/ml of test culture) against P. falciparum in vitro, with Al gummifera showing the highest activity (eman IC{sub 50} of 5.98 {+-} 2.9 SD, n=6), followed by A. mossambicensis (mean IC{sub 50} 73.36 {+-} 59.3 SD, n=18). The mean antimalarial activity of chloroquine (in ug/ml) was 0.037 ({+-} 0.04 SD, n=10), far higher than that of the plant extracts. (author). 5 refs, 2 tabs.

Antimalarial and cytotoxic activities of roots and fruits fractions of Astrodaucus persicus extract

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Saied Goodarzi

2017-12-01

Full Text Available Objective(s:Astrodaucus persicus (Apiaceae is one of the two species of this genus which grows in different parts of Iran. Roots of this plant were rich in benzodioxoles and used as food additive or salad in Iran and near countries. The aim of present study was evaluation of antimalarial and cytotoxic effects of different fractions of A. persicus fruits and roots extracts. Materials and Methods: Ripe fruits and roots of A. persicuswere extracted and fractionated by hexane, chloroform, ethyl acetate and methanol, separately. Antimalarial activities of fractions were performed based on Plasmodium berghei suppressive test in mice model and percentage of parasitemia and suppression were determined for each sample. Cytotoxicity of fruits and roots fractions were investigated against human breast adenocarcinoma (MCF-7, colorectal carcinoma (SW480 and normal (L929 cell lines by MTT assay and IC50 of them were measured. Results: Hexane fraction of roots extract (RHE and ethyl acetate fraction of fruits extract (FEA of A. persicus demonstrated highest parasite inhibition (73.3 and 72.3%, respectively at 500 mg/kg/day which were significantly different from negative control group (P

The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

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Marrelli, Mauro Toledo; Brotto, Marco

2016-11-02

Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

Anti-protozoal and anti-bacterial antibiotics that inhibit protein synthesis kill cancer subtypes enriched for stem cell-like properties.

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Cuyàs, Elisabet; Martin-Castillo, Begoña; Corominas-Faja, Bruna; Massaguer, Anna; Bosch-Barrera, Joaquim; Menendez, Javier A

2015-01-01

Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues.

Targetting the hemozoin synthesis pathway for antimalarial drug and detected by TEM (Transmission electron microscope)

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Abbas, Jamilah; Artanti, Nina; Sundowo, Andini; Dewijanti, Indah Dwiatmi; Hanafi, Muhammad; Lisa, Syafrudin, Din

2017-11-01

Malaria is a major public health problem mainly due to the development of resistance by the most lethal causative parasite species, the alarming spread of drug resistance and limited number of effective drug available now. Therefore it is important to discover new antimalarial drug. Malaria is caused by a singlecelled parasite from the genus Plasmodium. Plasmodium falciparum parasite infect red blood cells, ingesting and degradation hemoglobin in the acidic food vacuola trough a sequential metabolic process involving multiple proteases. During these process, hemoglobin is utilized as the predominant source of nutrition. Proteolysis of hemoglobin yields amino acid for protein synthesis as well as toxic heme. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria parasite has evolved a distinct mechanism for detoxification of heme through conversion into insoluble crystalline pigment, known as hemozoin (β hematoin). Hemozoin synthesis is an indispensable process for the parasite and is the target for action of several known antimalarial drug. TEM (Transmission Electron Microscope) technology for hemozoin formation in vitro assay was done in this research. Calophyllum aerophyllum Lauterb as medicinal plants was used as a source of antimalarial drug. Acetone extracts of C. lowii showed growth inhibition against parasite P. falciparum with IC50 = 5.2 µg/mL. Whereas from hexane, acetone and methanol fraction of C. aerophyllum showed growth inhibition with IC50 = 0.054, 0.055 and 0.0054 µg/mL respectively. New drug from Calophyllum might have potential compounds that have unique structures and mechanism of action which required to develop new drug for treatment of sensitive and drug resistant strain of malaria.

Antimalarial efficacy of Albizia lebbeck (Leguminosae) against Plasmodium falciparum in vitro & P. berghei in vivo.

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Kalia, Shagun; Walter, Neha Sylvia; Bagai, Upma

2015-12-01

Albizia lebbeck Benth. (Leguminosae) has long been used in Indian traditional medicine. The current study was designed to test antimalarial activity of ethanolic bark extract of A. lebbeck (EBEAL). EBEAL was prepared by soxhlet extraction and subjected to phytochemical analysis. The extract was evaluated for its in vitro antimalarial activity against Plasmodium falciparum chloroquine (CQ) sensitive (MRC2) and CQ resistant (RKL9) strains. Cytotoxicity (CC 50 ) of extract against HeLa cells was evaluated. Median lethal dose (LD 50 ) was determined to assess safety of EBEAL in BALB/c mice. Schizonticidal (100-1000 mg/kg) and preventive (100-750 mg/kg) activities of EBEAL were evaluated against P. berghei. Curative activity (100-750 mg/kg) of extract was also evaluated. Phytochemical screening revealed presence of alkaloids, flavonoids, phenols, saponins, terpenes and phytosterols. The extract exhibited IC 50 of 8.2 µg/ml (MRC2) and 5.1 µg/ml (RKL9). CC 50 of extract on HeLa cell line was calculated to be >1000 µg/ml. EBEAL showed selectivity indices (SI) of >121.9 and >196.07 against MRC2 and RKL9 strains of P. falciparum, respectively. LD 50 of EBEAL was observed to be >5 g/kg. Dose-dependent chemosuppression was observed with significant ( p50 >100 mg/kg. Significant (P50 mg/kg concentration of extract on D7. The present investigation reports antiplasmodial efficacy of EBEAL in vitro against P. falciparum as evident by high SI values. ED 50 of <100 mg/kg against P. berghei categorizes EBEAL as active antimalarial. Further studies need to be done to exploit its antiplasmodial activity further.

Cysteine-stabilised peptide extract of Morinda lucida (Benth) leaf exhibits antimalarial activity and augments antioxidant defense system in P. berghei-infected mice.

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Adebayo, Joseph O; Adewole, Kayode E; Krettli, Antoniana U

2017-07-31

Cysteine-stabilised peptides (CSP) are majorly explored for their bioactivities with applications in medicine and agriculture. Morinda lucida leaf is used indigenously for the treatment of malaria; it also contains CSP but the role of CSP in the antimalarial activity of the leaf has not been evaluated. This study was therefore performed to evaluate the antimalarial activity of partially purified cysteine-stabilised peptide extract (PPCPE) of Morinda lucida leaf and its possible augmentation of the antioxidant systems of liver and erythrocytes in murine malaria. PPCPE was prepared from Morinda lucida leaf. The activity of PPCPE was evaluated in vitro against Plasmodium falciparum W2 and its cytotoxicity against a BGM kidney cell line. PPCPE was also evaluated for its antimalarial activity and its effects on selected liver and erythrocyte antioxidant parameters in P. berghei NK65-infected mice. PPCPE was not active against P. falciparum W2 (IC 50 : >50µg/ml) neither was it cytotoxic (MLD 50 : >1000µg/ml). However, PPCPE was active against P. berghei NK65 in vivo, causing 51.52% reduction in parasitaemia at 31.25mg/Kg body weight on day 4 post-inoculation. PPCPE significantly reduced (P activities of glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase in a dose-dependent manner, which was significant (P antimalarial effect and that PPCPE may augment the antioxidant defense system to alleviate the reactive oxygen species-mediated complications of malaria. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Evaluation of antimalarial, free-radical-scavenging and insecticidal activities of Artemisia scoparia and A. Spicigera, Asteraceae

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Fariba H. Afshar

2011-12-01

Full Text Available Artemisia species (Asteraceae, widespread throughout the world, are a group of important medicinal plants. The extracts of two medicinal plants of this genus, Artemisia scoparia Waldst. & Kit. and A. spicigera C. Koch, were evaluated for potential antimalarial, free-radical-scavenging and insecticidal properties, using the heme biocrystallisation and inhibition assay, the DPPH assay and the contact toxicity bioassay using the pest Tribolium castaneum, respectively. The methanol extracts of both species showed strong free-radical-scavenging activity and the RC50 values were 0.0317 and 0.0458 mg/mL, respectively, for A. scoparia and A. spicigera. The dichloromethane extracts of both species displayed a moderate level of potential antimalarial activity providing IC50 at 0.778 and 0.999 mg/mL for A. scoparia and A. spicigera, respectively. Both species of Artemisia showed insecticidal properties. However, A. spicigera was more effective than A. scoparia.

Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids.

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Maurya, Shiv Shyam; Khan, Shabana I; Bahuguna, Aparna; Kumar, Deepak; Rawat, Diwan S

2017-03-31

A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Preliminary assessment of medicinal plants used as antimalarials in the southeastern Venezuelan Amazon

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Caraballo Alejandro

2004-01-01

Full Text Available Eighteen species of medicinal plants used in the treatment of malaria in Bolívar State, Venezuela were recorded and they belonged to Compositae, Meliaceae, Anacardiaceae, Bixaceae, Boraginaceae, Caricaceae, Cucurbitaceae, Euphorbiaceae, Leguminosae, Myrtaceae, Phytolaccaceae, Plantaginaceae, Scrophulariaceae, Solanaceae and Verbenaceae families. Antimalarial plant activities have been linked to a range of compounds including anthroquinones, berberine, flavonoids, limonoids, naphthquinones, sesquiterpenes, quassinoids, indol and quinoline alkaloids.

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

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Allman, Erik L.; Painter, Heather J.; Samra, Jasmeet; Carrasquilla, Manuela

2016-01-01

The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field. PMID:27572391

Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

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Zaloumis Sophie

2012-08-01

Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

Got ACTs? Availability, price, market share and provider knowledge of anti-malarial medicines in public and private sector outlets in six malaria-endemic countries.

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O'Connell, Kathryn A; Gatakaa, Hellen; Poyer, Stephen; Njogu, Julius; Evance, Illah; Munroe, Erik; Solomon, Tsione; Goodman, Catherine; Hanson, Kara; Zinsou, Cyprien; Akulayi, Louis; Raharinjatovo, Jacky; Arogundade, Ekundayo; Buyungo, Peter; Mpasela, Felton; Adjibabi, Chérifatou Bello; Agbango, Jean Angbalu; Ramarosandratana, Benjamin Fanomezana; Coker, Babajide; Rubahika, Denis; Hamainza, Busiku; Chapman, Steven; Shewchuk, Tanya; Chavasse, Desmond

2011-10-31

Artemisinin-based combination therapy (ACT) is the first-line malaria treatment throughout most of the malaria-endemic world. Data on ACT availability, price and market share are needed to provide a firm evidence base from which to assess the current situation concerning quality-assured ACT supply. This paper presents supply side data from ACTwatch outlet surveys in Benin, the Democratic Republic of Congo (DRC), Madagascar, Nigeria, Uganda and Zambia. Between March 2009 and June 2010, nationally representative surveys of outlets providing anti-malarials to consumers were conducted. A census of all outlets with the potential to provide anti-malarials was conducted in clusters sampled randomly. 28,263 outlets were censused, 51,158 anti-malarials were audited, and 9,118 providers interviewed. The proportion of public health facilities with at least one first-line quality-assured ACT in stock ranged between 43% and 85%. Among private sector outlets stocking at least one anti-malarial, non-artemisinin therapies, such as chloroquine and sulphadoxine-pyrimethamine, were widely available (> 95% of outlets) as compared to first-line quality-assured ACT (sector, first-line quality-assured ACT was available for free in all countries except Benin and the DRC (US$1.29 [Inter Quartile Range (IQR): $1.29-$1.29] and $0.52[IQR: $0.00-$1.29] per adult equivalent dose respectively). In the private sector, first-line quality-assured ACT was 5-24 times more expensive than non-artemisinin therapies. The exception was Madagascar where, due to national social marketing of subsidized ACT, the price of first-line quality-assured ACT ($0.14 [IQR: $0.10, $0.57]) was significantly lower than the most popular treatment (chloroquine, $0.36 [IQR: $0.36, $0.36]). Quality-assured ACT accounted for less than 25% of total anti-malarial volumes; private-sector quality-assured ACT volumes represented less than 6% of the total market share. Most anti-malarials were distributed through the private sector

In Vivo antiplatelet activity aggregation assay of bromelain fractionate by ethanol from extract pineapple core (Ananas comosus [l.] merr.)

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Musfiroh, F. F.; Setiasih, S.; Handayani, S.; Hudiyono, S.; Ilyas, N. M.

2018-01-01

Processed fruit from pineapple is one of largest commodities tropical fruit production in Indonesia and will bring the waste from the skin and core. This study aims to isolate bromelain from the pineapple core (Ananas comusus) are purified by fractionation using ethanol and continued by activity test as an antiplatelets agent by in vivo method using white mice male ddy type with acetosal as positive control. Fractionation of crude enzyme bromelain with ethanol produces highest specific activity on ethanol 30-60% fraction (fraction 2) 3.107 Unit/mg and the protein content 61.25 mg with the degree of purity of 155 times compared to crude enzyme. Antiplatelet aggregation tests from in vivo method shows that faction of bromelain with doses 70 μg/KgBW, 140 μg/KgBW, and 210 μg/KgBW can increase a meaningful bleeding time. The highest percentage of increase shown by the isolate at a dose of 210 μg/KgBW in the amount of 515.10 ± 182.23%, when compared to aspirin (231.20 ± 140.66), the value is relatively higher.

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

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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 (P0.05). 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.

Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.

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Lau, Kui Kai; Lovelock, Caroline E; Li, Linxin; Simoni, Michela; Gutnikov, Sergei; Küker, Wilhelm; Mak, Henry Ka Fung; Rothwell, Peter M

2018-06-01

In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P <0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden ( P trend =0.87), but the 5-year risk of ICH was steeply related ( P trend <0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden ( P trend =0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events ( P trend =0.007), the association with ICH was accounted for ( P trend <0.0001) by disabling/fatal events (≥5 microbleeds