Antimalarial activity of the bisquinoline trans-N1,N2-bis (7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737.

1997 ◽  
Vol 41 (3) ◽  
pp. 677-686 ◽  
Author(s):  
R G Ridley ◽  
H Matile ◽  
C Jaquet ◽  
A Dorn ◽  
W Hofheinz ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Ex Vivo ◽  
The Other ◽  
Parasite Resistance ◽  
Curative Effect ◽  
Specific Process ◽  
Terminal Half Life ◽  
Detailed Evaluation ◽  
Oral Doses

The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine, Ro 47-7737, is significantly more potent against chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are more potent inhibitors of heme polymerization than chloroquine, and their activities are probably mediated by inhibition of this parasite-specific process. The S,S enantiomer, Ro 47-7737, was studied in more detail and proved to be a potent antimalarial in the treatment of P. vivax ex vivo and P. berghei in vivo. Its suppression of P. berghei growth in a mouse model (50% effective dose, 2.3 mg/kg of body weight) was equal to that of chloroquine and mefloquine, and Ro 47-7737 was found to be more potent than these two drugs in the Rane test, in which the curative effect of a single dose is monitored. The dose at which 50% of animals were permanently cured (34 mg/kg) was markedly superior to those of chloroquine (285 mg/kg) and mefloquine (> 250 mg/kg). When administered orally at 50 mg/kg, Ro 47-7737 also showed a faster clearance of parasites than either chloroquine or mefloquine, and unlike the other two compounds, Ro 47-7737 showed no recrudescence. In a study to compare prophylactic efficacies of oral doses of 50 mg/kg, Ro 47-7737 provided protection for 14 days compared to 3 days for mefloquine and 1 day for chloroquine. The good curative and prophylactic properties of the compound can be explained in part by its long terminal half-life. The ability to generate parasite resistance to Ro 47-7737 was also assessed. With a rodent model, resistance could be generated over eight passages. This rate of resistance generation is comparable to that of mefloquine, which has proved to be an effective antimalarial for many years. Toxicity liabilities, however, ruled out this compound as a candidate for drug development.

scholarly journals In VivoAntimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

2015 ◽  
Vol 59 (6) ◽  
pp. 3271-3280 ◽  
Author(s):  
Luiz Francisco Rocha e Silva ◽  
Karla Lagos Nogueira ◽  
Ana Cristina da Silva Pinto ◽  
Alejandro Miguel Katzin ◽  
Rodrigo A. C. Sussmann ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Antimalarial Activity ◽  
Isoprenoid Biosynthesis ◽  
Metabolic Labeling ◽  
Mouse Blood ◽  
Content Type ◽  
Improved Stability ◽  
Oral Doses

ABSTRACT4-Nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated fromPiper peltatumroots.O-Acylation orO-alkylation of compound1provides derivatives exhibiting improved stability and significantin vitroantiplasmodial activity. The aim of this work was to study thein vitroinhibition of hemozoin formation, inhibition of isoprenoid biosynthesis inPlasmodium falciparumcultures, andin vivoantimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-O,O-Diacetyl-4-nerolidylcatechol (2) inhibitedin vitrohemozoin formation by up to 50%. In metabolic labeling studies using [1-(n)-3H]geranylgeranyl pyrophosphate, diester2significantly inhibited the biosynthesis of isoprenoid metabolites ubiquinone8, menaquinone4, and dolichol12in cultures ofP. falciparum3D7. Similarly, 2-O-benzyl-4-nerolidylcatechol (3) significantly inhibited the biosynthesis of dolichol12.P. falciparumin vitroprotein synthesis was not affected by compounds2or3. At oral doses of 50 mg per kg of body weight per day, compound2suppressedPlasmodium bergheiNK65 in infected BALB/c mice by 44%. Thisin vivoresult for derivative2represents marked improvement over that obtained previously for natural product1. Compound2was not detected in mouse blood 1 h after oral ingestion or in mixtures with mouse blood/blood plasmain vitro. However, it was detected afterin vitrocontact with human blood or blood plasma. Derivatives of 4-nerolidylcatechol exhibit parasite-specific modes of action, such as inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation, and they therefore merit further investigation for their antimalarial potential.

scholarly journals Evaluation of in vitro and in vivo Antiplasmodial Activity of the Leaf Latex of Aloe Weloensis (Aloaceae)

2020 ◽  
Author(s):  
Gedefaw Getnet Amare ◽  
Tadesse Awgichew ◽  
Solomon Ahmed ◽  
Zemene Demelash Kifle
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
Antimalarial Activity ◽  
Potential Effect ◽  
Pack Cell Volume ◽  
Curative Effect ◽  
Parasitemia Level ◽  
Dose Dependent

Abstract Background: Nature has gifted a variety of plants having potential effect against plasmodium parasites. The present study was aimed to determine in vitro and in vivo antimalarial activity of the leaf latex of Aloe weloensis.Methods: In vitro antimalarial activity of the leaf latex of A. weloensis was determined against 3D7 strain of P. falciparum. Antimalarial activity of the three doses the latex was evaluated in 4 day-suppressive and curative models against P. berghei infected mice. Antioxidant activity of the leaf latex of A. weloensis was assessed in 2,2- diphenyl 1- picrylhydrazine assay model. Results: Antioxidant activity of the latex was concentration dependent; the strongest inhibition was measured at 400 μg/mL (73.54%). The leaf latex of A. weloensis was demonstrated inhibitory activity against 3D7 malarial strain (IC50 = 9.14 μg/ml). Suppressive and curative effect of the latex was found to be dose dependent. Parasitemia reduction was significant (200 mg/kg, p<0.01, 400 and ,600 mg/kg, p<0.001) in 4-day suppressive test compared to vehicle control. Parasitemia level of the mice treated with 200, 400 and 600 mg/kg doses of the latex significantly (p<0.001) reduced with suppression of 36%, 58% and 64% respectively in curative test. Administration of the leaf latex of A. weloensis significantly (p<0.01) improved mean survival time, pack cell volume, rectal temperature and body weight of P. berghei infected mice. Conclusion: The finding showed that the leaf latex of Aloe weloensis endowed prominent antimalarial and antioxidant activities. The result can serve as a step towards the development of safe and effective herbal therapy against plasmodium parasites.

A Thromboxane Synthetase Inhibitor Which Prolongs Bleeding Time In The Rat At Oral Doses Which Fail To Inhibit Platelet Aggregation In Vivo Or Ex Vivo

1981 ◽  
Author(s):  
K D Butler ◽  
E D Maguire ◽  
A A Turnbull ◽  
R B Wallis ◽  
A M White
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Inhibit Platelet Aggregation ◽  
Thromboxane Synthetase ◽  
Oral Doses ◽  
Rat Tail ◽  
Platelet Thromboxane

The role of thromboxane A2 (TXA2) in haemostasis was investigated with the use of a selective inhibitor of platelet thromboxane synthetase used in conjunction with radioimmunoassay of thromboxane B2 (TXB2). N-Carboxyheptylimidazole is such an inhibitor having no effect on platelet cyclooxygenase. An oral dose of this substance (10 mg/kg) to rats resulted in 85% (P < 0.001) suppression of platelet TXB2 production induced by collagen ex vivo while the ED50 and maximum rate of platelet aggregation were unchanged. It also caused a prolongation of tail bleeding time from 153±13 to 284±22 secs (P < 0.01). The thrombocytopenia resulting from the Arthus reaction in rats was unchanged, and the prothrombin and activated partial thromboplastin coagulation times were not affected by either 10 or 30 mg/kg p.o. It is concluded that the role of TXA2 in prevention of rat tail bleeding is not as an activator of platelet aggregation or blood coagulation. It is more likely that TXA2 prevents bleeding via its potent vaso-constricting properties. In addition the increased bleeding time may be due to change in the equilibrium of other vasoactive prostanoids.

scholarly journals Various Parts of Helianthus annuus Plants as New Sources of Antimalarial Drugs

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Wiwied Ekasari ◽  
Dwi Widya Pratiwi ◽  
Zelmira Amanda ◽  
Suciati ◽  
Aty Widyawaruyanti ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Helianthus Annuus ◽  
Antimalarial Activity ◽  
Ethanol Extract ◽  
The Other ◽  
Antimalarial Agent ◽  
A Value ◽  
Ethanol Extracts

Background. Each part of H. annuus plants is traditionally used as medicinal remedies for several diseases, including malaria. Antimalarial activity of the leaf and the seed has already been observed; however, there is no report about antimalarial activity of the other parts of H. annuus plants. In this study, we assess in vitro and in vivo antimalarial activity of each part of the plants and its mechanism as antimalarial agent against inhibition of heme detoxification. Objective. To investigate the antimalarial activity of various parts of H. annuus. Methods. Various parts of the H. annuus plant were tested for in vitro antimalarial activity against Plasmodium falciparum 3D7 strain (chloroquine-sensitive), in vivo antimalarial activity against P. berghei using Peters’ 4-day suppressive test in BALB/c mice, curative and prophylaxis assay, and inhibition of heme detoxification by evaluating β-hematin level. Results. Ethanol extract of the roots showed the highest antimalarial activity, followed by ethanol extract of leaves, with IC50 values of 2.3 ± 1.4 and 4.3 ± 2.2 μg/mL, respectively and the percentage inhibition of P. berghei of 63.6 ± 8.0 and 59.3 ± 13.2 at a dose of 100 mg/kg, respectively. Ethanol extract of roots produced an ED50 value of 10.6 ± 0.2 mg/kg in the curative test and showed an inhibition of 79.2% at a dose of 400 mg/kg in the prophylactic assay. In inhibition of heme detoxification assay, root and leaf ethanol extracts yielded a lower IC50 value than positive (chloroquine) control with a value of 0.4 ± 0.0 and 0.5 ± 0.0 mg/mL, respectively. Conclusion. There were promising results of the ethanol extracts of root of H. annuus as a new source for the development of a new plant-based antimalarial agent.

INHIBITION OF GUINEA-PIG PLATELET FUNCTION IN VIVO AND EX VIVO USING THE THROMBOXANE A2 ANTAGONISTS, AH23848 AND GR32191

1987 ◽  
Author(s):  
P J McCabe ◽  
L E Stratton ◽  
E J Hornby ◽  
M Foster
Keyword(s):  
Platelet Aggregation ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Ex Vivo ◽  
Thromboxane A2 ◽  
In Vivo Studies ◽  
Maximum Inhibition ◽  
Platelet Deposition ◽  
Oral Doses

The thromboxane A2 antagonist, GR32191 (Lumley et al., this meeting) was tested as an inhibitor of platelet aggregation in the guinea-pig and compared with another Tx-antagonist, AH23848 (Brittain et al, 1985). Guinea-pigs were dosed with AH23848 or GR32191 at 0.01-1.0mg/kg. At intervals, blood was taken and PRP was prepared for ex vivo aggregation studies. Collagen concentrations causing half maximal aggregation (IC50) were calculated for test and vehicle-dosed groups. Inhibition was expressed as a concentration ratio (IC50 test/IC50 vehicle). For in vivo studies, 111In-labelled platelets (12μCi, 200μl) were injected into anaesthetised guinea-pigs and 24 hrs later oral doses of AH23848 or GR32191 (0.01-1.0mg/kg) or indomethacin (5mg/kg) were given. After one hour, blood was taken for platelet and radioactivity counting. The carotid artery was exposed under anaesthesia and a current of 2mA was applied for 60 sec. After 90 min, 1cm of the damaged and contralateral carotid vessels were removed for gamma-counting. Inhibition of accumulation of platelets on the injured artery was measured by comparison with the undamaged contralateral artery. Numbers of platelets deposited were calculated from the radioactivity of each section of artery and the radioactivity and platelet count in the blood. Oral doses of AH23848 or GR32191 inhibited ex vivo platelet aggregation induced by collagen. Maximum inhibition occurred one hour after dosing, and was still present at 6 hours for AH23848 (l.Omg/kg) and GR32191 (0.3mg/kg). GR32191 and AH23848 were active in vivo causing inhibition of platelet deposition at doses of 0.01-lmg/kg. The maximum inhibition of deposition was 58% for AH23848 (0.1mg/kg) and 63% for GR32191 (0.1mg/kg), with 50% inhibition at 0.02mg/kg for both. Indomethacin (5mg/kg p.o.) caused maximum inhibition of 58% at 5mg/kg p.o. suggesting that this represents the total thromboxane involvement in platelet deposition. GR32191 and AH23848 are thromboxane A2 antagonists with antithrombotic activity after oral dosing to guinea-pigs.Brittain R.T. et al Circulation, 72, 1208-1218, 1985.

scholarly journals Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors

2008 ◽  
Vol 52 (10) ◽  
pp. 3467-3477 ◽  
Author(s):  
Geoffrey S. Dow ◽  
Yufeng Chen ◽  
Katherine T. Andrews ◽  
Diana Caridha ◽  
Lucia Gerena ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Half Life ◽  
Histone Deacetylase Inhibitors ◽  
Antimalarial Activity ◽  
Relative Bioavailability ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Oral Doses

ABSTRACT The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of Plasmodium falciparum. The range of 50% inhibitory concentrations (IC50s) was 0.0005 to >1 μM. Five analogs exhibited IC50s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of P. falciparum histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in P. berghei-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in P. falciparum-infected Aotus lemurinus lemurinus monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in P. berghei-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.

scholarly journals Antimalarial Activity of Hydromethanolic Crude Extract and Chloroform Fraction of Brucea antidysenterica Leaves in Plasmodium berghei-Infected Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Tezera Jemere Aragaw ◽  
Kefyalew Ayalew Getahun
Keyword(s):  
Crude Extract ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Negative Control ◽  
Chloroform Fraction ◽  
Curative Effect ◽  
Antimalarial Agents ◽  
Different Doses

Background. Different parts of Brucea antidysenterica are used in traditional and alternative medicine in Ethiopia for the treatment of different health problems including malaria and have good in vitro antimalarial activity. However, no in vivo study was conducted to substantiate the claim. Our study planned to determine the antimalarial effect of B. antidysenterica extract. Methods. Swiss albino mice (6–8 weeks old, 20–28 g) were inoculated with Plasmodium berghei. Different doses of both hydromethanolic extract and chloroform fraction were orally given at 100, 200, and 400 mg/kg/day. Results. The parasitemia suppression percent of hydromethanolic crude extract and chloroform fraction in chemosuppressive tests ranged between 33.48 and 75.93% and 38.32 and 76.64%, respectively. The hydromethanolic crude extract and chloroform fraction exhibited the curative effect of 46.75–70.91% and 50.30–80.06% parasitemia suppression, respectively ( p  < 0.001), compared with negative control. Conclusion. From our study, it is concluded that the hydromethanolic crude extract and chloroform fraction of B. antidysenterica leaves showed promising antiplasmodial effects against Plasmodium berghei. This upholds the folkloric use of B. antidysenterica leaves and the thought of as a possible source to develop new antimalarial agents.

scholarly journals Transmembrane H+ fluxes and the regulation of neural induction in Xenopus laevis

Zygote ◽  
2021 ◽  
pp. 1-12
Author(s):  
Ho Chi Leung ◽  
Catherine Leclerc ◽  
Marc Moreau ◽  
Alan M. Shipley ◽  
Andrew L. Miller ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Ex Vivo ◽  
Neural Induction ◽  
Dorsal Side ◽  
The Other ◽  
Bafilomycin A1 ◽  
Selective Electrode ◽  
Solvent Control ◽  
Dorsal Ectoderm

Summary It has previously been reported that in ex vivo planar explants prepared from Xenopus laevis embryos, the intracellular pH (pHi) increases in cells of the dorsal ectoderm from stage 10.5 to 11.5 (i.e. 11–12.5 hpf). It was proposed that such increases (potentially due to H+ being extruded, sequestered, or buffered in some manner), play a role in regulating neural induction. Here, we used an extracellular ion-selective electrode to non-invasively measure H+ fluxes at eight locations around the equatorial circumference of intact X. laevis embryos between stages 9–12 (˜7–13.25 hpf). We showed that at stages 9–11, there was a small H+ efflux recorded from all the measuring positions. At stage 12 there was a small, but significant, increase in the efflux of H+ from most locations, but the efflux from the dorsal side of the embryo was significantly greater than from the other positions. Embryos were also treated from stages 9–12 with bafilomycin A1, to block the activity of the ATP-driven H+ pump. By stage 22 (24 hpf), these embryos displayed retarded development, arresting before the end of gastrulation and therefore did not display the usual anterior and neural structures, which were observed in the solvent-control embryos. In addition, expression of the early neural gene, Zic3, was absent in treated embryos compared with the solvent controls. Together, our new in vivo data corroborated and extended the earlier explant-derived report describing changes in pHi that were suggested to play a role during neural induction in X. laevis embryos.

The Effect of Dietary Cholesterol on Platelet Survival in the Rabbit – A Study Using 14C-Serotonin and 51Chromium Double-Labelled Platelets

1984 ◽  
Vol 52 (01) ◽  
pp. 085-089 ◽  
Author(s):  
Ian R Wanless
Keyword(s):  
Ex Vivo ◽  
Dietary Cholesterol ◽  
The Other ◽  
Cholesterol Feeding ◽  
Control Groups ◽  
Platelet Survival ◽  
Double Label ◽  
And Control

SummaryHypercholesterolemic men and monkeys have shortened platelet survival but attempts to demonstrate this in rabbits have been unsuccessful. The present study examines platelet survival in cholesterol-fed rabbits. Platelets were double-labelled in vitro with 51Cr and 14C-serotonin or in vivo by intravenous injection of 14C-serotonin.In the double-label experiments 51Cr survival was always shorter than 14C survival but changes in survival of one label were accompanied by similar changes in the other label. Survival was shortened after 4 and 7 weeks of cholesterol feeding. This was demonstrated when the donor platelets were from normal rabbits for both cholesterol and control recipients but no shortening was demonstrated when cholesterol-rich platelets were injected into cholesterol-fed recipients and normal platelets were injected into the control rabbits. When 14C-serotonin was injected intravenously 14C survival was the same as when platelets were labelled ex vivo prior to injection and 14C survival was shortened in rabbits fed cholesterol for 1,2, and 6 weeks.These results indicate that cholesterol-feeding shortens platelet survival. This effect may be masked if the test platelets are not identical in both test and control groups.

scholarly journals Evaluation of the Antimalarial Activity of the Leaf Latex of Aloe weloensis (Aloaceae) against Plasmodium Parasites

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Gedefaw Getnet Amare ◽  
Amsalu Degu ◽  
Peter Njogu ◽  
Zemene Demelash Kifle
Keyword(s):  
Antimalarial Activity ◽  
Folk Medicine ◽  
Negative Control ◽  
Dpph Assay ◽  
Curative Effect ◽  
Traditional Use ◽  
Mean Survival Time ◽  
Parasitemia Level ◽  
Dose Dependent

Background. The lack of available vaccines and the emerging resistance to antimalarial drugs have provided the necessity to find noble antimalarial plant-based medicines. The leaf latex Aloe weloensis has been used in folk medicine against malarial and other human ailments in Ethiopia. Hence, the present study aimed to investigate the antimalarial activity of the leaf latex of A. weloensis against Plasmodium parasites. Materials and Methods. The prophylactic and curative models were employed to determine the in vivo antimalarial activity of the leaf latex A. weloensis against P. berghei infected mice, and the antioxidant activity of the latex was assessed using diphenyl-1-picrylhydrazine (DPPH) assay. Female mice were recruited for toxicity study, and the leaf latex was administered to fasted mice at a dose of 5000 mg/kg. The mice were kept under continuous observation for fourteen days for any signs of overt toxicity. Results. The leaf latex of A. weloensis was safe up to 5000 mg/kg, and the latex endowed free radical inhibition activity (IC50 = 10.25 μg/ml). The latex of A. weloensis leaf demonstrated the inhibitory activity against the 3D7 strain of P. falciparum (IC50 = 9.14 μg/ml). The prophylactic and curative effect of the latex was found to be dose-dependent. The mice’s parasitemia level was significantly ( p < 0.001 ) reduced at all tested doses of the leaf latex compared to negative control in the curative test. Parasitemia reduction was significant (200 mg/kg, p < 0.01 , and 400 and 600 mg/kg, p < 0.001 ) in the prophylactic test compared to the control. In addition, the leaf latex significantly ( p < 0.01 ) improved mean survival time, packed cell volume, rectal temperature, and bodyweight of P. berghei infected mice. Conclusion. The leaf latex of Aloe weloensis was endowed with the antimalarial activity at various doses, corroborating the plant’s claimed traditional use.

Sign in / Sign up

Export Citation Format

Share Document