Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

ABSTRACTArtemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, thein vivoantimalarial activities of the lipid emulsions developed were tested inPlasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and thein vivoperformance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation.

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Medicinal Plants Used for Malaria Treatment in Gamba Village, North Region of Cameroon: Ethnopharmacological Survey; In Vivo Antimalarial Activity of Aqueous Extracts of Khaya Senegalensis Bark.

10.21203/rs.3.rs-438203/v1 ◽

2021 ◽

Author(s):

Davy-Hyacinthe Anguechia Gouissi ◽

Roselyne Teponging Nzangue ◽

Josue Haskandi Kalaza ◽

Willy Pabo ◽

Siméon Pierre Fodouop Chegaing

Keyword(s):

Medicinal Plants ◽

Traditional Medicine ◽

Aqueous Extract ◽

Antimalarial Activity ◽

Traditional Healers ◽

Positive Control ◽

Control Group ◽

Aqueous Extracts ◽

Khaya Senegalensis

Abstract Background: In traditional medicine, the floral diversity permits the inhabitants of North Cameroon to use a great number of plants to fight against Malaria. The aim of this study was to identify plants used in traditional medicine to treat malaria, and to verify the scientific basis for the use of one of these plants in the locality of Gamba.Methods: An Ethnopharmacological survey was carried out on 15 traditional healers. We collected data on use of medicinal plants using questionnaires. Then in-vivo antimalarial activity of the decoctioned and macerated aqueous extracts of khaya senegalensis trunk bark was evaluated. The 4-day suppressive peters test was realised on mus musculus swiss albino mice. On day one, mice were infected with 107 plasmodium berghei parasitized red blood cells through intra-peritoneal inoculation. 2 hours after infestation, mice in batches of 6 were treated orally at a dose of 75, 150.300 mg/Kg for macerated aqueous extract and 65, 120.260 mg/Kg for decoctioned extract daily during 3 days at an administration volume of 10 ml/Kg. An extract was considered (% reduction): Highly active (between 100-90 %); moderate (between 90-50 %); weak (between 50-10 %); Inactive (between 0 %). P-values <0.05 were considered statistically significant.Results: A total of 18 plant species belonging to 12 families were identified for the preparation of 12 recipes. The decocted aqueous extract of khaya senegalensis showed moderate anti-plasmodial activity (% reduction = 52.46%) at the highest dose of 260 mg/kg with p<0.001 compared to the positive control group. The aqueous macerate at doses of 150 and 300mg/kg gave respectively a percentage reduction of parasitaemia of 59.42% and 71.80% and also showed moderate anti-plasmodial activity; with p<0.001 between the different extracts and the positive control (99.18%).Conclusion: In conclusion, extracts of khaya senegalensis showed moderate anti-plasmodial activity. It would therefore be necessary to evaluate the anti-malarial activity in-vivo and the toxicity of the aqueous extracts macerated using other solvents and also test the other plants listed.

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In vivo antidiarrheal study of ethanolic extracts of Mikania cordata and Litsea monopetala leaves

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i3.23402 ◽

2015 ◽

Vol 10 (3) ◽

pp. 562 ◽

Cited By ~ 2

Author(s):

Fatema Nasrin ◽

Md. Lukman Hakim

Keyword(s):

Body Weight ◽

Castor Oil ◽

Leaf Extract ◽

Positive Control ◽

Control Group ◽

P Value ◽

Leaf Extracts ◽

Ethanolic Extracts ◽

Antidiarrheal Activity

In this study the antidiarrheal activity of ethanolic extracts of the leaves of Mikania cordata and Litsea monopetala was evaluated. Diarrhea was induced in mice by oral administration of castor oil (0.5 mL) 30 min after the administration of the extracts. During a 4 hour study the number of diarrheal feces and percentage inhibition of the extracts (200 and 400 mg/kg body weight) was determined. Loperamide (3 mg/kg body weight) served as standard and belonged to the positive control group. The extracts exhibited potent antidiarrheal activity as well as achieved statistically significant p value (p<0.01 and p<0.05) compared to control group. Among the extracts the highest percentage inhibition of defecation (60%) was recorded for leaf extract (400 mg/kg body weight) of L. monopetala. So, the study corroborates the significant antidiarrheal activity of M. cordata and L. monopetala leaf extracts and raises the demand of further sophisticated investigation.

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Sequestration of erythrocytes infected with Plasmodium berghei ANKA in BALB/c mice treated with goat bile

Qanun Medika - Medical Journal Faculty of Medicine Muhammadiyah Surabaya ◽

10.30651/jqm.v4i2.3539 ◽

2020 ◽

Vol 4 (2) ◽

pp. 179

Author(s):

Kartika Arum Wardani ◽

Kholida Nur Aini ◽

Heny Arwati ◽

Willy Sandhika

Keyword(s):

Plasmodium Berghei ◽

Antimalarial Activity ◽

Negative Control ◽

Control Group ◽

Dependent Manner ◽

Plasmodium Berghei Anka ◽

Concentration Dependent Manner ◽

Control Group Design ◽

Bile Concentration

Abstract Sequestration of Plasmodium berghei ANKA-infected erythrocytes occurs in BALB/c mice as characteristic of Plasmodium falciparum infection in humans. Animals’ bile has been widely used for centuries in Traditional Chinese Medicine. Goat bile has been used in healing infectious and non-infectious diseases; however, no report on the use of goat bile against malaria infection and sequestration. The purpose of this study was to analyze the correlation between parasitemia and sequestration in the liver of P.berghei ANKA-infected BALB/c mice treated with goat bile. This research was an in vivo experimental study using the post-test control group design. The male BALB/c mice aged ± 6 weeks, body weight 20-25 g were used. The mice were divided into five groups where Group 1-3 were mice treated with goat bile 25%, 50%, and 100%, respectively. Group 4-5 were negative (sterile water) and positive controls (DHP). Parasitemia was observed daily from each mouse and the number of sequestered infected erythrocytes on the endothelium of sinusoids. The data were analyzed using t independent test. Antimalarial activity of goat bile was shown by the lower parasitemia in goat bile-treated mice compared with the negative control. The average number of sequestration was goat bile concentration-dependent manner. The higher the concentration, the lower the number of sequestration. Sequestration was correlated with parasitemia (p=0,0001). Sequestration of P.berghei ANKA-infected erythrocytes correlated with parasitemia, and was goat bile concentration-dependent manner. Keywords: Malaria, parasitemia, sequestration, goat bileCorrespondence: [email protected]

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Study the effect of the mixture alcoholic extract of Peganum harmala seeds and cones of Cupressus sempervirens and their effect on viability of protoscolices of Echinococcus granulosus in vivo

Journal of Biotechnology Research Center ◽

10.24126/jobrc.2011.5.2.162 ◽

2011 ◽

Vol 5 (2) ◽

pp. 44-52

Author(s):

Noor Nihad Baker ◽

Fawzia Ahmed AL-Shanawi

Keyword(s):

Hydatid Cyst ◽

Positive Control ◽

Negative Control ◽

Control Group ◽

Alcoholic Extract ◽

Peganum Harmala ◽

Cupressus Sempervirens ◽

Positive Group ◽

Plant Mixture

this study included the using of the mixture of alcoholic extract Peganum harmala seeds and cones of Cupressus sempervirens at concentrations (1+50) mgml. And then experimentation on the mice injected with protoscolices and its comparison with the mice injected with only protoscolices (as positive control group), and the mice injected with normal saline (as negative control) to investigate the effect of plant mixture in vivo, it appeared of getting the reduction of hydatid cyst with percentage 100% in processed group with the mixture compared with positive group as its absence of the hydatid cyst in processed group. The lowering significantly occurred in the averages of the weights of the liver and spleen and the averages of its distension in processed groups and about of the positive group and which was approach to the negative group. Also study the tissular changes occurred in the liver and spleen, in the liver it occurred of changes in the liver cell and increase in the number of the kupffer cell as a defensive in the processed group were less than what it appeared in the positive control, but the spleen, it appeared the dilation of the whit pulp and the appearance of the cell composing of the hemic platelets (megakaryocyte cells) in the mice processed in comparison with negative control. These changes were of less acuity in the group processed. Thus from the results of this study at appeared the possibility of using the mixture in vivo in successful and safe way by it a capability of initiating the immunity system to the inhibition of the protoscolices and prevent the development of the secondary hydatid cyst in vivo without causing the negative side effect.

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In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05039-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 703-707 ◽

Cited By ~ 11

Author(s):

Sergio Wittlin ◽

Eric Ekland ◽

J Carl Craft ◽

Julie Lotharius ◽

Ian Bathurst ◽

...

Keyword(s):

Drug Exposure ◽

Antimalarial Activity ◽

Plasmodium Species ◽

Parasite Clearance ◽

Response To Treatment ◽

Cross Resistance ◽

Asexual Blood Stage ◽

Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

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Comparison of Biocompatibility of Experimental Tricalcium Phosphate Cement versus Biodentin and Mineral Trioxide Aggregate used for Furcation Perforation Repair (in vivo study)

The Open Dentistry Journal ◽

10.2174/1874210602115010532 ◽

2021 ◽

Vol 15 (1) ◽

pp. 532-538

Author(s):

Mostafa M. El-Bialy ◽

Magdy M. Ali ◽

Engy M. Kataia ◽

Reham S. El Nemr ◽

Reham Hassan

Keyword(s):

Tricalcium Phosphate ◽

Mineral Trioxide Aggregate ◽

Positive Control ◽

Control Group ◽

Tooth Survival ◽

Significant Difference ◽

Operative Evaluation ◽

Root Canal System ◽

Bone Deposition

Background: The interaction between the root canal system and the oral cavity caused by iatrogenic perforations significantly affects the treatment outcome and tooth survival. Objectives: This study was directed to compare the biocompatibility of an experimental tricalcium phosphate cement versus biodentine and mineral Trioxide aggregate used for furcation perforation repair in dogs. Methods: Perforations were done in 60 teeth (premolars and molars) of six adult dogs. Animals were divided randomly into 3 equal groups of 2 animals each according to the post-operative evaluation period of 1 week, 1 month, and 3-months. Each group was further subdivided into 4 subgroups according to either being repaired with the experimental tricalcium phosphate cement (n=6), or Biodentine (n=6), Mineral Trioxide Aggregate (MTA) (n=6), and positive control(n=2). After evaluation periods, tissue blocks were harvested and histologically examined. Results: No statistically significant difference was found regarding bone deposition scores and inflammatory reaction in the three groups after 1 week, 1 month, or 3 months. All three groups showed a statistically significant difference between all three time periods. Regardless of the repair material used, inflammation scores at 1-week showed the highest scores, decreasing over time except for the control group. Conclusion: The experimental material could be considered as a successful treatment option for repairing furcation perforation.

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AMPHOTERICIN B TOPICAL EXTEMPORANEOUS PREPARATIONS FOR THE TREATMENT OF NON-DERMATOPHYTIC ONYCHOMYCOSIS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i12.39645 ◽

2020 ◽

pp. 135-139

Author(s):

KOMESMUNEEBORIRAK PHOJANA ◽

WERAWATGANONE PORNPEN ◽

MUANGSIRI WALAISIRI

Keyword(s):

Amphotericin B ◽

Chemical Stability ◽

High Performance ◽

Sodium Lauryl Sulfate ◽

Physical Stability ◽

Lauryl Sulfate ◽

Physical And Chemical ◽

Injection Product

Objective: At present, the nail preparation to cure onychomycosis, caused by non-dermatophyte molds, is not commercially available in Thailand. The physical and chemical stability of amphotericin B (AmB) extemporaneous preparations in the presence of 30% dimethyl sulfoxide (DMSO) and their in vitro nail permeation was evaluated. Methods: AmB extemporaneous preparations in the presence of 30% DMSO were prepared from a commercial sterile injection product, and cream or hydrophilic ointment. Physical stability was tested at 30°C for 2 months, or using 6 heating-cooling cycles. The chemical stability and in vitro nail permeation of AmB content were analyzed using high-performance liquid chromatography (HPLC). In vitro nail permeation was performed by applying 3.5 mg/mm2 of the tested formulation on nail clippings for 5 consecutive days. Results: The AmB cream and ointment extemporaneous preparations containing 30% DMSO, a permeation enhancer, were homogeneous and pale yellow to yellow cream or ointment. The AmB ointment was stable for up to 60 days. The ointment preparation allows in vitro penetration through nails up to 14.17 μg/cm2. The ointment preparation allows significantly better penetration through than the cream preparation due to the presence of DMSO, sodium lauryl sulfate (SLS), and water in the ointment preparation. Conclusion: The AmB extemporaneous ointment was successfully compounded from a commercial sterile injection product with a beyond-use date of 60 days. The ointment preparation is currently under further investigation for in vivo efficacy.

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Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02041-19 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Letícia Tiburcio Ferreira ◽

Juliana Rodrigues ◽

Gustavo Capatti Cassiano ◽

Tatyana Almeida Tavella ◽

Kaira Cristina Peralis Tomaz ◽

...

Keyword(s):

Plasmodium Falciparum ◽

In Silico ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Dna Gyrase ◽

Plasmodium Yoelii ◽

Computer Assisted ◽

Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

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In vivo antimalarial activity and pharmacokinetics of artelinic acid-choline derivative liposomes in rodents

Parasitology ◽

10.1017/s0031182019001306 ◽

2019 ◽

Vol 147 (1) ◽

pp. 58-64

Author(s):

Shuai Duan ◽

Ruili Wang ◽

Rongrong Wang ◽

Jiaqi Tang ◽

Xiaoyang Xiao ◽

...

Keyword(s):

Drug Resistance ◽

Antimalarial Activity ◽

Positive Control ◽

Plasmodium Yoelii ◽

Esterification Reaction ◽

Therapeutic Effects ◽

Control Groups ◽

Time Curve ◽

Survival Fraction

AbstractIt is urgent to develop new antimalarial drugs with good therapeutic effects to address the emergence of drug resistance. Here, the artelinic acid-choline derivative (AD) was synthesized by dehydration reaction and esterification reaction, aimed to avoid the emergence of drug resistance by synergistic effect of artemisinins and choline derivative, which could compete with choline for rate-limiting enzymes in the phosphatidylcholine (PC) biosynthetic pathway. AD was formulated into liposomes (ADLs) by the thin-film hydration method. Efficacy of ADLs was evaluated by Peters 4-day suppression test. The suppression percentage against Plasmodium yoelii BY265 (PyBY265) in ADLs group was higher than those of positive control groups (dihydroartemisinin liposomes, P < 0.05) and other control groups (P ⩽ 0.05) at the doses of 4.4, 8.8, 17.6 µmol (kg·d)−1, respectively. The negative conversion fraction, recrudescence fraction and survival fraction of ADLs group were superior to other control groups. Pharmacokinetics in rats after intravenous injection suggested that ADLs exhibited higher exposure levels (indexed by area under concentration-time curve) than that of AD solution, artelinic acid liposomes or artelinic acid solution (P < 0.01). Taken together, ADLs exhibited promising antimalarial efficacy and pharmacokinetic characteristics.

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New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01628-19 ◽

2019 ◽

Vol 64 (2) ◽

Cited By ~ 1

Author(s):

Ren-Yi Lu ◽

Ting-Jun-Hong Ni ◽

Jing Wu ◽

Lan Yan ◽

Quan-Zhen Lv ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Pathogenic Fungi ◽

Control Group ◽

Survival Times ◽

Content Type ◽

Fungal Burden ◽

Wide Range

ABSTRACT In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

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