Artemether-Loaded Zein Nanoparticles: An Innovative Intravenous Dosage Form for the Management of Severe Malaria.

Artemether, an artemisinin derivative, is used in the management of life-threatening severe malaria. This study aimed to develop an intravenous dosage form of artemether using nanotechnology. Artemether-loaded zein nanoparticles were prepared by modified antisolvent precipitation using sodium caseinate as a stabilizer. Subsequently, the physicochemical properties of the nanoparticles were characterized; the in vitro hemolytic property was examined with red blood cells, while the pharmacokinetic profile was evaluated in Sprague-Dawley rats after intravenous administration. The artemether-loaded zein nanoparticles were found to display good encapsulation efficiency, excellent physical stability and offer an in vitro extended-release property. Interestingly, encapsulation of artemether into zein nanoparticles substantially suppressed hemolysis, a common clinical phenomenon occurring after artemisinin-based antimalarial therapy. Upon intravenous administration, artemether-loaded zein nanoparticles extended the mean residence time of artemether by ~80% in comparison to the free artemether formulation (82.9 ± 15.2 versus 45.6 ± 16.4 min, p < 0.01), suggesting that the nanoparticles may prolong the therapeutic duration and reduce the dosing frequency in a clinical setting. In conclusion, intravenous delivery of artemether by artemether-loaded zein nanoparticles appears to be a promising therapeutic option for severe malaria.

Artemether for severe malaria.

BACKGROUND: In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This Cochrane Review evaluates intramuscular artemether compared with both quinine and artesunate. OBJECTIVES: To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in the treatment of severe malaria in adults and children. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, and LILACS, ISI Web of Science, conference proceedings, and reference lists of articles. We also searched the WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 7 September 2018. We checked the reference lists of all studies identified by the search. We examined references listed in review articles and previously compiled bibliographies to look for eligible studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous/intramuscular quinine or artesunate for treating severe malaria. DATA COLLECTION AND ANALYSIS: The primary outcome was all-cause death. Two review authors independently screened each article by title and abstract, and examined potentially relevant studies for inclusion using an eligibility form. Two review authors independently extracted data and assessed risk of bias of included studies. We summarized dichotomous outcomes using risk ratios (RRs) and continuous outcomes using mean differences (MDs), and have presented both measures with 95% confidence intervals (CIs). Where appropriate, we combined data in meta-analyses and used the GRADE approach to summarize the certainty of the evidence. MAIN RESULTS: We included 19 RCTs, enrolling 2874 adults and children with severe malaria, carried out in Africa (12 trials) and in Asia (7 trials).Artemether versus quinineFor children, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.97, 95% CI 0.77 to 1.21; 13 trials, 1659 participants, moderate-certainty evidence). Coma resolution time may be about five hours shorter with artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low-certainty evidence). Artemether may make little difference to neurological sequelae (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low-certainty evidence). Compared to quinine, artemether probably shortens the parasite clearance time by about nine hours (MD -9.03, 95% CI -11.43 to -6.63; seven trials, 420 participants, moderate-certainty evidence), and may shorten the fever clearance time by about three hours (MD -3.73, 95% CI -6.55 to -0.92; eight trials, 457 participants, low-certainty evidence).For adults, treatment with intramuscular artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate-certainty evidence).Artemether versus artesunateArtemether and artesunate have not been directly compared in randomized trials in children.For adults, mortality is probably higher with intramuscular artemether (RR 1.80, 95% CI 1.09 to 2.97; two trials, 494 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS: Artemether appears to be more effective than quinine in children and adults. Artemether compared to artesunate has not been extensively studied, but in adults it appears inferior. These findings are consistent with the WHO recommendations that artesunate is the drug of choice, but artemether is acceptable when artesunate is not available.

Development and in vitro/in vivo evaluation of artemether and lumefantrine co-loaded nanoliposomes for parenteral delivery.

Combination therapy of artemether (ART) and lumefantrine (LUM) is well-established for the treatment of uncomplicated malaria worldwide. Nanoliposomes (NLs) encapsulating both drugs were prepared and freeze-dried. The lyophilized nanoliposomes exhibited high entrapment efficiency of artemether (66.18%), relatively low entrapment efficiency of lumefantrine (53.46%), low average size diameter (125.3 nm) and found to be stable at 4 °C for 60 days without significant change in mean particle diameter and drug entrapment efficiencies. In vitro drug release study has shown initial burst effect and then sustained release pattern over a time period of 30 h. In vivo toxicity study was examined by liver and kidney function test as well as histopathological examination. Nanoliposomes showed lower hemolytic potential (∼10%) compared to all the components when studied individually. There was no significant change (p > 0.05) in biochemical parametes between control and treated group of animals. Pharmacokinetic data of ART + LUM NLs showed higher the area under the plasma concentration-time curve (AUC) values and prolonged residence time of drug in the blood circulation compared with ART + LUM solution. The tissue distribution demonstrated high uptake of ART + LUM-NLs in RES organs particularly in liver and spleen. Biocompatibility was confirmed by hepato- and nephrotoxicity analysis showed no sign of fibrosis, fatty infiltration, centrilobular necrosis and lymphocyte infiltration confirmed the suitability of developed formulation for treatment of malaria.

In vitro assessment of cytotoxic, genotoxic and mutagenic effects of antimalarial drugs artemisinin and artemether in human lymphocytes.

Artemisinin is a substance extracted from the Chinese plant Artemisia annua L. widely used in natural medicine for the treatment of various diseases. Artemether is a substance synthesized from artemisinin, and both drugs are commonly administered in the treatment of malaria. Although considered effective antimalarial drugs, very little is known about the genotoxic, cytotoxic and mutagenic effects of these drugs. Therefore, in the present study, we evaluated the genotoxic, mutagenic and cytotoxic effects of artemisinin (12.5, 25 and 50 µg/mL) and artemether (7.46; 14.92 and 29.84 µg/mL) in cultured human lymphocytes using the comet assay, the micronucleus test and the cytotoxicity assay for detection of necrosis and apoptosis by acridine orange/ethidium bromide staining. Our results showed a significant increase (p < 0.05) in the rate of DNA damage measured by comet assay and in the micronucleus frequency after treatment with both drugs. It was also observed that only artemisinin induced a statistically significant increase (p < 0.05) in the number of lymphocytes with death by necrosis 48 h after treatment. The results demonstrated that these two drugs induce mutagenic, genotoxic and cytotoxic effects in cultured human lymphocytes. Our data indicate the need for caution in the use of such drugs, since genotoxic/mutagenic effects may increase the risk of carcinogenesis.

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice.

Artemether (ATM) cardiotoxicity, its short half-life and low oral bioavailability are the major limiting factors for its use to treat malaria. The purposes of this work were to study free-ATM and ATM-loaded poly-ε-caprolactone nanocapules (ATM-NC) cardiotoxicity and oral efficacy on Plasmodium berghei-infected mice. ATM-NC was obtained by interfacial polymer deposition and ATM was associated with polymeric NC oily core. For cardiotoxicity evaluation, male black C57BL6 uninfected or P. berghei-infected mice received, by oral route twice daily/4 days, vehicle (sorbitol/carboxymethylcellulose), blank-NC, free-ATM or ATM-NC at doses 40, 80 or 120 mg kg-1. Electrocardiogram (ECG) lead II signal was obtained before and after treatment. For ATM efficacy evaluation, female P. berghei-infected mice were treated the same way. ATM-NC improved antimalarial in vivo efficacy and reduced mice mortality. Free-ATM induced significantly QT and QTc intervals prolongation. ATM-NC (120 mg kg-1) given to uninfected mice reduced QT and QTc intervals prolongation 34 and 30%, respectively, compared with free-ATM. ATM-NC given to infected mice also reduced QT and QTc intervals prolongation, 28 and 27%, respectively. For the first time, the study showed a nanocarrier reducing cardiotoxicity of ATM given by oral route and it was more effective against P. berghei than free-ATM as monotherapy.

Market for Artemether-Lumefantrine to treat childhood malaria in a district of southern Mozambique.

Malaria is one of the leading causes of death in sub-Saharan Africa. Artemisinin-based combination therapies are used as first-line treatment drugs, but their market is far from competitive. Market failures include limited availability, low quality, lack of information, and high costs of access. We estimated the theoretical demand for one of the most common artemisinin-based combination therapies, artemether-lumefantrine (AL), and its determinants among caregivers of children with malaria seeking care at public health facilities, thus, entitled to receive drugs for free, in southern Mozambique (year 2012). The predicted theoretical demand was contrasted with international and local private market AL prices. Respondents stated high willingness to pay but lower ability to pay (ATP), which was defined as the theoretical demand. The ATP was on average of 0.94 USD for the treatment of a malaria episode. This implied an average gap of 1.04 USD between average local private prices and theoretical demand. Predicted ATP decreased by 14% for every additional malaria episode that the child had suffered during the malaria season. The market price was unaffordable for a large share of our sample, highlighting an unequal welfare distribution between suppliers and potential consumers, as well as issues of inequity in the private delivery of AL.

Developing Self-Nanoemulsifying Drug Delivery Systems Comprising an Artemether-Lumefantrine Fixed-Dose Combination to Treat Malaria.

BACKGROUND: Despite attempts to control malaria, poor drug bioavailability means malaria still places enormous pressure on health globally. It has been found that the solubility of highly lipophilic compounds can be enhanced through lipid formulations, e.g., self-emulsifying drug delivery systems (SEDDSs). Thus, quality-by-design and characterization were used to justify the development and determine the feasibility of oral oil-in-water SEDDSs comprising a fixed-dose combination (FDC) of artemether-lumefantrine to treat malaria more effectively without the aid of a fatty meal. These formulations were compared to a commercial product containing the same active compounds. METHODS: Excipient compatibility and spontaneous emulsification capacity of different FDC-excipient combinations were identified by employing isothermal microcalorimetry, solubility, and water titration tests. Pseudoternary phase diagrams were constructed, and checkpoint formulations were selected within the self-emulsification region by reviewing formulation properties essential for optimized drug delivery. SEDDSs capable of enduring phase separation within 24 h were subjected to characterization experiments, i.e., drug concentration determination, cloud point, droplet size, size distribution, self-emulsification time, self-emulsification efficacy, viscosity, zeta potential, and thermodynamic stability analysis. SEDDSs with favorable characteristics were identified in the micro or nano range (SNEDDSs) before being subjected to drug release studies. RESULTS: All final formulations depicted enhanced artemether and lumefantrine release compared to the commercial product, which could not release lumefantrine at a quantifiable concentration in this study. The avocado oil (AVO)4:6 and olive oil (OLV)3:7 SNEDDSs overall portrayed the ideal characteristics and depicted the highest percentage of drug release. CONCLUSIONS: This study offers evidence that SNEDDSs from selected natural oils comprising an artemether-lumefantrine FDC can potentially enhance the bioavailability of these lipophilic drugs.

Preparation, characterization, and evaluation of the anticancer activity of artemether-loaded nano-niosomes against breast cancer.

BACKGROUND: The aim of this study was to develop nonionic surfactant vesicles (niosomes) as a promising nanocarrier to enhance the anticancer activity of artemether. METHODS: The niosomes were prepared by thin-film hydration method containing a mixture of Span, Tween and cholesterol (Chol) in different molar ratios. All formulations were characterized in terms of size, entrapment efficiency (%EE), release profile and morphology. The optimized niosomal formulation (F7), artemether and phosphate buffered saline (PBS) were intratumorally administrated to mice as the nano-niosome group, the free drug group and the control group, respectively (n = 4 per group). Tumor volume was measured during the 12-day experiment, then mice were sacrificed to evaluate the necrosis, angiogenesis, and cell proliferation of tumor tissues by H&E, CD34 and Ki-67 immunostaining, respectively. RESULTS: Both artemether and nano-niosome groups could decrease angiogenesis and proliferation of tumor cells. However, in nano-niosome group superior tumor necrosis and smaller tumor volume were observed compared to both artemether and control groups. CONCLUSIONS: The niosomal formulation could be a promising carrier for breast cancer treatment.

Post-Marketing Surveillance of Quality of Artemether Injection Marketed in Southwest Nigeria.

Access to good-quality medicines remains a contentious issue in developing countries. This development is worrisome, particularly in a setting with a high incidence of malaria. Monitoring of antimalarial drugs in the commercial domain becomes necessary; thus, we evaluated the quality of artemether injection marketed in Southwest Nigeria. A cross-sectional survey was conducted to obtain 22 different brands of artemether injections within Southwest Nigeria. The samples were examined for their sources, lot numbers, containers for injection, oil base used for preparation, and dates of expiration. Further analysis involved visual inspection, assessment of extractable volume, identity tests, and an assay of active pharmaceutical ingredient. The pharmaceutical quality of each sample was determined according to the criteria set in the International Pharmacopoeia 2019. None of the products had any particulate matter, but there were certain irregularities in their presentation. Eighteen of the 22 products (81.7%) were packaged in plain instead of amber-colored ampoules, and 77.3% (17/22) did not indicate the oil base used as the vehicle on the label as against the pharmacopoeial standard. Sixteen products (72.7%) passed the extractable volume test, although the remaining 22.3% did not conform to the extractable volume per unit dose. Artemether was present in all the samples, although only 40.9% (9/22) met the recommended percentage content of 90-110% of artemether. The study revealed the presence of a high percentage of substandard artemether injection products marketed in Nigeria. Further surveillance is warranted to confirm the quality of artemether injection circulated in other regions within Nigeria.

Synthesis of Nanostructured Lipid Carriers Loaded Chitosan/ Carbopol Hybrid Nanocomposite Gel for Oral Delivery of Artemether and Curcumin.

BACKGROUND: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in the liver and red blood cells. The application of these therapeutic agents is hampered by their improper application, hepato-toxicity caused by their continuous use, and degradation by hepatic enzymes. METHODS: Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Nanostructured lipid carriers (NLCs) loaded chitosan (CH)/Carbopol (CB) hybrid gel was prepared using glycerol monostearate (GMS) as solid lipid and clove oil as a liquid lipid for artemether (ART) and curcumin (CR) for its localized effect on the liver. RESULTS: The smaller particle size (~118 ± 1.0 nm) and high zeta potential (- 41.1 ± 6.46 mV) confirm the formulation and stability of NLCs. On the other hand, the shape and morphology of prepared NLCs and gel showed a spherical and wrinkled surface with a size range of 150-250 nm. The release studies of the NLC's showed a controlled release of artemether (~ 92%) and curcumin (~ 83%) for up to 30 h. Photostability data showed that, approximately, ~86.5 ± 0.3% and ~60 ± 0.9% of nanoencapsulated artemether and curcumin were still detected on exposure to sunlight, respectively. It has been found from the permeation study that 69.8% and 49.1% of the drug was permeated across the mucus membrane in 24 h with a significant increase (P < 0.05) in flux as well as permeability coefficients. CONCLUSION: The overall results showed that prepared CH/CB/NLCs hybrid gel could be a promising vehicle for the effective delivery of ART and CR for the management of malarial parasites. Lay Summary: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in liver and red blood cells. Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Application of these therapeutic agents hampered by their improper application, hepato-toxicity caused by their continuous use and degradation by hepatic enzymes. To manage the above issues, we synthesize nanostructured lipid carriers (NLC's) loaded chitosan (CH)/Carbopol (CB) hybrid gel using glycerol monostearate (GMS) as solid lipid and clove oil as liquid lipid for artemether (ATR) and curcumin (CR) for its local action in liver and the major criteria were to find a protective barrier with hepatoprotective nature of the curcumin.

Fabrication and in vivo evaluation of ligand appended paclitaxel and artemether loaded lipid nanoparticulate systems for the treatment of NSCLC: A nanoparticle assisted combination oncotherapy.

The aim of present study was to develop folate appended PEGylated solid lipid nanoparticles(SLNs) of paclitaxel(FPS) and artemether(FAS). The SLNs were prepared by employing high pressure homogenization technique. The results of MTT assays revealed better cytotoxicity of FPS when given in combination with FAS on human lung cancer cell line H-1299 as compared to pure drugs, unconjugated SLNs and FPS alone. The cellular uptake of FPS and FAS was confirmed by fluorescence imaging and flow cytometric analysis. In-vivo pharmacokinetic study revealed better absorption and long circulation of FPS and FAS, which further leads to increased relative bioavailability of drugs(13.81-folds and 7.07-folds for PTX and ART, respectively) as compared to their solutions counterpart. In-vivo pharmacodynamic study confirmed tumor regression of developed SLNs formulations, which was observed highest when used in combination of FPS and FAS. Serum creatinine, blood urea nitrogen(BUN), SGOT, albumin and total protein levels revealed that formulated FPS and FAS does not exhibit any renal and hepatic toxicity. It can be concluded that by administering ART-SLNs along with PTX-SLNs via oral route, anticancer potential of PTX was improved without any toxicity (both renal, hepatic), thus, indicating the potential of developed formulations in reducing dose related toxicity of PTX.

Semisynthetic Derivative of Artemisia annua-Loaded Transdermal Bioadhesive for the Treatment of Uncomplicated Malaria Caused by Plasmodium falciparum in Children.

According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 µm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 µg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation.

Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats.

Artemisinin and its derivatives have been widely used for treatment of malaria and the therapeutic targets are considered within the red blood cells. In the recent studies on the erythrocytes' uptake of artemisinin-derivatives in vitro, applying the radioisotope-labeled technology, it was trying to predict the in vivo disposition properties, but different distribution results were revealed from a preliminary study in one human. The pharmacokinetic differences among blood cells and plasma still remain unclear. To explore the therapeutic related pharmacokinetics and compare the in vitro-in vivo blood distribution in rats, an improving blood sample preparation and LC-MS/MS detection method was developed and successfully validated. The lower limit of quantification was smaller than the previous studies. In the in vitro blood distribution studies, the content ratios from blood cells to plasma were compared in the concentrations from 20 ng/mL to 1000 ng/mL. Such ratios were determined to be 1.1-1.6 for artemisinin, 0.9-1.2 for artemether, and around 0.7 for dihydroartemisinin. In the oral administration pharmacokinetic studies in rats, the concentration ratios from blood cells to plasma were from high (2.6-3.6) to medium (1.3-2.5), and low (0.5-1.5) for artemisinin, artemether, and dihydroartemisinin respectively in all measuring time points, displaying the similar affinity order toward blood cells in artemisinin > artemether > dihydroartemisinin as the in vitro measurements. The dosages of 10 mg/kg for intravenous administrations of artemisinin and 200 mg/kg for oral administrations of artemisinin or artemether were used for the pharmacokinetic study in rats. The geometric mean exposures (AUC(0-t)) of artemisinin, artemether and dihydroartemisinin in blood cells were determined to be 2.6 folds, 1.7 folds, or 1.2 folds greater than those in plasma, respectively. Referring to the in vitro distribution, the AUC(0-t) ratios from the blood cells measurements to the plasma measurements of these three antimalarial drugs were also in a similar trend as the in vitro distribution measurements. Furthermore, the half-life (t1/2) of artemether in blood cells was even longer than that in plasma, while the clearance of artemisinin, artemether, or dihydroartemisinin in blood cells was slower than that in plasma. Particularly, it was found that the concentrations of artemisinin and artemether were presented in blood cells over longer time period than in plasma above their antimalarial IC50, which might result from both the affinity toward blood cells and the drugs clearance differences between blood cells and plasma. These results were indicated that the exposures and pharmacokinetic properties in the whole blood or the blood cells should be taken into account for the drug candidates with higher distribution affinity toward blood cells especially for the antimalarial drugs.

Effect of omega-3 fatty acids administered as monotherapy or combined with artemether on experimental Schistosoma mansoni infection.

Schistosomiasis is on the top list of endemic diseases in sub-Saharan Africa. Praziquantel is the drug of choice for treatment of human schistosomiasis. Yet, the sole dependence on the drug raises concerns about the potential for increased drug resistance, which would subsequently result in searching for alternative preventive chemotherapy options, ideally among natural compounds. Therefore, we conducted this work to assess the effect of omega-3 polyunsaturated fatty acids [(ω-3) PUFAs] monotherapy or combined therapy with artemether (ART) against Schistosoma mansoni infection in a mouse model. A total of 42 mice were divided into 4 groups and infected with 50 ± 5 S. mansoni cercariae for 10 weeks. Mice were treated orally with either (ω-3) PUFAs as 273 mg/ kg, 4 times/ week throughout the experiment, ART as a single dose of 400 mg/ kg, 3 weeks post-infection, or combined ART + (ω-3) PUFAs using the same respective treatment regimen, while infected untreated mice were served as controls. The study explored that combined administration of (ω-3) PUFAs and ART has the best schistosomicidal efficacy as it significantly reduced liver and spleen indices, worm count, egg burdens, and granulomas count as well as diameter. Besides, the combined regimen was associated with a significant decrease in both hepatic nitric oxide and serum interleukin-4 level. The results highlighted the possibility of using (ω-3) PUFA combined with ART as a novel anti-schistosomal combination therapy. However, further researches should be conducted to clarify the possible synergistic mechanism/s between the two natural compounds.

Optimization and evaluation of lipid emulsions for intravenous co-delivery of artemether and lumefantrine in severe malaria treatment.

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that Cmax of artemether and lumefantrine for the optimized lipid emulsions were significantly increased than the injectable solution, which was critical for rapid antimalarial activity. Furthermore, the AUC0-t of artemether and lumefantrine in the lipid emulsion group were 5.01- and 1.39-fold of those from the solution, respectively, suggesting enhanced bioavailability. With these findings, the developed lipid emulsion is a promising alternative parenteral therapy for the malaria treatment, especially for severe or complicated malaria.

Development of a paediatric physiologically based pharmacokinetic model to assess the impact of drug-drug interactions in tuberculosis co-infected malaria subjects: A case study with artemether-lumefantrine and the CYP3A4-inducer rifampicin.

The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure. This study developed a population-based PBPK model for AL in adults capable of predicting the pharmacokinetics of AL under non-DDI and DDI conditions, as well as predicting AL pharmacokinetics in paediatrics of 2-12years of age. The validated model was utilised to assess the concomitant treatment of rifampicin and lumefantrine under standard body-weight based treatment regimens for 2-5year olds, and demonstrated that no subjects attained the target day 7 concentration (Cd7) of 280ng/mL, highlighting the importance of this DDI and the potential risk of malaria-TB based DDIs. An adapted 7-day treatment regimen was simulated and resulted in 63% and 74.5% of subjects attaining the target Cd7 for 1-tablet and 2-tablet regimens respectively.

Study of erythrocytes as a novel drug carrier for the delivery of artemether

Resealed erythrocytes have been explored in various dimensions of drug delivery, owing to their high biocompatibility and inability to initiate immune response. The present research was designed to evaluate the drug delivery potential of erythrocytes by loading a hydrophobic anti-malarial drug, Artemether. Three different loading techniques were applied to achieve maximum optimized drug loading. A HPLC method was validated for drug quantification in erythrocytes. The relatively high loading was achieved using hypotonic treatment was 31.39% as compared to other two methods. These, drug loaded erythrocytes were characterized for membrane integrity via ESR showing higher ESR values for drug loaded cells as compared to normal cells. Moreover, microscopic evaluation was done to observe morphological changes in erythrocytes after successful loading which showed swollen cells with slight rough surface as compared to smooth surface of normal cells. Drug release was studied for 8 h which showed more than 80% release within 3-7 h from erythrocytes treated with different hypotonic methods. Overall, the study revealed a potential application of erythrocytes in delivery of hydrophobic drugs using hypotonic treatment as compared to other methods.

The Neurotoxic Effects of Artemether on the Cytoarchitecture of the Trapezoid Nuclei of Adult Male Wistar Rats (Rattus novegicus) / Efectos Neurotóxicos del Artemeter sobre la Citoarquitectura del Núcleo Trapezoide en Ratas Machos Adultas Wistar (Rattus novegicus)

In Man, artemether is given at 160mg/kg/bodyweight for three days in the treatment of malarial. This study investigated the effects of corresponding 1.23/mg/kg/bodyweight of artemether for a period of seven days on the trapezoid nuclei and the behavioural functions on day 7 after drug administration in rats. This study observed no gross or morphological differences between the two groups of animals (control and experimental groups) on day 7 at the completion of experimental procedure. A significant statistical increase in average body weight was observed in the control groups C1 (which received only standard diet and water) and C2 (which received 1.23mg/kg/bodyweight of normal saline intramuscularly in addition to standard diet and water) from 140- + 19.65g on day 1 to 146 + 19.90g on Day 1 and 151 + 12.0g on Day 1 to 156.2 + 12.2g on Day 7 respectively. There was a non-statistically significant apparent reduction in body weight in the experimental group E, (which received intramuscular injection of 1.23mg/kg/bodyweight of artemether) from 160 + 9.0g on Day 1 to 157.4 + 8.0g on Day 7. The assessment of brainstem nuclei showed patchychromatic appearance of neurons of the trapezoid nuclei in the experimental group as against the normal vesicular appearance of neurons of the trapezoid nuclei in the Control Group C. The rats in the control groups CI and C2 displayed normal balance and co-ordination, while rats in the experimental group E, showed abnormalities of balance and co-ordination. Using t-test analysis technique at 95% confidence interval i.e t < 0.05 and P - value = 2.26, no significant difference was observed between the average brain weight in the control groups C1 and C2 and the experimental group E.

En el Hombre, el artemeter es dado en el tratamiento de la malaria en dosis de 160 mg/kg de peso, por tres días. Este estudio abordó los efectos de un tratamiento con artemeter, durante 7 días (en dosis de 1,23 mg/kg de peso) sobre el núcleo trapezoide de ratas y las funciones de conducta, en el día 7 después de la administración de la droga. No se observaron ni macro ni diferencias morfológicas entre dos grupos de animales (grupos control y experimental) en el día 7 de la completación del procedimiento. Un incremento estadísticamente significativo en el promedio del peso del cuerpo fue encontrado en el grupo control C1 (el que recibió solamente una dieta standard y agua) y C2 (que recibió 1,23 mg/kg de peso de solución salina intramuscular agregada a la dieta y al agua) que fue desde 140± 19,65 g y 146 ± 19,9 g en el día 1, respectivamente y de 151 ± 12 g y de 156,2 ± 12,2 g en el día 7, respectivamente. No hubo una reducción aparente estadísticamente significativa en el peso del cuerpo del grupo experimental (el cual recibió inyección intramuscular de 1,23 mg/kg de peso de artemeter), la que fue desde 160 ± 9 g en el día 1 y de 157,4 ± 8, en el día 7. La evaluación de núcleos del tronco encefálico mostró apariencia cromática irregular de las neuronas del núcleo trapezoide en el grupo experimental contrariamente a la apariencia vesicular normal de las neuronas de este núcleo en el grupo control. Las ratas de los grupos controles C1 y C2 presentaron un normal balanceo y coordinación, mientras que las ratas del grupo experimental, mostraron anormalidades de balanceo y coordinación. Usando el test t con 95% de intervalo de confianza, p 0,05 y con un valor p=2,26, no se observaron diferencias estadísticamente significativas entre el promedio de los grupos C1 y C2 y del grupo experimental.