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Treatment and prevention of malaria
Published in David A Warrell, Herbert M Gilles, Essential Malariology, 2017
David A Warrell, William M Watkins, Peter A Winstanley
Artemether and arteether are neurotoxic in rats and dogs at doses higher than those used in the treatment of malaria in humans (Brewer et al., 1993). However, few adverse effects have been reported in patients monitored during clinical trials of artemisinin or its derivatives. It is estimated that over 2 million malaria cases have been treated, with no reports of gross toxicity, suggesting that immediate and severe complications associated with this group of drugs are rare.
Artemisinins
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Kamala Thriemer, Julie A. Simpson, James S. McCarthy, Ric N. Price
Artemisinin and its derivatives are absorbed rapidly after oral administration. The maximum plasma concentration occurs at 2–3 hours for artemisinin (Table 169.1), less than 1 hour in the case of artesunate (Table 169.2), and 1–3 hours for artemether (Table 169.3). For rectal administration the maximum concentration is achieved later, at 4–7 hours for artemisinin (see Table 169.1), but relatively rapidly for artesunate (see Table 169.2). Of note, absorption of intramuscular artemether is highly variable, with maximum concentrations occurring 2–10 hours after administration (see Table 169.3). Variable absorption has also been observed for intramuscular arteether (Looareesuwan et al., 2002). Following its intramuscular or intravenous administration, artesunate is rapidly metabolized to DHA, with maximum concentrations of artesunate occurring within the first 15 minutes (see Table 169.2). Maximum concentrations of the active metabolite, DHA, occur at 5–10 minutes after an intravenous injection of artesunate, at 30–45 minutes after intramuscular injection of artesunate, and at 1–2 hours after oral and rectal artesunate (Table 169.4).
Therapeutics of Artemisia annua
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
Artether is prepared in two steps using artemisinin batches of 10 g. The first step in the preparation of arteether involving the reduction of artemisinin with sodium borohydride into DHA and subsequent esterification of DHA by Lewis acid catalyzed reaction, affording an epimeric (80:20 mixtures of β- and α- isomers) ether of DHA. Both the epimers are separated by column chromatography and crystallized to yield crystalline β arteether and oily α arteether (Jain et al., 2000). An arteether capsule containing 40 mg of the drug is now available. It is also available as an injection of 150 mg in 2 mL. The dosage is 3 mg/kg once a day for 3 days as deep intramuscular injection. On the basis of pharmacokinetic experiments on the derivatives of artemisinin, Kager et al. (1994) concluded that arteether may have the longest half-life of all the artemisinin derivatives studied so far. The study of Dutta et al. (1989) strongly advocated for the future clinical evaluation of arteether for the control of multidrug-resistant and high-risk P. falciparum cases in areas especially of chloroquine-, mefloquine-, and quinine-resistant malaria. The objectives of the WHOCHEMAL’s programme encouraged the development of arteether as a single dose parenteral treatment for severe and complicated P. falciparum infection. The choice to develop β-arteether rather than artemether was based on the fact that arteether would be more lipophilic and its metabolic breakdown gives ethanol and not methanol, which would avoid the problems of methanol toxicity that can arise from the metabolic formation of formaldehyde and formic acid (Ritchi, 1985; Brossi et al.,1988). India has made a significant contribution in this worldwide effort, through the development of a highly efficacious variant of arteether. It developed alpha–beta (α−β) arteether (30:70 mixture of enantiomers) as a fast-acting blood schizontocide especially for the control of drug-resistant and cerebral malaria (Dutta et al., 1994). For the clinical trial, as per requirement, the Central Institute of Medicinal and Aromatic Plants (CIMAP) has prepared purified arteether and separated it into α- and β-enantiomers. Both the isomers of arteether are equally effective. α-arteether has advantage over β-arteether particularly with regard to higher solubility in lipids. Conversion of β-isomer to α-isomer is a tedious operation but Jain et al. (2000) have achieved it with anhydrous FeCl3 under specific reaction conditions. Pharmaceutical grade of α–β-arteether (30:70) was formulated and supplied to the Central Drug Research Institute, Lucknow, India (a Council of Scientific and Industrial Research lab, established by the Government of India) for clinical trial. This drug is now being manufactured and marketed by Themis Medicare Pvt. Ltd., Mumbai, India, under the brand name E-MAL (Eradicate Malaria) since April 1997. The drug is being extensively used under National Antimalarial Programme (NAMP) since 1999.
Progress in nano-drug delivery of artemisinin and its derivatives: towards to use in immunomodulatory approaches
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Ives Charlie-Silva, Leonardo Fernandes Fraceto, Nathalie Ferreira Silva de Melo
Arteether (ARE), a potent anticancer drug, was encapsulated in pH-sensitive polyurethane nanomicelles (PU NMs). ARE loaded PU NMs inhibited 4T1 cell line, reduced tumour growth in breast cancer model and increased INF-γ levels, indicating there was a stimulus of Th1 immune response by nanosystem containing ARE [19]. Manjili and coworkers prepared nanomicelles of PCL-PEG-PCL triblock copolymers containing ART. The pharmacokinetic study in rats showed improved bioavailability of ART by intravenous administration of the PMs formulation compared to the free drug as well as toxicity specific for 4T1 and MCF7 tumour cell lines [20]. Another study with the same nanocarrier, its antiplasmodial effect was evaluated in animal malaria model. PCL-PEG-PCL micelles containing ART provided an appropriate drug delivery to Plasmodium berghei infected erythrocytes, reducing parasitemia. These results make PMs containing ART a candidate for malaria treatment [21].
Recent advances in targeting malaria with nanotechnology-based drug carriers
Published in Pharmaceutical Development and Technology, 2021
Hamid Rashidzadeh, Seyed Jamal Tabatabaei Rezaei, Seyed Masih Adyani, Morteza Abazari, Samaneh Rahamooz Haghighi, Hossien Abdollahi, Ali Ramazani
Despite all these statements, some major limitations remained that are associated with hydrogels, when utilized as drug vehicles such as burst drug release and drug leakage. Owonubiet al. in their study developed hydrogel biocomposites loaded with antimalarial drugs (chloroquine diphosphate and proguanil hydrochloride) and then investigated its drug release kinetics. Accordingly, the hydrogels were biodegradable and in vitro drug release indicated that the carrier is pH-sensitive, so it could be applied for controlling the delivery of therapeutic agents like antimalarial drugs (Owonubi et al. 2018). Moreover, Dandekar et al. fabricated the nano-hydrogel based on polyvinyl pyrrolidone and hydroxyl propyl methyl cellulose. Curcumin was encapsulated within a hydrogel nanoparticle as an antimalarial agent and its in vivo antimalarial potential was then investigated. The results demonstrated that the curcumin-loaded nanohydrogrel display more significantly superior antiplasmodial activity when compared to free curcumin (Dandekar et al. 2010). Aderibigbe et al. fabricated a hydrogel composed of polyacrylamide and soy protein isolates–carbopol for co-delivery of antimalarial drugs curcumin and chloroquine diphosphate. Correspondingly, their results showed that the hydrogels were biodegradable and pH-sensitive, and they can also be considered as potential drug delivery systems to overcome the problems associated with drug resistance (Aderibigbe and Mhlwatika 2016). Spreading and development of resistance of P. falciparum to most antimalarials are major challenges in malaria eradication and control. Thereby, the rationale combination of two antimalarials with distinct modes of action is to synergize fast onset with the prolonged action, in order to prevent recrudescence, enhance efficacy, and reduce resistance. Additionally, it was observed that frequent administration of antimalarials results in the evolution of drug resistance. In this regard, Dawre et al. fabricated in situ forming gel based on a biodegradable polymer loaded with Arteether and LMF. These unique polymeric gels provided sustained release of Arteether–LUM over 72 h (Figure 8). This prolonged-release pattern then allowed for diminishing dose frequency, which minimized the drug’s toxicity. Employing this delivery system for Arteether–LUM was highly efficacious in comparison to marketed formulation. Altogether, the one-shot therapy is likely to enhance patient compliance and consequently help to reduce the emergence of drug resistance (Dawre et al. 2018).
Curcumin and curcumin-loaded nanoparticles: antipathogenic and antiparasitic activities
Published in Expert Review of Anti-infective Therapy, 2020
Mahendra Rai, Avinash P. Ingle, Raksha Pandit, Priti Paralikar, Netravati Anasane, Carolina Alves Dos Santos
It is a well-known fact that the binding of curcumin with nanomaterials like chitosan nanoparticles improves its bioavailability and chemical stability. Hence, curcumin encapsulated nanoparticles have gained wide standing in the treatment of diverse diseases including malaria and leishmaniasis. In a study, Akhtar et al. [6] reported that orally delivered curcumin loaded chitosan nanoparticles can control Plasmodium yoelii (N-67) infection in mice. The data obtained from in vitro study showed that curcumin loaded chitosan nanoparticles inhibited hemozoin synthesis which is lethal to P. yoelii (N-67). Similarly, Nayak et al. [82] reported that curcuminoids loaded lipid nanoparticles showed potential antimalarial and pharmacodynamics activity against Plasmodium berghei in in vitro and in vivo conditions. Moreover, Busari et al. [83] also found the antiplasmodial activity of curcumin incorporated poly lactic-co-glycolic acid (PLGA) nanoparticles. The authors studied in vivo antiplasmodial activity using Peter’s 4-day suppressive test in mice model. The hematological activity and toxicity assays were also performed on whole blood and plasma, respectively. At the concentration of 1000 and 500 µg/ml of curcumin-PLGA entrapped nanoparticles showed higher toxicity as compared to free drugs. The administration of formulated curcumin drugs at lower concentrations showed significantly higher toxicity in vitro assay, while the long-term administration of curcumin-PLGA nanoformulation can prevent parasite recrudescence in vivo assays. Moreover, Oyeyemi et al. [84] assessed the antiplasmodial efficacy of novel, simple and nontoxic curcumin artesunate entrapped nanoparticles in mice model. The results revealed that the activity of formulated nano-drug was effective against malarial parasite Plasmodium berghei at a very low concentration (5 mg/kg dose). From the above-mentioned studies, it is clear that the combination of curcumin with nanoparticles has potential applicability because of their improved bioavailability, bio-distribution and decreased toxicity. Similarly, Memvanga et al. [85] developed curcumin-loaded lipid-based drug delivery systems combined with β-arteether (a potential antimalarial drug) and tested its activity on Plasmodium berghei–infected mice. The authors reported that the transport of the above-mentioned nanoformulation across Caco-2 monolayers was enhanced which ultimately resulted in an increase in protection and survival rate in infected mice. Moreover, Ghosh et al. [86] prepared nanotized curcumin by a modified emulsion-diffusion-evaporation method and evaluated their antimalarial efficacy against Plasmodium falciparum. The authors claimed that thus prepared nanoformulation of curcumin (i.e. nanotized curcumin) was 10-fold more effective against P. falciparum than curcumin alone because of its superior bioavailability over its native counterpart.