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Antimalarial Combinations
Abstract
Multidrug resistance has rendered monotherapy for malaria useless in most parts of the world, and has also compromised the usefulness of many of the available combination chemotherapies. New antimalarial regimens are, therefore, urgently needed. We review the various antimalarial combinations that can be used to treat otherwise drug-resistant disease, and discuss what defines an ideal antimalarial combination regimen.
... Currently, combined therapy is already a successful strategy in the treatment of several infectious diseases such as tuberculosis, malaria and HIV/AIDS (Mitchison and Davies 2012;Kremsner and Krishna, 2004;Yazdanpanah et al., 2004). This approach can increase drug efficacy, and reduce the total number of required doses as well as the duration of therapy, therefore reducing toxic effects and the costs of treatment while minimizing the evolution of resistance in parasite strains (Bryceson, 2001;Olliaro 2010). ...
Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (∼40%) and lymph nodes (∼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.
... Currently, combined therapy is already a successful strategy in the treatment of several infectious diseases such as tuberculosis, malaria and HIV/AIDS (Mitchison and Davies 2012;Kremsner and Krishna, 2004;Yazdanpanah et al., 2004). This approach can increase drug efficacy, and reduce the total number of required doses as well as the duration of therapy, therefore reducing toxic effects and the costs of treatment while minimizing the evolution of resistance in parasite strains (Bryceson, 2001;Olliaro 2010). ...
... It thus represents a huge financial burden for populations and consequently the disease constitutes an obstacle to the development of the countries concerned, particularly in Africa [5]. Many antimalarial drugs are currently available, but the parasite has developed chemoresistance, especially to the most affordable molecules for populations at risk (chloroquine and sulfadoxine/ pyrimethamine combination) [6,7]. ...
... [5,6] This highlights the urgent need for alternative drug candidates that can be deployed as mono-therapeutics or as partners in combination therapy against established therapeutic targets. [7,8] Simão-Gurge and his colleagues identified P. falciparum's isoprenoid synthesis, which occurs via the 2-C-methyl-D-erythritol-4-phosphate (MEP) route, as one target for the study of novel antimalarial drugs. [9] Heme is a prosthetic group made up of a big heterocyclic protoporphyrin IX ring with a coordinated iron atom in the middle. ...
... [5,6] This highlights the urgent need for alternative drug candidates that can be deployed as mono-therapeutics or as partners in combination therapy against established therapeutic targets. [7,8] Simão-Gurge and his colleagues identified P. falciparum's isoprenoid synthesis, which occurs via the 2-C-methyl-D-erythritol-4-phosphate (MEP) route, as one target for the study of novel antimalarial drugs. [9] Heme is a prosthetic group made up of a big heterocyclic protoporphyrin IX ring with a coordinated iron atom in the middle. ...
The enzyme Heme O Synthase (HOS) is essential for producing heme A and heme O, which are critical for defense against reactive oxygen species, drug detoxification, gas synthesis, transport, and electron transport in Plasmodium species. It has become vital to discover inhibitory molecules/compounds/medicines that target the synthesis of heme due to the emergence of drug‐resistant strains of Plasmodium falciparum. Therefore, in this study, we employed molecular mechanics with Generalized Born surface area (MMGBSA) calculations and docking studies to investigate potential antimalarial compounds targeting HOS from antimalarial botanicals. Screening these compounds, we have identified 2 compounds; Meliantrol and Tamarixetin with better binding affinities (−8.4 Kcal/mol and −8.3 Kcal/mol respectively) than the current standard inhibitor(Inabenfide) of HOS (−8.0 Kcal/mol). The MMGBSA calculations provided insight into the thermodynamics of the binding process and helped identify key interactions responsible for the stability of the HOS‐ligand complex. In addition, the 2 compounds were further screened comparatively with the standard HOS inhibitor considering their protein‐ligand interaction profile and ADMET profile and these 2 selected compounds outperformed Inabenfide. Our results predict that these compounds are potential drug candidates with domiciled therapeutic functions against Malaria therefore, open doors for more experimental validations for drug development.
... Artemisinins are a group of molecules extracted by the Artemisia annua widely used as antimalarial agents [87]. More recently, dihydroartemisinin, an artemisinin derivative, has been shown to function as a putative FXR agonist [88,89]. ...
... This method could be taken without considering the possibility of antagonistic effects from a herbedrug combination. According to the literature, this combination therapy is widespread in malaria-endemic nations where standard antimalarial medications are expensive and out of reach for most rural residents [7,8]. Most of anti-malaria medications, such as primaquine, exert their antiplasmodial effect while also releasing free radicals [9]. ...
Background: It has been observed that most malaria patients especially G6PD-deficient patients usually experience oxidative stress and severe anemia when treated with primaquine. This calls for the need to search for a treatment option that will ameliorate these side effects. Objective: The effect of co-treatment of malaria with aqueous extract of Ocimum gratissimum leaves (AEOGL) and primaquine on G6PD activity, antioxidant indices and hematological parameters in Plasmodium berghei-infected mice was investigated. Materials and methods: Thirty mice divided into six groups of five mice each were recruited for this study. Whilst Group 1 (G1) served as the negative control (group not infected with plasmodium parasite), Groups 2 to 6 (G2-G6) were inoculated intraperitoneally with 0.2 ml of 1 × 105/ml Plasmodium berghei (NK 65 strain) infected erythrocytes. G2 (parasite control) received no treatment. Groups 3,4,5 and 6 were administered 0.25 mg/kg bw of primaquine only; 100 mg/kg b. w of AEOGL +0.25 mg/kg bw of primaquine; 200 mg/kg b. w of AEOGL +0.25 mg/kg bw of primaquine; 200 mg/kg b. w of AEOGL respectively, for 14 days. Results: Treatment with only primaquine gave the highest mean malaria parasite clearance (82.10 ± 0.45 percent), followed by 100 mg/kg b. w of AEOGL + Primaquine (75.59 ± 0.47 percent), 200 mg/kg b. w of AEOGL + Primaquine (67.35 ± 0.67 percent), and AEOGL alone (55 ± 0.56 percent). In comparison with the untreated malaria groups, co-treatment with AEOGL + Primaquine produced a significant (p
... The combination SP is the most commonly used antimalarial treatment in almost all malaria-endemic areas between the 1960s and the 1980s [26] and remains in use to treat patients with P. falciparum infections in few counties [10] and as an intermittent prophylactic treatment for infants and pregnant women in Africa [7,8]. Prior to the introduction of SP combination therapy, pyrimethamine resistance in 1953 and sulfadoxine resistance in 1957 had already been reported [27]. ...
The dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of Plasmodium vivax, as antifolate resistance-associated genes were used for drug resistance surveillance. A total of 375 P. vivax isolates collected from different geographical locations in China in 2009-2019 were used to sequence Pvdhfr and Pvdhps. The majority of the isolates harbored a mutant type allele for Pvdhfr (94.5%) and Pvdhps (68.2%). The most predominant point mutations were S117T/N (77.7%) in Pvdhfr and A383G (66.8%) in Pvdhps. Amino acid changes were identified at nine residues in Pvdhfr. A quadruple-mutant haplotype at 57, 58, 61, and 117 was the most frequent (57.4%) among 16 distinct Pvdhfr haplotypes. Mutations in Pvdhps were detected at six codons, and the double-mutant A383G/A553G was the most prevalent (39.3%). Pvdhfr exhibited a higher mutation prevalence and greater diversity than Pvdhps in China. Most isolates from Yunnan carried multiple mutant haplotypes, while the majority of samples from temperate regions and Hainan Island harbored the wild type or single mutant type. This study indicated that the antifolate resistance levels of P. vivax parasites were different across China and molecular markers could be used to rapidly monitor drug resistance. Results provided evidence for updating national drug policy and treatment guidelines.
... 136 Artesunate is another antimalarial drug and is derived from artemisinin, and is widely administered via oral, rectal, and parental routes. 137,138 The anticancer effects of artemisinins are already reported and many studies using in vitro and in vivo models confirmed their broad antitumoral effect, by affecting cell proliferation, angiogenesis, and apoptosis. [139][140][141] A randomised, double-blind, placebo-controlled pilot study evaluated the effect of artesunate for the therapy of CRC and found that this drug has antiproliferative properties in CRC and is generally well tolerated. ...
The drug development process, especially of antineoplastic agents, has become increasingly costly and ineffective. Drug repurposing and drug combination are alternatives to de novo drug development, being low cost, rapid, and easy to apply. These strategies allow higher efficacy, decreased toxicity, and overcoming of drug resistance. The combination of antineoplastic agents is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical development. In this review, we provide a set of pharmacological concepts focusing on drug repurposing for treating colorectal cancer (CRC) and that are relevant for the application of new drug combinations against this disease.
... In an attempt to delay antimalarial resistance, the use of combination therapies, such as the so-called artemisinin-based therapies (ACTs), which include an artemisinin analog in conjunction with another longer-acting compound, has been established (Kremsner and Krishna, 2004). In many cases, resistance is associated with mutations in the genes for carrier proteins such as Plasmodium falciparum chloroquine resistance transporter (PfCRT) and Plasmodium falciparum multidrug resistance 1 (PfMDR1; Reed et al., 2000;Le Bras and Durand, 2003;Lee et al., 2018, Wicht et al., 2020. ...
Previously we have reported that the G protein-coupled receptor (GPCR)-like PfSR25 in Plasmodium falciparum is a potassium (K+) sensor linked to intracellular calcium signaling and that knockout parasites (PfSR25-) are more susceptible to oxidative stress and antimalarial compounds. Here, we explore the potential role of PfSR25 in susceptibility to the antimalarial compounds atovaquone, chloroquine, dihydroartemisinin, lumefantrine, mefloquine, piperaquine, primaquine, and pyrimethamine and the Medicine for Malaria Venture (MMV) compounds previously described to act on egress/invasion (MMV006429, MMV396715, MMV019127, MMV665874, MMV665878, MMV665785, and MMV66583) through comparative assays with PfSR25- and 3D7 parasite strains, using flow cytometry assays. The IC50 and IC90 results show that lumefantrine and piperaquine have greater activity on the PfSR25- parasite strain when compared to 3D7. For MMV compounds, we found no differences between the strains except for the compound MMV665831, which we used to investigate the store-operated calcium entry (SOCE) mechanism. The results suggest that PfSR25 may be involved in the mechanism of action of the antimalarials lumefantrine and piperaquine. Our data clearly show that MMV665831 does not affect calcium entry in parasites after we depleted their internal calcium pools with thapsigargin. The results demonstrated here shed light on new possibilities on the antimalarial mechanism, bringing evidence of the involvement of the GPCR-like PfSR25.
... In addition, parasitic resistance to some of the existing antimalarial drugs is the biggest problem in overcoming this disease, especially in malaria endemic areas [14]. The combination therapy with artemisinin derivatives or commonly referred to artemisinin-based combination therapy (ACT) is highly recommended by WHO as the preferred therapy that is able to control the spread of resistance of P. falciparum [15,16]. ...
Background
In previous studies, Cassia spectabilis DC leaf has shown a good antiplasmodial activity. Therefore, this study is a follow-up study of the extract of leaf of C. spectabilis DC on its in vitro and in vivo antiplasmodial activity and mechanism as an antimalarial.
Methods
The extract was fractionated, sub-fractionated and isolated to obtain the purified compound. In vitro antiplasmodial activity test against Plasmodium falciparum to find out the active compound. In vivo test against P. berghei ANKA-infected mice was conducted to determine prophylactic activity and antiplasmodial activity either alone or in combination with artesunate. The inhibition of heme detoxification test as one of the antimalarial mechanisms was carried out using the Basilico method.
Results
The results showed that active antimalarial compound isolated from C. spectabilis DC leaf had a structural pattern that was identical to (−)-7-hydroxycassine. Prophylactic test of 90% ethanolic extract of C. spectabilis DC leaf alone against P. berghei ANKA-infected mice obtained the highest percentage inhibition was 68.61%, while positive control (doxycycline 13 mg/kg) was 73.54%. In combination with artesunate, 150 mg/kg three times a day of C. spectabilis DC (D0-D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate where the inhibition percentages were 99.18 and 92.88%, respectively. The IC50 of the extract for the inhibitory activity of heme detoxification was 0.375 mg/ml which was better than chloroquine diphosphate (0.682 mg/ml).
Conclusion
C. spectabilis DC leaf possessed potent antiplasmodial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.
... It is noteworthy that compound 85D which has a methyl group, was found to be the most effective in chloroquine resistant P. falciparum RKL9 strain with IC 50 value of 337 nM. It is reported that most prevalent drugs used for the treatment of clinical P. falciparum malaria target early intraerythrocytic stages (Famin & Ginsburg, 2002;Kremsner & Krishna, 2004). Our progression assay data revealed that dependensin analogs cause developmental interruption in ring stage parasites when compared with untreated parasites. ...
Malaria infection caused by Plasmodium falciparum is majorly responsible for millions of deaths in humans every year. Moreover, a rapid increase in resistance to existing drugs has posed an urgent need for new anti-malarials. Herein, we report the highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives, inspired from naturally occurring dependensin against chloroquine (CQ) sensitive and resistant P. falciparum strains. Chemically synthesized, four dependensin analogs 85(A–D) exhibited growth inhibition at nanomolar concentrations ranging from 63.96 to 725.8 nM by blocking the parasite development at the ring and early trophozoite stages. The growth inhibitory activity of dependensin analogs was correlated with their anti-plasmodial lactate dehydrogenase activity by computational analysis. Molecular docking, 50 ns simulation and a 2D-Quantitative Structure-Activity Relationship (2D-QSAR) modelling revealed the interaction with their putative target P. falciparum lactate dehydrogenase (PfLDH). Here, developing the predictive 2D descriptors such as thermodynamic, spatial, electronic, and topological with multiple linear regression analysis (MLRA), the structural requirements for potent and selective PfLDH inhibitory activity has been identified. The strong binding of compound 85D to the catalytic Nicotinamide adenine dinucleotide (NADH) binding pocket of the PfLDH further supported the PfLDH targeting potential of dependensin analogs. Overall, this study revealed a highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives with their putative anti-PfLDH activity.
Communicated by Ramaswamy H. Sarma
... Malaria control primarily relies on chemotherapeutics due to an ineffective vaccine [7,8]. Chemotherapeutic treatment of malaria is based on chloroquine [9], primaquine [10], amodiaquine [11], sulfadoxine [12], artemisinin and its derivatives [13]. Despite these drugs, the emergence of resistance [14,15], particularly to front-line treatments such as artemisinin-based combination therapy (ACT) is worrying, since no alternative is available to treat malaria more effectively [16][17][18]. ...
Introduction: The unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria. Areas covered: In this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery. Expert opinion: Fluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F 2 and SF 4 used for fluorination, are not considered as safe, and therefore, this process remains challenging, particularly for the pharmaceutical industry. ARTICLE HISTORY
... In addition, parasitic resistance to some of the existing antimalarial drugs is the biggest problem in overcoming this disease, especially for malaria endemic areas (6). The combination therapy with artemisinin derivatives or commonly referred to artemisinin-based combination therapy (ACT) is highly recommended by WHO as the preferred therapy that is able to control the spread of resistance from P. falciparum (7,8). ...
Background In previous studies, Cassia spectabilis DC leaf has shown a good antimalarial activity. Therefore, this study is a follow-up study of leaf activity and mechanism of C. spectabilis DC as an antimalarial. Methods In vitro antimalarial activity testing using P. falciparum which was done with bioassay guide isolation in order to obtain the active compound. In vivo testing towards infected P. berghei mice was conducted to determine the effects of antimalarial prophylaxis and antimalarial activity in combination with artesunate. Whereas, heme detoxification inhibition testing as one of the antimalarial mechanisms was carried out using the Basilico method. Results The results showed that active antimalarial isolate obtained from C. spectabilis DC leaf had a structural pattern that was identical to (-)-7-hydroxyspectaline. Prophylactic test on infected P. berghei mice obtained the highest dose of inhibition percentage of 90% ethanol extract of C. spectabilis DC leaf was 68.61% while positive (doxycycline) control at 100 mg kg-1 was 73.54%. In antimalarial testing in combination with artesunate, it was found that administering 150 mg kg-1 (three times a day) of C. spectabilis DC (D0 − D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate with 99.18% and 92.88% inhibition percentage. For the inhibitory activity of heme detoxification from ethanol extract 90%, C. spectabilis DC leaf had IC50 value of 0.375 mg mL-1 which was better than chloroquine diphosphate. Conclusion These results showed that C. spectabilis DC leaves possesses potent antimalarial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.
... Specificity was assessed by analyzing both blank and spiked samples. To assess the linearity, matrix-fortified calibration samples were prepared at six concentrations (5,10,20,30,40, and 50 μg/kg) and curves were prepared by plotting the response factor. To estimate the accuracy (expressed as recovery) and precision (expressed as RSD), in a single day, blank matrixes (n = 3) were spiked with fortification levels of 5, 10, and 20 μg/kg. ...
An analytical approach using a modified quick, easy, cheap, effective, rugged, and safe extraction method followed by liquid chromatography with electrospray ioniza-tion tandem mass spectrometry was developed herein for the determination of arte-sunate and its metabolite, dihydroarteminsinin in porcine muscle, egg, eel, flatfish, and shrimp. 10% trichloroacetic acid in acetonitrile mixed with ethyl acetate was used as an extraction solvent. To obtain a good separation, a Phenomenex Kinetex reversed-phase analytical column was selected with mobile phase consisting of distilled water (A) and acetonitrile (B), both containing 0.05% formic acid. Good linear-ity was achieved using matrix-matched calibrations constructed from six concentrations (5-50 μg/kg) with determinant coefficients ≥0.9918. Recoveries estimated from three spiking concentrations (5, 10, and 20 μg/kg) ranged between 71.3 and 104.7% in all matrixes with relative standard deviations ≤8.3%. A variety of samples purchased from markets in Seoul were tested following the protocol described herein. The arte-sunate and dihydroarteminsinin were not detected in any matrix. The methodology proposed could be used for routine determination of artesunate and its metabolite, dihydroartemisinin in various animal products having variable percentages of fat and protein.
... Malaria control primarily relies on chemotherapeutics due to an ineffective vaccine [7,8]. Chemotherapeutic treatment of malaria is based on chloroquine [9], primaquine [10], amodiaquine [11], sulfadoxine [12], artemisinin and its derivatives [13]. Despite these drugs, the emergence of resistance [14,15], particularly to front-line treatments such as artemisinin-based combination therapy (ACT) is worrying, since no alternative is available to treat malaria more effectively [16][17][18]. ...
Introduction: The unique physicochemical properties and chemical diversity of organofluorine compounds have remarkably contributed for their wide utility in the area of pharmaceuticals, materials and agrochemicals. The noteworthy characteristics of fluorine include high electron affinity, lipophilicity and bioavailability, extending the half-life of the drugs. The incorporation of fluorine substituents, particularly trifluoromethyl groups, into organic molecules has led to their high potency against various diseases, including malaria. Hence, organofluorinated molecules offer valuable avenues for the design of new drug candidates against malaria.
Areas covered: In this review, the authors discuss the importance of fluorine substituents present in the chemical compounds, and their potential applications for antimalarial drug discovery.
Expert opinion: Fluorinated molecules represent a reliable strategy to develop new antimalarial drugs. Fluorine or fluorinated groups have been identified as a promising precursor, and their presence in approximately twenty-five percent of approved drugs is notable. Selective fluorination of chemical entities has the potential to be applied not only to improve the activity profile against the malaria parasite, but could be extrapolated for favorable pharmacological applications. Hazardous reagents such as HF, F2 and SF4 used for fluorination, are not considered as safe, and therefore, this process remains challenging, particularly for the pharmaceutical industry.
... Amodiaquine (13), a 4-aminoquinoline derivative, is among others a commonly-used antimalarial medicine in co-formulation with artesunate (11) as a first-line treatment of uncomplicated Plasmodium falciparum malaria, where it is the major constituent usually present in a ratio of 2.7 to 1 (amodiaquine/artesunate). [228,229,78] Due to the different intensities in UV absorption, it is challenging to simultaneously analyze amodiaquine (13) and any artemisinin derivatives, in particular when it comes to impurity profiling. Therefore, most of the available analytical methods have been designed either for the one or for the other agent. ...
Nowadays, the management of infectious diseases is especially threatened by the rapid emergence of drug resistance. It has been suggested that the medicine quality assurance combined with good medication adherence may help to reduce this impendence. Moreover, the search for new antimicrobial agents from medicinal plants is strongly encouraged for the exploration of alternatives to existing therapies. In this context, the present work focused on both the quality evaluation of commercialized antimalarial medicines from the Democratic Republic of the Congo and on the phytochemical investigations of a Congolese Ancistrocladus species.
... Quinine remains efficient, although it needs a long course of treatment, is poorly tolerated, especially by children, and must be combined with another drug, such as doxycycline or clindamycin. Uncomplicated vivax, malariae, and ovale malaria are handled with chloroquine except in case of chloroquine-resistant P. vivax when an ACT is used [7,29,[60][61][62]. ...
Malaria is a severe disease caused by parasites of the genus Plasmodium, which is transmitted to humans by a bite of an infected female mosquito of the species Anopheles. Malaria remains the leading cause of mortality around the world, and early diagnosis and fast-acting treatment prevent unwanted outcomes. It is the most common disease in Africa and some countries of Asia, while in the developed world malaria occurs as imported from endemic areas. The sweet sagewort plant was used as early as the second century BC to treat malaria fever in China. Much later, quinine started being used as an antimalaria drug. A global battle against malaria started in 1955, and Croatia declared 1964 to be the year of eradication of malaria. The World Health Organization carries out a malaria control program on a global scale, focusing on local strengthening of primary health care, early diagnosis of the disease, timely treatment, and disease prevention. Globally, the burden of malaria is lower than ten years ago. However, in the last few years, there has been an increase in the number of malaria cases around the world. It is moving towards targets established by the WHO, but that progress has slowed down.
... Artemisinin has been used in Chinese herbal medicine for more than 2,000 years (Kremsner and Krishna, 2004). The small molecule ART, a derivative of artemisinin, has been used to treat various kinds of diseases ranging from malaria to rheumatoid arthritis Jiang et al., 2018). ...
Osteoarthritis (OA) is a common and debilitating joint disease worldwide without interventions available to reverse its progression. Artesunate (ART), an anti-malaria agent, possesses diverse biological activities, including the inhibition of osteoclastogenesis and angiogenesis in various cells, but its role in subchondral bone during OA progression is not known. Here, we explored the curative effects of ART on the pathogenesis of OA in anterior cruciate ligament transection (ACLT) mice models. We found that ART attenuated articular cartilage degeneration, defined by lowered histologic scoring of OA and retarded calcification of the cartilage zone. Moreover, ART improved the expression of lubricin and aggrecan and reduced the expression of collagen X (Col X) and matrix metalloproteinase-13 (MMP-13). In parallel, ART normalized abnormal subchondral bone remodeling by maintaining bone volume fraction (BV/TV) and subchondral bone plate thickness (SBP Th) and reducing trabecular pattern factor (Tb.pf) compared to the vehicle-treated mice. Our results indicated that ART suppressed osteoclastic bone resorption through regulating RANKL-OPG system, restored coupled bone remodeling by indirectly inhibiting TGF-β/Smad2/3 signaling. Additionally, ART abrogated CD31hiEmcnhi vessel formation via downregulating the expression of vascular endothelial growth factor (VEGF) and angiogenin-1 in subchondral bone. In conclusion, ART attenuates ACLT-induced OA by blocking bone resorption and CD31hiEmcnhi vessel formation in subchondral bone, indicating that this may be a new therapeutic alternative for OA.
... Resistance develops rapidly when monotherapy is employed, and thus combination therapy with at least two medications with different mechanisms of action helps mitigate this. Other important considerations to make when determining which partner drugs to use include the following: matching half-lives so that a drug with a long half-life does not persist as monotherapy, pairing drugs with synergistic mechanisms of action and avoiding a combination with antagonistic pharmacokinetics [184,185]. Clinical trials of triple drug regimens with additional partner drugs added to established ACTs are currently underway in Southeast Asia [186,187]. Fast acting compounds such as artemisinin are also less likely to generate resistance rapidly compared to slower-acting compounds like clindamycin or MFQ, as demonstrated by in vitro experiments [188,189] and experience in the field. ...
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
... To circumvent the difficulties that arise from current therapies, an ideal antimalarial drug should have high efficacy and low toxicity, with few adverse effects and low rates of drug resistance (Kremsner and Krishna 2004). Thus, new, safe, and affordable medications are needed to overcome these limitations in disease control (Wells et al. 2015). ...
Malaria is a global public health problem that causes approximately 445 000 deaths annually worldwide, especially in underdeveloped countries. Because of the high prevalence and mortality of the disease, new and less toxic therapeutic agents need to be developed, such as MEFAS, a low-cost hybrid salt that consists of artesunate and mefloquine. However, the efficacy of MEFAS has been systematically demonstrated, its safety requires further investigation. This study investigated the acute toxicity of MEFAS and its precursors, artesunate, and mefloquine. A total of 42 female Swiss mice were divided into seven groups (n = 6/group) that were treated orally by gavage with vehicle (filtered water, negative control), MEFAS (50, 500, and 1000 mg/kg), and 1:1 concentrations of artesunate + mefloquine (50, 500, and 1000 mg/kg). Clinical signs of toxicity were observed for 14 d after treatment. On day 15, the animals were weighed, deeply anesthetized with isoflurane, and euthanized for subsequent collection of the liver, spleen, and kidneys. The relative organ weights were determined, followed by histopathological analysis. Artesunate + mefloquine produced toxic effects compared with the negative control group, reflected by changes in clinical signs, relative organ weights, and histopathological alterations. In MEFAS-treated animals, no changes were observed compared with the negative control group. These findings demonstrate that MEFAS is safer than artesunate + mefloquine after acute administration in mice.
... Plasmodium species [9][10][11]. Despite this strategy, artemisinin-resistant Plasmodium isolates have already emerged [12][13][14][15][16]. ...
Artemisinins are widely used to treat Plasmodium infections due to their high clinical efficacy; however, the antimalarial mechanism of artemisinin remains unresolved. Mutations in P. falciparum ATPase6 (PfATP6), a sarcoplasmic endoplasmic reticulum Ca ²⁺ -transporting ATPase, are associated with increased tolerance to artemisinin. We utilized Saccharomyces cerevisiae as a model to examine the involvement of Pmr1p, a functional homolog of PfATP6, on the toxicity of artemisinin. Our analysis demonstrated that cells lacking Pmr1p are less susceptible to growth inhibition from artemisinin and its derivatives. No association between sensitivity to artemisinin and altered trafficking of the drug efflux pump Pdr5p, calcium homeostasis, or protein glycosylation was found in pmr1∆ yeast. Basal ROS levels are elevated in pmr1∆ yeast and artemisinin exposure does not enhance ROS accumulation. This is in contrast to WT cells that exhibit a significant increase in ROS production following treatment with artemisinin. Yeast deleted for PMR1 are known to accumulate excess manganese ions that can function as ROS-scavenging molecules, but no correlation between manganese content and artemisinin resistance was observed. We propose that loss of function mutations in Pmr1p in yeast cells and PfATP6 in P. falciparum are protective against artemisinin toxicity due to reduced intracellular oxidative damage.
... In various studies, artesunate (11) has shown superior potency and efficacy as compared to quinine-1 against P. falciparum [70][71]. In the year 2004, for the development of artesunate (11) as a fast-acting drug and further industrialized its production to meet the increasing demand, researchers from different countries conducted various clinical trials on parenteral preparation of artesunate (11) [72]. However, in later studies, in case of children, where parenteral therapy cannot be given both artesunate (11) in suppositories formulation and artemether (9) via intramuscular route were found to show equal potency [73]. ...
According to WHO “World health statistics 2018”, malaria, alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children’s death in between the age of 1-5 years. Similarly, according to another report (2016), malaria accounts for approximately 3.14% of the total disease burden by cause of the world. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin 8, a major breakthrough in the antimalarial chemotherapy, was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether 9, arteether 10, and artesunic acid 11 are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. In spite of exhibiting excellent antimalarial activity by artemisinin and its derivatives; parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation by medicinal chemists all over the world. In this efforts, after extensive research, natural ozonide (1,2,4-trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. Thus, in 1992, first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported. Thus, an unusual entry to the antimalarial chemotherapy of ozonides occurred in early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).
... Our compound, N-251, is also orallyadministered and acts through a different mode of action from miltefosine, making it a good candidate for possible combination with miltefosine. According to the WHO, combination therapy is an important strategy to improve leishmaniasis therapy and also delay the emergence of resistance [63,64], as can be seen in the case of malaria, tuberculosis, and HIV [65][66][67]. In future studies, we will therefore evaluate the combinatory effect of N-251 and miltefosine in experimental VL. ...
Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.
... ACTs were recommended for the treatment of uncomplicated malaria infection which had been observed to reduce mortality rate in susceptible children (Thwing, 2011). The approved ACTs which are in circulation in the region are artesunate + amodiaquine, dihydroartemisinin + piperaquine, artesunate + mefloquine, artemether + lumefantrine and artesunate + sulfadoxinepyrimethamine (Kremsner and Krishna, 2004). ...
African countries due to resistance to conventional antimalarial drugs adopted use of artemisinin-based combination therapy (ACTs). This study aimed at evaluating the effect of ACTs on liver and renal functions. Upon approval, patients attending the University Health Centre for treatment of uncomplicated malaria after receiving prescription for ACTs were recruited for the study following their consent. A 3ml blood was collected from the participants immediately after recruitment (Day 0) and seven days later. The participants started ACTs on the day of recruitment. The blood was analysed in the laboratory for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and creatinine respectively. The data obtained at day 0 and 7 were compared by using descriptive analysis such as mean and standard deviation; t-test was used for statistical analysis and significance was considered at p ≤ 0.05. Seventy-four (74) patients participated including twenty-six (26) males and forty-eight (48) females with mean age of 37.56±13.96years and mean body mass index (BMI) of 25.92±2.99kg/m 2. ALT was elevated in participants from 6.66±5.27IU/L to 6.71±5.48IU/L while creatinine clearance of male participants reduced from 139.10±69.11mL/min to134.25±23.87mL/min. The study showed that ACTs were associated with elevated ALT in participants and reduced renal function in males.
... Phase II and III studies began in 2006 in a joint undertaking with the University of Tubingen in Germany (P. G. Kremsner), an industrial partner, and the Walter Reed Army Institute of Research, with the point of conveying an intravenous artesunate readiness to the business sector in 2009, to be made by medication controls [155]. Notwithstanding i.v. ...
... Specificity was assessed by analyzing both blank and spiked samples. To assess the linearity, matrix-fortified calibration samples were prepared at six concentrations (5,10,20,30,40, and 50 μg/kg) and curves were prepared by plotting the response factor. To estimate the accuracy (expressed as recovery) and precision (expressed as RSD), in a single day, blank matrixes (n = 3) were spiked with fortification levels of 5, 10, and 20 μg/kg. ...
An analytical approach using a modified quick, easy, cheap, effective, rugged, and safe extraction method followed by liquid chromatography with electrospray ionization tandem mass spectrometry was developed herein for the determination of artesunate and its metabolite dihydroarteminsinin, in porcine muscle, egg, eel, flatfish, and shrimp. 10% trichloroacetic acid in acetonitrile mixed with ethyl acetate was used as an extraction solvent. To obtain a good separation, a Phenomenex Kinetex reversed‐phase analytical column was selected with mobile phases consisting of distilled water (A) and acetonitrile (B), both containing 0.05% formic acid. Good linearity was achieved using matrix‐matched calibrations constructed from six concentrations (5–50 μg/kg) with determinant coefficients ≥ 0.9918. Recoveries estimated from three spiking concentrations (5, 10, and 20 μg/kg) ranged between 71.3 and 104.7% in all matrixes with relative standard deviations ≤8.3%. A variety of samples purchased from markets in Seoul were tested following the protocol described herein. The artesunate and dihydroarteminsinin were not detected in any matrix. The methodology proposed could be used for routine determination of artesunate and its metabolite, dihydroartemisinin in various animal products having variable percentages of fat and protein.
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... Artesunate, artemisinin, and their derivatives are now widely used as antimalarial drugs. [46][47][48][49][50] Iron(II)-induced cleavage of peroxide bonds in artesunate derivatives has been found to produce carbon-centered free radicals and to exert antimalarial activity as alkylated spe- =7.50 gauss for the DMPO/ •13 CH 3 adduct. C: Iron(II) and DMSO were introduced into a 500-mM DMPO solution in distilled water to give 2 mM and 1 M, respectively. ...
Artemisinin was discovered in 1971 as a constituent of the wormwood genus plant (Artemisia annua). This plant has been used as an herbal medicine to treat malaria since ancient times. The compound artemisinin has a sesquiterpene lactone bearing a peroxide group that offers its biological activity. In addition to anti-malarial activity, artemisinin derivatives have been reported to exert antitumor activity in cancer cells, and have attracted attention as potential anti-cancer drugs. Mechanisms that might explain the antitumor activities of artemisinin derivatives reportedly induction of apoptosis, angiogenesis inhibitory effects, inhibition of hypoxia-inducible factor-1α (HIF-1α) activation, and direct DNA injury. Reactive oxygen species (ROS) generation is involved in many cases. However, little is known about the mechanism of ROS formation from artemisinin derivatives and what types of ROS are produced. Therefore, we investigated the iron-induced ROS formation mechanism by using artesunate, a water-soluble artemisinin derivative, which is thought to be the underlying mechanism involved in artesunate-mediated cell death. The ROS generated by the coexistence of iron(II), artesunate, and molecular oxygen was a hydroxyl radical or hydroxyl radical-like ROS. Artesunate can reduce iron(III) to iron(II), which enables generation of ROS irrespective of the iron valence. We found that reduction from iron(III) to iron(II) was activated in the acidic rather than the neutral region and was proportional to the hydrogen ion concentration.
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... The most desirable profile for antimalarial combination therapies has been described previously. 36,[54][55][56] Besides an exemplary safety profile, which is even more essential for drugs being used to treat individuals without clinical symptoms of malaria, some characteristics of an ideal combination therapy include a stable product given at high enough doses to remain effective even if resistance is present to the other drug, independent modes of action of the combined drugs with different metabolic targets, matching post-treatment drug activity profiles (based on elimination half-lives, dosage, and drug sensitivity), and if possible, drugs that are robust to the evolution of resistance (ie, high-level resistance evolves by a complex rather than simple mechanism) with antagonisticresistant mechanisms. An example of antagonistic-resistant mechanisms might be those for mefloquine and piperaquine. ...
Based on the emergence and spread throughout the Greater Mekong Subregion (GMS) of multiple artemisinin-resistant lineages, the prevalence of multidrug resistance leading to high rates of artemisinin-based combination treatment failure in parts of the GMS, and the declining malaria burden in the region, the World Health Organization has recommended complete elimination of falciparum malaria from the GMS. Mass drug administration (MDA) is being piloted as one elimination intervention to be employed as part of this effort. However, concerns remain as to whether MDA might exacerbate the already prevalent problem of multidrug resistance in the region. In this review, we briefly discuss challenges of MDA, the use of MDA in the context of multidrug-resistant malaria, and the potential of different drug combinations and drug-based elimination strategies for mitigating the emergence and spread of resistance.
... Due to lack of effectiveness of most antimalarial drugs, traditional medicine used either solely or combined with orthodox medicines has become regular practice amongst people. This is prevailing in underdeveloped countries where the orthodox drugs are expensive to major part of the local community (Kremsner and Krishna 2004). Often times in West Africa, antimalarial traditional therapies are used simultaneously, before or after using these orthodox drugs. ...
Startling rate of malaria parasite resistance to artemisinin and its derivatives has led to possible herb–drug antimalarial combination therapy. This study assessed the effect of co-administration of artemisinin and Ricinodendron heudelotii extract on certain liver and antioxidant indices in rats. Four groups containing ten rats each were administered distilled water (group A), artemisinin only (group B), artemisinin with R. heudelotii extract (group C), and R. heudelotii extract only (group D). Serum biochemical values and antioxidant parameters were determined using standard methods respectively. The results revealed that the total protein level increased significantly (p < 0.05) in group C. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities increased significantly (p < 0.05) in the group administered artemisinin only but was regulated to control level both in groups C and D. The liver reduced gutathione (GSH) concentration decreased in the group administered artemisinin only. Similarly, malondialdehyde (MDA) level significantly increased (p < 0.05) in group A while groups C and D showed decrease in MDA and catalase concentrations. Histological examination showed that few of the hepatocytes were necrotic in the group administered artemisinin only while the group administered artemisinin and extract showed mild to moderate central venous congestion and periportal cellular infiltration. The study indicates that the bioactive constituents of the R. heudelotii extract might either have a regulatory effect on artemisinin toxicity or synergistically enhance its activity. Such bioconstituents can further be isolated and characterized for drug development to tackle Plasmodium falciparum resistance.
... However, the choice of the right partner drug will be critical for the success of these new molecules, as the WHO enforces the application of antimalarials in combination therapy (3). In addition to protecting each other from drug resistance, two molecules to be combined need to be compatible for coformulation, should have matching pharmacokinetic profiles, and must not have unfavorable polypharmacology (4)(5)(6). Ideally, the two molecules would potentiate each other, thereby decreasing the duration of treatment and the required doses. Thus, combinatorial chemotherapy not only can reduce the risk of drug resistance but also can enhance drug safety and drug efficacy, enabling the ambitious goal of a "single-exposure radical cure" (7,8). ...
Combinatorial chemotherapy is imperative for the treatment of malaria. However, finding a suitable partner drug for a new candidate is challenging. Here we develop an algorithm that identifies all the gene pairs of Plasmodium falciparum which possess orthologues in yeast that have a synthetic lethal interaction, but are absent in humans. This suggests new options for drug combinations, in particular for inhibitors of targets like P. falciparum calcineurin, cation ATPase 4, or phosphatidylinositol 4-kinase.
... Due to lack of effectiveness of most antimalarial drugs, traditional medicine used either solely or combined with orthodox medicines has become regular practice amongst people. This is prevailing in underdeveloped countries where the orthodox drugs are expensive to major part of the local community (Kremsner and Krishna 2004). Often times in West Africa, antimalarial traditional therapies are used simultaneously, before or after using these orthodox drugs. ...
Compounds containing 4-aminoquinoline moiety are known to exhibit various pharmacological properties such as antimalarial, anticancer, antitubercular and antivirus. Chloroquine, hydroxyquinoline and amodiaquine are a few well-known 4-aminoquinoline-based medications. Many new derivatives of this compound have also been synthesized and developed as lead molecules in the drug development process. The already existing 4-aminoquinoline-based drugs are also explored for the treatment of more recent diseases like coronavirus disease 2019 (COVID-19). Drug resistance also gives scope for testing newer molecules against various other pathogenic infections. This molecule has always drawn the attention of medicinal chemists for the synthesis of new derivatives. This article gives an overview of the recent development of 4-aminoquinoline derivatives and their pharmacological activities.KeywordsAnticancerAntimalarialAntitubercularCoronavirus
Due to the outbreak of the SARS-CoV-2 virus, drug repurposing and Emergency Use Authorization have been proposed to treat the coronavirus disease 2019 (COVID-19) during the pandemic. While the efficiency of the drugs has been discussed, it was identified that certain compounds, such as chloroquine and hydroxychloroquine, cause QT interval prolongation and potential cardiotoxic effects. Drug-induced cardiotoxicity and QT prolongation may lead to life-threatening arrhythmias such as torsades de pointes (TdP), a potentially fatal arrhythmic symptom. Here, we evaluated the risk of repurposed pyronaridine or artesunate-mediated cardiac arrhythmias alone and in combination for COVID-19 treatment through in vitro and in silico investigations using the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. The potential effects of each drug or in combinations on cardiac action potential (AP) and ion channels were explored using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Chinese hamster ovary (CHO) cells transiently expressing cardiac ion channels (Nav1.5, Cav1.2, and hERG). We also performed in silico computer simulation using the optimized O’Hara-Rudy human ventricular myocyte model (ORd model) to classify TdP risk. Artesunate and dihydroartemisinin (DHA), the active metabolite of artesunate, are classified as a low risk of inducing TdP based on the torsade metric score (TMS). Moreover, artesunate does not significantly affect the cardiac APs of hiPSC-CMs even at concentrations up to 100 times the maximum serum concentration (C max ). DHA modestly prolonged at APD 90 (10.16%) at 100 times the C max . When considering C max , pyronaridine, and the combination of both drugs (pyronaridine and artesunate) are classified as having an intermediate risk of inducing TdP. However, when considering the unbound concentration (the free fraction not bound to carrier proteins or other tissues inducing pharmacological activity), both drugs are classified as having a low risk of inducing TdP. In summary, pyronaridine, artesunate, and a combination of both drugs have been confirmed to pose a low proarrhythmogenic risk at therapeutic and supratherapeutic (up to 4 times) free C max . Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.
Medicinal chemists around the world have been inspired by nature and have successfully extracted chemicals from plants. Research on enzymatic modifications of naturally occurring compounds has played a critical role in the search for biologically active molecules to treat diseases.
This book set explores compounds of interest to researchers and clinicians. It presents a comprehensive analysis about the medicinal chemistry (drug design, structure-activity relationships, permeability data, cytotoxicity, appropriate statistical procedures, molecular modelling studies) of different compounds. Each chapter brings contributions from known scientists explaining experimental results which can be translated into clinical practice.
Volume 2 gives (1) a detailed overview of the sesquiterpenes polypharmacology, (2) an interesting journey around the world of cannabinoids that reveals the development of new synthetic Δ9-THC derivatives, (3) the design of specific formulations to overcome the volatility of small sized terpenes-based essential oils, (4) an update on the latest generations of endoperoxides endowed with antimalarial activity and finally (5) a summary of MedChem strategies to fix the most common issues in formulating terpene derivatives (like low potency and poor solubility).
The objective of this book set is to fulfill gaps in currently acquired knowledge with information from the recent years. It serves as a guide for academic and professional researchers and clinicians.
The utilization of nanomaterials to release therapeutic agents under the control of light stimuli to enhance the therapeutic efficacy is one of the major challenges in nanomedicine. Because of their wide variety, good biocompatibility and facile functionalization, many inorganic nanoparticles (NPs) offer great potential in this respect. Their engineering with suitable photoactivatable components can open up exciting avenues in the field of the most intriguing unconventional therapeutic approaches for fighting cancer and bacterial diseases, such as photodynamic therapy (PDT), nitric oxide (NO) photodynamic therapy (NO-PDT) and photothermal therapy (PTT). These emerging treatment modalities are based on the localized cytotoxic action induced by a “burst” of singlet oxygen, nitric oxide or heat, generated with superb spatiotemporal control by appropriate photoprecursors, and in principle, they can be alternatives to, or used in combination with, conventional chemotherapeutic and antibiotic drugs. This account illustrates an overview of the work carried out in our research group over the last years and specifically focuses on inorganic NPs based on non-metallic- and noble metal scaffolds, highlighting the logical design and their potential applications in PDT, NO-PDT and PTT.
Background
Medicinal plants have been successfully used as an alternative source of drugs for the treatment of microbial diseases. Finding a novel treatment for malaria is still challenging, and various extracts from different wild desert plants have been reported to have multiple medicinal uses for human public health, this study evaluated the antimalarial efficacy of several Egyptian plant extracts.
Methods
We assessed the cytotoxic potential of 13 plant extracts and their abilities to inhibit the in vitro growth of Plasmodium falciparum (3D7), and to treat infection with non-lethal Plasmodium yoelii 17XNL in an in vivo malaria model in BALB/c mice.
Results
In vitro screening identified four promising candidates, Trichodesma africanum, Artemisia judaica, Cleome droserifolia , and Vachellia tortilis , with weak-to-moderate activity against P. falciparum erythrocytic blood stages with mean half-maximal inhibitory concentration 50 (IC 50 ) of 11.7 μg/ml, 20.0 μg/ml, 32.1 μg/ml, and 40.0 μg/ml, respectively. Their selectivity index values were 35.2, 15.8, 11.5, and 13.8, respectively. Among these four candidates, T. africanum crude extract exhibited the highest parasite suppression in a murine malaria model against P. yoelii .
Conclusion
Our study identified novel natural antimalarial agents of plant origin that have potential for development into therapeutics for treating malaria.
Parasitic infections have enormous health, social, and economic influence worldwide, predominantly in tropical and subtropical areas. Diseases caused by protozoan parasites, like malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, giardiasis, etc. have major contributions in the global death rate due to infections. The burden of these parasitic protozoans has increased around the globe due to the lack of effective, commercially-availablevaccines, and the production of less efficacious drugs with poor pharmacokinetics. Unfortunately, in areas with endemic protozoan infections, antiparasitic drugs use and efficacy have been compromised by drug resistance. The development of resistance has been found to be associated with decreased drug uptake, the export of drugs from parasites, genetic modifications, loss of drug activity, and alteration of the drug target. Recently, the isolation and characterization of resistance-related genes and proteins have increased the knowledge about drug resistance greatly and provided a way forward for the identification of new drug candidates. In this chapter, our focus will be on the mode of action and mechanism of resistance development of those drugs used to treat protozoal infections in human including malaria, toxoplasmosis, trypanosomiasis, giardiasis, cystoisosporiasis, babesiosis, and leishmaniasis.
Background:
The inflammatory reaction is an important mechanism of pathogenesis of abdominal aortic aneurysm (AAA). Artesunate (AS) has been found to have anti-inflammatory effects in cardiovascular disease. The purpose of this study was to investigate whether AS could inhibit the development of AAA.
Materials and methods:
AngII infused ApoE (-/-) male mice were selected as AAA model. Mice were spilt into three groups, the experimental control group (AngII), the AS treatment group (AngII + AS) and the negative control group (Vehicle) with 14 in each group. Daily administration of AS (100 mg/kg/d) or vehicle performed 3 day before the perfusion. At the end of the 28-day experiment, animal ultrasound and electronic digital caliper were used to measure the diameter of abdominal aorta. Histologic assays were performed to observe the microstructure of the aorta wall. Immunofluorescence staining was performed to detect inflammatory cells, as well as the levels of matrix metalloproteinases (MMPs). The transcription of cytokines and adhesion molecules were investigated by real-time fluorescence quantitative PCR (qPCR). Western blotting was performed to determine whether the NF-κB pathway is involved in the mechanism.
Results:
While AS failed to reduce the incidence of AAA, AS effectively reduced the diameter of AAA independently of blood pressure effects. Immunofluorescence detection showed that AS effectively reduced the levels of CD45+ cells and MAC3+ macrophages as well as MMP-2 and MMP-9. qPCR revealed that AS reduced mRNA transcription levels of MMP-2, MMP-9, the cytokine IL-1β, TNF-α, adhesion molecules ICAM-1, VCAM-1. AS decreased the levels of NF-κB signaling pathway in aorta.
Conclusions:
AS can attenuate the development of AAA in mice. The possible mechanism is anti-inflammation.
In the present study, a novel series of side chain-modified quinoline β-enaminones were synthesized in good-to-excellent yields. The structures of all the synthesized compounds have been established with the help of spectral and analytical data and also by X-ray crystallography. All the compounds were screened for their potential in vitro anti-malarial activity against chloroquine resistant strain K1 and chloroquine sensitive strain 3D7. The compounds were also evaluated for their in vitro microfilaricidal and adulticidal effect against B. malayi microfilariae and adult worms using ivermectin as positive control. The cytotoxicity of the compounds was checked against Vero cell line and all the compounds were found to be non-toxic. The compounds showed low antimalarial activities against both the plasmodial strains compared to the standard drug chloroquine. However, four of the evaluated compounds have shown significant in vitro adulticidal activity and their percentage inhibition were found to be 68, 55, 64, and 66, respectively. Two of these were selected for further preliminary in vivo activity studies.Graphical abstract
Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of “Chimeric Bitherapy (CB)” which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.
Development of resistance by malaria parasites to conventional antimalarial drugs has rejuvenated the exploration of herbal medicine as alternatives. Also, the increasing rate of the use of herbal antimalarial remedies in combination with conventional antimalarial drugs (both synthetic and semi-synthetic) has inspired researchers to validate their herb-drug interaction effects. This review evaluated the interaction outcomes between herbal antimalarial drugs in combination with conventional antimalarial drugs. With the aid of electronic databases, Pubmed and Google scholar, articles related to this subject were sourced from English peer reviewed scientific journals published from 2003 to 2020. Search terms used include “antimalarial-herbal drugs interaction”, “antimalarial medicinal plant interactions with conventional antimalarial drugs”, “drug-herbal interactions, “antimalarial drugs and medicinal plants”. Synergistic, antagonistic and none effects were reported among 30 studies reviewed. Among 18 in vivo studies on P. berghei and P. yoelii nigerense infected mice model, 14 showed synergism, 3 showed antagonism and 1 involving three plants showed both effects. Among 9 in-vivo studies involving normal animal (non-infected), 2 showed antagonism, 2 showed synergism and 5 showed none-effects. Two (2) studies on human volunteers and one (1) in vitro quantitative study showed that Garcinia kola reduced plasma concentrations of quinine and halofantrine. Generally, majority of herbal antimalarial drugs showed synergistic effects with CAMDs. Vernonia amygdalina was the most studied plant compared to others. Consequently, herbal remedies that produced synergistic effects with conventional antimalarial drugs may be prospects for standardization and development of antimalarial-medicinal plant combination therapy that could curtail malaria resistance to conventional antimalarial therapies.
Ursolic acid (UA) is a triterpene with a broad array of pharmacological activities. In leishmaniasis, UA killed different species of parasites, and it was active in the experimental model of cutaneous and visceral leishmaniasis. Thus, the objective of this work was to study the therapeutic efficacy of the conventional drugs amphotericin B (AmB) or glucantime (Glu) combined with UA in experimental visceral and cutaneous leishmaniasis, respectively. L. (L.) infantum-infected hamsters were treated with AmB alone or combined with UA. L. (L.) amazonensis-infected BALB/c mice were treated with Glu alone or combined with UA. Animals were treated for 15 consecutive days by intraperitoneal or intralesional routes. Following one week after the last dose, the tissue parasitism and cellular immune responses were analyzed. Hamsters treated with 0.2 and 1.0 mg/kg of AmB plus 1.0 mg/kg of UA showed low hepatic and splenic parasitisms; however, AmB given as monotherapy did not reduce the number of viable parasites in the spleen of treated animals. In cutaneous leishmaniasis, Glu given as monotherapy was inactive at 2.0 mg/kg, showed mild activity at 10.0 mg/kg, and at 50.0 mg/kg was highly active at eliminating parasites in the skin. When animals were treated with Glu plus UA, higher leishmanicidal activity was observed in comparison to all groups treated with monotherapy schemes, and such activity was related to lesion improvement and upregulation of IFN-γ production. Altogether, data suggest that the association of drugs for the treatment of leishmaniasis can increase the efficiency of the treatment and decrease the toxicity associated to the conventional drugs.
Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC 50 : 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that ( -)-R,S- dehydroemetine mimicked the bound pose of emetine more closely than ( -)-S,S- dehydroisoemetine. ( -)-R,S- dehydroemetine (IC 50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with ( -)-S,S- dehydroisoemetine (IC 50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum , the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed ( -)-R,S- dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and ( -)-R,S- dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action.
According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite‐resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 “Nobel Prize in Physiology or Medicine” was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as “Nobel medicine.” The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971‐2019) in the medicinal chemistry of ART‐derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.
8-Methoxy-γ-humulene, (E)-8-methoxy-β-farnesene, 12-methoxy-β-sesquiphellandrene and 12-methoxyzingiberene can be synthesised in amorphadiene synthase-catalysed reactions from 8- and 12-methoxyfarnesyl diphosphates due to the highly plastic yet tightly controlled carbocationic chemistry of this sesquiterpene cyclase.
Multidrug resistance in Plasmodium falciparum has been associated with gene amplification of pfmdr1. We studied the corresponding gene amplification in P. falciparum from blood samples of malaria patients in the Sifontes Municipality, Bolívar State, Venezuela, known as the highest region of incidence of malaria. Fifty-five P. falciparum DNA samples were extracted from different hosts and used for qPCR assessment of the copy number of pfmdr1. The assay detected four copies of the multidrug-resistant line P. falciparum Dd2 in comparison with the P. falciparum 3D7 that had only one copy. In the patients’ samples, the copy number of pfmdr1 was a single copy in 80% and 20% left distributed in different copy numbers up to seven.
Osteosarcoma is the most common bone tumor and characterizes a high metastatic potential. In osteosarcoma, angiogenesis is reported to be closely associated with tumor metastasis. Understanding the underlying mechanisms and accordingly developing therapeutic strategies are urgently desired. Antimalarial agent, artemisinin, has been reported to inhibit tumor angiogenesis. However, we still knew little about the effects of artemisinin on angiogenesis and its potential molecular mechanisms in human osteosarcoma. In this study, we found that artemisinin could induce both the expression and secretion of thrombospondin‐1 (TSP‐1) in a dose‐dependent way in osteosarcoma cells. In addition, TSP‐1 could effectively restore the artemisinin‐induced suppression of angiogenesis in human umbilical vein endothelial cells (HUVECs). More importantly, we further found that phosphorylation of cAMP response element‐binding protein (CREB) bond specifically to the promoter of TSP‐1 and promoted its transcriptional activation. Moreover, our results showed that artemisinin could induce the phosphorylation of CREB via the activation of p38 mitogen‐activated protein kinase (MAPK) signaling pathway in osteosarcoma cells. In vivo, we also found that artemisinin could inhibit osteosarcoma proliferation and angiogenesis by regulating the p38 MAPK/CREB/TSP‐1 signaling pathway. Taken together, our findings indicated that artemisinin could inhibit angiogenesis by regulating the p38 MAPK/CREB/TSP‐1 signaling pathway in osteosarcoma.
Introduction
Artemisinin-based combination therapies (ACTs) are the first-line antimalarial drugs used to treat uncomplicated Plasmodium falciparum alaria in many endemic countries worldwide. The present work reviewed the therapeutic efficacy of ACT in Cameroon more than 10 years after the initial change in national drug policy in 2004.
Methods
A PubMed literature search was performed to analyse clinical trials conducted in Cameroon from 2001 to May 2017. Clinical studies that evaluated ACT for the treatment of uncomplicated falciparum malaria in children or adults, and reported efficacy and/or safety, were included. In addition, a small network meta-analysis (NMA) with a frequentist approach was performed.
Results
Six papers were selected from 48 articles screened and were full-text reviewed. The efficacy of both artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) ranged from moderate to high, with polymerase chain reaction-corrected cure rates ranging from 96.7 to 100% and 88.2 to 100%, respectively, in per-protocol analysis, and 86.2 to 96.7% and 74.0 to 90.6%, respectively, in intention-to-treat analysis. The malaria evidence network suggested that AL and ASAQ efficacies were comparable. The highest day 3 parasite positivity rate was 8.2% for ASAQ and 4% for AL. A novel ACT, artesunate-atovaquoneproguanil (ASATPG) was tested once and showed a cure rate of 100%. Based on an ITT approach, the NMA revealed that AL was more efficacious than ASAQ, but the difference was not statistical significant (706 participants, three randomised clinical trials (RCT); OR 1.25, 95%CI 0.78–2.00). Adverse events ranged from mild to moderate severity but were not directly attributed to drug intake.
Conclusion
ACTs are still effective and safe in Cameroon; however, there are insufficient data on their efficacy, safety and tolerability, therefore more RCTs should be conducted, including novel ACTs.
Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance; Pgh1 has also been implicated in resistance to mefloquine and halofantrine. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.
Several antibiotics which inhibit protein synthesis on 70S ribosomes, including clindamycin, pirlimycin, 4'-pentyl-N-demethyl
clindamycin, four tetracyclines, chloramphenicol, thiamphenicol, and erythromycin, had antimalarial effects against Plasmodium
falciparum in culture which were greatly influenced by the duration of drug exposure and by oxygen tension. In 96-h incubations,
potency was increased by a factor of up to 10(6) over the first 48-h period and by a factor of up to 10(4) in 15% O2 versus
1% O2. Two aminoglycosides, kanamycin and tobramycin, had no antimalarial activity. Rifampin and nalidixic acid, which inhibit
nucleic acid synthesis, were not similar to the 70S inhibitors. The mitochondrial inhibitors Janus Green, rhodamine 123, antimycin
A1, and 8-methylamino-8-desmethyl riboflavin had activities which were influenced by the duration of exposure and oxygen tension.
Quinoline-containing antimalarial agents, ionophores, and other antimalarial drugs were influenced to a minor extent by the
duration of exposure but were not affected by oxygen tension. These data can best be explained by the hypothesis that antimalarial
70S ribosome-specific protein synthesis inhibitors are toxic to the parasites by acting on the mitochondrion.
In a randomized trial, a 4-day quinine-clindamycin regimen was compared with the standard 7-day quinine regimen for 100 Gabonese
children (50 children in each group) with severe Plasmodium falciparum malaria. In each group, only one patient died. Parasite
clearance and fever clearance times were significantly shorter in the quinine-clindamycin group (P = 0.03 and P = 0.01, respectively)
than in the quinine group, and significantly more recurring fever episodes occurred in the quinine group than in the quinine-clindamycin
group shortly after initial fever clearance and parasite clearance (P < 0.001).
In order to characterize the delayed effect of clindamycin and macrolide antibiotics against Toxoplasma gondii tachyzoites (E. R. Pfefferkorn and S. E. Borotz, Antimicrob. Agents Chemother. 38:31-37, 1994), we have carefully examined the replication of parasites as a function of time after drug addition. Intracellular tachyzoites treated with up to 20 microM clindamycin (> 1,000 times the 50% inhibitory concentration) exhibit doubling times indistinguishable from those of controls (approximately 7 h). Drug-treated parasites emerge from infected cells and establish parasitophorous vacuoles inside new host cells as efficiently as untreated controls, but replication within the second vacuole is dramatically slowed. Growth inhibition in the second vacuole does not require continued presence of drug, but it is dependent solely on the concentration and duration of drug treatment in the first (previous) vacuole. The susceptibility of intracellular parasites to nanomolar concentrations of clindamycin contrasts with that of extracellular tachyzoites, which are completely resistant to treatment, even through several cycles of subsequent intracellular replication. This peculiar phenotype, in which drug effects are observed only in the second infectious cycle, also characterizes azithromycin and chloramphenicol treatment, but not treatment with cycloheximide, tetracycline, or anisomycin. These findings provide new insights into the mode of clindamycin and macrolide action against T. gondii, although the relevant target for their action remains unknown.
In a randomized trial, a three-dose quinine monotherapy was compared with short-term combination regimens of quinine-clindamycin
and quinine-doxycycline for treating adult Gabonese patients with Plasmodium falciparum malaria. In quinine-treated patients,
only 38% were ultimately cured. In contrast, more than 90% of patients were cured after treatment with either combination
regimen.
Studies of 652 adults and children with acute uncomplicated falciparum malaria were done to determine the optimum treatment
of multidrug-resistant Plasmodium falciparum malaria on the Thai-Burmese border. Single-dose artesunate (4 mg/kg) plus mefloquine (25 mg of base/kg) gave more rapid symptomatic
and parasitologic responses than high-dose mefloquine alone but did not improve cure rates. Three days of artesunate (total
dose, 10 rug/kg) plus mefloquine was 98% effective compared with a 28-day failure rate of 31% with high-dose mefloquine alone
(relative risk [RR], 0.06; 95% confidence interval [CI], 0.02–0.2; P < .0001). By day 63, the reinfection adjusted failure rates were 2% and 44%, respectively (P < .0001). Artesunate also prevented high-grade failures. Both drugs were well tolerated. No adverse effects were attributable
to artesunate. Vomiting was reduced significantly by giving mefloquine on day 2 of treatment (RR, 0.40; 95% CI, 0.20–0.79;
P = .009. Artesunate (10 mg/kg over 3 days) plus mefloquine (25 mg/kg) is currently the most effective treatment for falciparum
malaria in this area of increasing mefloquine resistance.
The in vivo and in vitro effects of antimalarials on cytoadherence and rosette formation were studied in 17 patients with
severe and 46 with uncomplicated falciparum malaria. Cytoadherence was increased in severe malaria (P < .001). Artesunate and artemether were more potent than quinine in inhibiting both adherence properties. Artesunate was
the most rapidly acting drug tested, producing >50% inhibition of both cytoadherence and rosetting in vivo and in vitro within
2 h of drug exposure. Exposure to quinine for ⩾4 h in vivo reduced rosetting by >50%, but not cytoadherence. Quinine did not
reduce cytoadherence or rosetting significantly in vitro with exposure times of ⩽8 h. These results suggest that artemisinin
derivatives are more effective than quinine in preventing pathologic processes in parasitized erythrocytes that contribute
to microvascular obstruction in severe malaria.
Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to novel unrelated antimalarials. To test this hypothesis, different Plasmodium falciparum clones having varying numbers of preexisting resistance mechanisms were treated with two new antimalarial agents: 5-fluoroorotate and atovaquone. All parasite populations were equally susceptible in small numbers. However, when large populations of these clones were challenged with either of the two compounds, significant variations in frequencies of resistance became apparent. On one extreme, clone D6 from West Africa, which was sensitive to all traditional antimalarial agents, failed to develop resistance under simple nonmutagenic conditions in vitro. In sharp contrast, the Indochina clone W2, which was known to be resistant to all traditional antimalarial drugs, independently acquired resistance to both new compounds as much as a 1,000 times more frequently than D6. Additional clones that were resistant to some (but not all) traditional antimalarial agents acquired resistance to atovaquone at high frequency, but not to 5-fluoroorotate. These findings were unexpected and surprising based on current views of the evolution of drug resistance in P. falciparum populations. Such new phenotypes, named accelerated resistance to multiple drugs (ARMD), raise important questions about the genetic and biochemical mechanisms related to the initiation of drug resistance in malarial parasites. Some potential mechanisms underlying ARMD phenotypes have public health implications that are ominous.
We conducted a meta-analysis using individual patient data from randomized controlled trials comparing artemether and quinine in severe falciparum malaria. Eleven trials were identified, of which 8 were clearly randomized. Original individual patient data on 1919 patients were obtained from 7 trials, representing 85% of the patients in the original 11 studies. Overall there were 136 deaths among the 961 patients treated with artemether, compared with 164 in the 958 treated with quinine [14% vs 17%, odds ratio (95% confidence interval) 0·8 (0·62 to 1·02), P = 0·08]. There were no differences between the 2 treatment groups in coma recovery or fever clearance times, or the development of neurological sequelae. However, the combined ‘adverse outcome’ of either death or neurological sequelae was significantly less common in the artemether group [odds ratio (95% CI) 0·77 (0·62 to 0·96), P = 0·02], and treatment with artemether was associated with significantly faster parasite clearance [hazard ratio (95% CI) 0·62 (0·56 to 0·69), P < 0·001]. In subgroup analyses artemether was associated with a significantly lower mortality than quinine in adults with multisystem failure. In the treatment of severe falciparum malaria artemether is at least as effective as quinine in terms of mortality and superior to quinine in terms of overall serious adverse events. There was no evidence of clinical neurotoxicity or any other major side-effects associated with its use.
The efficacy of artemisinin monotherapy was studied in 227 patients with uncomplicated falciparum malaria. They all received artemisinin at t = 0 hr, t = 8 hr, and thereafter once daily; treatment was extended at random until they had taken either 5 days of artemisinin followed by 2 days of placebo (A5), or 7 days (A7) of artemisinin. The adult artemisinin dose was 500 mg; children aged < 15 years received 10 mg/kg per dose. The median (range) parasite clearance time was 39 (8-112) hr for A5 and 43 (38-104) hr for A7 (P = 0.085). The recrudescence rates were similar between the groups. The lowest parasite count achieved during treatment (Pterm) was associated with the occurrence of recrudescence (P = 0.046, Cox regression model); it was lower for patients with a radical cure or late recrudescence than for early recrudescence (P = 0.034, t-test). Artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. Extending the duration of monotherapy from 5 days to 7 days does not reduce recrudescence.
A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and
December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14 017 (85%)
individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single
dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under
surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance
period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and
2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates,
was 0.91 (95% CI 0.68–1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the
incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA
could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive
number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.
The impact of climate change on disease patterns is controversial. However, global burden of disease studies suggest that
infectious diseases will contribute a proportionately smaller burden of disease over the next 2 decades as non-communicable
diseases emerge as public health problems. However, infectious diseases contribute proportionately more in the poorest quintile
of the population. Notwithstanding the different views of the impact of global warming on vector-borne infections this paper
reviews the conditions which drive the changing epidemiology of these infections and suggests that such change is linked by
common themes including interactions of generalist vectors and reservoir hosts at interfaces with humans, reduced biodiversity
associated with anthropogenic environmental changes, increases in Plasmodium falciparum: P. vivax ratios and well-described land use changes such as hydrological, urbanization, agricultural, mining and forest-associated
impacts (extractive activities, road building, deforestation and migration) which are seen on a global scale.
The emergence of Plasmodium falciparum resistance to widely used antimalarial drugs such as chloroquine (CQ) has made malaria control and treatment much more difficult. This is particularly dramatic for Africa, as few affordable alternatives are available. Drug pressure has been identified as one of the key factors for the emergence and spread of resistance. The contribution of the extensive use and misuse of antimalarial drugs to the selection of resistant parasites became particularly evident during the Global Malaria Eradication campaign, launched by World Health Organization (WHO) in 1955. The first reports confirming P. falciparum resistance to CQ came almost simultaneously in the early 1960s from South America and South-East Asia, where direct or indirect (through use of medicated cooking salt) mass drug administration (MDA) had been implemented. Similar approaches were very limited in Africa, where P. falciparum resistance to CQ was first reported from the eastern region in the late 1970s and spread progressively west. Most African countries still rely heavily on CQ as first-line treatment despite various levels of resistance, although some states have changed to sulphadoxine-pyrimethamine (SP) as the first-line drug. Unfortunately, the predicted SP useful therapeutic life might be very short, probably because of its prolonged half-life, causing a higher probability of selecting resistant strains and a consequent fast development of resistance. CQ resistance is not evenly distributed and important differences can be found within and between countries. It seems to have spread more rapidly in East than in West Africa. Considering the high level of CQ use in West Africa, other factors such as intensity of transmission, population immunity or population movements should be considered when explaining the different levels of resistance. Understanding such factors may help us in devising strategies to contain the spread of drug resistance.
Background:
Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment.
Methods:
We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared.
Findings:
The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment.
Interpretation:
The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.
The combination of atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis.
320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear.
25 of 140 children in the placebo group and none of the 125 children in the atovaquone plus proguanil group had positive smears during chemosuppression (p<0.001). Adverse events during the chemosuppression phase did not differ between the groups.
The combination of atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.
Summary:
Background: Addition of artemisinin derivatives to existing drug regimens for malaria could reduce treatment failure and transmission potential. We assessed the evidence for this hypothesis from randomised controlled trials.
Methods: We undertook a meta-analysis of individual patients' data from 16 randomised trials (n=5948) that studied the effects of the addition of artesunate to standard treatment of Plasmodium falciparum malaria. We estimated odds ratios (OR) of parasitological failure at days 14 and 28 (artesunate combination compared with standard treatment) and calculated combined summary ORs across trials using standard methods.
Findings: For all trials combined, parasitological failure was lower with 3 days of artesunate at day 14 (OR 0·20, 95% CI 0·17–0·25, n=4504) and at day 28 (excluding new infections, 0·23, 0·19–0·28, n=2908; including re-infections, 0·30, 0·26–0·35, n=4332). Parasite clearance was significantly faster (rate ratio 1·98, 95% CI 1·85–2·12, n=3517) with artesunate. In participants with no gametocytes at baseline, artesunate reduced gametocyte count on day 7 (OR 0·11, 95% CI 0·09–0·15, n=2734), with larger effects at days 14 and 28. Adding artesunate for 1 day (six trials) was associated with fewer failures by day 14 (0·61, 0·48–0·77, n=1980) and day 28 (adjusted to exclude new infections 0·68, 0·53– 0·89, n=1205; unadjusted including reinfections 0·77, 0·63–0·95, n=1958). In these trials, gametocytes were reduced by day 7 (in participants with no gametocytes at baseline 0·11, 0·09–0·15, n=2734). The occurrence of serious adverse events did not differ significantly between artesunate and placebo.
Interpretation: The addition of 3 days of artesunate to standard antimalarial treatments substantially reduce treatment failure, recrudescence, and gametocyte carriage.
Evidence of emerging resistance to chloroquine by Plasmodium vivax is described from Irian Jaya (Indonesian New Guinea). Sixteen of 24 residents in the village of Arso PIR II taking supervised weekly chloroquine prophylaxis (5 mg base/kg) had asexual parasitemia with P. vivax at least once during eight weeks of surveillance. An American working in the same village developed symptomatic P. vivax parasitemia despite chloroquine prophylaxis. Five days after therapy with 600 mg chloroquine base, the asexual parasitemia in the American increased 40-fold, but cleared after treatment with 1,500 mg chloroquine base. Serum samples were not available from many of the cases, but six local residents and the American had serum levels of chloroquine in excess of the ordinarily suppressive 15 ng/ml at the time of their asexual parasitemias (16-70 ng/ml). The weekly 300 mg base tablet of chloroquine, which has been the standard for prophylaxis against malaria for more than 40 years, was not effective against P. vivax in Arso PIR, Irian Jaya.
A double blind randomized comparative trial of the efficacy of 7-day and 5-day courses of oral artesunate at 600 mg was studied in 89 Thai patients with uncomplicated falciparum malaria. Eighty patients completed the 28-day follow-up period. Artesunate was found to be well tolerated in either regimen. There was an increase of 7% in the cure rate obtained from a 7-day regimen. In 43 patients with a 7-day regimen, the cure rate was 92.5% and 15 patients showed P. vivax in their peripheral blood between days 12 and 34. The mean fever and parasite clearance times were 20 and 40 hours, respectively. In 46 patients with a 5-day regimen, the cure rate was 85% and 8 patients showed P. vivax during days 13 and 24. The mean fever and parasite clearance times were 29 and 40 hours, respectively. Although the cure rates of oral artesunate were high in both regimens, the efficacy was considered unsatisfactory since the aim of the treatment is to achieve 100% cure rate. We suggest however that the extension of the duration of treatment to 7 days together with the increase in total dose may improve therapeutic efficacy of artesunate in falciparum malaria.
The deployment of antiprotozoal drugs on a large scale for prophylaxis or monotherapy inevitably results in the selection of drug-resistance. The use of appropriately selected drug combinations may impede this process. Point mutations underlie resistance to dihydrofolate reductase inhibitors such as pyrimethamine. Potentiating combinations of such compounds with sulfonamides or sulfones have effectively delayed resistance to them. The use of triple combinations may be of value in protecting such compounds as chloroquine and mefloquine, resistance to which is associated in some cases with gene amplification. It is essential to seek partner compounds for any new antimalarials, e.g. artemisinin. Past experience with existing compounds is discussed and the need to make use of all available means of interrupting malaria transmission is stressed, rather than depending entirely on drugs.
The currently used methods for assessing the therapeutic response to antimalarial drugs are relatively imprecise and insensitive.
These methods are inadequate in severe malaria when the objectives of treatment are to save life and prevent complications.
Very large studies are needed to demonstrate significant differences in mortality, but measurement of the rates of clinical,
biochemical, and parasitological response may provide useful comparative information. Definitions, assessment criteria, procedures,
and data collection forms should be standardized and evaluated prospectively. Antimalarial drug treatment in different clinical
situations should be assessed in terms of the balance between the risks of drug toxicity and the benefits of the antimalarial
drug action. This balance is considerably different in severe falciparum malaria compared with uncomplicated malaria infections.
6 out of 7 patients with severe neutropenia associated with the use of amodiaquine for malaria prophylaxis amodiaquine (400 mg weekly) plus proguanil (200 mg daily); 1 of these patients had also taken cotrimoxazole and another had taken sulphaguanidine. The 7th patient had taken amodiaquine alone, but at a higher dose. A retrospective analysis suggests that the frequency of severe neutropenia complicating amodiaquine taken prophylactically may be as high as 1 in 2000.
We decided to investigte oral, short-term regimens of the combination of quinine and sulfadoxine/pyrimethamine and of quinine and clindamycin. We also used amodiaquine in this comparative trial, because it is the drug officially recommended by the health authorities and generally used by public health agencies like Superintendencia de Campanhas de Saude Publica (SUCAM). The patients were from an area of the Brazilian rain forest that had recently been colonized. In this area, multi-drug-resistant strains of P. falciparum account for > 70% of the isolates.
Fifty patients with Plasmodium vivax infection were treated with the standard regimen of chloroquine phosphate (1500 mg over 3 d) followed by primaquine (45 mg
immediately and then weekly for 8 weeks); 43 patients had sensitive infections but recrudescences of parasitaemia occurred
between days 3 and 14 with RI, RII and RIII patterns in one, 3 and 3 patients, respectively. All the chloroquine-resistant
cases were again treated with chloroquine (1500 mg) and no further recrudescence or relapse was detected on days 21 and 28.
This study indicates that chloroquine is losing its efficacy against P. vivax in Myanmar.
A series of Plasmodium falciparum in vitro drug sensitivity studies were conducted in order to evaluate atovaquone in combination with other antimalarial drugs and thus to identify a potential partner for a fixed combination. The derived isobolograms indicated that drug interactions ranged from antagonism through addition to synergy. Of particular note were the quinolines and artemisinin analogues, which were all antagonistic, and the biguanides and tetracycline, which showed synergy. Proguanil emerged as the most promising of the current antimalarials as a partner for atovaquone in a fixed combination, with tetracycline as back-up.
Between 1981 and 1992, 196 Thai adults with severe falciparum malaria were treated with a quinine loading dose regimen. Nineteen
patients died (10%) and 6 developed late hypoglycaemia. There was no serious cardiovascular or nervous system toxicity. Although
there was no evidence of high grade resistance, and no change in the mortality rate, in recent years an increasing proportion
of patients had a delayed clinical and parasitological response to treatment. Since 1988, 78% (29/37) of patients with cerebral
malaria were unconscious for >72 h compared with 41% (11/27) between 1981 and 1987 (P = 0 · 002). In the past 2 years parasite clearance times have exceeded 96 h in 33% (26/78) of patients compared with 14%
(15/102) previously (P = 0 · 006). Quinine remains an effective treatment for severe multi-drug resistant falciparum malaria in this area, but there
is now evidence of a decline in the immediate therapeutic response, and its efficacy will need close monitoring as resistance
increases further.
There is much confusion over which malaria chemoprophylaxis should be used in areas such as East Africa. We did two consecutive studies between 1985 and 1991 to assess the efficacy and side-effects of malaria chemoprophylaxis in short-term travellers to East Africa. All passengers returning from Kenya to Europe received an in-flight questionnaire and a second one three months later. Any report of documented malaria or of admission to hospital for possible side-effects was verified with the physician. 145 003 travellers completed questionnaires. Among the 139 164 who stayed in East Africa for less than one year, 296 cases of confirmed malaria were reported (275 due to P falciparum). In people who used no chemoprophylaxis, the incidence of falciparum malaria was 1.2% per month. Prophylactic effectiveness was 91% (95% Cl 85 to 94) for mefloquine, 82% (71 to 89) for pyrimethamine and sulfadoxine, 72% (56 to 82) for chloroquine plus proguanil, and 10 to 42% for chloroquine at various doses. Rates of side-effects, which were usually mild, were 18.8% for mefloquine users, 17.1% and 18.6% for chloroquine 300 mg and 600 mg base per week, respectively, 30.1% for chloroquine plus proguanil, and 11.7% for sulfadoxine and pyrimethamine. Mefloquine is significantly more effective than chloroquine plus proguanil for malaria prophylaxis in short-term tourists visiting East Africa and has a tolerance similar to that of chloroquine used alone.
Multidrug resistance of Plasmodium falciparum is becoming common in Africa. In a randomized trial, four short-term regimens were compared for treating uncomplicated P. falciparum malaria in children 4–15 years old in Gabon. One hundred thirty patients received chloroquine (25 mg/kg over 48 h; group
C), chloroquine (as above) plus c1indamycin (5 mg/kg every 12 h for 6 doses; group CCI), quinine (12 mg/kg every 12 h for
6 doses; group Q), or quinine (as above) plus c1indamycin (as above; group QCI). In group C, only 9% of patients were cured
by day 28, 44% showed recrudescent malaria (RI), and 47% showed intermediate or high-grade resistance (RII/RIII). In group
CCI, 70% of patients were cured and 30% showed recrudescences. In group Q, 32% were cured and 68% showed recrudescences. In
group QCI, 88% were cured and 12% showed recrudescences after day 14. All treatment regimens were well tolerated. Thus, the
combination of c1indamycin with chloroquine or quinine enhances parasite clearance and improves response to therapy.
In the late 1950's chloroquine resistance to Plasmodium falciparum occurred in South America and on the Indochina Subcontinent. Since then it has conquered most of the areas where the parasite species is endemic. This has necessitated the use of alternative drugs such as sulphonamide-pyrimethamine combinations, quinine/tetracyclines, mefloquine, halofantrine, and recently also artemisinin-based compounds. In wide areas of South-east Asia, western Oceania and South America sulphonamide-pyrimethamine combinations have lost adequate efficacy. The situation is most serious in the Thai/Cambodia and Thai/Myanmar border areas where multiresistance necessitated the shift to the last line drug, i.e., the artemisinin derivatives. Selection of resistant parasites due to drug pressure, and their subsequent propagation by local transmission and migration of reservoirs are key factors in the dynamics of drug resistance. Selection is the result of the interplay of parasite, drug and human host, and is largely influenced by immune factors and the pharmacokinetics and pharmacodynamics of the drug. Spread of resistance is determined by eco-epidemiological factors among which migration and vectorial parameters play a major role. Rational drug use, especially adequate, monitored, therapeutic administration according to strict criteria, should curb the onset and spread of resistance, but this concept may not be readily accepted by health services whose primary goal is clinical amelioration of the disease rather than the more stringent target of epidemiologically desirable results.
A randomized comparative trial for treating adult patients with Plasmodium falciparum malaria was performed in Lambarene, Gabon. Forty-two patients received chloroquine (25 mg/kg for 48 hr) and 38 patients received clindamycin (5 mg/kg twice a day, for five days). Chloroquine treatment cured 15 patients (36%). Twenty patients (48%) showed recrudescent malaria by day 28 of follow-up (RI resistance) and seven patients (17%) showed persistent parasitemia after chloroquine treatment (RII/III resistance). In contrast, clindamycin treatment cured 37 of 38 patients (97%) and only one (3%) showed a recrudescence by day 28 (P < 0.001). Although the parasite clearance time was significantly longer after clindamycin treatment (median five days, range 3-6) than after chloroquine treatment (median four days, range 2-8) (P < 0.01), no differences were seen in the duration of symptoms after chemotherapy. In both treatment groups, no severe side effects occurred. Clindamycin can be used as a safe alternative to achieve radical cure in semi-immune adult patients with chloroquine-resistant P. falciparum malaria in Central Africa.
Two chloroquine-resistant cloned isolates of Plasmodium falciparum were subjected to mefloquine selection to test if this resulted in alterations in chloroquine sensitivity and amplification of the pfmdr1 gene. The mefloquine-resistant lines derived by this selection were shown to have amplified and overexpressed the pfmdr1 gene and its protein product (Pgh1). Macrorestriction maps of chromosome 5, where pfmdr1 is encoded, showed that this chromosome has increased in size in response to mefloquine selection, indicating the presence of a gene(s) in this area of the genome that confers a selective advantage in the presence of mefloquine. Concomitant with the increase in mefloquine resistance was a corresponding increase in the level of resistance to halofantrine and quinine, suggesting a true multidrug-resistance phenotype. The mefloquine-selected parasite lines also showed an inverse relationship between the level of chloroquine resistance and increased pfmdr1 gene copy number. These results have important implications for the derivation of amplified copies of the pfmdr1 gene in field isolates, as they suggest that quinine pressure may be involved.
A method of monitoring Plasmodium falciparum viability ex vivo was used to compare the ability of different antimalarial drugs to arrest the progression of young parasites to mature, potentially damaging stages. Neither pyrimethamine-sulfadoxine nor quinine, the treatment of choice for severe, life-threatening malaria, had a demonstrable effect on circulating parasites during the first 24 hr of therapy. In contrast, in vivo exposure to halofantrine for as little as six hours was sufficient to arrest parasite development. The method of assessing ex vivo parasite viability permits a comparison of antimalarial drug action at a time that may be critical for the therapy of life-threatening disease. If parenteral formulations of halofantrine prove to be safe and effective, they may have a role in the therapy of severe malaria.
Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Although these drugs are known to accumulate by a weak base mechanism in the acidic food vacuoles of intraerythrocytic trophozoites and thereby prevent hemoglobin degradation from occurring in that organelle, the mechanism by which their selective toxicity for lysosomes of malaria trophozoites is achieved has been subject to much discussion and argument. In this review the recent discovery that chloroquine and related quinolines inhibit the novel heme polymerase enzyme that is also present in the trophozoite food vacuole is introduced. The proposal that this inhibition of heme polymerase can explain the specific toxicity of these drugs for the intraerythrocytic malaria parasite is then developed by showing that it is consistent with much of the disparate information currently available. The clinical usefulness of chloroquine, and in some recent cases of quinine as well, has been much reduced by the evolution and spread of chloroquine resistant malaria parasites. The mechanism of resistance involves a reduced accumulation of the drug, although again the mechanism involved is controversial. Possible explanations include an energy-dependent efflux of preaccumulated drug via an unidentified transmembrane protein pump, or an increase in vacuolar pH such that the proton gradient responsible for drug concentration is reduced. New data are also presented which show that heme polymerase isolated from chloroquine resistant trophozoites retains full sensitivity to drug inhibition, consistent with the observation that resistance involves a reduced accumulation of the drug at the (still vulnerable) target site. The significance of this result is discussed in relation to developing new strategies to overcome the problem presented by chloroquine resistant malaria parasites.
The speed and stage specificity of antimalarial drug action on the metabolic activities of cultured Plasmodium falciparum were studied for chloroquine (CQ), quinine (QN), artemisinin (AR), and sodium artelinate (SA). CQ had the most rapid onset of action on [3H]hypoxanthine and [3H]isoleucine uptake, reaching 50% of its maximum effect in 1.8 hr compared with 3.5-7.4 hr for the other three drugs. In contrast there was a lag time of 1-4 hr before AR and SA had a measurable inhibitory effect, although after this delay antimalarial action was very rapid. Parasite glycolysis was relatively drug resistant; the inhibition of lactate production was < 60% of that for [3H]hypoxanthine and [3H]isoleucine uptake. The susceptibility of P. falciparum changed markedly as the parasite matured. Maximum drug effects occurred at the late ring and early trophozoite stage, which corresponds to the time at which the most rapid increases in synthetic and glycolytic activities occur. Mature schizonts and young rings were relatively unaffected by the antimalarial drugs. Young rings were particularly resistant to QN. Schizonts multiplied successfully in the presence of relatively high concentrations of all four drugs. The two artemisinin compounds had the broadest time window of action and may be particularly suitable for the treatment of severe malaria.
Various drugs are widely used in the prophylaxis and treatment of malaria. In the prevention of malaria in travellers, a careful risk-benefit analysis is required to balance the risk of acquiring potentially serious malaria against the risk of harm from the prophylactic agent. Unfortunately, the information needed to perform accurate analyses of this type is not available for most antimalarials.
In the prophylaxis of malaria, chloroquine and proguanil have an excellent safety record, being very rarely associated with severe adverse reactions in the recommended dosages. However, in many parts of the world they are no longer effective prophylactic agents. Pyrimethamine-dapsone (Maloprim®) is associated with agranulocytosis, especially if the recommended dose is exceeded, and should be reserved as a second-line agent for travellers to high risk areas. Pyrimethaminesulfadoxine (Fansidar®) and amodiaquine are associated with a relatively high incidence of potentially fatal reactions, and are no longer recommended for prophylaxis. Mefloquine, a relative newcomer, may provoke severe neuropsychiatric reactions with a frequency of 1 in 15 000 to 20 000 users at the prophylactic dosage.
In the treatment of Plasmodium falciparum malaria, which has a high mortality if untreated, a greater risk of adverse reactions to antimalarial drugs is acceptable. As chloroquine resistance has become widespread, alternative agents including quinine, mefloquine, pyrimethamine-sulfadoxine, tetracyclines, halofantrine and artemisinin (qinghaosu) and its derivatives may be used in treatment regimens. The therapeutic ratios for chloroquine, quinine and mefloquine are narrow and toxicity is frequent when recommended treatment dosages are exceeded; parenteral administration above the recommended dose range is especially associated with the hazards of cardiac and neurological toxicity.
Cerebral malaria has a mortality rate of 10 to 30 percent despite treatment with parenteral quinine, a situation that may worsen with the spread of quinine resistance. Artemether is a new antimalarial agent that clears parasites from the circulation more rapidly than quinine, but its effect on mortality is unclear.
We conducted a randomized, unblinded comparison of intramuscular artemether and intramuscular quinine in 576 Gambian children with cerebral malaria. The primary end points of the study were mortality and residual neurologic sequelae.
Fifty-nine of the 288 children treated with artemether died in the hospital (20.5 percent), as compared with 62 of the 288 treated with quinine (21.5 percent). Among the 418 children analyzed at approximately five months for neurologic disease, residual neurologic sequelae were detected in 7 of 209 survivors treated with artemether (3.3 percent) and 11 of 209 survivors treated with quinine (5.3 percent, P = 0.5). After adjustment for potential confounders, the odds ratio for death was 0.84 (95 percent confidence interval, 0.53 to 1.32) in the artemether group, and for residual neurologic sequelae, 0.51 (95 percent confidence interval, 0.17 to 1.47). There were fewer local reactions at the injection site with artemether than with quinine (0.7 percent vs. 5.9 percent, P = 0.001).
Artemether is as effective as quinine in the treatment of cerebral malaria in children.
The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.
The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of atovaquone and proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambaréné, Gabon.
142 adults were randomly allocated either a combination treatment of atovaquone 1000 mg daily and proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence.
In the atovaquone plus proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0.022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with atovaquone plus proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%).
Atovaquone and proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon.
Atovaquone (566C80), a hydroxynaphthoquinone, was investigated for activity against Plasmodium falciparum gametocytes (NF54 strain) in vitro. After 96 h of continuous exposure to the drug at 1.4 × 10−7M (a concentration achievable in humans 14 d after administration of a therapeutic dose of 10 mg/kg) reductions of 75%, 54%
and 20% in the number of gametocyte stages 2, 3 and 4, respectively, were achieved. A small increase (14%) in stage 5 gametocytes
was seen. At the same concentration, atovaquone showed greater activity against the asexual stages of P. falciparum, reductions of 93%, 96% and 43% in the number of rings, schizonts and trophozoites, respectively, being achieved. These data
are consistent with inhibition of maturation of trophozoites. The observed effect on maturation of gametocytes is similarly
consistent with blockade of gametocyte recruitment from merozoites produced by the preceding schizogony, or to stasis of intraerythrocytic
sexual development before the formation of stage 2 gametocytes.
Opinion and policy over the use of amodiaquine for treating malaria vary. Amodiaquine is more palatable than chloroquine and may be more effective but serious adverse events have been reported in travellers taking it as prophylaxis. It is not recommended as first-line treatment. In the light of the global debate over the use of this drug, we conducted a systematic review of the effectiveness and tolerability of amodiaquine in the treatment of uncomplicated falciparum malaria.
This is a systematic review of published and unpublished randomised or pseudorandomised trials of amodiaquine. Observational reports were also systematically identified and reviewed to access evidence of serious adverse events.
40 trials met the inclusion criteria. Symptomatic patients were enrolled in 24 studies in comparisons of amodiaquine (n = 1071) with chloroquine (n = 1097). Amodiaquine was significantly more effective than chloroquine, with odds ratios and 99% confidence intervals (OR [99% CI]) of 4.29 (3.30-5.58) on day 7 and 6.00 (3.97-9.06) on day 14. Time to parasite clearance was significantly shorter with amodiaquine and fever clearance times were marginally faster. Eight studies compared amodiaquine with chloroquine in asymptomatic parasitaemia, with effects on parasitological outcomes similar to those for symptomatic malaria. At twelve sites, 692 amodiaquine and 679 sulfadoxine/pyrimethamine (S/P) recipients were enrolled. The two drugs did not differ significantly on day 7 (OR 0.74 [0.48-1.15]) but the odds ratios favoured S/P on day 14 (OR 0.51 [0.28-0.93]) and on day 28 (OR 0.30 [0.16-0.55]). The time to parasitological clearance was similar in the two groups; fever clearance times were significantly shorter with amodiaquine. Tolerability was assessed for both comparative and non-comparative trials. The rates of adverse events in controlled trials were 10.7%, 8.8%, and 14.3% with amodiaquine, chloroquine, and S/P, respectively. No life-threatening adverse events and no significant shifts in laboratory indices were reported.
This systematic review of published and unpublished trials supports the use of amodiaquine in the treatment of uncomplicated malaria. However, there is partial cross-resistance between chloroquine and amodiaquine, and monitoring of the effectiveness of this drug and surveillance for evidence of toxicity must continue.
Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.
The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CL/F) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CL/F is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (V area/F) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of V area/F is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CL/F nor V area/F were significantly affected by age, gender, and the coadministration with chloroguanide (proguanil), pyrimethamine, and tetracycline. Half-life (t1/2) showed a 0.326 power relationship with weight; thus, the population estimate of t1/2 in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CL/F and V area/F were 68% and 49%, respectively.
Clinical studies have shown atovaquone (ATQ), a new blood schizontocidal drug, in combination with proguanil (PROG) to be very effective in the treatment of acute multidrug-resistant falciparum malaria. The multiple dose pharmacokinetics of PROG were determined in Thai patients with acute falciparum malaria given PROG alone (200 mg PROG twice a day for 3 days, n = 4) and concurrently PROG and ATQ (200 mg PROG and 500 mg ATQ twice a day for 3 days, n = 12). There were no statistical differences (p > 0.05) in the area under the plasma drug concentration-time curve (AUC), apparent oral clearance (CL/F) and elimination half-life (t1/2) of PROG between patients given PROG alone and PROG/ ATQ. The median (range) kinetic values of PROG in patients given PROG alone and PROG/ATQ were respectively: CL/F = 1.25 l/h/kg (0.99-1.45) and 0.95 (0.73-1.32) l/h/kg, and t1/2 = 14.2 hours (9.3-16.8) and 13.6 hours (9.1-17.6). The CL/F and t1/2 of PROG in the Thai patients treated with the 2 treatment regimens were also comparable to values reported in healthy Thai volunteers given a standard prophylactic dose (200 mg PROG). The results of this preliminary study suggest that ATQ is unlikely to affect the pharmacokinetics of PROG to a clinically important extent at an ATQ dosage of 500 mg twice a day for 3 days in malaria infected patients.