Promising New Antimalarial Combination Drugs: Garlic and Arteether in Pregnant Mice Infected with Plasmodium berghei.

BACKGROUND: Antimalarial prescription remains a challenge in pregnant women because of maternal and fetal complications. Recently, garlic and α-ß-arteether combination treatment in malariainfected mice conferred protection. The purpose of this study is to evaluate the efficacy of these drugs during malaria in pregnancy and its safety measures. OBJECTIVE: The study evaluates the efficacy of arteether and garlic combination drugs in protection against malaria-infected pregnant mice. METHODS: Plasmodium berghei-infected pregnant mouse model was used to assess the combination drug efficacy and the outcome of abnormalities of the disease after drug treatment. After optimizing the dose and gestation period, maternal protection was confirmed by parasite clearance in smear and mortality observation. In addition, maternal hematological parameters, different organ histopathology, and IgG levels were documented along with the fetal and infant outcomes. RESULTS: Arteether monotherapy resulted in spontaneous fetal abortion or resorption, while dosage optimization and garlic combination resulted in pregnancy completion and malaria protection. The derangements observed in the histoarchitecture of organs and hematological parameters caused by malaria infection revealed improvement after drug treatment, and the smear observation confirms the clearance of malaria parasite in the peripheral blood, but IgG level was maintained at the same higher level as in malaria-infected mice. CONCLUSION: The first report of an arteether and garlic combination demonstrating high efficacy in protecting against malaria-infected pregnant mice establishes its safety as a viable possible treatment for pregnancy-associated malaria.

Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases.

Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making it effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its anti-viral and anti-inflammatory properties.

Immunomodulatory and antiparasitic effects of garlic-arteether combination via nitric oxide pathway in Plasmodium berghei-infected mice.

Many reports indicate medicinal value of garlic (Allium sativum), a popular herbal medicine used worldwide, and its therapeutic effect against several diseases. Earlier studies in our laboratory have shown a potential therapeutic role of garlic-artemisinin combination in mice infected with Plasmodium berghei. A single dose of α, ß-arteether with three oral doses of garlic provides almost 95% protection. The present study aims to understand the mode of action of this combination. We have documented the level of nitric oxide (NO), a key molecule of protection and have seen in the reversal of organ morphology caused by malaria infection. The combination effects on the (a) survival rate and degree of parasitemia and (b) NO levels in blood, liver, spleen and thymus of malaria-infected mice were investigated. During the study, liver, spleen and thymus cell suspensions were assessed for immunobiochemical alterations of NO levels. The increase in NO level after infection appears to be unable to protect, whereas striking increase in spleen and thymus leads to protection against infection, and is further confirmed by detection of increased inducible nitric oxide synthase mRNA expression levels in different organs by RT-PCR. In addition, the role of T cell subsets during combination treatment was also studied. All these results indicate a potential mechanism of protection through NO pathway in combination-treated animals after malaria infection and may lead to an immunotherapy trial of malaria disease.

Artemisinin-derived antimalarial endoperoxides from bench-side to bed-side: Chronological advancements and future challenges.

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.

Assessment of in vivo antimalarial activity of arteether and garlic oil combination therapy.

The study evaluates in vivo antimalarial activity of arteether and garlic pearl oil combination in Plasmodium berghei-infected mouse model of malaria. 72 h (Day 3) post infection, at 2-4% parasitemia, mice were treated with single dose intramuscular injection of α-ß arteether, at 750 µg, in combination with three 100 µL oral doses of garlic pearl oil on Day 3, Day 4 and Day 5. Following the treatment, 100% protection and survival of mice were observed. Inhibition of parasitemia in combination treated animals and protection during recrudescence interval of α-ß arteether monotherapy was observed in Giemsa-stained blood smears. In addition, a striking increase in anti-parasite antibody IgG contributing protective immunity during the recrudescence phase was observed. These results correlate with western blot analysis, where sera from the recrudescence stage and later period of arteether and garlic oil combination treated animals found to interact with several parasite specific proteins as compared to controls. The present approach shows that arteether and garlic pearl oil combination provides complete protection in P. berghei-infected mice. Thus, for the first time, garlic pearl oil appears to be an ideal antimalarial candidate in artemisinin combination therapy.

Histological and biochemical effects of arteether™ on the liver of Wistar rats.

Arteether™ is among the recent drugs that are used to combat chloroquine-resistant malarial parasites. This study examined the effects of arteether™ on enzyme biomarkers of the liver, serum protein concentrations, and liver morphology. Twenty (20) adult albino Wistar rats weighing 200 - 250 g were randomly divided into four groups (A, B, C and D) of five animals each, and used in this study. Group A rats were given intramuscular (i. m.) arteether™ (3 mg/kg b. w.) daily for 3 days. Group B rats received i. m. arteether™ (6 mg/kg b. w.) daily for 3 days. Group C rats were given i. m. arteether™ (3 mg/kg b. w.) daily for 3 days. The same dose was repeated at two-weekly intervals for 4 further weeks, while group D rats which received normal saline (0.9 % w/ v, 3 ml/kg b.w.), served as controls. At the end of the experiment, the body weights of the animals were determined and recorded. Serum levels of alanine transaminase (ALT), aspartate transaminase (ASP), alkaline phosphatase (ALP), total protein (TP) and albumin were assayed, and histological studies were performed. Results obtained show no significant difference (P<0.05) in liver enzymes (ALT, ASP, ALP). TP and albumin were significantly reduced in group C rats. Histological studies revealed no cyto-architectural changes. It is concluded that at therapeutic doses, arteether™ is well tolerated in Wistar rats.

An oral malaria therapy: curcumin-loaded lipid-based drug delivery systems combined with ß-arteether.

Curcumin (CC), a potential antimalarial drug, has poor water solubility, stability and oral bioavailability. To circumvent these pitfalls, lipid-based drug delivery systems (LBDDSs) with a high CC loading (30 mg/g) were formulated. In a biorelevant gastric medium, CC-LBDDSs formed particle sizes in the range of 30-40 nm. During in vitro lipolysis, 90-95% of the CC remained solubilized, whereas 5-10% of the CC precipitated as an amorphous solid, with a high rate of re-dissolution in a biorelevant intestinal medium. The transport of the CC-LBDDS across Caco-2 monolayers was enhanced compared with the transport of free drug because of the increased CC solubility. In Plasmodium berghei-infected mice, modest antimalarial efficacy was observed following oral treatment with CC-LBDDSs. However, the combination therapy of CC-LBDDS with a subtherapeutic dose of ß-arteether-LBDDS provided an increase in protection and survival rate that was associated with a significant delay in recrudescence. These findings suggest that the combination of oral CC and ß-arteether lipid-based formulations may constitute a promising approach for the treatment of malaria.