Investigation of imported malaria cases at a COVID-19 isolation point in Qingdao

The epidemiological data were collected from travellers who returned from Guinea on the 23rd of September, 2020 and were diagnosed with malaria at a C OVID -19 quarantine site in Qingdao, Shandong Province. The epidemiological characteristics, diagnosis and treatment of the cases and the epidemiology investigation and the rapid test screening results for other travellers on from the same flight and the interventions in reaction to the imported malaria cases were analyzed. The results showed that 4 out of 231 Guinean returned travellers had developed malaria symptoms, including chills and fever, during the isolation period. Rapid diagnostic test (RDT) indicated Plasmodium falciparum infection. Considering the patients ' travel history, clinical manifestations, and laboratory RDT test results, a confirmed diagnosis of imported P. falciparum malaria was made. The four malaria cases, who are male workers aged 29 to 55, were transferred to Jiaozhou People ' s Hospital for treatment. All four patients were administrated of artemether tablets upon diagnosis. One of the cases experienced severe malaria complications and were administrated with 12 doses (60 mg/dose) of artesunate intravenously for five days. The other three patients were treated with dihydroartemisinin and piperaquine phosphate tablets for one course of 8 tablets in 2 days (40 mg dihydroartemisinin and 320 mg piperaquine phosphate), respectively. Among the 231 returned travellers, 111 (48.1 %) had a history of malaria overseas. There were 23 positive cases detected by RDT, including the four symptomatic cases. The other 19 cases were asymptomatic. One of the asymptomatic cases became symptomatic three months later and was diagnosed as an imported P. malariae infection. Laboratory blood smear microscopic tests at the Jiaozhou City and Qingdao Municipal Center For Disease Control and Prevention showed negative results for the four malaria cases and the 19 RDT positive case. The samples from the four malaria cases were rechecked by the provincial reference laboratory of Shandong Institute of parasitic Disease. The results were negative for malaria infection by microscopic examination but positive for P. falciparum infection by nucleic acid test. It is suggested that during the routine control of COVID-19, the awareness of COVID-19 and malaria should be established among the returned travellers from high malaria-endemic areas. The health education "gate" should be moved forward to improve the treatment compliance for malaria cases and reduce the relapse or recrudescence caused by sub-optimal treatment.Copyright © 2022, Chin J Parasitol Parasit Dis. All rights reserved.

The CARAMAL study could not assess the effectiveness of rectal artesunate in treating suspected severe malaria.

CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that "pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival". We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment.

Application of Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung and Trachea Exposure of Pyronaridine and Artesunate in Hamsters.

A fixed-dose combination of pyronaridine and artesunate, one of the artemisinin-based combination therapies, has been used as a potent antimalarial treatment regimen. Recently, several studies have reported the antiviral effects of both drugs against severe acute respiratory syndrome coronavirus two (SARS-CoV-2). However, there are limited data on the pharmacokinetics (PKs), lung, and trachea exposures that could be correlated with the antiviral effects of pyronaridine and artesunate. The purpose of this study was to evaluate the pharmacokinetics, lung, and trachea distribution of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) using a minimal physiologically-based pharmacokinetic (PBPK) model. The major target tissues for evaluating dose metrics are blood, lung, and trachea, and the nontarget tissues were lumped together into the rest of the body. The predictive performance of the minimal PBPK model was evaluated using visual inspection between observations and model predictions, (average) fold error, and sensitivity analysis. The developed PBPK models were applied for the multiple-dosing simulation of daily oral pyronaridine and artesunate. A steady state was reached about three to four days after the first dosing of pyronaridine and an accumulation ratio was calculated to be 1.8. However, the accumulation ratio of artesunate and dihydroartemisinin could not be calculated since the steady state of both compounds was not achieved by daily multiple dosing. The elimination half-life of pyronaridine and artesunate was estimated to be 19.8 and 0.4 h, respectively. Pyronaridine was extensively distributed to the lung and trachea with the lung-to-blood and trachea-to-blood concentration ratios (=Cavg,tissue/Cavg,blood) of 25.83 and 12.41 at the steady state, respectively. Also, the lung-to-blood and trachea-to-blood AUC ratios for artesunate (dihydroartemisinin) were calculated to be 3.34 (1.51) and 0.34 (0.15). The results of this study could provide a scientific basis for interpreting the dose-exposure-response relationship of pyronaridine and artesunate for COVID-19 drug repurposing.

The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types.

Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated pandemic of the corona virus disease (COVID-19) has led to enormous efforts in the development of medical countermeasures. Although innovative vaccines have scaled back the number of severe COVID cases, the emergence of the omicron variant (B.1.1.529) illustrates how vaccine development struggles to keep pace with viral evolution. On the other hand, while the recently approved antiviral drugs remdesivir, molnupiravir, and Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir and Paxlovid are orally available and none of these drugs are recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, and antiviral mechanisms are urgently needed to address issues in the current pandemic and in putative future outbreaks of newly emerging variants of concern. Recently, we and others have described the anti-infective potential and particularly the pronounced antiviral activity of artesunate and related compounds of the trioxane/sesquiterpene class. In particular, the trimeric derivative TF27 demonstrated strong anti-cytomegalovirus activity at nanomolar concentrations in vitro as well as in vivo efficacy after oral administration in therapeutic and even prophylactic treatment settings. Here, we extended this analysis by evaluating TF27 for its anti-SARS-CoV-2 potential. Our main findings are as follows: (i) compound TF27 exerted strong anti-SARS-CoV-2 activity in vitro (EC50 = 0.46 ± 0.20 µM), (ii) antiviral activity was clearly distinct from the induction of cytotoxicity, (iii) pretreatment with TF27 prevented virus replication in cultured cells, (iv) antiviral activity has likewise been demonstrated in Calu-3 human lung and Caco-2 human colon cells infected with wild-type, delta, or omicron SARS-CoV-2, respectively, and (v) analysis of TF27 combination treatments has revealed synergistic interaction with GC376, but antagonistic interaction with EIDD-1931. Combined, the data demonstrated the pronounced anti-SARS-CoV-2 activity of TF27 and thus highlight the potential of trioxane compounds for further pharmacologic development towards improved options for COVID-specific medication.

Return to Travel in the Coronavirus Disease 2019 Pandemic Recovery Period and Implications for Imported Malaria: Reinforcing Prevention, Early Diagnosis, and Appropriate Treatment of Malaria.

Return to international travel in the COVID-19 pandemic recovery period is expected to increase the number of patients with imported malaria in the United States (US). Malaria prevention in travelers and preparedness for timely diagnosis and appropriate treatment are key to minimize imported malaria morbidity and mortality. Intravenous artesunate (IVAS) is now available from commercial distributors in the US for the treatment of severe malaria. Hospitals and pharmacists should have a plan for malaria treatment, including stocking artemether-lumefantrine for uncomplicated malaria, and stocking or planning for rapid procurement of IVAS for the treatment of severe malaria.

Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial.

BACKGROUND: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19. METHODS: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint was the incidence of viral clearance, i.e., the proportion of patients with a negative SARS-CoV-2 RT-PCR on day 7, compared to SOC using a log-binomial model in the modified intention-to-treat (mITT) population. FINDINGS: The mITT population included 186 patients: mean age (SD) 34.9 (10.3) years, body weight 78.2 (17.1) kg. Day 7 SARS-CoV-2 clearance rates (n/N; risk ratio [95% CI]) were: SOC 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV + NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) and SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; SOF-DCV 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There were no deaths. Adverse events occurred in 55.3% (105/190) of patients, including one serious adverse event (pancytopenia; FPV + NTZ). INTERPRETATION: There was no statistical difference in viral clearance for any regimen compared to SOC. All treatments were well tolerated. FUNDING: Medicines for Malaria Venture, with funding from the UK Foreign, Commonwealth and Development Office, within the Covid-19 Therapeutics Accelerator in partnership with Wellcome, the Bill and Melinda Gates Foundation, and Mastercard.

Readiness of the Kenyan public health sector to provide pre-referral care for severe paediatric malaria.

OBJECTIVE: To assess readiness among primary public health facilities in Kenya to provide pre-referral antimalarials for severe malaria. METHODS: Nine national surveys of randomly selected primary public health facilities undertaken bi-annually between 2017 and 2021 were analysed. The outcomes included the availability of pre-referral antimalarial drugs at the health facilities and health worker knowledge of recommended pre-referral treatment for severe malaria. RESULTS: A total of 1540 health workers from 1355 health facilities were interviewed. Injectable artesunate was available at 46%, injectable quinine at 7%, and artemether at 3% of the health facilities. None of the facilities had rectal artesunate suppositories in stock. A total of 960 (62%) health workers were trained on the use of injectable artesunate. 73% of the health workers who had ever referred a child with severe malaria were aware that artesunate was the recommended treatment, 49% said that intramuscular injection was the preferred route of administration, and 60% stated the correct dose. The overall knowledge level of the treatment policy was low at 21% and only slightly higher among trained than untrained health workers (24% vs 14%; p < 0.001) and those with access to guidelines versus those without access (29% vs 17%; p < 0.001). CONCLUSIONS: The readiness of primary health facilities and health workers to deliver appropriate pre-referral care to children with complicated malaria in Kenya is inadequate. Further investments are required to ensure (a) availability of nationally recommended pre-referral antimalarials; (b) appropriate training and supervision in their administration, and (c) monitoring of the entire referral process.

Investigation of imported malaria cases at a COVID-19 isolation point in Qingdao

The epidemiological data were collected from travellers who returned from Guinea on the 23rd of September, 2020 and were diagnosed with malaria at a COVID-19 quarantine site in Qingdao, Shandong Province. The epidemiological characteristics, diagnosis and treatment of the cases and the epidemiology investigation and the rapid test screening results for other travellers on from the same flight and the interventions in reaction to the imported malaria cases were analyzed. The results showed that 4 out of 231 Guinean returned travellers had developed malaria symptoms, including chills and fever, during the isolation period. Rapid diagnostic test (RDT) indicated Plasmodium falciparum infection. Considering the patients' travel history, clinical manifestations, and laboratory RDT test results, a confirmed diagnosis of imported P. falciparum malaria was made. The four malaria cases, who are male workers aged 29 to 55, were transferred to Jiaozhou People's Hospital for treatment. All four patients were administrated of artemether tablets upon diagnosis. One of the cases experienced severe malaria complications and were administrated with 12 doses (60 mg/dose) of artesunate intravenously for five days. The other three patients were treated with dihydroartemisinin and piperaquine phosphate tablets for one course of 8 tablets in 2 days (40 mg dihydroartemisinin and 320 mg piperaquine phosphate), respectively. Among the 231 returned travellers, 111(48.1%) had a history of malaria overseas. There were 23 positive cases detected by RDT, including the four symptomatic cases. The other 19 cases were asymptomatic. One of the asymptomatic cases became symptomatic three months later and was diagnosed as an imported P. malariae infection. Laboratory blood smear microscopic tests at the Jiaozhou City and Qingdao Municipal Center For Disease Control and Prevention showed negative results for the four malaria cases and the 19 RDT positive case. The samples from the four malaria cases were rechecked by the provincial reference laboratory of Shandong Institute of parasitic Disease. The results were negative for malaria infection by microscopic examination but positive for P. falciparum infection by nucleic acid test. It is suggested that during the routine control of COVID-19, the awareness of COVID-19 and malaria should be established among the returned travellers from high malaria-endemic areas. The health education "gate" should be moved forward to improve the treatment compliance for malaria cases and reduce the relapse or recrudescence caused by sub-optimal treatment.

ARTEMISIA SPECIES AND ARTEMISININ DERIVATIVES AS ANTIVIRAL AGENTS AGAINST COVID-19. CURRENT KNOWLEDGE: CHEMISTRY, PHARMACOLOGY AND CLINICAL EVIDENCE

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been the reason behind the third zoonotic outbreak from the Coronaviridae family during the 21st century. COVID-19 was declared a pandemic by the WHO on 11 March 2020, and it has been posing a challenge for the health care system all around the world. Research groups worldwide are trying to find potential leads for drugs against SARS-CoV-2. Investigating natural products and extracts from known medicinal plants has been one area of focus in searching for potential inhibitors of SARS-CoV-2. This review aims to highlight the importance of including natural plants and plants derived compounds in this investigation. We particularly focused on compounds from Artemisia species (artemisinin and its derivatives), as this plant is highly valuable and has various pharmacological profiles.

Artesunate: A review of its therapeutic insights in respiratory diseases.

BACKGROUND: Artesunate, as a semi-synthetic artemisinin derivative of sesquiterpene lactone, is widely used in clinical antimalarial treatment due to its endoperoxide group. Recent studies have found that artesunate may have multiple pharmacological effects, indicating its significant therapeutic potential in multiple respiratory diseases. PURPOSE: This review aims to summarize proven and potential therapeutic effects of artesunate in common respiratory disorders. STUDY DESIGN: This review summarizes the pharmacological properties of artesunate and then interprets the function of artesunate in various respiratory diseases in detail, such as bronchial asthma, chronic obstructive pulmonary disease, lung injury, lung cancer, pulmonary fibrosis, coronavirus disease 2019, etc., on different target cells and receptors according to completed and ongoing in silico, in vitro, and in vivo studies (including clinical trials). METHODS: Literature was searched in electronic databases, including Pubmed, Web of Science and CNKI with the primary keywords of 'artesunate', 'pharmacology', 'pharmacokinetics', 'respiratory disorders', 'lung', 'pulmonary', and secondary search terms of 'Artemisia annua L.', 'artemisinin', 'asthma', 'chronic obstructive lung disease', 'lung injury', 'lung cancer', 'pulmonary fibrosis', 'COVID-19' and 'virus' in English and Chinese. All experiments were included. Reviews and irrelevant studies to the therapeutic effects of artesunate on respiratory diseases were excluded. Information was sort out according to study design, subject, intervention, and outcome. RESULTS: Artesunate is promising to treat multiple common respiratory disorders via various mechanisms, such as anti-inflammation, anti-oxidative stress, anti-hyperresponsiveness, anti-proliferation, airway remodeling reverse, induction of cell death, cell cycle arrest, etc. CONCLUSION: Artesunate has great potential to treat various respiratory diseases.

Drug Repurposing: A Potentially Emerging Discipline

Drug repurposing is the remodeling of already existing drugs to reduce the time frame, costs, and efforts in developing a new novel drug. This strategy has secured significant momentum in the previous decade. It overcomes the snags and pitfalls in the traditional means of drug discovery. This core research strategy has now become the sole approach to containing many deadly diseases that have no cure in the present. In astound, for pandemics like COVID-19 that is spreading like a wildfire worldwide, large-scale research programs and trials have been carried out to identify and modify existing drugs to counter the novel virus. Thus, this technology of drug repurposing offers a new lease of life, and greatly promotes the progress of the medicine, health, and pharma sectors. The purpose of this study is to understand the current status of drug repurposing in the field of virology, bacteriology, mycology, and oncology for clinical translatability.

Artesunate, imatinib, and infliximab in COVID-19: A rapid review and meta-analysis of current evidence.

BACKGROUND AND OBJECTIVE: Despite the pervasive vaccination program against coronavirus disease 2019 (COVID-19), fully vaccinated people are still being infected by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID-19. METHODS: A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar up to January 2022. Furthermore, the clinical trial databases were screened to find more citations. The Cochrane Collaboration tool and Newcastle-Ottawa scale were used to assess the included studies. Meta-analysis was performed using RevMan 5.4.1. RESULTS: Five published studies were identified as eligible. Meta-analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65; 95% confidence interval [CI]: 0.40-1.07; p = 0.09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37; 95% CI: 1.04-1.80; p = 0.03). No remarkable clinical benefit was observed in favor of using imatinib for COVID-19 patients. Artesunate showed significant improvement in patients with COVID-19. CONCLUSION: In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID-19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions.

Delays in Malaria Recognition and Door to Anti-malarial Time in a South London Hospital

Background. The prompt recognition and treatment of Plasmodium falciparum is necessary to prevent death. We reviewed data from a cohort of patients presenting with malaria to Kings College Hospital NHS Trust, London. Methods. Retrospective review of electronic records and drug charts of patients diagnosed with malaria from Jan 2019- March 2021. Results. 109 cases of malaria were identified representing travellers from 11 Sub-Saharan African countries: Nigeria(38%), Sierra Leone(33%), Ivory Coast(10%). The age range varied from 4 to 76 years with a mean of 44, 66% of the cohort was male. 22 cases occurred during the COVID-19 Pandemic. The commonest symptoms were Fever (97%), Headache (92%) and malaise (72%). P. falciparum was present in 99% cases. A travel history was taken in 94% of cases. Malaria was considered by the first clinician in 82% of cases with the second highest differential being a viral illness. In 6 cases, it took 4 to 11 medical reviews before malaria was considered. 29 patients met the UK criteria for severe malaria. Door to antimalarial time varied from 1 to 128 hours, with a median of 7.4 hours. 46% of the cohort received intravenous Artesunate as their first antimalarial. Extreme delays occurred were clinicians did not consider malaria, patients had negative films or a patient did not declare a travel history when asked. 1 patient died of cerebral malaria with a door to needle time of 2hr 3min. Where a reason for delay is documented, drug availability represented the highest cause with mean delay from prescribing antimalarial to giving antimalarial of 2.7 hours. There was no difference in door to antimalarial administration during the COVID-19 Pandemic, but patients did have a delay in presentation to hospital from onset of symptoms, mean 6.2 days pre-pandemic, 10.5 days during pandemic, this was not statistically significant (P= 0.198). 3 patients presenting during the Pandemic had covid-19 swabs prior to admission and 10 had attended primary care services. Number of days between onset of malaria symptoms and presentation to the Emergency Department Box plot demonstrating that patients were waiting longer post symptom onset to access care in the Emergency Department. 3 patients had covid swabs in the community and 10 accessed care through their primary care physician. Conclusion. Our data show that malaria is being considered early in the emergency department however there remain significant delays in administration of treatment. In 6 cases where malaria was not considered early there were delays in diagnosis of up to 5 days. An audit cycle will be completed with the aim of reducing door to antimalarial time.

Recent Advances in the Therapeutic Efficacy of Artesunate.

Artesunate, a semisynthetic artemisinin derivative, is well-known and used as the first-line drug for treating malaria. Apart from treating malaria, artesunate has also been found to have biological activity against a variety of cancers and viruses. It also exhibits antidiabetic, anti-inflammatory, anti-atherosclerosis, immunosuppressive activities, etc. During its administration, artesunate can be loaded in liposomes, alone or in combination with other therapeutic agents. Administration routes include intragastrical, intravenous, oral, and parenteral. The biological activity of artesunate is based on its ability to regulate some biological pathways. This manuscript reports a critical review of the recent advances in the therapeutic efficacy of artesunate.

Pandemic-related delay of falciparum malaria diagnosis in a traveller leading to cerebral malaria.

We report the case of a 29-year-old male in whom COVID-19 concerns led to a delayed diagnosis of falciparum malaria. The patient developed symptoms of cerebral malaria with cytotoxic lesions of the corpus callosum in magnetic resonance imaging.

Artesunate induces substantial topological alterations in the SARS-CoV-2 Nsp1 protein structure.

The need for novel antiviral treatments for coronavirus disease 2019 (COVID-19) continues with the widespread infections and fatalities throughout the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the deadly disease, relies on the non-structural protein Nsp1 for multiplication within the host cells and disarms the host immune defences by various mechanisms. Herein, we investigated the potential of artemisinin and its derivatives as possible inhibitors of SARS-CoV-2 Nsp1 through various computational approaches. Molecular docking results show that artemisinin (CID68827) binds to Nsp1 with a binding energy of -6.53 kcal/mol and an inhibition constant of 16.43 µM. The top 3 derivatives Artesunate (CID6917864), Artemiside (CID53323323) and Artemisone (CID11531457) show binding energies of -7.92 kcal/mol, -7.46 kcal/mol and -7.36 kcal/mol respectively. Hydrophobic interactions and hydrogen bonding with Val10, Arg11, and Gln50 helped to stabilize the protein-ligand complexes. The pharmacokinetic properties of these molecules show acceptable properties. The geometric parameters derived from large-scale MD simulation studies provided insights into the changes in the structural topology of Nsp1 upon binding of Artesunate. Thus, the findings of our research highlight the importance of artemisinin and its derivatives in the development of drugs to inhibit SARS-CoV-2 Nsp1 protein.

COVID-19 and Plasmodium ovale Malaria: A Rare Case of Co-Infection.

The COVID-19 pandemic continues to be a major health problem worldwide. Timely diagnosis of co-infections mimicking COVID-19, such as malaria, might be challenging particularly in non-endemic areas. We report the first case of COVID-19 and Plasmodium ovale malaria co-infection from our region aiming to highligt the importance of travel history and prophylaxis in malaria management in the context of pandemic. The galloping sound can sometimes be a harbinger of zebra besides the horse.

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.

Synthesis of novel artesunate-benzothiophene and artemisinin-benzothiophene derivatives.

Natural products are used for the treatment of a variety of diseases for many years. Last decades, design and synthesis of novel biologically active hybrid molecules including natural product is gained big importance due to their unique and new biological properties. In the present study, novel artemisinin-benzothiophene derivatives (12 A-F) are synthesised. Initially, benzothiophene derivatives (4 A-4F) are prepared via the Pd-catalyzed coupling reactions and iodocyclisation reactions. Then, Suzuki-Miyaura coupling reactions were used for the formation of intermediates 6 A-6F (between 64% and 91% yields). Finally, the Steglich esterification reaction between intermediate 6 and artesunate formed the artemisinin-benzothiophene hybrids (9 A-9F) in moderate to excellent yields under very mild reaction conditions. When intermediate 6 was reacted with dihydroartemisinin, product 12 A-12F was also obtained with high yields.[Formula: see text].

Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. has been used for millennia in Southeast Asia to treat "fever". Many infectious microbial and viral diseases have been shown to respond to A. annua and communities around the world use the plant as a medicinal tea, especially for treating malaria. AIM OF THE STUDY: SARS-CoV-2 (the cause of Covid-19) globally has infected and killed millions of people. Because of the broad-spectrum antiviral activity of artemisinin that includes blockade of SARS-CoV-1, we queried whether A. annua suppressed SARS-CoV-2. MATERIALS AND METHODS: Using Vero E6 and Calu-3 cells, we measured anti SARS-CoV-2 activity against fully infectious virus of dried leaf extracts of seven cultivars of A. annua sourced from four continents. IC50s were calculated and defined as the concentrations that inhibited viral replication by 50%; CC50s were also calculated and defined as the concentrations that kill 50% of cells. RESULTS: Hot-water leaf extracts based on artemisinin, total flavonoids, or dry leaf mass showed antiviral activity with IC50 values of 0.1-8.7 µM, 0.01-0.14 µg, and 23.4-57.4 µg, respectively. Antiviral efficacy did not correlate with artemisinin or total flavonoid contents of the extracts. One dried leaf sample was >12 years old, yet its hot-water extract was still found to be active. The UK and South African variants, B1.1.7 and B1.351, were similarly inhibited. While all hot water extracts were effective, concentrations of artemisinin and total flavonoids varied by nearly 100-fold in the extracts. Artemisinin alone showed an estimated IC50 of about 70 µM, and the clinically used artemisinin derivatives artesunate, artemether, and dihydroartemisinin were ineffective or cytotoxic at elevated micromolar concentrations. In contrast, the antimalarial drug amodiaquine had an IC50 = 5.8 µM. Extracts had minimal effects on infection of Vero E6 or Calu-3 cells by a reporter virus pseudotyped by the SARS-CoV-2 spike protein. There was no cytotoxicity within an order of magnitude above the antiviral IC90 values. CONCLUSIONS: A. annua extracts inhibit SARS-CoV-2 infection, and the active component(s) in the extracts is likely something besides artemisinin or a combination of components that block virus infection at a step downstream of virus entry. Further studies will determine in vivo efficacy to assess whether A. annua might provide a cost-effective therapeutic to treat SARS-CoV-2 infections.