Advances in COVID-19 therapies

Scientists have advanced more cures for COVID-19. Top on the list are: combination of ivermeticin, zinc and vitamin C; Andrographis paniculata, the key ingredient of IHP Detox Tea; extract of Artemisia annua, which interferes with replication of SARS-CoV-2; snake venom enzyme; metformin; colchicine, melatonin; and essential oils.

Reacting to the advances in traditional medicine as cures for COVID-19, the pioneer of natural cures for COVID-19 in Nigeria, Chief Executive Officer (CEO) of Bioresources Development and Conservation Programme (BDCP) and a professor of pharmacognosy, Maurice Iwu, told The Guardian: “The containment of the pandemic has not failed. It is rather a work in progress. We understand the virus better now. I believe that soon Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS CoV-2) will be like any other persistent virus and not so deadly.”

On why his product has not been massively deployed by the Federal Government to contain COVID-19, Iwu said there are three stages in the producing a new therapeutic agent. “The discovery of the biological activity of a putative medicinal agent. The development phase which includes the determination of its mechanism of action, safety, absorption and excretion. The clinical studies are done in three phases. At the end the medicinal agent is given approval for limited release while post-marketing evaluation continues. So what the universities and institutes are announcing are discoveries, which still have a long way to go to become an approved medicinal agent or drug,” he said.

The pharmacognocist, however, said the regulatory agencies sometimes grant evidence-based authorisation for emergency use of medicines still under investigation. “As you must have heard, the government of Thailand recently approved the use of Andrographis paniculata, the key ingredient of IHP Detox Tea for the management of COVID-19. Here in Nigeria IHP Detox Tea is used by people and increasingly prescribed by doctors, although the phytomedicine is still undergoing clinical trials at Lagos University Teaching Hospital (LUTH),” he said.

Iwu said the National Agency for Food and Drug Administration and Control (NAFDAC) has a crucial and pivotal role to play in regulating the process. “They can be annoyingly slow but it is good for the agency to be conservative. Nothing prevents anybody from using his or her own extemporaneous preparations. The agency also lists some herbal medicines for sale, without allowing their use for specific therapeutic indications or claims,” he said.

To an advocate of natural medicine, a botanist and pharmacognocist at University of Lagos, Dr. Joy Odimegwu, herbal medicine has been relegated to the back burners in this serious fight against a virus causing rampaging pandemic.
She said herbal medicine is very relevant for Africans of tropical origin to combat COVID-19 successfully.

How? Odimegwu explained: “Even from the point of behavioural changes; hand washing, hand sanitizers, herbal medicine is playing a great role. Most sanitisers have environmentally harmful chemicals and there are increased reports of poisoning or chemical burns from these synthetic sanitisers and over the years more harm will be discovered. There are natural hand and surface sanitizers available; https://www.jbspr.com/article-3-volume-1-supplement-1-2020/. So, it helps to have the long game in sight. Hand washing with local soaps instead of soaps filled with parabens etc.”

Why has herbal medicine not been adequately deployed? She said: “To my understanding, herbal medicines have not been deployed because we have a mentality of foreign is better. If scientists in the United Kingdom (UK) are promoting herbal medicine, the World Health Organisation (WHO) would have approved it and it is a big pity. In this case, it is so wrong.”

What have been the challenges especially in advancing claims by universities and renowned professors? “These findings are published but people keep asking for clinical trials. There is ignorance about the validation of herbal medicine. Most of the components are foods so are deemed safe. In the British Pharmacopoeias any crude drug that has been in use for over 50 years, with no reported toxicities is included as a drug,” Odimegwu said.

What is the way forward? The pharmacognocist said: “We need to accept that we are superior in this case of COVID-19 management. We don’t need the vaccine because it is like the flu shot that people living in the tropics usually take in the winter months. An eminent professor of pharmacognosy, Prof. M. Iwu once said that ‘Nigerians living in Nigeria who take the vaccine is like wearing a fur coat and gloves and walking about in Abuja.’”

What is the role of NAFDAC here? She said NAFDAC should set the pace and confidently encourage people to go natural.
Odimegwu said herbal medicines must not go through clinical trials before they are used.

The botanist said the agencies set up by the Federal Government such as Nigeria Natural Medicine Development Agency (NNMDA) Lagos, Nigerian Institute for Pharmaceutical Research and Development (NIPRID) Abuja and Federal Institute for Industrial Research Oshodi (FIIRO) Lagos have solutions to COVID-19 but the lukewarm reception by government does not encourage sharing.

Medical Director, Medical Art Centre (MART) Maryland, Ikeja, Lagos and Joint Pioneer of In Vitro Fertilisation (IVF) in Nigeria, Prof. Oladapo Ashiru, said: “Countries like India, and some informed countries are given out Ivermectin tablets, Vitamin D, and Zinc as protection. None of these countries have any vaccine.”

Ashiru’s claim is supported by science.
A team of researchers based in Peru and the U.S. recently examined the role of the anti-parasitic drug ivermectin in treating COVID-19. The team has released their findings on the medRxiv* preprint server.

Ivermectin is a semisynthetic drug, used to treat helmintic infestations. Its mode of operation is via binding to glutamate-gated chloride ion channels, found in invertebrate nerve and muscle cells.

As part of the avermectins, ivermectin is extensively used to treat and control parasitic infestations in large animals, including tick infestations and scabies. It has also been used to prevent human filariasis and to treat scabies in humans. With a good safety profile at recommended dosages, and with FDA (U.S. Food and Drug Administration) approval, it became a mainstream drug in the treatment of COVID-19.

Earlier reports suggested that it had antiviral activity in both Ribo Nucleic Acid (RNA) and Deoxy ribonucleic Acid (DNA) viruses. This was followed by another study examining its pharmacokinetics, which concluded that even at tenfold the approved human dosage, the compound could not inhibit SARS-CoV-2 in lung tissue.

Ivermectin was not significantly associated with a lower mortality or higher recovery of patients in this meta-analysis. However, the majority of studies were preprints, allowing for later changes in the data on which these conclusions are based.

The basis of ivermectin use was because of a study published in Australia that reported this drug’s in vitro efficacy in Vero cells in culture. The clinical applicability of this finding is far from certain, but physicians rapidly began to use ivermectin in the treatment of hospitalized COVID-19 patients.

This was more likely in hard-hit countries such as Peru, where ivermectin became a first-line treatment and preventive against SARS-CoV-2 infection.

However, the safety and efficacy of this drug in preventing and treating this illness is not yet proven, especially because the studies were poorly designed. This has cast doubt on the accuracy of the effect measures. Even when the odds ratio showed a significant benefit for ivermectin use in terms of an 85 per cent reduction in mortality, the certainty of evidence was conceded to be very low.

Thirdly, the dose effective in human SARS-CoV-2 infections is still unknown, with the study doses ranging from 120 uM/kg to 200 uM/kg per dose, and the route of administration varying from intramuscular to oral. Such high doses have not been approved for human use.

Finally, efficacy testing of ivermectin in humans must be based on a dose-response trial with a placebo control group. In the absence of such studies, the optimal high dosage of ivermectin remains unclear.

Meanwhile, researchers in the United States have shown that extracts of an aromatic herb called Artemisia annua inhibit the replication of severe acute respiratory coronavirus (SARS-CoV-2) – the agent responsible for the current coronavirus disease 2019 (COVID-19) pandemic.

Also known as “Sweet wormwood,” Artemisia annua (A. annua) is an herb from Asia that produces the antimalarial agent artemisinin. Artemisinin is the active ingredient in the malaria drug of choice Artemisinin Combination Therapies (ACTs).

Now, researchers at Columbia University in New York, the University of Washington, and Worcester Polytechnic Institute have demonstrated that hot-water leaf A. annua extracts based on artemisinin, total flavonoids, or dry leaf mass show antiviral activity against SARS-CoV-2.

“This is the first report of anti-SARS-CoV-2 efficacy of hot water extracts of a wide variety of cultivars of A. annua sourced from four continents,” said Pamela Weathers and colleagues. “Further studies will determine in vivo efficacy to assess whether A. annua might provide a cost-effective therapeutic to treat SARS-CoV-2 infections.”

A pre-print version of the paper is available on the bioRxiv* server, while the article undergoes peer review. Also, melatonin synthesized in the lungs acts as a barrier against SARS-CoV-2, preventing expression of genes that encode proteins in cells such as resident macrophages in the nose and pulmonary alveoli, and epithelial cells lining the alveoli, all of which are entry points for the virus.

The hormone, therefore, prevents infection of these cells by the virus and inhibits the immune response so that the virus remains in the respiratory tract for a few days, eventually leaving to find another host.

The discovery by researchers at the University of São Paulo (USP), in Brazil, helps understand why some people are not infected or do not manifest symptoms of COVID-19 even when reliably diagnosed as carriers of the virus by RT-PCR. In addition, it offers the prospect of nasal administration of melatonin, in drops or as a spray, to prevent disease from developing in pre-symptomatic patients.

Pre-clinical and clinical trials will be needed to prove the therapeutic efficacy of melatonin against the virus, the researchers stress in an article on the study published in the journal Melatonin Research.

Meanwhile, in a new study, published in the journal Strahlentherapie und Onkologie, researchers at the Department of Radiation Oncology, La Milagrosa Hospital, GenesisCare, Madrid, Spain, showed the potential benefit of treating COVID-19 pneumonia with ultra-low doses of radiotherapy, called ULTRA-COVID.

The team believes that Ultra-Low Doses of Therapy with Radiation Applied to COVID-19 (ULTRA-COVID) could play an imperative role in reducing the pulmonary inflammatory response, counteracting the cytokine storm, and preventing the progression into the critical state, which may require ventilation.

Meanwhile, a team of researchers in China – at Guangzhou University of Chinese Medicine and Yunnan University of Chinese Medicine – recently explored the therapeutic properties of Yinqiao powder in treating COVID-19 symptoms. Their findings were recently published in Phytotherapy Research.

Traditional Chinese medicine (TCM) has a comprehensive system that plays a key role in the prevention and treatment of infectious diseases. Several provinces in China have been following TCM-based prevention and treatment plans for COVID-19, with remarkable results.

Based on big data analysis, it was found that Yinqiao powder is the basic formulation used to treat the early stages of COVID-19. According to pharmacological studies, Yinqiao powder has an antitussive and expectorant effect, alleviates acute lung injury, improves lung function, relieves pulmonary fibrosis, improves immune response to viruses, and eases the adverse reactions of modern drugs.

The active ingredients in Yinqiao powder were identified using high-performance liquid chromatography analysis are rutin and hesperidin. Rutin binds to the main protease (3CLpro) of SARS-CoV-2 with more affinity than drugs such as remdesivir, chloroquine, and hydroxychloroquine. Studies show that rutin may inhibit SARS-CoV-2 by downregulating interleukin-6 (IL-6).

Meanwhile, a new study published in the journal Endocrine in January 2021 shows that low levels of vitamin D are associated with a higher risk of COVID-19 hospitalisation.

If this is confirmed, vitamin D supplementation may be an inexpensive and rapid method to ensure better outcomes in such patients.

Also, researchers in Greece have demonstrated the antiviral effects of Cretan aromatic plant oils on SARS-CoV-2.

The team showed that a combination of essential oils from Mediterranean thyme (Thymbra capitata L. Cav.), Greek sage (Salvia fruticosa Mill.), and Cretan dittany (Origanum dictamnus L.), exhibited remarkable antiviral activity against SARC-CoV-2 in Vero E6 cells.

Prof. Christos Lionis and colleagues propose that if the findings are validated in clinical trials, the essential oil mix (called CAPeo) could provide a novel, inexpensive option for the treatment of mild COVID-19.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.
Also, an interesting new study appearing on the bioRxiv* preprint server reports the virucidal and fusion-inhibiting attributes of snake venom against the COVID-19 agent, SARS-CoV-2.

Snake venom has been reported to contain compounds with multiple physiological activities, including antibacterial, antifungal, antiparasitic and antiviral properties. The current study explores one component of snake venom, the secreted phospholipase A2 enzymes (sPLA2s), which have a wide range of diverse sequences and biological functions. These are primarily involved in lipid metabolism and signaling pathways.

Also, new study by researchers in China and the U.S. describes a round up of the effects of commonly used hypoglycemic drugs on the outcomes of COVID-19 in diabetic patients.

The research team’s findings have been released on the medRxiv* preprint server. While diabetes has been established to be a risk factor for short-term mortality in hospitalized COVID-19 patients, the role of the drugs used to treat diabetes is less well known. The drugs in common use include metformin, dipeptidyl-peptidase 4 inhibitors (DPP-4i), sulfonylurea, glinides, sodium-glucose co-transporter 2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), α-glycosidase inhibitors and thiazolidinediones (TZDs).

Metformin is among the most widely used first-line drugs for diabetes. Despite five ongoing clinical trials, this drug is still not seen to have either clearly beneficial or harmful effects on the outcome of COVID-19. DDP-4i may not protect diabetics from being infected with SARS-CoV-2, but could possibly prevent organ failure and fibrosis of the lung secondary to pneumonia in such patients with COVID-19.

The study showed that metformin-using diabetics with COVID-19 have lower odds of death by 44 per cent. When adjusted for variables like geographical location and time of use, whether in hospital or earlier, the odds were lowered still more, by 60 per cent.

Also, a new study – involving an international team of researchers from Canada, the U.S. and Brazil – describes the results of colchicine in mitigating the inflammatory storm associated with COVID-19, illustrating the drug’s potential for preventing a percentage of severe and critical cases.

The team has released their findings on the medRxiv* preprint server. Evidence is building up that the so-called “cytokine storm” is key in triggering severe or critical COVID-19 disease by the associated severe and systemic inflammatory damage caused by high levels of circulating cytokines on multiple organs. Drugs that prevent or regulate inflammation could thus be helpful in reducing the risk of poor outcomes in this condition.

One such drug is the corticosteroid dexamethasone, which has been found to reduce mortality in COVID-19 patients on mechanical ventilation or supplemental oxygen. Another is tocilizumab, the IL-6 receptor antagonist, which seems to effectively reduce the chances of requiring mechanical ventilation in patients hospitalized for COVID-19 pneumonia.

The mechanism of severe inflammation may be via the viral activation of the NLRP3 inflammasome, an intracellular complex of inflammatory mediators. The resulting activation of multiple interleukins leads to a cascade of inflammation. Indeed, high IL-6 levels are a marker of poor outcome in COVID-19.

The ideal anti-inflammatory in this setting would be one that is readily available, cheap and orally administered, with a good safety profile, well tolerated, and that prevents or modulates inflammasome activation. The researchers selected colchicine for their study.

Colchicine is a powerful anti-inflammatory agent used to treat gout, coronary disease, viral pericarditis and familial Mediterranean fever. It has been found to act by preventing the polymerization of the protein called tubulin, thus inhibiting inflammasome activation, pro-inflammatory chemokines, and cellular adhesion molecules.

In an earlier experiment, colchicine was found to prevent the activation and recruitment of leukocytes, and thus reduce inflammatory lung injury, and respiratory failure, in acute respiratory distress syndrome (ARDS).
Study details

In the current trial, called the COLchicine CORONAvirus SARS-CoV-2 (COLCORONA) trial, the researchers studied almost 4,500 non-hospitalized patients with COVID-19 who were randomly assigned to either colchicine or placebo for 30 days. All were 40 years or above, and had one or more high-risk features such as fever, diabetes, coronary heart disease, obesity, known respiratory disease, or a high neutrophil count accompanied by a low lymphocyte count. All had been diagnosed by one of three methods: polymerase chain reaction testing on a nasopharyngeal swab, close contact with a positive family member along with suspicious symptoms, or by a clinical algorithm if symptoms were present without other obvious cause.