Review of Trial of combination therapy to Treat COVID-19 Infection - Tapamoy Chakraborty (Quality Assurance Specialist)
Review of Trial of combination therapy to Treat COVID-19 Infection -Tapamoy Chakraborty (Quality Assurance Specialist)
The COVID-19 pandemic in India is part of the worldwide pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first case of COVID-19 in India, which originated from China, was reported on 30 January 2020. India currently has the largest number of confirmed cases in Asia, and has the second-highest number of confirmed cases in the world after the United States, with more than 9 million reported cases of COVID-19 infection and more than 100 thousand deaths. By mid of 2020, India had approached in position of conducting highest number of daily tests in the world which subsequently translated into highest number of daily new cases in world and has sustained highest number of daily cases spike since then.
Overview
Coronavirus disease 2019 (COVID-19) is defined as illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; formerly called 2019-nCoV), which was first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. It was initially reported to the World Health Organization (WHO) on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009.
As of October 22, 2020, remdesivir, an antiviral agent, is the only drug approved for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg.
A World in Chaos
The COVID-19 pandemic has ground the world economy to a halt, killed more than a million people so far, and affected many millions of lives. Still, the sadder reality is that it has not affected everyone equally. What‘s more, the hard lessons, science, and research learned by early affected countries were not employed and shared properly to maximize effective treatment by later countries. The three strongest epidemic outbreaks surprised populations before any NPIs (non-pharmaceutical-interventions) were employed: Wuhan, Lombardy, Italy, and New York City, are evidence that an unaware civilian population will be devastated, specialists on the ground calling each epicenter equivalent to a battleground with impossible triage decisions being made of whom to treat and whom to euthanize. Most other places did not fare so badly, due to various measures such as masks, strict handwashing and mindfulness of surface contamination, lockdowns, and social distancing. Some places, such as Japan, had mainly asymptomatic cases and low death rates despite large, dense populations, with no lockdowns, evidence that a trained population in NPIs and ‗astronaut protocols‘ will fare drastically better by every metric. Other countries such as Vietnam, Mongolia, and Uganda had great success with contact tracing and isolation. Until now, it has not been entirely clear which non-pharmaceutical-interventions (NPIs) are most effective, and why, while many countries have argued about the efficacies of each, namely do masks work and are lockdowns necessary.
In this trial patients will be treated with either a combination of therapies to treat COVID-19 or a placebo. Treatment will last 10 days, and patients will be followed for 6 months.
https://www.smartpatients.com/trials/NCT04482686
Inclusion Criteria:
1. Signed informed consent, demonstrating that the subject understands the procedures required for the study and the purpose of the study.
2. Healthy male or female subjects 18 years of age to 75 years of age.
3. Diabetic and obese (BMI > 30) patients will be included in the Trial but randomization will be stratified.
4. Positive test for COVID-19 by RT-PCR at screening
5. Subjects must agree to practice at least two highly effective methods of birth control for the duration of the study. One of these must be a barrier method. Exceptions for females and partners of females that are not of childbearing potential. (e.g. surgically sterilized, post-menopausal)
6. Subjects must agree they will attend the treatment facility daily for 10d in the event of failure to attend, the patient will be visited at their home to collect the nasal swab and review data.
Exclusion Criteria:
1. Refusal to sign informed consent form
2. Negative test for COVID-19 by RT-PCR at screening
3. Severe disease symptomatically including pneumonia, respiratory distress, tachypnoea, shortness of breath, temperature > 38 degrees C (100.4 degrees F), pleuritic pain, or frequent cough.
4. Known drug allergy to any of the investigational medications
5. Currently taking medication with known drug interactions with investigational medications
6. Prescription or other antiviral medications
7. Any comorbidities which constitute health risk for the subject including known cardiac arrhythmias - but will be limited to those on hydroxychloroquine
8. Inability to attend daily for 10 days
Elaborating on the effective methods being followed for treating COVID-19 across the globe, Shashikanth Manikappa, a specialist cardiac anaesthetist working at Monash Health in Melbourne, Australia, has strongly advised what he termed Quadruple Therapy involving four medicines — Ivermectin, Doxycycline, Zinc and Vitamin D3 — as a preventive as well as treating method.
Addressing a media conference in Kalaburagi on Monday, the senior doctor said that the use of Ivermectin would be more effective than that of Hydroxychloroquine which was widely being used worldwide, right from the outbreak of the pandemic.
https://www.thehindu.com/news/national/karnataka/quadruple-therapy-with-ivermectinis-effective-in-treating-covid-19/article32601262.ece
On the side effects, Dr. Manikappa said that Ivermectin was being used in 3.7 billion people for intestinal parasites and was found to be safe. ―These are not new medicine. They are already in use for treating different ailments and are found to be safe. They can be prescribed by any doctor to control the pandemic,‖ he said.
While some countries, nations, and peoples have fared quite well against the COVID-19 pandemic outbreak in their area, others have been much harder hit. The disparity between hospitalizations and fatalities highlights a lack of information sharing and knowledge about the most efficacious way to treat the disease. Also, for many, the economic consequences of lockdowns are dire, and applying our best information to smart reopenings that do not cause renewed severe outbreaks is central to good public and economic health. This paper intends to share some recent discoveries about the prevention and minimization of the COVID-19 disease, treatment and recovery, and macro aspects that can be applied to assist in smart reopenings of some economic sectors. It has been shown that in instances where mask compliance was near 100%, the vast majority of cases of COVID-19 are asymptomatic to mild, that viral load (inoculum) is a massive component of COVID-19 severity and case outcome, and that a relationship between Vitamin D deficiency and the production of ACE2 receptors in the body leads to more severe COVID-19. Many of the most effective drugs for treatment are generic and affordable on a global scale. Still, they must be given in the appropriate doses, often early onset, and with supplements such as Zinc and Vitamin D as well as antibiotics such as Azithromycin. Several vital aspects in early detection, such as sniffer dogs and wastewater detection, could be used en masse to catch outbreaks before they spread, and contact tracing and isolation are effective methods to control and limit the spread.
Vitamin D Deficiency Key to Mild Outcome
Studies show that Vitamin D deficiency is central to a bad outcome of COVID-19. While many people, especially in the winter, will be vitamin D deficient, it is harder for those with melanin to receive the needed amount of vitamin D. Researchers released data that tens of thousands of lives could be saved worldwide by boosting Vitamin D deficiencies into healthy ranges. Vitamin D is produced by a reaction in the skin to the UV rays in sunlight. Many people are low in Vitamin D, but those with darker skin are at a disadvantage because melanin protects the skin from burning in hot climates and inhibits Vitamin D production. An Indian-American might need twice the amount of time in the sun to generate the needed vitamin D levels, so they should take a daily dose of 5,000 international units as a daily supplement. Having low Vitamin D levels was studied and linked to increased symptomatic COVID-19 and respiratory distress and hospital admission to intensive care, whereas healthy Vitamin D levels were linked to mild COVID-19, says a new study from Italy. A recent JAMA study showed that Vitamin D deficiency, even in an urban metro area, meant a patient was 77% more likely to be hospitalized for COVID-19. (8) Once hospitalized, a Reina Sofia University in Spain study showed that adding high doses of Vitamin D to the patient‘s care resulted in much less admittance to the ICU. None of the patients with their medicine + Vitamin D cocktail died. In contrast, 8% of the patients that didn‘t receive the Vitamin D treatment did die. This is because when deficient in Vitamin D, the body creates ACE2 receptors in the lungs, and other organs, and ACE2 receptors are the primary bonding vehicle COVID-19 uses to attack the body. The more ACE2 receptors you have, the more COVD-19 you can get and that has been proven to result in a stronger case of the disease. How does one get enough vitamin D? Spend half the time in the sun every day it takes for you to burn, longer if you have darker skin. You can also eat the flesh of fatty fish (such as trout, salmon, tuna, and mackerel) and fish liver oils are among the best sources, as well as egg yolks, mushrooms, cow‘s milk or soy milk (fortified), or orange juice or take supplements, such as a daily vitamin D intake of 1000–4000 IU, or 25–100 micrograms, 4000 IU is the safe upper limit according to the Institute of Medicine (IOM), although the toxic dose of Vitamin D is more than 50,000 IU/day. Selenium, Zinc, and Vitamin C and E have also been shown to have an immune-boosting role in various studies, especially important for the elderly and immuno-compromised. In a recent study in Barcelona, Zinc was shown to slow and inhibit COVID-19 virus replication and lower inflammation, delaying or disrupting acute respiratory distress syndrome (ARDS), a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs.
Viral Load Critical To Avoiding Serious Cases
How much SARSCOV2 you are exposed to does matter. According to many studies when exposed to large doses of the virus, your body does not have time to mount a defense and becomes quickly overwhelmed. This is why we sometimes see young and healthy doctors succumb to fatal cases of COVD-19 because, as health care workers, they simply were exposed to too much of the virus and possibly not properly protectedwith the right mask, eye gear or somehow otherwise exposed to toxic doses. Masks have been shown to be the best form of protection. When we look back to Japan, we see a large, very dense population that did not go into lockdown but almost uniformly complied with voluntary mask usage in all public situations. A recent study shows that 95% of the cases were asymptomatic. We now understand that receiving a low innocuous of the virus (a low viral load, low dose) either might not infect you with the virus or, even if hitting that threshold, is much more likely to present as an asymptomatic case. When the general population is effectively using masks in situations, there is a huge decrease in virus transmission, and when it is being passed, because we know masks are not 100% effective, we see the weak form of the virus being spread through a masked carrier to a masked patient results 95% of the time in a very weak, mild or asymptomatic COVID-19 case, where serious complications and fatalities are very rare. So we now have proof that while the transmission may occur with or without masks, when two unmasked people (a carrier and a patient) transmit the virus in an enclosed indoor, poorly ventilated space, there is a much higher chance the virus will be transmitted in huge doses, leading to very strong, and often toxic or fatal cases of COVID-19. When the virus spreads in outdoor, well-ventilated areas from masked person to person, the virus is overwhelming of a mild or asymptomatic nature. Some evidence has come out that wearing masks can even create some immunity (17), by exposing people gradually to sub-toxic levels of the SARSCOV2 virus so that the COVID-19 disease does not present itself, but the body creates a natural B or T cell response or produces antibodies that would fight off a potentially larger exposure in the future. So we now understand the true power of masks in protecting the population. The results are incredibly important: both for public health and in understanding what sectors of the economy can be reopened and which should be closed and subsided. One cannot eat or drink in public without removing a mask, so restaurants and bars are huge vectors of serious COVID transmission and should be avoided, for example.
Politiciciation and Profit in a Pandemic
When dealing with serious cases of COVID-19 when they occur, we should look at developing nations rather than the west for the lead of effective treatments. While Oxford and the WHO found HCQ was a dangerous treatment for COVID-19 , it was revealed in the study they were using toxic daily doses, often 400% of the textbook guidelines within 24 hours and at late stages where antivirals in high doses might do more harm than good. According to the FDA, ―The recommended adult dosage is 200 to 400 mg (155 to 310 mg base) daily, administered as a single daily dose or in two divided doses. Doses above 400 mg‖ are considered toxic and dangerous. In contrast, a Bangladesh study, showed that when used early and with an appropriate textbook dose, HCQ combined with antibiotics such as AZ and Vitamin D and Zinc proved very effective, reducing fatalities by 30% and reducing hospital stay times. Another incredible and multipurpose/broadband antiviral is Ivermectin, which recently showed that reducing hospital stays to an average of 7 days and fatalities by 30% also. These medicines are generic and less than $1 a pill and accessible around the world for the treatment of serious COVID and prevention of unneeded case fatalities.Ivermectin has been shown to be an efficacious broad-band antiviral for a very low cost that may prove not only instrumental to ending this pandemic but possibly a future one as well. In a recent Indian study, Ivermectin is being used both as preventative prophylactic medicine as well as an effective treatment for serious onset of COVID-19. Dr. Manikappa said that 93 % of primary contacts who received Ivermectin did not develop any symptoms and 58 % of primary contacts who did not receive Ivermectin did progress to have symptoms of the pandemic. ―Quadruple Therapy includes Ivermectin 12 mg one dose, Doxycycline 100 mg once a day for four days, Zinc 50 mg once a day for four days and Vitamin D3 once a week. Ivermectin, Doxycycline, and Zinc are to be repeated every 14 days and Vitamin D3 every week with blood levels monitored. The synergistic effect of these medicine acts to prevent viral multiplication and also stop the virus from entering human cells. Thomas Borody, an Australian gastroenterologist who is known for curing peptic ulcers with triple antibiotic therapy, has revealed that one block in South America that received Ivermectin combination prophylaxis did not contract coronavirus infection while others did,‖ he said.
Unfortunately, the American NIH does not recommend either of these medicines to treat COVID-19, instead suggesting Remdisivir by Gilead. Remdisivir has been found to reduce the hospital stay from 15 days to 11 days (compared to 7) and shows no significant reduction in case fatalities. It‘s also $3000 a pill, an amount not available to many Americans, let alone many countries worldwide. More than 1 billion people survive on less than $2 a day, and half the world is living on less than $5.50 a day. (23) This is a puzzling recommendation and might have something to do with 19/40 people on the NIH board reporting conflicts of interest and 10/40 of them being sponsored by Remdisivir‘s pharmaceutical giant, Gilead. If this is not the reason for this recommendation, none other is obvious or apparent.
Applying Best Case Outcomes across
the Board What does this mean for distressed communities being ravaged by COVID-19? Suppose we look at countries and populations that have managed the better/best outcomes. In that case, we see that certain procedures and protocols will allow for the most freedom and least serious cases, hospitalization a and fatalities, and in rural areas such as the Amazon populations where some people are days from the nearest field hospital, not requiring hospitalization might be a life-saving factor. In the west and Europe, we saw 10-15 % of cases requiring hospitalization and 1-4% fatalities. Supplements such as Vitamin D3 and Zinc, we can minimize the amount of a population that will suffer COVID-19 severe cases and fatalities by a factor of 95%. By using cheap, generic, and effective medications such as HCQ, AZ, Ivermectin, and Zinc/Vitamin D, we can again minimize the number of patients, and can level the playing field, so we do not see whole swaths of the population, be in countries, nations, or people‘s that are drastically and negatively impacted by COVID-19 while other populations manage to dodge the worst of it, seemingly barely affected by the pandemic. This can be incredibly helpful in terms of implications for the public and lockdowns. China saw a heavy lockdown for eight weeks and almost universal mask compliance and now is mostly back to normal with vigilant protocols. Japan did not enforce a lockdown and instead relied strictly on mask use ventilation and social distancing. By examining their successes, other countries can manage to reopen certain sectors of the economy/society, subsidize/protect the restaurants and bars, etc. that they have to keep closed. For example, on recent cruise ships, when all staff and customers received masks the moment an outbreak occurred, a majority of infections were stopped or became milder and more asymptomatic, and this kind of proactive adaptation can protect the cruise industry from a complete shutdown . What is clear is that the priority should be a population masked at all times in public to attempt to recreate the Japanese results of 1) reduced infections and 2) the majority of asymptomatic or mild disease for the infected. This means that all efforts should be made to outlaw and deter anti-maskers, mask enforcement, and the education and work sectors that can operate masked and safely monitored and opened. Sectors, where masking is impossible (sit down public eating halls, private rooms with shared ventilation, or bars, since eating and drinking with a mask on is not feasible or possible), should be closed and efforts made to subsidize those businesses to convert to take out or give rent and insurance break government-mandated, so they will be possible after the pandemic is over or community spread is terminated, under close supervision. This clearer mandate should be implemented everywhere, as it is more focused and will give leaders clear directives from which to operate safely and effectively.
Kai shares his diaries exclusively with iChongqing. His first book ‗The Invisible War‘ aka Kai‘s Diary: A Canadian‘s Pandemic Diary in Chongqing is on sale now, in English and Chinese versions, both in print and online. You can also see his research and blog at www.theinvisiblewar.co
Brief Summary: In this trial patients will be treated with either a combination of therapies to treat COVID-19 or a placebo. Treatment will last 10 days, and patients will be followed for 6 months. https://clinicaltrials.gov/ct2/show/study/NCT04482686
Drugs and Vaccines Under Investigation for COVID-19 Treatment and Prophylaxis
https://www.forcemed.com/services/resources
India’s national research organization known as the Indian Council of Medical Research (ICMR) is now reviewing the benefits of ivermectin and doxycycline as a potential therapy for COVID-19. The combination was tested by Dr. Tarek Alam at the Bangladesh Medical College who interviewed with TrialSite News. Hailed as “astounding results” in the hospital approved off-label protocol study of 60 patients, they have all recovered. This got the attention of the national research agency in India.
https://www.trialsitenews.com/icmr-indias-national-research-agency-investigating-ivermectin-doxycycline-as-potential-treatment-for-covid-19/
The interest in ivermectin accelerates worldwide now as the world‘s second most populous country‘s elite national research agency, ICMR, investigates the U.S. Food and Drug Administration (FDA)-approved anti-parasite drug. Nivedita Gupta, senior scientist with ICMR, reports, ―We are closely studying the drug ivermectin and its possible efficacy against COVID-19. It needs to be studied more closely,‖ reports The Print in India.
The Bangladesh Medical College
As TrialSite News reported in its interview with Dr. Tarek Alam, the Bangladesh Medical College approved an off-label protocol to treat sick COVID-19 patients with the ivermectin and Doxycycline combination yielding ―astounding results.‖ Dr. Alam reported that although the results were clearly beneficial to dozens of patients (n=60), he still acknowledged that a randomized controlled trial would be required to substantiate the mounting evidence from these off-label hospital approved efforts. He reported that Bangladesh Medical College approved his effort that includes the ivermectin 200 mcg/kg once orally with Doxycycline.
Dr. Alam was inspired by the Monash University study showing the ivermectin zapped COVID-19 in a cell culture in a lab setting. With a known safety profile (ivermectin has been around for decades), he mentioned that there is a push at Bangladesh Medical College to launch a full clinical trial with approval from the Bangladesh Directorate General of Drug Administration (DGDA). This is apparently in the planning stages.
ICMR Starts Ivermectin Investigation
Now the ICMR is carefully looking into ivermectin. Ms. Gupta reports that ―In in-vitro studies, it has shown effectiveness but there are no studies on human beings‖ she said. She continued, ―We are continuously studying the evolution of the use of this drug in the treatment protocol of COVID-19 patients. However, we need solid evidence or a published study, backed by statistically significant data on a bigger sample size to conclude anything.‖ Ivermectin Momentum & Need for Patient Registry Ms. Gupta doesn‘t need to look to far. There are currently at least 18 randomized controlled studies now planned or ongoing that have been disclosed to the U.S. government. TrialSite News has been at the forefront of tracking, monitoring, and reporting on ivermectin and COVID-19 studies.
These studies are led by investigators from Egypt, Iraq, Mexico, Argentina, Brazil, India and the United States (University of Kentucky and Johns Hopkins University). Moreover we are privy to hundreds of cases where ivermectin has in fact worked and patients are around to talk about it.
TrialSite News reported on an innovative doctor in the U.S. who is working on reporting his findings and others are going to publish soon. In Peru, ivermectin is now approved for at least mild cases of COVID-19 and in Bolivia ivermectin is approved at least in the northeaster Beni region. Those approvals were not based on data derived from randomized controlled trials. Moreover the Australian team that conducted the breakthrough lab study recently received funds from the Helmsley Charitable Trust to advance ivermectin targeting COVID-19. Ivermectin is being used a treatment against COVID-19 throughout Latin America. Moreover, a major university in a major East African nation, approached TrialSite News to facilitate a meeting with Dr. Alam as this university seeks to sponsor a major clinical trial. ICMR‘s position is the right one—there is still no conclusive evidence that ivermectin works until more of this data is aggregated, analyzed, and presented to the world for critical review. TrialSite News has proposed an ivermectin/COVID-19 patient registry.
Povidone-Iodine Effectively Limits COVID-19 Spread:
Antiseptic First Aid products should only be used to help prevent infection in minor cuts, scrapes and burns. Antiseptic products have not been demonstrated to be effective for the treatment or prevention of COVID-19 or any other viruses. It is an established fact that, corona virus spread through the respiratory droplets. Colonization of the virus in oropharynx and/or nasopharynx is considered to be major factor for transmissibility of the virus through respiratory secretions. Preventing colonization of the virus by administrating povidone iodine in the nasal passage therefore, a rational thought which is supported by recent evidence of in-vitro virucidal action of povidone iodine in Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS CoV-2). Therefore, the study is designed to assess the virucidal effect of povidone iodine on COVID-19 virus in-vivo.This open label randomized clinical trial will be conducted at Department of Otorhinolaryngology and Head Neck Surgery, in collaboration with Department of Virology and Department of Medicine in Dhaka Medical College (DMC) Hospital. The study will be conducted from September 2020 to October 2020. Total 175 confirmed cases of COVID-19 disease, proven by Reverse transcription polymerase chain reaction (RT-PCR) testing will be enrolled in this study. Written informed consent will be ensured before participation. In case of no literacy, finger print will be considered for written permission.Consent will be sought from the legal guardian in case of minor or underaged.Formal ethical clearance will be taken from Ethical Review Committee (ERC) of Dhaka Medical College. All of the Participants will be divided into seven groups: Group A will receive Povidone iodine (PVP-I) nasal irrigation at concentration of 0.4%, Group B and Group C will received 0.5% and 0.6%; Group D will receive PVP-I nasal spray at concentration of 0.5% and Group E will received at 0.6% concentration. Group F (Placebo comparator group) will receive nasal irrigation by distilled water (DW) and Group G (Placebo comparator group) will received nasal spray by distilled water. The contact time will be minimum 30 seconds. After the individual application of PVP-I and distilled water in respective participant, they will be tested again for RT-PCR for COVID-19 from nasopharyngeal and oropharyngeal sample. All patients will be subjected to detail history, physical examination and adverse events. Block Randomization will be followed for randomization. Data will be recorded in a semi-structured questionnaire and will be analyzed by 'R-4.0.2' data analysis software.
https://clinicaltrials.gov/ct2/show/NCT04549376
CLINICAL PHARMACOLOGY:
A placebo-controlled study in 38 normal volunteers yielded data for 36 subjects who showed a mean log10 reduction of 3.05 log10 units in total aerobes at 10 minutes following prepping the skin with BETADINE* 5% Sterile Ophthalmic Prep Solution compared with reduction of 1.58 log10 units after prepping with vehicle free of the iodine complex. This placebo-controlled study indicates a mean log10 reduction by the iodine complex compared with the control solution of 1.47 log10 units at 10 minutes and 1.79 log10 units at 45 minutes. The base-line mean aerobic bacterial count was 7,586 organisms/cm2.
Hydroxychloroquine:
Pharmacokinetics: Following a single 200 mg oral dose of hydroxychloroquine sulfate tablets to healthy male volunteers, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half-life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL reached in 3.74 hours with a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted as the parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Peak blood concentrations of metabolites were observed at the same time was peak levels of hydroxychloroquine. The mean fraction of the dose absorbed was 0.74. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics.
Following chronic oral administration of hydroxychloroquine, significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), esethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) have been found in plasma and blood, with DHCQ being the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue uptake rather than through decreased excretion. Peak plasma levels of hydroxychloroquine were seen in about 3 to 4 hours. Renal clearance in rheumatoid arthritis (RA) patients taking hydroxychloroquine sulfate tablets for at least six months seemed to be similar to that of the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients with renal impairment. In RA patients, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Cellular levels of patients on daily hydroxychloroquine have been shown to be higher in mononuclear cells than polymorphonuclear leucocytes.
Remdesivir:
Pharmacology- Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells. Remdesivir triphosphate (GS-443902) acts as an adenosine triphosphate analog and competes for incorporation into RNA chains by the SARS-CoV-2 RdRp, resulting in delayed chain termination during viral RNA replication. Remdesivir triphosphate can also inhibit viral RNA synthesis due to incorporation into the viral RNA template.
Ivermectin :
Pharmacokinetics- Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of ivermectin in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4 to 101.1) and 30.6 (±15.6) (range: 13.9 to 68.4) ng/mL, respectively, at approximately 4 hours after dosing. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of ivermectin in man is approximately 18 hours following oral administration.
The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose clinical pharmacokinetic study involving healthy volunteers. Subjects received oral doses of 30 to 120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 to 600 mcg/kg) ivermectin following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state.
Doxycycline
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Cross resistance with other tetracyclines is common.
Azithromycin
Azithromycin Tablets are a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Recommended dosages and durations of therapy in adult and pediatric patient populations vary in these indications.
Usage: To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Azithromycin is commonly used for bacterial respiratory infections, and could potentially treat or prevent co-infection with SARS-CoV-2. Azithromycin might also have antiviral activity against some RNA viruses.
Azithromycin has been shown to be effective in vitro against viruses such as Zika and rhinovirus, in addition to SARS-CoV-2, and to have antiviral effects in bronchial epithelial cells. Azithromycin has also been shown to be immunomodulatory, and can reduce exacerbations in chronic airway diseases. Azithromycin is widely available and has an excellent safety profile; thus, if shown to be effective, could be easily scaled up as a first-line treatment for patients with COVID-19.
Zinc
Clinical Pharmacology Zinc is an essential nutritional requirement and serves as a cofactor for more than 70 different enzymes including carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase, and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration, and the senses of taste and smell.
Zinc resides in muscle, bone, skin, kidney, liver, pancreas, retina, prostate and particularly in the red and white blood cells. Zinc binds to plasma albumin, α2-macroglobulin, and some plasma amino acids including histidine, cysteine, threonine, glycine, and asparagine. Ingested Zinc is excreted mainly in the stool (approximately 90%), and to a lesser extent in the urine and in perspiration.
Providing Zinc helps prevent development of deficiency symptoms such as: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly.
The initial manifestations of hypoZincemia in total parenteral nutrition are diarrhea, apathy and depression. At plasma levels below 20 mcg Zinc/100 mL dermatitis followed by alopecia has been reported for total parenteral nutrition patients. Normal Zinc plasma levels are 100 ± 12 mcg/100 mL.
A lot of debates and discussions are going on the potential role of zinc in mitigating COVID-19, at a time when the possibility of having any effective vaccine is months away, if not years. Until then, if any safe medicine could be developed to treat the COVID-19 patients, it would be a welcome move. In this context, zinc is being explored for any potential solution in this human crisis and a number of trials are being conducted globally.
Vitamin C
With COVID-19, we know that the main reason for the extensive lung injury is the excessive free radicals and oxidative stress mounted by the dysfunctional immune system in an effort to kill the virus but end up harming the patient instead. Vitamin C, a water soluble powerful anti-oxidant, can neutralise these free radicals and reduce oxidative damage to the lungs. When the balance between oxidants and anti-oxidants is lost, that‘s when the damage happens and patients progress to severe disease. By administering adequate Vitamin C, we can increase the anti-oxidant status of our body. Vitamin C levels in white blood cells (immune cells) are ten times higher than in plasma, which indicates functional role of the vitamin in these immune cells. Vitamin C has been shown to affect the functions of phagocytes, production of interferon, replication of viruses, and maturation of T-lymphocytes. Vitamin C at doses of 4-6g is absolutely safe and causes no side effects whatsoever. It is especially useful for the elderly and for those with pre-existing conditions to strengthen their immunity.Vitamin D
Vitamin D has to be one of science‘s most misunderstood vitamins. For a start, it is not actually a vitamin, but a prohormone, which means that it is converted into a hormone by our body. It is also not just one substance, but five different substances, of which two have been identified as being the most important to humans. These are: Vitamin D2 (ergocalciferol) Vitamin D3 (cholecalciferol). In addition, research has discovered that vitamin D is not only vital for calcium absorption and bone growth and remodeling, but several other important processes as well, such as modulating cell growth and immune system function. Interest in a potential role for vitamin D in the prevention or treatment of acute respiratory infections dates back to the 1930s, when cod liver oil was investigated as a means to reduce industrial absenteeism due to the common cold. Meta-analyses of randomised controlled trials conducted from 2007–20 reveal protective effects of vitamin D against acute respiratory infections, albeit these effects were of modest size and with substantial heterogeneity. The striking overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin, has led some researchers to hypothesise that vitamin D supplementation could hold promise as a preventive or therapeutic agent for COVID-19.
https://www.drugs.com/
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