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A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline

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A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline

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Background: A definitive treatment of SARS CoV-2 is yet to arrive and the human death toll rises exponentially globally. In this health emergency, it might be useful to look into the old therapies which could be effective against the virus. In vitro research showed Ivermectin could decrease the concentration of coronavirus 4000 to 5000 folds in living lung tissue. Aim: In this prospective study a combination of Ivermectin and Doxycycline will be evaluated therapeutically to treat COVID-19 patients. Methods: 100 COVID-19 patients were enrolled in this study with a predefined inclusion and exclusion criteria. RT- PCR of the SERS-CoV-2 will be done at designated government hospitals. The clinical features and response to treatment were noted according to a dedicated protocol. Results: In this study male and female were 64 and 36 respectively, the age ranged between 8 to 84 years. Retesting was done between 4 and 18 days of starting medication. All patients tested negative and their symptoms improved within 72 hours. There were no noticeable side effects. Conclusion: Combination of Ivermectin and doxycycline was found to be very effective in viral clearance in mild and moderately sick COVID-19 patients. Medical societies and institutions should undertake larger multi center studies to validate and recommend this combination therapy to include in national guidelines
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p-ISSN 1015-0870
e-ISSN 2309-6365
Supplement 2020
COVID-19
Journal of
Bangladesh College of Physicians and Surgeons
Official Journal of
The Bangladesh College of Physicians and Surgeons
www.bcpsbd.org & www.banglajol.info/index.php/JBCPS
Enlisted in DOAJ/HINARI/AsiaJOL/BanglaJOL
Indexed in: IndexCopernicus,Ulrichsweb,Google Scholar,ProQuest,CrossRef,EBSCO
Vol. 38, COVID-19
Supplement 2020
Abstract:
Background: A definitive treatment of SARS CoV-2 is yet to
arrive and the human death toll rises exponentially globally.
In this health emergency, it might be useful to look into the
old therapies which could be effective against the virus. In
vitro research showed Ivermectin could decrease the
concentration of coronavirus 4000 to 5000 folds in living
lung tissue.
Aim: In this prospective study a combination of Ivermectin
and Doxycycline will be evaluated therapeutically to treat
COVID-19 patients.
Methods: 100 COVID-19 patients were enrolled in this study
with a predefined inclusion and exclusion criteria. RT- PCR
of the SERS-CoV-2 will be done at designated government
hospitals. The clinical features and response to treatment
were noted according to a dedicated protocol.
Results: In this study male and female were 64 and 36
respectively, the age ranged between 8 to 84 years. Retesting
was done between 4 and 18 days of starting medication. All
patients tested negative and their symptoms improved within
72 hours. There were no noticeable side effects.
Conclusion: Combination of Ivermectin and doxycycline
was found to be very effective in viral clearance in mild and
moderately sick COVID-19 patients. Medical societies and
institutions should undertake larger multi center studies to
validate and recommend this combination therapy to include
in national guidelines.
Keywords: Covid-19, Doxycycline, Ivermectin
Bangladesh Coll Phys Surg 2020; 38: 10-15)
DOI: https://doi.org/10.3329/jbcps.v38i0.47512
a. Prof. Mohammed Tarek Alam, Professor and Head of
Department of Medicine, Bangladesh Medical College,
House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh
b. Rubaiul Murshed, Chairperson, Shomman Foundation,
House # 71/1, Road # 15/A, Dhanmondi R/A, Dhaka-1209,
Bangladesh & Chief Consultant, Central Police Hospital, 2
DIT Ave, Dhaka 1000, Bangladesh
c. Dr. Elias Bhiuyan, Assistant Professor, Department of
Medicine, Bangladesh Medical College, House # 34, Road #
14/A, R/A, Dhaka-1209, Bangladesh
d. Dr. Sadia Saber, Assistant Professor, Department of
Medicine, Bangladesh Medical College, House # 34, Road #
14/A, R/A, Dhaka-1209, Bangladesh
e. Rafa Faaria Alam, Medical Officer, Department of Medicine,
Bangladesh Medical College, House # 34, Road # 14/A, R/
A, Dhaka-1209, Bangladesh
f. Rishad Choudhury Robin, Associate Project Lead, Shomman
Foundation, House # 71/1, Road # 15/A, Dhanmondi R/A,
Dhaka-1209, Bangladesh and Faculty Member, School of
Public Health and Life Science, University of South Asia,
Dhaka-1212, Bangladesh
Address of Correspondence: Dr. Mohammed Tarek Alam,
Professor and Head of Department of Medicine, Bangladesh Medical
College, House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh.
E-mail: mtarekalam16@gmail.com, Phone: +8801819-185449
A Case Series of 100 COVID-19 Positive Patients Treated
with Combination of Ivermectin and Doxycycline
MT ALAMa, R MURSHEDb , E BHIUYANc, S SABERd, RF ALAMe, RC ROBINf
Background:
One hundred years after the Spanish flu pandemic in
1918-20, the whole world is again facing devastation
due to the Covid-19 (SARS CoV-2) pandemic. This
virulent virus SARS CoV-2 has high infectivity, morbidity
and remarkable fatality rate. No specific treatment or
vaccine has been invented to save mankind yet.
Scientists, physicians and concerned multidisciplinary
professional including political leaders are united to
explore a quick effective treatment and vaccine before it
is too late. Empirical applications of some drugs have
been assumed to work with success, but without having
a clinical trial, they cannot be validated. Until anything
comes up, it might be useful to repurpose old therapies
which could be effective against the virus.
In the beginning of April 2020, Caly et al. from Monash
University, Australia published their research article
stating that a single dose of Ivermectin (an anti-
parasitic drug) could decrease the concentration of
coronavirus in vitro. In the lab, Caly et al. bathed Vero-
hSLAM cells with Ivermectin at a concentration of
5µM from 2 hours post-infection SARS-CoV-2 isolate
Australia/VIC01/2020 until the conclusion of the
experiment. SARS-CoV-2 RNA was determined by RT-
PCR at days 0-3 in both supernatant and cell pellet
experiments. The authors noted 93-99.8% reduction in
viral RNA for Ivermection versus DMSO control at
24h in the supernatant (released virions) and cell
associated viral RNA (total virus) respectively. They
also describe by 48 hours about 5000 fold reduction of
viral RNA and maintenance of effect at 72 hours.1
They concluded that the human dose needed to be
ascertained in further studies. In the current SARS-CoV-
2 pandemic, this news was a ray of hope.
Journal of Bangladesh College of Physicians and Surgeons
Vol. 38, COVID-19 (Supplement Issue), July 2020
Methodology:
Study design
Observational /Cross-sectional study
Study Population
All RT-PCR SARS- CoV-2 positive patients fulfilling the
selection criteria. Mild and moderate cases purposively
selected from Bangladesh Medical College.
Selection criteria
Inclusion Criteria
Subjects within age group 5 years and above
With either sex, male or female
Confirmed cases of Covid-19 by RT-PCR test
Patients who are classified as asymptomatic,
Mild and moderate cases with typical symptoms
Patients who are not already treated with any other
antiviral drugs
Exclusion criteria
Patients who are severe and critically ill.
Patients with chronic liver diseases
Patients with pregnancy and on lactation
Children less than 5 years of age or less than 15kg
weight.
Procedure
100 patients RT-PCR confirmed cases of SARS CoV-2
met the selection criteria and was enrolled in the study.
They were given a combination treatment of Tab
Ivermectin and Cap Doxycycline along with
supportive treatment. The dose of ivermectin was 0.2
mg/kg single dose. Doxycycline 100 mg daily was given
to patients aged 8 years and above for 10 days. Patients
were given the choice to go to a COVID 19 designated
hospital but they went home and continued treatment.
Follow up was done every day for all symptomatic
patients over telephone about remission of
symptoms. RT-PCR test was repeated with sample of
nasal swab for all patients according to availability
of testing centers between 4 to 18 days. Six weeks
after testing negative, we plan to follow up on the
patient about their health conditions.
Result:
This observational study, consisting of 64 males and
36 females was conducted from April to May 2020
(Figure 2) in Bangladesh Medical College. The oldest
patient was 84 years and the youngest one was 8 years
with most patients between the ages of 21 to 40 years
(Figure 3). Patients were divided in 3 groups: Mild (73),
Moderate (20) and Severe (7), based on their symptoms.
From the severe patients, three had fever more than
103 Fahrenheit for seven days with severe cough and
lung infiltrates , three had severe loose motion and
one had uncontrolled diabetes. Out of the rest, 20
patients had moderate symptoms of mild fever (100
Fahrenheit) and mild cough. Moreover, 73 had mild
symptoms of malaise, sore throat, loss of smell, loss of
taste, and body ache. Fifty percent symptomatic
improvement of mild to moderate patients was seen
between 3rd to 5th day after starting treatment. All 7
severe patients’ symptoms subsided by 50 percent by
7th day of treatment. Retesting was done between 4 to
18 days of starting medication (Figure 4). Twenty five
patients underwent retesting between 4th to 8th days,
51 between 9th to 13th days and 24 between 14th to 18th
days from starting medication. All of the patients tested
negative. None needed intensive care admission and
no deaths were reported.
Fig 1: Schematic of Ivermectin’s proposed antiviral
action on coronavirus .
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
11
Discussion:
An elderly female colleague with co-morbidities, who
tested positive for SARS-CoV2, was referred to the
Medicine Out Patient Department. As she was
asymptomatic, she was advised isolation but she wanted
to be treated without Hydroxychloroquine and
Azythromycin fearing cardiac toxicity.
Fig.-2: Gender of Covid-19 Positive patients (N=100)
64
36
Male
Female
Fig.- 3: Male and female ratio in different age groups
of Covid-19 positive patients (N=100)
18
22
12 11
11
16
10
432
0
5
10
15
20
25
<20 21-30 31-40 41-50 51-60 >60
Male Female
Fig.-4: Number of Patients testing Negative on Days
after Starting Treatment (N=100)
0
10
20
30
40
50
60
4th to 8th Day 9th to13th Day 14th to 18th Days
She was informed about the recent findings on
Ivermectin and agreed to take an oral combination of
200mcg/kg single dose of Ivermectin along with
Doxycycline 100mg orally daily for 10 days. She tested
negative in seven days.
This observation correlates with the findings of Caly et
al.1 We had given the standard single dose of Ivermectin
that is normally given for the treatment of scabies and
head lice although a very high dose was used in vitro.
Doxycycline, a trusted antibiotic, anti-malarial, anti-
typhus, and anti-viral which also decreases cytokine
production without any cardiac toxicity has been a good
combination in our small observational study2. We only
treated asymptomatic and mostly mildly symptomatic
patients.
Ivermectin was discovered in 1975 and came into medical
use in 1981.3,4 It is on the World Health Organization’s
List of Essential Medicines.5 Ivermectin is a FDA
approved drug, it is used for prevention, treatment, and
control of river blindness (onchocerciasis) in
populations where the disease is common. It is also
used for treatment of Strongyloidosis, enterobiasis,
Trichuris trichura, Loa Loa, Scabies, human lice, malaria
and is also known to have wide-spectrum antiviral
activity against number of viruses under in-vitro
conditions. 6,7,8,9 SARS-CoV-2 is a single stranded RNA
virus which is closely related to SARS coronavirus
(SARS-CoV). Recent study on Ivermectin against SARS-
CoV-2 under in-vitro conditions revealed that it can
inhibit the viral replication. The single treatment of this
drug was able to reduce the virus up to 5000-fold in
Vero-hSLAM cells bathed with Ivermectin within 48
hours. However, no further reduction was reported with
further increase in time period i.e up to 72 hours.
Moreover, no toxicity was seen with the drug at any
point of time10. Mechanism by which Ivermectin
responded against the SARS CoV-2 virus is not known
and was believed to be working similarly as it acted on
other viruses. It was known to inhibit the nuclear import
of viral and host proteins. Integrase protein of viruses
and the importin IMPα/β1 heterodimer was responsible
for IN nuclear import which further increases the
infection. As most of the RNA viruses are dependent
Journal of Bangladesh College of Physicians and Surgeons Vol. 38, COVID-19 (Supplement Issue), July 2020
12
upon IMPα/β1 during infection, Ivermectin acts on it
and inhibits the import with the increase in antiviral
response 1,10.
Fig 1 shows a schematic of Ivermectin’s proposed
antiviral action on coronavirus. IMPα/β1 binds to the
coronavirus cargo protein in the cytoplasm (top) and
translocates it through the nuclear pore complex (NPC)
into the nucleus where the complex falls apart and the
viral cargo can reduce the host cell’s antiviral response,
leading to enhanced infection. Ivermectin binds to and
destabilizes the IMPα/β1 heterodimer thereby
preventing IMPα/β1 from binding to the viral protein
(bottom) and preventing it from entering the nucleus.
This, likely, results in reduced inhibition of the antiviral
responses, leading to a normal, more efficient antiviral
response1.
Ivermectin is well tolerated by uninfected humans. It is
primarily metabolized in the liver by CYP450-3A47 and
has a plasma half-life of 16 hours and is almost
exclusively excreted in faeces with minimal clearance by
the kidneys. Therefore, it does not require dose
adjustment for people with renal failure. There have been
some reports of a mild anticoagulation effect. However,
this is usually not significant enough to alter coagulation
parameters such as the prothrombin ratio.
Side effects of oral Ivermectin are rare and usually
minor. These include transient tachycardia, flushing,
nausea and lightheadedness. More severe
neurological side effects are theoretically possible in
rare susceptible individuals. Moreover, FDA
describes some of the side-effects that may be
associated with Ivermectin include skin rash,
vomiting, diarrhea, stomach pain, facial or limb
swelling, neurologic adverse events (dizziness,
seizures, confusion), sudden drop in blood pressure,
severe skin rash potentially requiring hospitalization
and liver injury (hepatitis) 11. The safety of Ivermectin
in pregnant women has not been studied and such
use is not recommended. Studies in animals have
shown an increase in birth defects. Safety and
effectiveness in children below 5 years and under 15
kg and pregnant women have not been established.
Ivermectin passes into breast milk and use during
breast feeding is not recommended12. No significant
drug interactions with Ivermectin are recognized.
In vitro studies showed Doxycycline to exert anti
inflammatory effects at low (20 - 40mg/day) and high
(100 or 200mg/day) doses with inhibitory action on
metalloproteases and modulating effects of pro
inflammatory cytokines IL 6, IL 8 and tumor necrosis
factor alpha. The anti inflammatory properties of
Doxycycline and other components of tetracycline
has been demonstrated for several inflammatory
airway diseases, including, acute respiratory distress
syndrome. Thereby, low Doxycycline doses have
been shown to be more effective than high doses to
prevent induction of pro inflammatory cytokines (such
as IL 6) in inflammatory diseases13. Doxycycline is
rapidly and almost completely absorbed after oral
administration and has half life of 16-18 hours. Based
on the available evidence, we believe Tetracyclines
may be effective agents in the treatment of Covid-19
due to their ability to chelate Zinc compounds on
matrix metalloprotienases (MMP) on which corona-
viruses rely heavily for survival, cell infiltration, cell
to cell adhesion and replication, many of which has
Zinc as part of their MMP complex.14 It is a safe and
inexpensive drug with a minimal toxicity14.
Doxycycline is largely excreted unchanged both in
the bile and urine and the dose does not require
adjustment in patients with renal failure, because of
their enterohepatic circulation this drug may remain
in the body for a long time after cessation of therapy.
Doxycycline can produce GI irritation most commonly
after oral administration. Tolerability can be improved
by administering it with food. Doxycycline can be
safely used in children aged 8 years and above15.
Currently global scenario is not stable as there is no
effective drugs could be prescribed under sufficient
evidence based clinical trials. Already efficacy and
effectiveness of Hydroxychloroquine is
questionable16,17,18. As Doxycycline is safe to use in
treatment of ARDS it alone could be a better option
for Covid-19 treatment.
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
13
Conclusion:
It is too early in this pandemic to claim major successes
of the effectivity of our combination therapy (Ivermectin
and Doxycycline) as our number is small and there is no
control group. Nevertheless, the results encourage us
to continue the clinical study for people of the world in
this improbable crisis as each and every life counts.
We urge the different medical societies and International
organizations to take up this unique observation and
quickly give it a trial and clearance because these drugs
are FDA approved for many years with excellent safety
and efficacy reviews. At the very least, using them in
the first few days of being positive with or without
symptoms may save the admissions of those 20% who
suffer and the unnecessary deaths on ventilators. We
can also stop the community transmission by
asymptomatic carriers by treating the asymptomatic
COVID-19 positive patients. Above all it is a very cheap
combination, and if fast tracked by a quick trial would
cost pennies and save a lot of lives, specifically designed
for resource-poor settings.
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A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.
15
... Several clinical studies have found a beneficial effect of ivermectin in treating COVID-19 [5][6][7][8][9]. One recent meta-analysis found that ivermectin reduced the risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; ...
... However, patients receiving ivermectin revealed a tendency to recover from certain symptoms earlier than those in the placebo group although without statistical significance. Several related studies reported more rapid viral clearance with the use of ivermectin [5,7,21]. However, other studies have not reported such a benefical outcome [22,23]. ...
Article
Full-text available
Background The emergent outbreak of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emphasized the requirement for therapeutic opportunities to overcome this pandemic. Ivermectin is an antiparasitic drug that has shown effectiveness against various agents, including SARS-CoV-2. This study aimed to assess the efficacy of ivermectin treatment compared with the standard of care (SOC) among people with mild to moderate COVID-19 symptoms. Methods In this randomized, double-blind, placebo-controlled, single-center, parallel-arm, superiority trial among adult hospitalized patients with mild to moderate COVID-19, 72 patients (mean age 48.57 ± 14.80 years) were randomly assigned to either the ivermectin (n=36) or placebo (n=36) group, along with receiving standard care. We aimed to compare the negativity of reverse transcription polymerase chain reaction (RT-PCR) result at days 7 and 14 of enrolment as the primary outcome. The secondary outcomes were duration of hospitalization, frequency of clinical worsening, survival on day 28, and adverse events. Results At days 7 and 14, no differences were observed in the proportion of PCR-positive patients (RR 0.97 at day 7 (p=0.759) and 0.95 at day 14 (p=0.813). No significant differences were found between the groups for any of the secondary endpoints, and no adverse events were reported. Conclusion No difference was found in the proportion of PCR-positive cases after treatment with ivermectin compared with standard care among patients with mild to moderate COVID-19 symptoms. However, early symptomatic recovery was observed without side effects. Trial registration ClinicalTrials.gov NCT05076253. Registered on 8 October 2021, prospectively.
... The first three studies were conducted in Bangladesh in the summer of 2020, demonstrating that mild-moderate COVID-19 patients receiving IVM in combination with doxycycline showed a faster negative conversion in PCR and significantly faster symptom resolution compared to the HCQ-AZ-treated group [255]. Moreover, IVM-doxycycline also resulted in a faster viral clearance [256] in severe COVID-19 patients [257], together with improvements in early recovery and prevention to progression to more serious disease [258]. In addition, in a case series of SARS-CoV-2 positive patients hospitalized in Pakistan, IVM combined with doxycycline, remdesivir, tocilizumab, enoxaparin sodium and steroids, emerged as potential new treatment options by reducing the disease-associated severity and recovery rate [259]. ...
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More than two years have passed since the viral outbreak that led to the novel infectious respiratory disease COVID-19, caused by the SARS-CoV-2 coronavirus. Since then, the urgency for effective treatments resulted in unprecedented efforts to develop new vaccines and to accelerate the drug discovery pipeline, mainly through the repurposing of well-known compounds with broad antiviral effects. In particular, antiparasitic drugs historically used against human infections due to protozoa or helminth parasites have entered the main stage as a miracle cure in the fight against SARS-CoV-2. Despite having demonstrated promising anti-SARS-CoV-2 activities in vitro, conflicting results have made their translation into clinical practice more difficult than expected. Since many studies involving antiparasitic drugs are currently under investigation, the window of opportunity might be not closed yet. Here, we will review the (controversial) journey of these old antiparasitic drugs to combat the human infection caused by the novel coronavirus SARS-CoV-2.
... In multi-drug treatment studies, Alam et al. 7 found that a combination of IVM and DOX was effective for viral clearance in patients with mild and moderate COVID-19. Prasad 8 reported on a patient where COVID-19 accompanied by pulmonary lesion was successfully treated with the early administration of IVM (6 mg twice daily for 3 days), AZM (500 mg daily for 5 days), DOX (100 mg twice daily for 5 days), and prednisolone (50 mg daily for 5 days) followed by dexamethasone (6 mg daily). ...
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Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), broke out in late 2019 to become a serious global threat to human health. In the absence of specific treatments for COVID-19, treatment options are being examined. Recently, the anti-SARS-CoV-2 activities of tetracyclines, macrolide antibiotics, and ivermectin (IVM), have attracted considerable attention for their potential as a single or multi-drug treatment regimen. Moreover, tetracyclines, macrolide antibiotics, and IVM possess anti-inflammatory and immunomodulatory effects to reduce the production of cytokines. COVID-19 is characterized by early exponential viral replication, cytokine storm-associated organ damage, including acute respiratory distress syndrome (ARDS) and thrombosis. Considering anti-inflammatory and immunomodulatory effects of the aforementioned drugs and corticosteroids, early treatment with doxycycline, azithromycin, IVM, and corticosteroids is thought to be the most promising option for combating COVID-19-induced ARDS. Key words: COVID-19, doxycycline, azithromycin, ivermectin, corticosteroids.
... In another randomized double-blind clinical trial, three groups of patients were administered ivermectin 24 mg, ivermectin 12 mg, and a placebo, respectively. The negative RT-PCR at day 5 failed to show statistical significances ( were observed, no other treatment was required, and there was no death in this study [61]. Another clinical trial in Iraq was conducted with 70 COVID-19 patients (48 mild-moderate, 11 severe, and 11 critical patients) who were treated with 200 µg/kg of oral ivermectin per day for 2-3 days along with 100 mg PO doxycycline twice per day for 5-10 days plus standard therapy. ...
Article
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The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for ster-oids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.
... A case series of 100 mild and moderate COVID-19 positive patients treated with the combination of IVM (0.2 mg/kg, single dose) and Doxy (100 mg daily for 10 days) was found to be very effective in viral clearance [32]. Another retrospective case series [33] with 148 patients reported that triple combination therapy with IVM (12 mg, single dose), atorvastatin (10 mg daily), and N-acetylcysteine (NAC) could be used as an adjunct to the standard of care. ...
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Ivermectin (IVM), an approved anthelminthic drug, has been reported to have antiviral, antibacterial, and anticancer activities. Antiviral activity is due to the inhibition of nuclear cargo importin (IMP) protein. The anti-SARS CoV-2 activity through in vitro study was first reported by an Australian team. Later, many studies were conducted, and most of the study results were available as non-peer reviewed preprints. In this narrative review, literature on the clinical studies conducted with ivermectin from published articles, preprints, and unpublished evidence are collected till 13th June 2021 and they are discussed based on the severity of COVID-19 disease. Out of the 23 peer-reviewed published articles, 13 studies were randomized controlled trials and the remaining were either prospective interventional, prospective observational, retrospective cohort, cross-sectional, or case series type of studies; additionally, there were 10 randomized controlled trials available as preprints. In most of the studies, ivermectin was used in combination with doxycycline, azithromycin or other drugs. Some of the studies suggested either higher dose and/ or increased duration of ivermectin use to achieve favorable effects. In this review, articles on the prophylactic role of ivermectin in COVID-19 are also discussed – wherein the results are more promising. Despite accumulating evidence suggest the possible use of ivermectin, the final call to incorporate ivermectin in the management of COVID-19 is still inconclusive.
... In multi-drug treatment studies, Alam et al. (7) found that a combination of IVM and DOX was effective for viral clearance in patients with mild and moderate COVID-19. ...
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), broke out in late 2019 to become a serious global threat to human health. In the absence of specific treatments for COVID-19, treatment options are being examined. Recently, the anti-SARS-CoV-2 activities of tetracyclines, macrolide antibiotics, and ivermectin, have attracted considerable attention for their potential as single or multi-drug treatment regimen. Moreover, tetracyclines, macrolide antibiotics, and ivermectin possess anti-inflammatory and immunomodulatory effects to reduce the production of cytokines. COVID-19 is characterized by early exponential viral replication, cytokine storm-associated organ damage, including acute respiratory distress syndrome (ARDS) and thrombosis. Considering anti-inflammatory and immunomodulatory effects of the aforementioned drugs and corticosteroids, early treatment with ivermectin, doxycycline, azithromycin, and u n c o r r e c t e d p r o o f corticosteroids is thought to be the most promising option for combating COVID-19-induced ARDS.
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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has enveloped the world into an unprecedented pandemic since 2019. Significant damage to multiple organs, such as the lungs and heart, has been extensively reported. Cardiovascular injury by ACE2 downregulation, hypoxia-induced myocardial injury, and systemic inflammatory responses complicate the disease. This virus causes multisystem inflammatory syndrome in children with similar symptoms to adult SARS-CoV-2-induced myocarditis. While several treatment strategies and immunization programs have been implemented to control the menace of this disease, the risk of long-term cardiovascular damage associated with the disease has not been adequately assessed. In this review, we surveyed and summarized all the available information on the effects of COVID-19 on cardiovascular health as well as comorbidities. We also examined several case reports on post-immunization cardiovascular complications.
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Ivermectin, an FDA-approved and popular anti-parasitic agent, has been used against mild novel coronavirus disease 2019 (COVID-19). It has demonstrated efficacy in the prophylaxis and treatment of COVID-19 patients. The evidence, so far, is based on in-vitro studies. The literature found is in pre-print form. Ivermectin is a cheap agent with a safe side effect profile. It prevents viral and hosts proteins from entering into the host cell nuclei.
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Objective To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). Design Multicentre, open label, randomised controlled trial. Setting 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. Participants 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). Interventions Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). Main outcome measure Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. Results Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. Conclusions Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. Trial registration ChiCTR2000029868.
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Objective To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. Design Comparative observational study using data collected from routine care. Setting Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. Participants 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. Interventions Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). Main outcome measures The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. Results In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. Conclusions Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.
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Alarming situation has been caused due to the emergence of COVID-19 infection around the world. There is an urgency of developing a therapeutic strategy in order to control the spread of COVID-19. Towards that initiative, potential drugs like hydroxychloroquine, ivermectin and azithromycin have been tested by diverse group of researchers worldwide for their potential against novel coronavirus. The present report presents together the comprehensive knowledge derived from the major researches about the above drugs altogether in context of the current health emergency around the world. Hydroxychloroquine and ivermectin were known to act by creating the acidic environment and inhibiting the importin (IMPα/β1) mediated viral import. Azithromycin was found to act similar to the hydroxychloroquine as an acidotropic lipophilic weak base. All the three categories of drugs seemed to potentially act against novel coronavirus infection. However, their efficacies need to be studied in detail individually and in combination in-vivo in order to combat COVID-19 infection.
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Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic.
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Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events. Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19. Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020. Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation). Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings. Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
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Currently there is a race against time to identify prophylactic and therapeutic treatments against COVID‐19. Until these treatments are developed, tested and mass produced, it might be prudent to look into existing therapies that could be effective against this virus. Based on the available evidence we believe that tetracyclines may be effective agents in the treatment of COVID‐19. Tetracyclines (e.g. tetracycline, doxycycline, and minocycline) are highly lipophilic antibiotics that are known to chelate zinc compounds on matrix metalloproteinases (MMPs)1. Coronaviruses are also known to heavily rely on host MMPs for survival, cell infiltration, cell to cell adhesion, and replication, many of which have zinc as part of their MMP complex2,3. It is possible that the zinc chelating properties of tetracyclines may also aid in inhibiting COVID‐19 infection in humans limiting their ability to replicate within the host.
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The 5th edition of this world renowned textbook is the result of a thorough updating of every chapter with respect to the mechanism of action and use of older agents and the addition of important new drugs. The philosophy and objectives of the earlier editions are continued, however, together with the same thoughtful organization, clarity and authority that have long made 'Goodman and Gilman' the standard book in the field. Although less dynamic or outmoded sections have been condensed or eliminated, the basic organization remains the same, with major attention being given to the well established, safe and effective prototypal drugs. After a discussion of the general principles of pharmacokinetics, special attention is given to drugs acting on the CNS, local anesthetics, drugs acting at synaptic and neuroeffector junctions, autacoids, cardiovascular drugs, water, salts and ions, drugs affecting renal function and electrolyte metabolism, drugs affecting uterine motility, gases and vapors, heavy metals and antagonists, locally acting drugs, antiparasitic drugs, antimicrobial drugs, antineoplastic drugs, drugs acting on the blood and hematopoietic system, hormones and hormone antagonists, vitamins and even the principles of prescription writing and patient compliance instruction. There is a detailed subject index referring to both medical concepts and drug names, generic as well as proprietary. This book will prove invaluable to both students and graduates in many areas of the biomedical sciences.