Journal of Bangladesh College of Physicians and Surgeons

Vol. 38, COVID-19 (Supplement Issue), July 2020

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

Abstract: Results: In this study male and female were 64 and 36

Background: A definitive treatment of SARS CoV-2 is yet to respectively, the age ranged between 8 to 84 years. Retesting
arrive and the human death toll rises exponentially globally. was done between 4 and 18 days of starting medication. All
In this health emergency, it might be useful to look into the patients tested negative and their symptoms improved within
old therapies which could be effective against the virus. In 72 hours. There were no noticeable side effects.
vitro research showed Ivermectin could decrease the
concentration of coronavirus 4000 to 5000 folds in living Conclusion: Combination of Ivermectin and doxycycline
lung tissue. was found to be very effective in viral clearance in mild and
moderately sick COVID-19 patients. Medical societies and
Aim: In this prospective study a combination of Ivermectin
and Doxycycline will be evaluated therapeutically to treat institutions should undertake larger multi center studies to
COVID-19 patients. validate and recommend this combination therapy to include
in national guidelines.
Methods: 100 COVID-19 patients were enrolled in this study
with a predefined inclusion and exclusion criteria. RT- PCR Keywords: Covid-19, Doxycycline, Ivermectin
of the SERS-CoV-2 will be done at designated government
hospitals. The clinical features and response to treatment Bangladesh Coll Phys Surg 2020; 38: 10-15)
were noted according to a dedicated protocol. DOI: https://doi.org/10.3329/jbcps.v38i0.47512

Background: professional including political leaders are united to

One hundred years after the Spanish flu pandemic in explore a quick effective treatment and vaccine before it
1918-20, the whole world is again facing devastation is too late. Empirical applications of some drugs have
due to the Covid-19 (SARS CoV-2) pandemic. This been assumed to work with success, but without having
virulent virus SARS CoV-2 has high infectivity, morbidity a clinical trial, they cannot be validated. Until anything
and remarkable fatality rate. No specific treatment or comes up, it might be useful to repurpose old therapies
vaccine has been invented to save mankind yet. which could be effective against the virus.
Scientists, physicians and concerned multidisciplinary
In the beginning of April 2020, Caly et al. from Monash
a. Prof. Mohammed Tarek Alam, Professor and Head of University, Australia published their research article
Department of Medicine, Bangladesh Medical College,
House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh
stating that a single dose of Ivermectin (an anti-
b. Rubaiul Murshed, Chairperson, Shomman Foundation, parasitic drug) could decrease the concentration of
House # 71/1, Road # 15/A, Dhanmondi R/A, Dhaka-1209, coronavirus in vitro. In the lab, Caly et al. bathed Vero-
Bangladesh & Chief Consultant, Central Police Hospital, 2 hSLAM cells with Ivermectin at a concentration of
DIT Ave, Dhaka 1000, Bangladesh
5µM from 2 hours post-infection SARS-CoV-2 isolate
c. Dr. Elias Bhiuyan, Assistant Professor, Department of
Medicine Bangladesh Medical College, House # 34, Road # Australia/VIC01/2020 until the conclusion of the
14/A, R/A, Dhaka-1209, Bangladesh experiment. SARS-CoV-2 RNA was determined by RT-
d. Dr. Sadia Saber, Medical Officer, Department of Medicine PCR at days 0-3 in both supernatant and cell pellet
Bangladesh Medical College, House # 34, Road # 14/A, R/
A, Dhaka-1209, Bangladesh experiments. The authors noted 93-99.8% reduction in
e. Rafa Faaria Alam , Faculty Member, School of Public Health viral RNA for Ivermection versus DMSO control at
and Life Science, University of South Asia, Dhaka-1212, 24h in the supernatant (released virions) and cell
Bangladesh
associated viral RNA (total virus) respectively. They
f. Rishad Choudhury Robin, Associate Project Lead, Shomman
Foundation, House # 71/1, Road # 15/A, Dhanmondi R/A,
also describe by 48 hours about 5000 fold reduction of
Dhaka-1209, Bangladesh viral RNA and maintenance of effect at 72 hours.1
Address of Correspondence: Dr. Mohammed Tarek Alam,
They concluded that the human dose needed to be
Professor and Head of Department of Medicine, Bangladesh Medical
College, House # 34, Road # 14/A, R/A, Dhaka-1209, Bangladesh. ascertained in further studies. In the current SARS-CoV-
E-mail: mtarekalam16@gmail.com, Phone: +8801819-185449 2 pandemic, this news was a ray of hope.
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.

Methodology: Result:
Study design This observational study, consisting of 64 males and
Observational /Cross-sectional study 36 females was conducted from April to May 2020
(Figure 2) in Bangladesh Medical College. The oldest
Study Population
patient was 84 years and the youngest one was 8 years
All RT-PCR SARS- CoV-2 positive patients fulfilling the with most patients between the ages of 21 to 40 years
selection criteria. Mild and moderate cases purposively (Figure 3). Patients were divided in 3 groups: Mild (73),
selected from Bangladesh Medical College. Moderate (20) and Severe (7), based on their symptoms.
From the severe patients, three had fever more than
Selection criteria
103 Fahrenheit for seven days with severe cough and
Inclusion Criteria
lung infiltrates , three had severe loose motion and
• Subjects within age group 5 years and above
one had uncontrolled diabetes. Out of the rest, 20
• With either sex, male or female patients had moderate symptoms of mild fever (100
• Confirmed cases of Covid-19 by RT-PCR test Fahrenheit) and mild cough. Moreover, 73 had mild
symptoms of malaise, sore throat, loss of smell, loss of
• Patients who are classified as asymptomatic,
taste, and body ache. Fifty percent symptomatic
• Mild and moderate cases with typical symptoms improvement of mild to moderate patients was seen
• Patients who are not already treated with any other between 3rd to 5th day after starting treatment. All 7
antiviral drugs severe patients’ symptoms subsided by 50 percent by
7th day of treatment. Retesting was done between 4 to
Exclusion criteria
18 days of starting medication (Figure 4). Twenty five
• Patients who are severe and critically ill. patients underwent retesting between 4th to 8th days,
• Patients with chronic liver diseases 51 between 9th to 13th days and 24 between 14th to 18th
days from starting medication. All of the patients tested
• Patients with pregnancy and on lactation
negative. None needed intensive care admission and
• Children less than 5 years of age or less than 15kg
no deaths were reported.
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 Fig 1: Schematic of Ivermectin’s proposed antiviral
patient about their health conditions. action on coronavirus .

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Journal of Bangladesh College of Physicians and Surgeons Vol. 38, COVID-19 (Supplement Issue), July 2020

She was informed about the recent findings on

Ivermectin and agreed to take an oral combination of
36
200mcg/kg single dose of Ivermectin along with
Doxycycline 100mg orally daily for 10 days. She tested
Male
Female negative in seven days.
This observation correlates with the findings of Caly et
64
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-
Fig.-2: Gender of Covid-19 Positive patients (N=100) typhus, and anti-viral which also decreases cytokine
production without any cardiac toxicity has been a good
25
combination in our small observational study2. We only
22
treated asymptomatic and mostly mildly symptomatic
20 18
16 patients.
15
12 11 Ivermectin was discovered in 1975 and came into medical
10
10
use in 1981.3,4 It is on the World Health Organization’s
5 4 3 2
List of Essential Medicines.5 Ivermectin is a FDA
1 1
0 approved drug, it is used for prevention, treatment, and
<20 21-30 31-40 41-50 51-60 >60
control of river blindness (onchocerciasis) in
Male Female
populations where the disease is common. It is also
Fig.- 3: Male and female ratio in different age groups used for treatment of Strongyloidosis, enterobiasis,
of Covid-19 positive patients (N=100) Trichuris trichura, Loa Loa, Scabies, human lice, malaria
and is also known to have wide-spectrum antiviral
60
activity against number of viruses under in-vitro
50 conditions. 6,7,8,9 SARS-CoV-2 is a single stranded RNA
40 virus which is closely related to SARS coronavirus
(SARS-CoV). Recent study on Ivermectin against SARS-
30
CoV-2 under in-vitro conditions revealed that it can
20 inhibit the viral replication. The single treatment of this
10 drug was able to reduce the virus up to 5000-fold in
0
Vero-hSLAM cells bathed with Ivermectin within 48
4th to 8th Day 9th to13th Day 14th to 18th Days hours. However, no further reduction was reported with
Fig.-4: Number of Patients testing Negative on Days further increase in time period i.e up to 72 hours.
after Starting Treatment (N=100) Moreover, no toxicity was seen with the drug at any
point of time 10. Mechanism by which Ivermectin
responded against the SARS CoV-2 virus is not known
Discussion:
An elderly female colleague with co-morbidities, who and was believed to be working similarly as it acted on
tested positive for SARS-CoV2, was referred to the other viruses. It was known to inhibit the nuclear import
Medicine Out Patient Department. As she was of viral and host proteins. Integrase protein of viruses
asymptomatic, she was advised isolation but she wanted and the importin IMPα/β1 heterodimer was responsible
to be treated without Hydroxychloroquine and for IN nuclear import which further increases the
Azythromycin fearing cardiac toxicity. infection. As most of the RNA viruses are dependent

12
A Case Series of 100 COVID-19 Positive Patients Treated with Combination MT Alam et al.

upon IMPα/β1 during infection, Ivermectin acts on it breast feeding is not recommended 12. No significant
and inhibits the import with the increase in antiviral drug interactions with Ivermectin are recognized.
response 1,10.
In vitro studies showed Doxycycline to exert anti
Fig 1 shows a schematic of Ivermectin’s proposed inflammatory effects at low (20 - 40mg/day) and high
antiviral action on coronavirus. IMPα/β1 binds to the (100 or 200mg/day) doses with inhibitory action on
coronavirus cargo protein in the cytoplasm (top) and metalloproteases and modulating effects of pro
translocates it through the nuclear pore complex (NPC)
inflammatory cytokines IL 6, IL 8 and tumor necrosis
into the nucleus where the complex falls apart and the
factor alpha. The anti inflammatory properties of
viral cargo can reduce the host cell’s antiviral response,
Doxycycline and other components of tetracycline
leading to enhanced infection. Ivermectin binds to and
has been demonstrated for several inflammatory
destabilizes the IMPα/β1 heterodimer thereby
preventing IMPα/β1 from binding to the viral protein airway diseases, including, acute respiratory distress
(bottom) and preventing it from entering the nucleus. syndrome. Thereby, low Doxycycline doses have
This, likely, results in reduced inhibition of the antiviral been shown to be more effective than high doses to
responses, leading to a normal, more efficient antiviral prevent induction of pro inflammatory cytokines (such
response1. as IL 6) in inflammatory diseases 13. Doxycycline is
Ivermectin is well tolerated by uninfected humans. It is rapidly and almost completely absorbed after oral
primarily metabolized in the liver by CYP450-3A47 and administration and has half life of 16-18 hours. Based
has a plasma half-life of 16 hours and is almost on the available evidence, we believe Tetracyclines
exclusively excreted in faeces with minimal clearance by may be effective agents in the treatment of Covid-19
the kidneys. Therefore, it does not require dose due to their ability to chelate Zinc compounds on
adjustment for people with renal failure. There have been matrix metalloprotienases (MMP) on which corona-
some reports of a mild anticoagulation effect. However, viruses rely heavily for survival, cell infiltration, cell
this is usually not significant enough to alter coagulation to cell adhesion and replication, many of which has
parameters such as the prothrombin ratio. Zinc as part of their MMP complex.14 It is a safe and
Side effects of oral Ivermectin are rare and usually inexpensive drug with a minimal toxicity 14 .
minor. These include transient tachycardia, flushing, Doxycycline is largely excreted unchanged both in
nausea and lightheadedness. More severe the bile and urine and the dose does not require
neurological side effects are theoretically possible in adjustment in patients with renal failure, because of
rare susceptible individuals. Moreover, FDA
their enterohepatic circulation this drug may remain
describes some of the side-effects that may be
in the body for a long time after cessation of therapy.
associated with Ivermectin include skin rash,
Doxycycline can produce GI irritation most commonly
vomiting, diarrhea, stomach pain, facial or limb
after oral administration. Tolerability can be improved
swelling, neurologic adverse events (dizziness,
by administering it with food. Doxycycline can be
seizures, confusion), sudden drop in blood pressure,
severe skin rash potentially requiring hospitalization safely used in children aged 8 years and above15.
and liver injury (hepatitis) 11. The safety of Ivermectin Currently global scenario is not stable as there is no
in pregnant women has not been studied and such effective drugs could be prescribed under sufficient
use is not recommended. Studies in animals have evidence based clinical trials. Already efficacy and
shown an increase in birth defects. Safety and effectiveness of Hydroxychloroquine is
effectiveness in children below 5 years and under 15 questionable 16,17,18. As Doxycycline is safe to use in
kg and pregnant women have not been established. treatment of ARDS it alone could be a better option
Ivermectin passes into breast milk and use during for Covid-19 treatment.

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Journal of Bangladesh College of Physicians and Surgeons Vol. 38, COVID-19 (Supplement Issue), July 2020

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