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RNI Title Code: MPENG01378
B.R. Nahata Smriti Sansthan
International Journal of
Pharmaceutical and Biological Archive
Volume 13 / Issue 1 / Jan-Mar-2022
B.R. Nahata Smriti Sansthan International Journal of Pharmaceutical and Biological Archive
Printed and published by Mr. Rahul Nahata on behalf of B.R. Nahata Smriti Sansthan and printed
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ISSN: 2582-6050[Online]

B. R. Nahata Smriti Sansthan International Journal of Pharmaceutical and Biological Archive
B. R. Nahata Smriti Sansthan International Journal of Pharmaceutical and Biological Archive • Jan-Mar 2022 • 13 (1) | i
EDITORIAL BOARD
Dr. M. A. Naidu
B.R. Nahata College of Pharmacy, Mandsaur University,
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EDITOR-IN-CHIEF
EDITORIAL BOARD TEAM
Dr. Wan Mohd Nuzul Hakimi W Salleh
Department of Chemistry, Faculty of Science and
Mathematics, Sultan Idris Education University, Tanjung
Malim, Perak Malaysia
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Dr. Nour Shafik Emam El-Gendy
Professor of Environmental Sciences & Nanobiotechnology,
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Zomer St., El Zohour Region, Nasr City, Cairo, Egypt
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Department of Chemistry, Faculty of Science, University of
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Dr. Hussein Mohamed Nabil Nassar
Researcher in the field of Petroleum and Environmental
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Ahmed El-Zomer St., El Zohour Region, Nasr City, Cairo, Egypt
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Dongwei Guo
Associate Principal Scientist, Ascendia Pharmaceuticals INC,
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Prof. Josphert N. Kimatu
Associate Professor, South Eastern Kenya University,
Department of Life Sciences, South Eastern Kenya University,
Kitui, Kenya
E-mail: jkimatu@seku.ac.ke
Jiayi Chen
Formulation Scientist, Ascendia Pharmaceuticals, Inc.
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Jersey
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Prof. (Dr.) Harish Dureja
M. Pharm. (Pharmaceutics), Ph.D. (Gold-Medalist), AIC,
Department of Pharmaceutical Sciences, Maharshi Dayanand.
University, Rohtak, Haryana, India
E-mail: harishdureja@mdu.ac.in
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B. R. Nahata Smriti Sansthan International Journal of Pharmaceutical and Biological Archive • Jan-Mar 2022 • 13 (1) | ii
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B. R. Nahata Smriti Sansthan International Journal of Pharmaceutical and Biological Archive • Jan-Mar 2022 • 13 (1) | iii
CotContents
RESEARCH ARTICLES
Pharmacological Evaluation of Novel Indole Derivative for Analgesic Activity in Experimental Rats
Munna Singh, Mohammad Arif, Mohd Aasif, Alimuddin Saifi, Sateesh Kumar, Huzaifa, Ambika Singh, Hussain Ahmad��1
Study on Initial Management of Sepsis in Tertiary Care Centre: A Prospective Study
Susmitha Biyyala, Raghavi Nagarigari, Sai Sharan Yanmangandla, Sarah Ahmed, Madhuri Rudraraju, Aparna Yerramilli��12
Measles outbreak in a vaccinated or never vaccinated children aged 1-5 years in Khyber
Pakhtunkhwa (KPK), Pakistan (Lower dir, Upper Dir and Bajawar): Chains of transmission
of virus and role of vaccine failure
Dharma D. Subedi��23
Congruity and Incongruity between Pratham Patala Gata Timir and Myopia
Riju Agarwal, Santosh Mulik, Ashok Kumar, Manju Rani, Manish Vyas, Medha Lakra��27

© 2022, IJPBA. All Rights Reserved 1
Available Online at www.ijpba.info
International Journal of Pharmaceutical Biological Archives 2022; 13(1):1-11
RESEARCH ARTICLE
Pharmacological Evaluation of Novel Indole Derivative for Analgesic Activity in
Experimental Rats
Munna Singh1
, Mohammad Arif2
, Mohd Aasif3
, Alimuddin Saifi4
, Sateesh Kumar5
, Huzaifa6
, Ambika
Singh6
, Hussain Ahmad3
1
Department of Pharmacology, School of Pharmaceutical Sciences, IFTM University, Moradabad, Uttar Pradesh,
India, 2
Department of Pharmaceutics, Radha Govind College of Pharmacy, Moradabad, Uttar Pradesh, India,
3
Department of Pharmacology, Katyayani College of Education, Badruddin Nagar, Meerut, Uttar Pradesh,
India, 4
Department of Pharmacognosy, Mahaveer College of Pharmacy, Sardhana Road, Meerut, Uttar Pradesh,
India, 5
Department of Pharmacology, Radha Govind College of Pharmacy, Moradabad, Uttar Pradesh, India,
6
Department of Pharmacology, Mahaveer College of Pharmacy, Sardhana Road, Meerut, Uttar Pradesh, India
Received: 30 November 2021; Revised: 17 December 2021; Accepted: 01 January 2022
ABSTRACT
Pain is an unpleasant sensory and emotional experience that is subjective. The prevalence of pain increases
in both developed and developing countries. In this paper, we report the synthesis of indole derivatives
(M1-M4) by reacting 2-chloro-1-(1H-indol-1-yl)ethanone which react with various substituted phenol.
The structure of synthesized indole derivatives was confirmed by infrared and proton nuclear magnetic
resonance spectral. The subacute toxicity and acute toxicity study demonstrated that compound M3 does
not significantly alter biochemicals and histopathology change in rats. The analgesic activity was evaluated
in vivo using rats’ acute pain models (Haffner’s tail clip, hot plate, and acetic acid-induced writhing tests).
Treatment of compound M3 significantly increased pain threshold in a tail clip and hot plate and reduced
the number of acetic acid writhing in rats. Hence, compound M3 showed good analgesic activity, which is
demonstrated by Haffner’s tail clip, hot plate, and acetic acid-induced writhing tests for acute pain models.
Overall, this study suggested that compound M3 is safe and promising analgesic activity.
Keywords: Pain, Indole derivatives, Compound M3
INTRODUCTION
Pain is a diverse, complex phenomenon that occurs
as a result of the body’s inflammatory reaction to
tissue injury. At the site of damage, immune cells
actively produce chemical mediators which lead
to vasodilation, change in vascular permeability,
and cellular infiltration.[1]
As per the International
Association for the Study of Pain (IASP), pain is
a distressing sensory and emotional experience
caused by acute or chronic tissue injury that is
subjective in nature (https://www. iasp-pain.org/
*Corresponding Authors:
Mohd Aasif,
E-mail: aasifsiddiqui1994@gmail.com
publications/iasp-news/iasp-announces-revised-
definition-of-pain accessed on January 10, 2022).
Pain is classified based on time of occurrence
(acute and chronic) and stimulus involvement
(e.g., autonomic pain, bone, joint pain, myalgia,
and neuralgia).[2]
Pain, on the other hand, has a
protective function in nature, sending messages
to the body to protect it from perceived harmful
external insults. The pain involved inhibitory
and excitatory pathways that influence pain’s
sensory and emotional components.[2]
According
to a comprehensive evaluation of data from 2000
to 2014, pain was reported 18 crores disability-
adjusted life years globally.[3]
The prevalence of
pain approximately 20% of adults worldwide
suffer from pain, and 10% of new cases are
ISSN 2582 – 6050

Singh, et al.: Pharmacological Evaluation of Novel Indole Derivative for Analgesic Activity in Experimental Rats
IJPBA/Jan-Mar-2022/Vol 13/Issue 1 2
diagnosed per year.[4]
According to the National
Health Interview Survey, 50.2 million individuals
(20.5%) in the United States experienced pain most
days or every day.[5]
The prevalence of pain also
is increased in India. The prevalence of chronic
pain was 19.23% among these individuals, with
women having a greater incidence.[6]
However,
the cross-sectional study of Primary Health Centre
reported that overall chronic pain prevalence was
19.23%. Chronic back pain was the most common
(24.84%), followed by body pain (22.98%),
knee (16.77%), chest (13.97%), and upper limb
(13.97%) (10.87%).[7]
Currently available options
for pain include pharmacological treatments, for
example, opioid agents (morphine and tramadol)
and non-opioids agents (NSAIDs drugs) and
non-pharmacological options include physical
therapy and alternative medicine (e.g., chiropractic
therapy, massage therapy, acupuncture, mind-body
therapies, and relaxation strategies). However,
existing pharmacology treatment options have
various major side effects, including dependence,
respiratory depression, gastrointestinal toxicity,
cardiovascular toxicity, allergic reaction, sedation,
and tolerance. To overall this sides effect, there is a
need to discover novel pharmacological pathways
and their modulators for better treatment of pain.
The discovery of novel compounds in a very short
period has become a focal point in the current
scenario.Lesstoxicityandhigherselectivityaretwo
key conditions for designing a new novel molecule.
[8]
Keep this motivation, our laboratory synthesized
indole derivatives that might have analgesic
activity. The compound which is synthesized in
our laboratory has an indole carbon ring. Indole is
a heterocyclic molecule, which means that one or
more ring carbons have been replaced by another
element. Heteroatoms are non-carbon atoms found
in such rings. Indoles are heterocyclic compounds
composed of a pyrrole ring joined to an a-b
position and a benzene ring. Indole is composed
of a benzene ring and a pyrrole ring joined by a
double bond. It has 10 electrons from four double
bonds and one from the nitrogen atom, making it a
heterocyclic structure.[9]
The literature survey thus
reveals that indole derivatives have good analgesic,
anti-inflammatory, and anticonvulsant activity.
No work has been reported on compounds that
were synthesized by reaction between 2-chloro-
1-(indoline-1-yl) ethanone which will be reacted
with various substituted phenols. Hence, the
present study was planned to evaluate the analgesic
efficacy of novel indole in the rat model of acute
pain.
MATERIALS AND METHODS
Chemical and Solvents
All laboratory and analytical graded chemicals
and solvents were purchased. The melting
point was determined by the capillary method.
Synthesized compound was characterized
by proton nuclear magnetic resonance
(1
H-NMR) (AV-300 BROKE JES at 300 MHz
spectrophotometer, IIT, Delhi), infrared (IR) in
KBr, and TLC analysis.
Synthesis Schemes for Indole Derivatives
Indole derivatives were synthesis using two steps
reaction. In the first step, indole moiety was allowed
to react with chloroacetyl chloride in toluene
which forms 2-chloro-1-(indoline-1-yl) ethanone.
In second step, 2-chloro-1-(indoline-1-yl) allows
to react acetone in the presence of potassium
carbonate with various substituted phenols to final
indole derivatives (2-(2-hydroxyphenyl)-1-(1H-
indol-1-yl) ethanone (M-2), 2-(2-nitrophenoxy)-
1-(1H-indol-1-yl) ethanone (M-1), 2-(2-amino
phenoxy)-1-(1H-indol-1-yl) ethanone (M-3),
and 1-(1H-indol-1-yl)-2-phenoxyethanone (M4).
Then, final synthesized molecules structure was
confirmed by 1
H-NMR and IR.
Animals
Albino rat’s male or female (between 150 and
200 g) was used in the experiment after ethics
approval (IAEC/2019/837ac/M. Pharm/07) of
IFTM University. Animals were fed a standard
diet and tap water ad libitum. All animals were
kept at standard controlled temperature (31 ± 1°C),
humidity (60 ± 0.2%), and a 12 h light and 12 h
dark cycle. All experiments were performed by
IAEC guidelines.

Acute Toxicity Studies
An acute oral toxicity study was carried out by
OECD-423 criteria (acute toxic class method).
In this study, albino rats of either sex were
chosen at random using random sampling
procedures. The animal was fasted overnight
and merely given water. The produced chemical
M3 was then delivered orally by intragastric
tube at doses of 5, 50, 300, and 2000 mg/kg
for 2 weeks to assess behavioral changes and
mortality.[10]
Subacute Toxicity Studies
An acute oral toxicity study was performed as
per OECD-407 guidelines (acute toxic class
method).[11]
In brief, albino rats of either sex
selected by random sampling techniques were
employed in this study. The animal was kept
fasting overnight, providing only water. The
single dose of M3 compound was administered
orally at 1000 mg/kg by intragastric tube, and
animals were observed for 2 weeks for morality
and behavioral changes. Finally, animals were
sacrificed for his to pathology analysis, and blood
was isolated for biochemical analysis. Based on
LD50
, three different doses were selected, that is,
low, medium, and high.
Experimental Design and Treatment Schedule
Compound M2 was selected for further research
based on the acute toxicity study. Compound
M3 was dissolved in normal saline and orally
administrated to rats. Animals were divided into
the followings groups:
Group I – Normal group (normal saline, p.o.)
Group II – Standard group diclofenac (20 mg/kg, i.p.)
Group III – Treated group low dose (100 mg/kg, p.o.)
GroupIV–Treatedgroupmediumdose(200mg/kg,p.o.)
GroupV–Treated group high dose (400 mg/kg, p.o.).
Induction of Acute Pain Models
Thermal-induced pain (hot plate method)
Hot plate methods were performed based on the
previously reported methods.[12]
Thermal pain was
induced in animals by a hot plate. In this procedure,
animals were kept on a hot plate with a temperature
of 55°C. Time is taken to show jumping, licking
behaviors were recoded, and cutoff time was kept at
about 15 s to avoid unnecessary pain and damage.
Mechanically induced pain (Haffner’s tail clip
method)
Haffner’s tail clip method was performed based on
the reported method.[13]
Briefly, the tail is tightly
clipped with the object that generates pain in the
tail. Thus, the rat will start biting that portion of the
tail. If given drugs have analgesic potential, the rat
will not bite its tail so frequently. The rats that did
not show any response within 15 s will reject the
experiments.
Chemical-induced pain (acetic acid-induced method)
Acetic acid-induced method was performed
based on the previously reported method.[14]
For
generating pain, acetic acid was induced into the
peritoneal cavity of rats, then when chemicals
writhing behavior was recorded in animals.
Statistical Analysis
Data were analyzed by GraphPad Prism (version
5.0). The result was expressed as mean ± SD.
Statistical difference between control and
experimental values was analyzed by one-way
analysis of variance (ANOVA), followed by
Tukey’s test level P 0.05, which was considered
statistically significant.
RESULTS
Characterization of Indole Derivatives
Compounds
Four different indole derivatives (M1, M2, M2,
and M4) were synthesized. The synthesized indole
derivatives’ physical characterization was done by
melting point, % of yield, and Rf value. The % yield
and melting point in M3 indole derivative were
higher (68%, 172°C) as compared to M1 (62%,
46°C), M2 (59%, 48°C), and M4 (65%, 40°C).
However, the M1 derivative showed a higher Rf

value than M2, M3, and M4 indole derivative
[Table 1].
Indole Derivative Structure Confirmation by
IR and 1
H-NMR
Synthesized indole derivative structure was
confirmed by IR spectroscopy and 1H-NMR.
IR and 1H-NMR spectra of synthesized indole
derivative present in Supplement file 1. Due to the
high % of the yield of M3, indole derivative was
selected for further experimentations.
Acute Toxicity Studies
Orally administered compound M3 at the dose
of 5, 50, 300, and 2000 mg/kg by the intragastric
route, and we do not observe any gross behavioral
changes and mortality until 2 weeks.They represent
that compound M3 was practically nontoxic, and it
can be used further to evaluate the subacute toxicity
and analgesic activity.
Subacute Toxicity Studies
In subacute toxicity studies, the single dose of M3
compound was administrated; then, animals were
observed for 2 weeks. Animals were sacrificed for
hematological and biochemical parameters analyzed
along with histological examination. Compound
M3 administration found non-significant changes in
hematology parameters of major organs (such as
heart, liver, and kidney) [Figure 1], hematological
parameters (hemoglobin, red blood cells [RBCs],
white blood cells [WBCs], deferential neutrophils,
lymphocytes, monocytes, eosinophil, basophils,
packed cell volume, mean corpuscular volume,
mean corpuscular hemoglobin [MCH], and MCH
concentration [MCHC] except platelets) [Table 2].
While biochemical parameters include Na+
, K+
, Ca2+
,
albumin,SGOT,SGPT,andtotalbilirubinalsoincrease
non-significant [Table 3]. Therefore, the subacute
studies suggested that synthesized compound M3
wassafewithnosignificanttoxicityeffectonthemajor
organs, biochemicals, and hematological parameters.
Effect of M3 Compound on Thermal-induced
Pain
Thermal pain in rats was induced using Eddy’s
hot plate. Treatment of compound M3 showed a
significantly increased maximum reaction time in
dose-dependent manners as compared to control
(P 0.001). However, the standard also showed
a significant increase in mean reaction time (P
0.001). However, compound M3 and standard
treatment effect were shown to be persistent till
180 min significantly [Table 4].
Table 1: Percentage yield, melting point, and Rf value of the synthetic compound
S. No. Compound code Compound chemical name Melting point °C % yield Rf
value
1. M1
2‑(2‑nitrophenoxy)‑1‑(1H‑indol‑1 yl) ethanone 46 62 4.7
2. M2
1‑(1H‑indol‑1‑yl)‑2‑phenoxyethanone 48 59 3.9
3. M3
2‑(2‑amino phenoxy)‑1‑(1H‑indol‑1‑yl) ethanone 172 68 4.3
4. M4
2‑(2‑hydroxyphenoxy)‑1‑(1H‑indol‑1‑yl) ethanone 40 65 4.6
Figure 1: Hematoxylin and eosin staining of major organs
(heart, liver, and kidney)

Effect of M3 Compound on Mechanical-
Induced Pain
Mechanical pain in rats was induced using
Haffner’s tail clip method which was presented.
Treatment of compound M3 was non-significantly
increased reaction times at low and high doses (P
0.05) while medium dose showed and standard
(diclofenac) significantly increase increased
reaction times (P 0.001) at 0 min. However,
after 15 min of treatment of standard (diclofenac
sodium) and compound M3 showed a significant
increase in mean reaction time at low dose,
medium dose as well as high dose (P 0.001).
The result indicated that the compound M3 has
analgesic potential and M3 showed an increase in
pain threshold throughout the entire observation
for 60 min [Table 5].
Table 2: Hematological parameters of treated rats in subacute toxicity
S. No. Parameters Unit Control Compound M3 (1000 mg/kg)
1. Hemoglobin g/L 149.53±0.53 148.44±0.27
2. Total RBCs 1012
/L 7.50±0.25 7.31±0.33
3. Total WBCS
109
/L 7.49±0.22 7.66±0.5
4. Deferential neutrophils % 13.5±1.52 13.55±1.48
5. Lymphocytes % 84.19±2.39 86.44±1.34
6. Monocytes % 3.33±0.05 3.1±0.09
7. Eosinophil’ % 00±00 00±00
8. Basophils % 00±00 00±00
9. Platelets 109
/L 820.21±33.33 825.70±41.11
10. Packed cell volume L/L 0.39±0.01 0.41±0.07
11. Mean corpuscular volume fL 53.41±0.75 54.88±0.11
12. MCH Pg 18.55±0.17 19.01±0.25
13. MHC g/L 300.12±1.11 303.15±2.11
Data expressed as Mean±SD (n=10) and statistical significance was analyzed using one‑way ANOVA followed by Tukey’s multiple comparison test
Table 3: Biochemical parameter of treated rats in subacute toxicity
S. No. Parameter Unit Control Compound M3 (1000 mg/kg)
1. Sodium mmol/L 124.3±0.56 128.00±0.94
2. Potassium mmol/L 5.33±0.01 5.98±0.04
3. Chloride mmol/L 97.8±0.03 99.89±0.04
4. Calcium mmol/L 9.55±0.04 9.78±0.05
5. Albumin g/L 29.83±0.03 32.31±0.01
6. SGPT (AST) U/L 53.67±1.23 56.33±2.42
7. SGOT (ALP) U/L 75.41±5.43 76.19±4.91
8. Total bilirubin mg/dl 0.45±00 0.47±0.02
Data expressed as Mean±SD (n=10) and statistical significance was analyzed using one‑way ANOVA followed by Tukey’s multiple comparison test
Table 4: Eddy’s hot plate observation
Group Treatment Dose mg/kg Reaction time (s) Mean±(SD)
0 min 30 min 60 min 120 min 180 min
I Control Normal saline 8.4±1.21 8.3±1.20 7.1±1.03 8.5±1.14 7.1±1.61
II Standard (Diclofenac sodium) 20 mg/kg 10.03±1.01** 14.1±1.00** 14.09±1.23** 13.33±1.11** 13.00±0.99**
III A low dose of M3 100 mg/kg 9.01±1.21** 11.11±1.31** 13.00±1.02** 13.11±1.00** 10.01±1.05**
IV Medium dose of M3 200 mg/kg 9.03±1.00** 12.01±1.00** 13.05±1.19** 14.05±1.15** 12.69±1.31**
V High dose of M3 400 mg/kg 8.99±1.21** 11.55±2.11** 13.99±1.31** 13.60±1.01** 12.89±2.05**
Data expressed as Mean±SD (n=6) and statistical significance was analyzed using one‑way ANOVA followed by Tukey’s multiple comparison test. **P0.01 represents
significance compared to control

Effect of M3 Compound on Chemical-Induced
Pain
Chemical-induced pain was caused by acetic
acid-induced writhing. The administration of
the compound M3 at 100, 200, and 400 mg/kg
showed a significantly reduced number of writhes
(acetic acid-induced abdominal constriction)
in experimental rats compared with control (P
0.001). The standard drug (diclofenac) also
considerably reduced the number of writhes as
compared to control [Table 6].
DISCUSSION
Literature review reported that indole derivatives
possess different biological activities, including
anti-inflammatory, antibacterial, antifungal,
analgesic, and anticonvulsant activity.[15]
Given
these observations, we have synthesized some
novel indole derivatives and evaluated them for
their analgesic activity. Thus, four molecules
(M1–M4) were synthesized by mixing indole with
chloroacetyl chloride in toluene to form 2-chloro-
1-(1H-indol-1-yl) ethanone, which interacts
with various substituted phenol in acetone in
the presence of potassium carbonate to yield
final indole derivatives. The compounds were
obtained in solid form, with yields ranging from
58% to 69%. The purity and homogeneity of all
compounds were shown by TLC and their melting
points. The structures of these compounds were
confirmed using IR and 1
H-NMR. Four molecules
(M1, M2, M3, and M4) were synthesized and
analyzed by IR and 1
H-NMR spectra, however, due
to the low percent yield, only one molecule with
a high percent yield (M3) was chosen for future
investigation. This chemical was investigated and
tested for in vivo analgesic efficacy. Assessing
toxicity is a critical preparatory step before
conducting effectiveness studies when screening
new compounds for pharmacological activity. The
calculation of LD50 is a basic step in the study
of toxicity.[16]
The acute oral toxicity study may
provide preliminary information about agents’
toxic action, which could help decide the dose of
the novel compound in vivo studies.
Furthermore, if the animals survive at a high
dosage (e.g., 2000 mg/kg), no additional acute
testing will be performed.[10]
In this investigation,
the compound M3 at a level of 2000 mg/kg had no
negative effects on the treated rats after 14 days
of observation. As a result of this investigation,
M2 did not induce acute toxicity effects at the
level evaluated, and the LD50 value might be
2000 mg/kg. Because no harmful effects were
discovered during the critical toxicity research, a
follow-up study was done to assess M3’s subacute
toxicity for up to 28 days. Subacute studies give
information on dosing regimens, target organ
toxicity, and identify visible adverse effects that
may impact the average life span of experimental
animals. After 28 days of M3 compound therapy,
no significant changes in histopathology of major
organs, biochemical analysis, or hematological
Table 5: Observation table of Haffner’s tail clip model
Group Treatment Dose mg/kg Reaction time (s)
0 min 15 min 30 min 60 min
I Control Normal saline 4.09±0.75 4.20±0.63 4.81±0.79 4.97±0.55
II Standard (diclofenac sodium) 20 mg/kg 5.79±0.13*** 6.93±0.11*** 9.84±0.19*** 9.66±0.21***
III Low dose of M3 100 mg/kg 5.03±1.19 5.93±0.89*** 6.87±0.91*** 7.00±0.92***
IV Medium dose of M3 200 mg/kg 5.89±0.82*** 6.01±1.00*** 6.89±0.83*** 7.22±0.91***
V High dose of M3 400 mg/kg 5.13±0.67 6.01±0.79*** 6.99±0.72*** 8.12±0.83***
Data expressed as Mean±SD (n=6) and statistical significance was analyzed using one‑way ANOVA followed by Tukey’s multiple comparison test. ***P0.001 represents
Table 6: Observation table of acetic acid‑induced model
Group Treatment Dose mg/kg No. of writhing
I Control 1% acetic acid 83.3±6.5
II Standard (diclofenac
sodium)
20 mg/kg 33.55±4.4***
III Low dose of M3 100 mg/kg 61.33±3.33***
IV Medium dose of M3 200 mg/kg 43.09±3.24***
V High dose of M3 400 mg/kg 40.11±2.25***
Values are expressed in Mean±SD (n=6) and statistical significance one‑way
ANOVA followed by Tukey’s multiple comparison test. ***P0.001 represents

parameters were identified. The hematological
findings revealed a non-significant change in RBC
indices, WBC counts, neutrophils, lymphocytes,
and monocytes levels. Serum biochemistry was
examined to discover potential changes in renal
and hepatic activities influenced by total compound
protein, with total bilirubin potentially influencing
hepatocellular and secretory processes of the
liver.[17,18]
The lack of significant changes in SGOT,
SGPT, ALP, and creatinine levels, which are strong
indices of liver and kidney function, indicates that
the compound M3 did not affect rat hepatocytes
and kidneys after a 28-day subacute administration.
Haffner’s tail clip, hot plate, and acetic acid-
induced writhing tests were used to assess
the compound’s analgesic efficacy. These
are common pharmacological paradigms for
assessing synthetic chemical analgesia.[19]
For
centrally active analgesics, both Haffner’s tail
clip and the hot plate procedures are commonly
utilized.[20]
While these tests are not applicable
to peripherally acting medications, they are
amenable to the acetic acid-induced writhing
test.[21]
The present study found that the chemical
generated significant antinociceptive actions
when tested utilizing various pain models. The
new findings further show that phenol derivatives
operate both centrally and peripherally. The pain
models utilized in this study were chosen to
measure both centrally and peripherally mediated
effects. The overall study suggested that indole
derivatives (M3) were safe and possessed good
analgesic activity.
ACKNOWLEDGMENTS
The authors acknowledge the financial assistance
for IFTM University for this work.
CONFLICTS OF INTEREST
The author declares that they have no conflicts of
interest.
INFORMED CONSENT
Not required.
REFERENCES
1. Osterweis M, Kleinman A, Mechanic D. Pain, and
Disability: Clinical, Behavioral, and Public Policy
Perspectives. Washington, DC, United States: National
Academies Press; 1987.
2. Swieboda P, Filip R, Prystupa A, Drozd M. Assessment
of pain: Types, mechanism, and treatment. Ann Agric
Environ Med 2013;1:2-7.
3. Henschke N, Kamper SJ, Maher CG. The epidemiology
and economic consequences of pain. Mayo Clin Proc
2015;90:139-47.
4. Goldberg DS, McGee SJ. Pain as a global public health
priority. BMC Public Health 2011;11:770.
5. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of
chronic pain among adults in the United States. Pain.
2022;163:e328-32.
6. Saxena AK, Jain PN, Bhatnagar S. The prevalence of
chronic pain among adults in India. Indian J Palliat Care
2018;24:472-7.
7. Deshpande A. Prevalence of chronic pain based on
primary health center data from a city in central India.
Indian J Pain 2018;32:81-5.
8. Arkin MR, Tang Y, Wells JA. Small-molecule inhibitors
of protein-protein interactions: Progressing toward the
reality. Chem Biol 2014;21:1102-14.
9. Sharma V, Kumar P, Pathak D. Biological importance
of the indole nucleus in recent years: A comprehensive
review. J Heterocycl Chem 2010;47:491-502.
10. OECD. Test No. 423: Acute Oral toxicity Acute Toxic
Class Method; 2002.
11. OECD. Test No. 407: Repeated Dose 28-day Oral
Toxicity Study in Rodents; 2008.
12. Mann DE Jr. Turner RA, editor. Screening Methods in
Pharmacology. Vol. 54. New York: Academic Press Inc.;
1965. p. 1394.
13. MoodP,JangdeCR,NarnawareS,RautSY.Experimental
evaluation of analgesic property of bark skin of Saraca
indica (Ashoka) and Shorea robusta (Shal). J Appl
Pharm 2014;4:62-5.
14. Hosen SM, Das R, Rahim ZB, Chowdhury N, Paul L, Saha
D. Study of analgesic activity of the methanolic extract of
Acorus calamus l. and Orxylem indicum vent by acetic acid-
induced writhing method. Bull Pharm Res 2011;1:63-7.
15. Kumar S, Ritika.Abrief review of the biological potential
of indole derivatives. Future J Pharm Sci 2020;6:121.
16. Parasuraman S. Toxicological screening. J Pharmacol
Pharmacother 2011;2:74-9.
17. Wolf PL. Biochemical diagnosis of liver disease. Indian
J Clin Biochem 1999;14:59-90.
18. Gowda S, Desai PB, Kulkarni SS, Hull VV, Math AA,
Vernekar SN. Markers of renal function tests. N Am J
Med Sci 2010;2:170.
19. Hasan M, Uddin N, Hasan R, Islam AF, Hossain M,
Rahman AB, et al. Analgesic and anti-inflammatory
activities of leaf extract of Mallotus repandus (Willd.)
Muell. Arg. Biomed Res Int 2014;2014:539807.

20. Carlsson KH, Jurina I. Depression by flupirtine, a
novel analgesic agent, of motor and sensory responses
of the nociceptive system in the rat spinal cord. Eur J
Pharmacol 1987;143:89-99.
21. Chen YF, Li N, Jiao YL, Wei P, Zhang QY, Rahman K,
et al.Antinociceptive activity of petroleum ether fraction
from the MeOH extracts of Paederia scandens in mice.
Phytomedicine 2008;15:427-36.

Figure 1: IR spectra of M1 compound
Table 1: IR interpretation of M1, M2, M3 and M4
compounds
S. No. Observed
peak (cm‑1
)
Functional
group assigned
Characteristic
peak
Compound M1 3190 C‑H str (aromatic) 2800‑3200
1240 C‑C str (aromatic) 1000‑1250
850 C‑Hbend (aromatic) 700‑900
2900 C‑H str (Aliphatic) 2900‑2700
1590 C=O str 1600‑1700
1190 C‑O str 1225‑1200
1380 C‑N str 1400‑1600
1010 C‑C str (aromatic) 1000‑1250
840 C‑H bend (aromatic) 700‑900
1630 C=O str 1600‑1700
1260 C‑O str 1225‑1200
1400 C‑N str 1400‑1600
1240 C‑C str (aromatic) 1000‑1250
850 C‑H bend
(aromatic)
700‑900
1590 C=O str 1600‑1700
1190 C‑O str 1225‑1200
1380 C‑N str 1400‑1600
1250 C‑C str (aromatic) 1000‑1250
710 C‑H bend
(aromatic)
700‑900
1660 C=O str 1600‑1700
1400 C‑O str 1225‑1200
1450 C‑N str 1400‑1600
SUPPLEMENT FILES
IR SPECTRA OF INDOLE DERIVATES
(M1-M4)

Figure 7: NMR spectra of M3 compound
Table 2: NMR interpretation of M1 compound
Compound
Name
Chemical
shift (δ)(ppm)
No. of
protons
Inferences
M1 6.50‑7.83 6 Indole
4.2 2 CH2
6.99‑7.34 5 Phenol
M3 6.50‑8.11 6 Indole
4.8‑5.00 2 CH2
6.52‑6.8 5 Phenol
M4 6.50‑7.10 6 Indole
4.1‑4.30 2 CH2
1H
NMR SPECTRA OF INDOLE
DERIVATES (M1-M4)

FINAL STRUCTURE OF INDOLE
DERIVATES (M1-M4)

RESEARCH ARTICLE
Study on Initial Management of Sepsis in Tertiary Care Centre: A Prospective Study
Susmitha Biyyala, Raghavi Nagarigari, Sai Sharan Yanmangandla, Sarah Ahmed, Madhuri Rudraraju,
Aparna Yerramilli
Doctor of Pharmacy, Sri Venkateshwara College of Pharmacy, Osmania University, Hyderabad, Telangana, India
Received: 10 November 2021; Revised: 27 December 2021; Accepted Date: 20 January 2022
ABSTRACT
Background: Sepsis and septic shock are the major health problems affecting millions of people
around the world each year and the incidence is as many as 1 in 4. According to Centers for Disease
Control and Prevention the incidence of sepsis continues to increase and is now the 3rd
leading cause
of infectious death. In India, sepsis claims more than 90,000 lives every year and is one of the leading
causes of death. Early effective management of sepsis as per Surviving sepsis Campaign guidelines
can improve the patient outcomes, prevent further complications, and decrease the mortality. Aim: Our
study aims to evaluate the Initial Management of Sepsis in an Institution and identify the areas of
improvement. Methods: It is a prospective observational study conducted in a tertiary care center.
A structured data collection form was designed to collect the information from medical records of
the patients. Sepsis investigation details such as source of infection, blood, and urine cultures were
collected. Additional information such as initial antibiotic started, door to first antibiotic, fluids used,
and other supportive care (Deep vein thrombosis and Stress ulcer prophylaxis) was collected, assessed,
and reviewed for the initial 2 days. Results: A total of 100 cases were collected. Number of patients
diagnosed with sepsis and septic shock was found to be (78%) and (22%), respectively. Males (55%)
were more affected compared to females (45%). Diabetes with hypertension and hypothyroidism (40%)
was the common comorbid observed. Common source of infections were found to be lower respiratory
tract infection (41%) followed by urinary tract infections (19%). Majority of the patients received
appropriate Antibiotics within 1 h as per guidelines. A Sequential Organ Failure Assessment score of
3 was found in 26%. Fluid therapy was given to 78% of the patients. Vasoactive medications were
given to all patients with septic shock (22%). Conclusion: In our hospital setting, the overall adherence
to guidelines was found to be optimal and satisfactory. However, there is need for improvement in
some areas.
Keywords: Sepsis, septic shock, surviving sepsis campaign guidelines, sequential organ failure
assessment score
INTRODUCTION
Sepsis and Septic Shock
Sepsisandsepticshockarethemajorhealthproblems
affecting millions of people around the world each
year and the incidence is as many as 1 in 4 [Table 1].
*Corresponding Author:
Susmitha Biyyala
E-mail: sushmithavarma27@gmail.com
Accordingtocenterfordiseasecontrolandprevention
the incidence of sepsis continues to increase and
is now the 3rd

leading cause of infectious death.[1]
Sepsis is a life threatening organ dysfunction caused
by dysregulated host response to infection. It affects
neonatal, pediatric, and adult patients worldwide.[2]
Organ dysfunction can be represented by an increase
in the Sequential Organ Failure Assessment score of
two points or more, which is associated with an in-
hospital mortality 10%.[3,4-6]
ISSN 2582 – 6050

Biyyala, et al.: Study on Initial Management of Sepsis
Epidemiology
Sepsis, defined as the condition arising when the
host response to infection causes organ dysfunction
in the host, remains a major killer. Probably the
most often quoted article on the epidemiology
of sepsis is the 2001 publication by Angus et al.,
which used administrative data to estimate that
there were 751,000 cases (3.0/1000 population) in
the United States each year, resulting in more than
200,000 deaths.[4]
More recent research suggests that sepsis causes or
contributes to between one-third and one-half of all
deaths occurring in hospitals in the United States,
with the majority of patients presenting to hospital
with sepsis rather than acquiring sepsis in hospital.[7]
In the most recent report, published in 2015, sepsis is
considered a pathway to death from an infection and
is referred to as a “garbage code,” with death being
attributed to the infection that initiated sepsis.[8-11]
Pathophysiology
The pathophysiologic sequelae resulting from
the interaction between the invading pathogen
and the human host are diverse, complex, and
incompletely understood. Definitive relationships
between infection and progression to sepsis have
been difficult to demonstrate.
CASCADE OF SEPSIS
Diagnosis
Evaluation of patient history
Evaluation of patient history, in this case, is done to
get information on the following:
• Whether the infection that caused sepsis was
community acquired.
• Whether it is nosocomially acquired.
• Whether the patient has an impaired immune
system.
Details of situation that can expose the patient to
specific infectious agents are collected [Figure 1].
Physical Examination
If the patient has neutropenic or other pelvic
infections, physical examination that can reveal
rectal, perirectal, or perineal abscesses, pelvic
inflammatory disease or abscesses, or prostatitis
should be done. It includes rectal, pelvic, and
genital examinations.[12-14]
Laboratory tests
For patients suspected with sepsis, a large number
of tests are ordered so that the doctor gets details
on the potentiality and severity of the patient’s
condition. The different tests done include urine
Figure 1: Sepsis cascade[16]

test, blood test, and tests related to other medical
conditions.[15, 16]
Blood tests
For patients with possible signs of sepsis, there are
various blood tests available are:
Complete blood count, lactate, C-Reactive Protein
test, blood culture, prothrombin time (PT) and
partial thromboplastin TIME, platelet count, and
D-dimer test.
Confirmatory Tests
There are three types of blood tests that can confirm
sepsis. They are:
Endotoxin test, Procalcitonin test, and Septicyte
test.
Urine test
Two types of urine tests are ordered in cases of sepsis.
Urinalysis: This tests urinary tract infections (UTI)
or problems with the kidneys.
Urine culture: Used to determine which bacteria or
fungi caused UTI.
Tests for Related Medical Conditions
Apart from blood and urine tests, tests related to
other diseases that can cause sepsis are also done.
Few examples are:
• Chest X-ray, Pulse Oximetry and Sputum test
for Pneumonia.
Lumbar puncture, magnetic resonance imaging,
and computed tomography scan for Meningitis.
• The rapid antigen test and the throat culture for
strep throat.
• Rapid influenza diagnostic tests and symptom
analysis for influenza.
• Skin culturing for infections related to skin.
Pseudosepsis is a common cause of misdiagnosis in
hospitalized patients, particularly in the emergency
department and in medical and surgical intensive
care unit (ICUs). The most common causes of
pseudosepsis include gastrointestinal hemorrhage,
pulmonary embolism, acute myocardial infarction,
acute pancreatitis (edematous or hemorrhagic),
diuretic-induced Hypovolemia, and relative adrenal
insufficiency. Patients with pseudosepsis may have
fever, chills, Leukocytosis, and a left shift, with or
without Hypotension. All causes of pseudosepsis
produce Swan-Ganz catheter readings that are
compatible with sepsis (e.g., increased cardiac
output and decreased peripheral resistance), which
could misdirect the unwary clinician [Table 2].[17]
Treatment for Sepsis
• Surviving sepsis guidelines recommendations
for initial management of Sepsis include,
appropriate antibiotics within 1 h, removal
of source of infection, rapid resuscitation,
Hemodynamic stabilisation, administration of
Vasoactive agents for cardiovascular support
and Deep vein thrombosis (DVT), Stress ulcer
prophylaxis.[18]
• Surviving Sepsis Campaign Guidelines are
mentioned in Appendix.
Table 1: Clinical conditions associated with sepsis
Associated with
sepsis (Fever≥102°F)
Not associated with
sepsis (Fever≤102°F)
GI tract source, Liver, Gallbladder,
Colon, Abscess, Intestinal
obstruction, Instrumentation
GI tract source, Esophagitis,
Gastritis
Pancreatitis, Small bowel
disorders,
GI bleeding
GU tract source, Pyelonephritis,
Intra‑ or perinephric abscess, Renal
calculi, Urinary tract obstruction,
Acute prostatitis/abscess, Renal
insufficiency
Instrumentation in patients with
bacteriuria
GU tract source, Urethritis,
Cystitis,
Cervicitis
Vaginitis
Catheter‑associated bacteriuria
(in otherwise healthy hosts without
genitourinary tract disease)
Pelvic source
Peritonitis
Upper respiratory tract source
Pharyngitis
Abscess Sinusitis, Bronchitis, Otitis
Lower respiratory tract source
Community‑acquired
pneumonia (with asplenia),
Empyema, Lung abscess
Lower respiratory tract source
Community‑acquired
pneumonia (in otherwise healthy
host)
Intravascular source
IV line sepsis, Infected
prosthetic device, Acute bacterial
endocarditis
Skin/soft‑tissue source
Osteomyelitis, Uncomplicated
wound infections
Cardiovascular source
Acute bacterial endocarditis
Myocardial/paravalvular ring
abscess
Cardiovascular source
Subacute bacterial endocarditis
CNS source
Bacterial meningitis

METHODOLOGY
Study Design
Design: Single-center, prospective, and
observational study.
Duration: 8 months (January–June 2018).
Sample size: 200.
Selection of Subjects
Inclusion criteria
The following criteria were included in the study:
• Age ≥18 years
• Patients in ICUs
• Patients with suspected or proven infection
(including hospital acquired infections)
• Patients for whom antibiotics are given for the
1st
time for a specific infection.
Exclusion criteria
The following criteria were excluded from the
study:
• Pediatric patients
• Pregnant women
• Cancer patients
• Outpatients.
Study Procedures
Data collection form was designed to collect the
demographics of the patients being treated with
antibiotics from patient charts who were admitted in
the hospital. The data regarding risk factors, clinical
presentation, suspected or confirmed infection,
diagnostic tests performed, radiology and pathologic
labs, culture and sensitivity tests, treatment regimen
that is antibiotics prescribed were collected. The
pattern of antibiotic use in each subject was studied
and analysis was done [Tables 3-6].
RESULTS
Gender No of patients
(n=100)
Female 45%
Male 55%
Age group (in years)
18–30 10%
31–50 15%
51‑70 51%
70 24%
History of present illness
Fever with chills and nausea and vomiting 42%
Fever with reduced Urine output 15%
SOB, followed by cough and greenish
expectoration, Bed ridden
23%
Table 2: Characteristics of pseudosepsis and sepsis
Parameters Pseudosepsis Sepsis
Microbiologic No definite source PLUS≥1 abnormalities
Negative blood cultures excluding contaminants
Proper identification/process/source PLUS≥1 microbiologic
abnormalities
Positive buffy coat smear result OR 2/3 or 3/3 positive
blood cultures
Hemodynamic ⇓ PVR
⇑ CO
⇓ PVR
⇑ CO
Left ventricular dilatation
Laboratory ⇑ WBC count (with left shift)
Normal platelet count
⇑ FSP
⇑ Lactate
⇑ D‑dimers
⇑ PT/Partial Thromboplastin Time
⇓ Albumin
⇓ Fibrinogen
⇓ Globulins
⇑ WBC count (with left shift)
⇓ Platelets
⇑ FSP
⇑ Lactate
⇑ D‑dimers
⇑ PT/Partial Thromboplastin Time
⇓ Albumin
Clinical ≤102°F±Tachycardia±Respiratory
alkalosis±Hypotension
≥102°F OR
Hypothermia±Mental status changes±Hypotension
⇑Increase, ⇓Decrease, ± Present/Absent

Generalized weakness, Headache, Fever with chills 12%
Abdominal pain, Fever and 2 episode vomiting
and SOB
8%
Co‑morbid conditions
Diabetes Mellitus 3%
Hypertension 4%
Hypothyroidism, Parkinsonism 2%
Diabetes Mellitus with Hypertension and
Hypothyroidism
40%
Chronic obstructive pulmonary disease 2%
Coronary artery disease 1%
Tuberculosis, AIDS 2%
None 14%
Hypertension and Diabetes Mellitus 13%
Hypertension, Diabetes Mellitus and Seizures 3%
Diabetes Mellitus and Cerebrovascular accident 1%
Diabetes Mellitus and Chronic kidney disease 4%
Diabetes Mellitus with Hypertension and
Hyperthyroidism
2%
Diabetes Mellitus with Hypertension and Coronary
artery disease
6%
Diabetes Mellitus with Hypertension and Chronic
kidney disease
3%
Comorbidities in sepsis patients.
Number of patients diagnosed with sepsis and
septic shock.
SEPSIS
78%
SEPTIC
SHOCK
22%
SEPSIS SEPTIC SHOCK
Other diseases include meningitis, peritonitis,
intravenous (IV) catheter, and Foleys catheter
related infections.
13
50
23
3 11
0
20
40
60
15mins 16-30mins 31-45mins 46-60mins 60mins
NO
OF
PATIENTS
DOOR TO FIRST ANTIBIOTIC
Antibiotic therapy in sepsis and septic shock
patients.
3
1 1 1 2 1 1 1
6
1 2 1 1 2
6
1
14
40
0
10
20
30
40
50
DM
Hypothyroidism
HTN
Parkinsonism
Chronic
obstructive
pulmonary
disease
Coronary
artery
disease
Tuberculosis
AIDS
Hypertension
and
Diabetes
Mellitus
Hypertension
and
seizures
DM
and
Coronary
artery
disease
Diabetes
Mellitus
and
cerebrovascular
accident
DM
and
chronic
kidney
disease
DM
with
HTN
and
hyperthyroidism
DM
with
HTN
and
Coronary
artery
DM
with
hypertension
and
chronic
kidney
None
DM
with
Hypertension,Hypothyroidism
NO OF PATIENTS

67%
33%
monotherapy combination therapy
Source Control in Sepsis Patients
• REMOVAL OFIV CATHETER
• SURGICAL PROPYLAXIS
22
78
0
20
40
60
80
100
YES NA
NO
OF
ATIENTS
SOURCE CONTROL
DISCUSSION
In our study, entitled “Initial Management of Sepsis
in Tertiary Care Centre: A Prospective Study,” we
observed the initial treatment for 2 days given to
about 100 subjects. The results are discussed below.
Patients newly diagnosed with sepsis and who
met the criteria of HR 90/min, RR 20/min,
temperature≥38°C and Altered Mental Status
(GCS 15) are included in our study.
During the course of our study period, data were
collected from 100 patients, newly diagnosed with
sepsis, among them 78 were diagnosed with sepsis
and 22 were diagnosed with septic shock [Tables
7-10].
Looking into the demographics, Males (55%) were
at higher risk for sepsis than women (45%). The
Table 3: Distribution based on source of infection
Source of infection No of patients
Lower respiratory tract infection 41%
Urinary tract infections 19%
Urosepsis 6%
Cellulitis 5%
IV catheter 3%
Other diseases 18%
Unknown source 8%
Table 4: Positive cultures in initial 2 days
Urine culture No of patients with
positive culture
Escherichia coli 3
Enterococcus 1
Klebsiella pneumonia 1
100 100
22
78
22
11 8
51
11
22
29
86
22
78
5
49
89
44
71
14
88 89 87
34
0
20
40
60
80
100
120
INITIAL
RESUSCITATION
ANTIMICOBIAL
THERAPY
SOURCE
CONTROL
FLUID
THERAPY
VASOACTIVE
MEDICATION
CORTICOSTEROIDS
BLOOD
PRODUCTS
MECHANICAL
VENTILATION
SEDATON
AND
VENTILATION
GLUOCOSE
CONTOLE
VTE
PROPHYLAXIS
STRESS
ULCER
PROPHYLAXIS
NO
OF
PATIENTS
yes no NA

possible reason could be direct and indirect effects
of sex steroids (DHT) in males synergistically
modulate immune and cardiovascular response.[19]
Comorbid plays a major role in the development
of sepsis and organ dysfunction after an infection.
In our study, diabetes with hypertension and
hypothyroidism (40%) was the common comorbid
observed. The possible reason might be defects in
immune function. In our study the most common
infections that led to sepsis were lower respiratory
tract infection (pneumonia) (41%) and UTI (19%),
followed by Meningitis, Peritonitis were most
common.
In our study, 95% of the urine culture reports were
negative (no growth) and only 5% of cultures
were positive in the initial 2 days. In our study, we
concluded that outcomes of septic patients
with
culture negative reports are similar to those
with culture-positive septic patients in nearly all
cases. Early appropriate antimicrobial therapy,
recognition and eradication of infection are the
most obvious effective strategy in both types of
patients to improve hospital survival.[20]
Surviving sepsis Campaign guidelines suggest
early administration of antibiotic within 1 h, fluid
resuscitation within 3 h, vasoactive medication for
Table 5: Door to first antibiotic
Time (min) No of patients (n=100)
60 11%
Within 1 h No of patients (n=89)
46–60 3%
31–45 23%
16–30 50%
15 13%
Table 6: Spectrum activity of antibiotics prescribed for sepsis in hospital setting
Class Spectrum activity Spectrum
Carbapenem
Meropenem
G+ve, G –ve, anerobicbacteria, against extended‑spectrum
β‑lactamase
Broad spectrum
Imipenem Aerobic and anaerobic and G+ve, G‑ve, against Pesudomonas
aeruginosa and Enterococcus species
Broad spectrum
Fluroquinolones
Moxifloxacn Both G+ve, G‑ve bacteria.
Broad spectrum
Levofloxacin G+ve, G‑ve bacteria and atypical respiratory pathogens and
against both penicillin susceptible and penicillin resistant
Strpotococcus pneumoniae
Broad spectrum
Cephalosporines
Cefoperazone
Enterobacteriaceae, Pseudomonas aeruginosa Broad spectrum
Ceftazidime Pseudomonas and G‑ve infection in debilitated patients Broad spectrum
Cefepime G+ve, G –ve bacteria Extended spectrum
Ceftriaxone G‑ve bacteria, but less than earlier generation of
cephalosporins against many G+ve bacteria
Broad spectrum
Penicillins
Piperacillin
G‑ve bacilli, G+ve cocci. S anerobic pathogens such as
clostridium difficile and bacteroides
Broad spectrum
Amoxicillin Broad range of G+ve, limited range of G‑ve organism. Moderate spectrum
Macrolide
Clarithromycin
G+ve, G‑ve bacteria, mycoplasma, Chlamydia and
mycobacteria
In vitro and in vivo activity, broad spectrum
Azithromycin G+ve organism, G‑ve bacilli, including Haemophilus
influenzae
In vitro and Broad spectrum
Nitroimidazole
Metronidazole
Various protozoans and most G‑ve anerobic bacteria Broad spectrum and fight broad range bacteria
Clindamicin Staphylococci, streptococci and pneuococci Broad spectrum
Tigecycline G+ve, G‑ve, anerobic organism, multi drug – resistant MRSA
and MRSE, penicillin‑resistant Streptococcus pneumoniae
Broad spectrum
Spemax G‑ve, G+ve Broad spectrum
Vancomycin Staphylococcal infection G+ve cocci bacteria and G‑ve cocci Narrow spectrum
Nitftron Most strains of multidrug‑resistant G‑ve bacilli, including
extended spectrum β‑lactamase producing strains
Broad spectrum

MAP maintenance, source control, corticosteroid
administration, blood transfusion, adequate
nutrition if required and supportive care like DVT
and Stress ulcer prophylaxis. Implementation of this
guidelines for initial management improves patient
outcomes, prevents complications and reduces the
risk for mortality. It is always necessary to initiate
any empiric antibiotic as early as possible in sepsis.
In our study the door to first antibiotic was recorded
and majority (89%) of the patients received
antibiotic within the 1st
h as per the guidelines.[21]
Antibiotics were initiated both as Monotherapy
and combination therapy for sepsis (78). Out of
78 patients, 52 patients received monotherapy
and 26 were on combination therapy, whereas
out of 22
patients diagnosed with septic shock
it was 15 and 7 patients, respectively. The most
common class of antibiotics prescribed were
Cephalosporins (71%) followed by carbapenams
(32%), Penicillins (9%).
Change of antibiotics from day 1 to day 2 was
recorded and observed in nearly 13% of the
patients. The most common change was from
cephalosporins to carbapenams followed by
Cephalosporins to Macrolide. The possible reason
might be no significant improvement in TLC
count following cephalosporin administration.
Optimization of antibiotic dosing was observed
in very few patients. Addition of antibiotic was
done in one patient. Tobramycin was added on
day 2 along with cefperazone. In our study, source
control was initiated in all the 22% patients who
had previously undergone any surgery or were
under catheterization.
In our study, 78% of the patients received fluid
therapy. Crystalloids like Normal Saline, Ringer
Lactate were given in fluid therapy. About 22% of
the patients did not receive any fluids. This study
concluded that Sepsis causes massive vasodilation
and increases membrane permeability leading
to an intravascular fluid deficit hence fluids need
to be administered within 3 h immediately after
administration. Among fluids, crystalloids should
be preferred as they reduce the mortality improving
lactate levels.[22]
Corticosteroids are given in septic shock patients
who are on vasoactive medications. In our
study Corticosteroid therapy was given to 11%
of the patients. All of them received 200
mg
Hydrocortisone. Remaining 11% of the patients did
notreceiveanycorticosteriods.Thestudyconcluded
that treatment with low doses of hydrocortisone
(200 mg) should be preferred as they reduce the
risk of death in patients by reducing inflammation,
relative adrenal insufficiency without increasing
adverse events and by improving outcomes.[23]
Generally there will be changes in Hemoglobin in
some of the sepsis patients during initial days after
admission. Further hemodyanamic changes can
lead to reduced tissue oxygenation. In our study,
out of 100 patients, 13 patients had Hb 7 g/dl, out
of 13, 8 patients were initiated on blood products
like RBC transfusion, and 5 patients were not
given any blood products.[24]
In our study, out of 100 cases, 66 patients had
a glucose level of 180 mg/dL, Out of which of
22 patients were treated with insulin for glucose
control and 44 patients were not treated for glucose
control. The study stating that hyperglycemia
Table 7: Change of antibiotic in sepsis patients
Day 1 Day 2 No of patients
(n=8)
Cefperazone+
Salbactum
(Magnexforte)
Meropenam 2
Cefperazone+Salbactum
(Magnexforte)
Clarithromycin
(Claribid)
2
(Magnexforte)
Ceftriaxone
(Oframax)
1
Moxifloxacin
(moxicip)
Piperacillin+
Tazobactum
(zosyn)
1
Clarithromycin
(Claribid)
Colistimethate
Sodium
(Xylistin)
1
Piperacillin+Tazobactum
(Zosyn)
Clarithromycin
(Claribid)
1
Table 8: Change of antibiotic in septic shock patients
Day 1 Day 2 No of
patients (n=5)
(Magnexfortm)
Meropenam 3
Meropenam
(Penmer)
Vancomycin
(Vancomycin)
1
Doxycycline+
(Doxycycline)+ Magnexforte
Piperacillin+
Tazobactum
(Piptaz)
1

is seen in sepsis condition due to uncontrolled
inflammatory response. Hence, a strict glycemic
control with Insulin is required.
In our study, VTE prophylaxis was given to 29%
of the patients and the remaining 71% patients did
not receive any VTE prophylaxis. Among 71% of
patients, 61% patients had some contraindications
like Increased PT, thrombocytopenia, this might
be the reason for not receiving any prophylaxis.
Remaining 10% of patients did not receive
prophylaxisthoughtheyhadnormalvalues.Majority
of the study population received Enoxaparin
40 mg[25]
followed by Inj Fragmin.[3]
The doses of
Enoxaparin varied from 20
mg,[2]
40 mg,[26]
and
60 mg.[1]
Stress Ulcer prophylaxis was given to 86% of the
patients in our study group. All of them received
IV pantoprazole 40 mg.
Table 9: Analysis of checklist
Initial Management of Sepsis in Tertiary Care Centre: A Prospective Study (SEPSIS CHECK LIST)
1. Initial resuscitation
üAt least 30 ml/kg of IV crystalloid fluid (within the first 3 h)
ü
Monitoring: (HR, BP, Arterial O2 sat, RR, Temp, Urine
output, Lactate levels)
Day 1 Day 2 Y (100) Y (100)
N
N
2. Diagnosis
Routine microbiologic cultures
Blood culture:
Urine culture: 5 Cultures
3. Antimicrobial therapy
ü IV antimicrobials (within 1 h)
ü Empiric broad‑spectrum therapy
ü Narrow Empiric antimicrobial therapy
ü Optimizing of doses
Measurement of procalcitonin levels
Y (100) N Y (100) N
4. Source control
ü
anatomic diagnosis of infection removal of
intravascular access devices
Y (22) NA (78) Y (22) NA (78)
5. Fluid therapy
ü Fluid administration
ü Crystalloids
ü Albumin in addition to crystalloids
Y (78) N (22) Y (78) N (22)
6. Vasoactive medications
ü Norepinephrine as the first‑choice
ü
Vasopressin (up to 0.03 U/min) or epinephrine to reach
goal MAP
ü Dopamine as an alternative vasopressor
ü Dobutamine (if persistent hypo perfusion)
Y (22) N (78) Y (22) N (78)
7. Corticosteroids
ü
IV hydrocortisone if fluid resuscitation and vasopressor
therapy do not restore
Y (11) N (89) Y (11) N (89)
8. Blood products
ü
RBC transfusion ‑ only if the Hb7 g/dl.
Prophylactic platelet transfusion
Y (8) N (5) NA (87) Y (8) N (5) NA (87)
9. Mechanical ventilation
Neuromuscular blocking agents for≤48hrs in ARDS and
PaO2
/FiO2
150 mmHg
Y (51) N (49) Y (51) N (49)
10. Sedation and analgesia
Minimized in mechanically ventilated patients
Y (11) N (89) Y (11) N (89)
11. Glucose control
ü When 2 consecutive blood glucose levels are180 mg/dl
ü Monitoring of glucose q. 1–2 h
Y (22) N (44) NA (34) Y (45) N (55) NA (34)
12. Renal replacement therapy (in AKI)
CRRT/Intermittent RRT
Y (3) N (97) Y (3) N (97)
13. VTE Prophylaxis
LMWH
Y (29) N (71) Y (29) N (71)
14. Stress ulcer prophylaxis
PPIs/H2RAs
Y (86) N (14) Y (86) N (14)
15. Nutrition
Early hypocaloric feed, Prokinetic agent
Y (100) N
Y (100) N
Y: YES (Received), N: NO (Not received), NA: Not Applicable

Adequate nutritional therapy optimizes the chance
of survival in sepsis patients. In our study, all the
patients received adequate nutritional therapy.
CONCLUSIONS
• Thepresentstudyindicatestheuseofantibiotics
in ICUs in a multispeciality hospital.
• Duration of antibiotics for prophylaxis is not as
per the standard guidelines.
• Colistin is found to be resistant in MDR
Klebsiella pneumonia.
• De-escalation of antibiotics is mostly preferred
in MDR organisms.
• Proper laboratory tests such as culture and
sensitivity patterns reports may aid in directing
the specific antibiotic treatment which favours
costminimizationduringthecourseoftreatment
and decreases the spread of resistance patterns.
• The patient must expect to receive the right
antibiotic, at the right time, with right dose and
duration.
REFERENCES
1. Angus D, Wax R. Epidemiology of sepsis: An update.
Crit Care Med 2001;29:S109-16.
2. Seymour C, Liu V, Iwashyna T, Brunkhorst F, Rea T,
Scherag A, et al. Assessment of clinical criteria for
sepsis. JAMA 2016;315:762.
3. Adhikari N, Fowler R, Bhagwanjee S, Rubenfeld G.
Critical care and the global burden of critical illness in
adults. Lancet 2010;376:1339-46.
4. Angus D, Linde-Zwirble W, Lidicker J, Clermont G,
Carcillo J, Pinsky MR. Epidemiology of severe sepsis in
the United States: Analysis of incidence, outcome, and
associated costs of care. Crit Care Med 2001;29:1303-10.
5. Fleischmann C, Scherag A, Adhikari N, Hartog C,
Tsaganos T, Schlattmann P, Angus DC, et al. Assessment
of global incidence and mortality of hospital-treated
sepsis. Current estimates and limitations. Am J Respir
Crit Care Med 2016;193:259-72.
6. BC Patient Safety and Quality Council. Sepsis Guide:
Improving Care for Sepsis. A “Getting Started Kit” for
Sepsis Improvement in Emergency Departments. BC
Sepsis Network; 2012.
7. Liu V, Escobar G, Greene J, Soule J, Whippy A,
Angus D, et al. hospital deaths in patients with sepsis
from 2 independent cohorts. JAMA 2014;312:90.
8. Global, regional, and national age-sex specific all-cause
and cause-specific mortality for 240 causes of death,
1990-2013: A systematic analysis for the global burden
of disease study 2013. Lancet 2015;385:117-71.
9. Center for Disease Control and Prevention. Health,
United States. 2010.
10. Bone R, Grodzin C, Balk R. Sepsis: A new hypothesis
for pathogenesis of the disease process. Chest
1997;112:235-43.
11. Martin G, Mannino D, Moss M. The effect of age on the
development and outcome of adult sepsis. Crit Care Med
2006;34:15-21.
12. Martin G, Mannino D, Eaton S, Moss M. The
epidemiology of sepsis in the United States from 1979
through 2000. N Engl J Med 2003;348:1546-54.
13. Van der Poll T, de Waal Malefyt R, Coyle S, Lowry S.
Antiinflammatory cytokine responses during clinical
sepsis and experimental endotoxemia: Sequential
measurements of plasma soluble interleukin (IL)-
1 receptor Type II, IL-10, and IL-13. J Infect Dis
1997;175:118-22.
14. Brun-Buisson C. Incidence, risk factors, and outcome of
severe sepsis and septic shock in adults. A multicenter
prospective study in intensive care units. French ICU
Group for Severe Sepsis. JAMA 1995;274:968-74.
15. Grabe M, Bjerklund-Johansen TE, Botto H, editors.
Sepsis syndrome in urology (urosepsis). In: Guidelines
on urological infections. Arnhem, The Netherlands:
European Association of Urology (EAU); 2011. p. 33-9.
16. Pulido J, Afessa B, Masaki M, Yuasa T, Gillespie S,
Herasevich V, et al. Clinical spectrum, frequency, and
significance of myocardial dysfunction in severe sepsis
and septic shock. Mayo Clin Proc 2012;87:620-8.
17. Frausto MR, Pittet D, Hwang T, Woolson RF, Wenzel
RP. The dynamics of disease progression in sepsis:
Markov modeling describing the natural history and the
likely impact of effective antisepsis agents. Clin Infect
Dis 1998;27:185-90.
18. Mouncey PR, Power GS, Coats TJ. Early, goal-
directed resuscitation for septic shock. N Engl J Med
2015;373:576-8.
19. Angele M, Pratschke S, Hubbard W, Chaudry I. Gender
differences in sepsis. Virulence 2013;5:12-9.
20. Wang H, Shapiro N, Griffin R, Safford MM, Judd S,
Howard G. Chronic medical conditions and risk of
sepsis. PLoS One 2012;7:e48307.
21. Kethireddy S, Bengier A, Kirchner HL, Ofoma UR,
Light RB, et al. Characteristics and outcomes of patients
with culture negative septic shock compared with patients
Table 10: Distribution based on vasoactive medication
Vasoactive
medication given
Yes No
22 78 MAP Goal65
mmHg
Medication No of patients
Noradrenaline 21 Yes
Vasopressin 1 Yes

with culture positive septic shock: A retrospective cohort
study. Crit Care 2013;17 Suppl 4:7.
22. Whiles B, Deis A, Simpson SQ. Increased time to
initial antimicrobial administration is associated with
progression to septic shock in severe sepsis patients. Crit
Care Med 2017;45:623-9.
23. Vincent J. International study of the prevalence and
outcomes of infection in intensive care units. JAMA
2009;302:2323.
24.
Marshall J. Principles of source control in the
early management of sepsis. Curr Infect Dis Rep
2010;12:345-53.
25. Capp R, Horton C, Takhar S, Ginde A, Peak D,
Zane R, et al. Predictors of patients who present to the
emergency department with sepsis and progress to septic
shock between 4 and 48 hours of emergency department
arrival. Crit Care Med 2015;43:983-8.
26. Edul VK, Enrico C, Laviolle B, Vazquez AR, Ince C,
DubinA. Quantitative assessment of the microcirculation
in healthy volunteers and in patients with septic shock.
Crit Care Med 2012;40:1443-8.

RESEARCH ARTICLE
Measles outbreak in a vaccinated or never vaccinated children aged 1-5 years in
Khyber Pakhtunkhwa (KPK), Pakistan (Lower dir, Upper Dir and Bajawar):
Chains of transmission of virus and role of vaccine failure
Dharma D. Subedi
Department of General Practice and Emergency Medicine, Karnali Academy of Health Sciences, Jumla, Nepal
Received: 10 December 2021; Revised: 20 January 2022; Accepted: 01 February 2022
ABSTRACT
This study aimed to estimate the level of failures of measles vaccine or the children were never vaccinated
against the measles in KPK (Lower Dir, Upper Dip, and Bajawar) aged 1–5 years. The outbreak of the
measles among the children in lower Dir is very high. We carried out in all three districts which covered
467 children mostly aged 1–5 years in KPK during the month of March–July, 2014. Compared to the
past year with 2014 (n = 467), the prevalence of the measles cases were very high (n = 1400) in 2013.
Spread of measles virus is highest in the month of March–May 80% (375 of 467). The highest numbers
of the measles cases 74% (347 of 467) were reported. In temperate areas, cases typically occur at the
end of winter and the beginning of spring. The prevalence of measles in male and female children was
nearly equal. Finally, we have observed that those children who were suffering from measles were mostly
unvaccinated aged 3 years having acute malnutrition, Vitamin A deficiency, and parasitic infestation.
Keywords: Measeles, Temperate areas, Vaccinated, Unvaccinated
INTRODUCTION
The compulsory immunization program is very
essential to improve the childhood immunization
status in KPK, Pakistan. This study aimed to
estimate the level of failures of measles vaccine
or the children were never vaccinated against
the measles in KPK (Lower Dir, Upper Dip, and
Bajawar) aged 1–5 years. The outbreak of the
measles among the children in lower Dir is very
high.
We used the data from the children 467 cases from
March 2014 to July 2014, who were admitted in the
measles ward in DHQ, Timergara with a history of
a fever and widespread skin rash associated with a
cough or conjunctivitis (red eyes and watery eyes)
or nasal discharge (runny nose). We carried out
in all three districts (L. Dip, U. Dir, and Bajawar)
which covered 467 children mostly aged 1–5 years
in KPK during the month of March–July, 2014.
RESULTS
There were total 467 cases of measles reported in
the measles ward in DHQ, Timergara in the month
of March–July, 2014. All children admitted to the
measles ward had a history of a fever and widespread
skin rash associated with a cough or conjunctivitis
(red eyes and watery eyes) or nasal discharge (runny
nose) virus. Only 30% (328 of 467) of children aged
1–5 yearshavereceivedthefullcourseofvaccination.
Children of the poor and illiterate mothers have also
not received full immunization. On the other hand,
in low vaccination coverage (below 50%), incidence
of measles viruses in the population is high, with
intense virus transmission. Measles is endemic, with
ISSN 2582 – 6050
Dharma D. Subedi,
E-mail: dharmasubedi92@gmail.com

Subedi: Assessment of failure of measles vaccine in KPK, Pakistan
closely-spaced spikes (every 1–2 years). Hence, as
compared to the past year with 2014 (n = 467), the
prevalence of the measles cases were very high (n
= 1400) in 2013. Spread of measles virus is highest
in the month of March–May 80% (375 of 467). The
highest numbers of the measles cases 74% (347
of 467) were reported in Timergara and Balambat
(Lower Dir) which belongs to the sub-tropical zone.
Hence, in temperate areas, cases typically occur at the
endofwinterandthebeginningofspring.Classically,
the disease spreads from high population density
to low population density areas. In the meantime,
we have in Timergara and Balambat (Lower Dir)
has a very high prevalence of measles cases 74%.
On the other hand, in rural settings in Bajawar and
Upper Dir where the transmission of measles virus
is lower 26% only, epidemic outbreaks are generally
localized, more widely spaced, and smaller in scale
than in urban settings as in Lower Dir, Timergara,
and Balambat.
DISCUSSION
Measles is an extremely contagious acute viral
infection, characterized by a fever and skin rash
with signs of respiratory infection.[1,2]
It mainly
affects those children who are not vaccinated with
measles vaccine, malnourished, and living in poor
socioeconomicstatus.Thereisnospecifictreatment
for measles. Measles is a highly contagious and
deadly disease, but can be easily prevented with
a vaccine. Measles immunization is one of the
most cost-effective medical interventions in public
health. However, it is estimated that approximately
millions of children are dying every year from
measles[3,4]
that are preventable by measles vaccine
recommended for children by the World Health
Organization.
The introduction of an effective inexpensive
vaccine in the 1960s helped reduce the scope of
the disease on a global level.[4]
However, measles
is still a major public health problem in countries
where low vaccination coverage (in Africa and
Asia, mainly) has allowed the disease to persist and
give rise to large-scale outbreaks [Figure 1].
In 2010, 181 countries together reported more than
254,000 cases of measles.
The highest numbers of the measles cases 74% (347
of 467) were reported in Timergara and Balambat
(Lower Dir) which belongs to the sub-tropical
zone. Hence, in temperate areas, cases typically
occur at the end of winter and the beginning of
spring. Classically, the disease spreads from high
population density to low population density
areas. In the meantime, we have in Timergara and
Balambat (Lower Dir) has a very high prevalence
of measles cases 74%. On the other hand, in rural
settings in Bajawar and Upper Dir where the
transmission of measles virus is lower only 26%,
epidemic outbreaks are generally localized, more
widely spaced, and smaller in scale than in urban
settings as in Lower Dir, Timergara, and Balambat.
Measles cases being seen across the country are
due to the number of people who are not being
vaccinated or failure of efficacy of measles vaccine
due to false technique or not maintained cold chain
system.[5]
Most of the children in the lower Dir,
Upper Dir, and Bajawar were not vaccinated (70%)
Figure 1: Spread of measles virus is highest in the month of March–May 80% (375 of 467)

and only 30% were vaccinated against the measles
virus.
In low vaccination coverage (below 50%),
incidence of measles viruses in the population is
high, with intense virus transmission. Measles
is endemic, with closely-spaced spikes (every
1–2 years). Hence, as compared to the past year
in 2013 (n = 1400), the prevalence of the measles
cases were very high whereas prevalence of
measles in 2014 was (n = 467).
When vaccination coverage increases and stays at
a high level, there is a decline in the incidence and
more widely-spaced outbreaks. Only maintaining
very high vaccination coverage[6]
(over 95%) can
prevent outbreaks. According to our data analysis,
the most of the children who suffered from measles
were unvaccinated or they did not have any record
of vaccination in their childhood. It is estimated that
in an unvaccinated population, nearly all children
will develop measles before adolescence. While the
age of occurrence is determined by the probability
of contact with an individual that has measles,
children under 5 years – and more specifically,
under 3 years – are usually affected most. When
vaccination is administered, a small percentage of
those vaccinated fail to develop immunity (vaccine
efficacy 80–95%). Those individuals will not be
protected by the vaccine and will be at risk of
developing the disease if infected.
Vaccination helps control measles and changes the
epidemiology of the disease. The vaccine protects
individuals from infection; it reduces the number
of susceptible individuals. When more than 90%
of the population are immunized, transmission is
reduced and the risk of exposure to the virus is
low for the whole population. This is known as
community, or herd, immunity; non-immunized
people are protected by the size of the immunized
group around them. High vaccination coverage will
help to reduce the measles incidence and mortality
rate; reduce the group of susceptible individuals;
increase the proportion of immunized people
among the cases; alter the age distribution of cases;
and increase the time between outbreaks.
A total of 467 cases of measles were identified
over a period of 4 month; maximum incidence of
measles was observed for children between 1 and
5 years of age. The most of the children presented in
the measles ward with underweight and having 1st
,
2nd
, and 3rd
degree of malnutrition. The maximum
numbers (n = 452) 96% of children were having
malnutrition of different degrees. The most of
the children reported with corne[7,8]
al opacities
and the lesions responded well to oral Vitamin A
therapy.[7,9,3,10,4]
Malnutrition and infection are the
two major public health problems in developing
countries. In South East Asia, there is a very high
incidence of protein energy malnutrition[11]
that
is seen in preschool children. The condition is
particularly serious during the post-weaning period
and is often associated with infection. Much has
been written about the synergistic interaction and
infection in turn adversely affects the nutritional
status.Although this relationship is well documented
with respect to bacterial infections, it is not clear
whether nutrition can influence the incidence or
course of viral diseases. Measles is one of the most
commonviralinfectionsthatoccurduringchildhood.
The interactions between measles and nutritional
status acquire considerable importance in situations
where as a result of inadequate food intake, chronic
malnutrition is widespread among children.[12,13,2]
CONCLUSION
The majority of the measles cases 82% were
admittedtothemeasleswardthroughtheemergency
ward. Most of them were belonging to the orange
and red triage groups. In the meantime, we can
easily find that the most of the measles children
who were admitted in the measles ward were
serious, so they first presented to the emergency
ward. Utmost of the children were not vaccinated
70% and only 30% were vaccinated against the
measles virus. The prevalence of measles in male
and female children was nearly equal. Finally,
we have observed that those children who were
suffering from measles were mostly unvaccinated
aged 3 years having acute malnutrition, Vitamin
A deficiency, and parasitic infestation.
REFERENCES
1. Bhaskaram P, Reddy V, Raj S, Bhatnagar RC. Effect of
measles on the nutritional status of preschool children.
J Trop Med Hyg 1984;87:21-5.

2. Piereira SM, Benjamin V. Measles in a South Indian
community. Trop Geogr Med 1972;24:124-9.
3. Inua M, Duggan MB, West CE, Whittle HC,
Kogbe OI, Sandford-Smith JH, et al. Post-measles
corneal ulceration in children in northern Nigeria: The
role of vitamin A, malnutrition and measles. Ann Trop
Paediatr 1983;3:181-91.
4. JohnTJ,JosephA,GeorgeTI,RadhakrishnanJ,SinghRP,
George K. Epidemiology and prevention of measles in
rural south India. Indian J Med Res 1980;72:153-8.
5. Morley D. Severe measles in the tropics. I. Br Med J
1969;1:297-300.
6. National Institute of Nutrition. Annual Report.
Hyderabad: National Institute of Nutrition; 1985. p. 64.
7. Awdry PN, Cobb B,Adams PC. Blindness in the Luapula
valley. Cent Afr J Med 1967;13:197-201.
8. Bhaskaram P, Mathur R, Rao V, Madhusudan J,
Radhakrishna KV, Raghuramulu N, et al. Pathogenesis
of corneal lesions in measles. Hum Nutr Clin Nutr
1986;40:197-204.
9. Franken S. Measles and xerophthalmia in East Africa.
Trop Geogr Med 1974;26:39-44.
10. James HO, West CE, Duggan MB, Ngwa M.A controlled
study on the effect of injected water-miscible retinyl
palmitate on plasma concentrations of retinol and retinol-
binding protein in children with measles in northern
Nigeria. Acta Paediatr Scand 1984;73:22-8.
11. Koster FT, Curlin GC, Aziz KM, Haque A. Synergistic
impact of measles and diarrhoea on nutrition and
mortality in Bangladesh. Bull World Health Organ
1981;59:901-8.
12. Morley DC. Measles in Nigeria. Am J Dis Child
1962;103:230-3.
13. Muller AS, Voorhoeve AM, Mannetje W, Schulpen TW.
The impact of measles in a rural area of Kenya. East Afr
Med J 1977;54:364-72.

RESEARCH ARTICLE
Congruity and Incongruity between Pratham Patala Gata Timir and Myopia
Riju Agarwal1
, Santosh Mulik2
, Ashok Kumar3
, Manju Rani4
, Manish Vyas5
, Medha Lakra6
1
Department of Shalakya, Chaudhary Brahm Prakash Ayurved Charak Sansthan, Guru Gobind Singh
Indraprastha University, Najafgarh, New Delhi, India, 2
Department of Shalakya, College of Ayurved, Bhartiya
Vidyapeeth, Pune, Maharashtra, India, 3
Department of Rog Nidan Evum Vikriti Vigyan, Chaudhary Brahm
Prakash Ayurved Charak Sansthan, Khera Dabar, Najafgarh, New Delhi, India, 4
Department of Shalya,
Chaudhary Brahm Prakash Ayurved Charak Sansthan, Khera Dabar, Najafgarh, New Delhi, India, 5
Department
of Ayurveda, Lovely Professional University, Phagwara, Punjab, India, 6
Department of Rog Nidan Evum Vikriti
Vigyan, Chaudhary Brahm Prakash Ayurved Charak Sansthan, Khera Dabar, Najafgarh, New Delhi, India
Received: 15 December 2021; Revised: 25 January 2022; Accepted: 10 February 2022
ABSTRACT
Eye diseases are much more important than any other physical disability, because once the vision is lost
then that person is disabled for doing all regular activities; day and night are same for the person. Timir
is a disease, which starts with simple visual disturbances (Avyakta Darshana) but if unattended, it may
lead to ends in profound loss of vision. According to site of lesion, Acharya Sushruta has explained 76
Netravyadhi among them vision-related disorders are studied under broad heading of “Drishtigata roga.”
The pathogenesis of Timir has been described in terms of involvement of successive Patalas (Layers).
Blurring of vision is the only clinical features found in Pratham Patala (first layer) and it is also cardinal
sign of myopia in Modern science. Uncorrected refractive errors are the one of the most important causes
of vision impairment and the leading cause of blindness in the developing countries. Although there
is availability of advanced technological aids such as spectacles, contact lenses and lasik surgeries but
limitations are there due to certain adverse effects, cost effectiveness etc. Hence, Ayurvedic science can be
explored to find a better alternative to manage this condition. In Ayurveda, there are number of preventive
and curative modalities explained to treat Timir in the form of Pathykaraahar-vihar, Rasayana Yoga,
Chakshushya drugs, Netra karma, Kriyakalpa, Panchkarma, etc.
Keywords: Myopia, Timir, Refractive error, Netra, Shalakya
INTRODUCTION
There is a description of different eye disease in
Ayurveda. In the Drishtigata Roga, Timir is one
of the primary symptoms/signs. In Ayurveda,
Timir is a broad term used to describe visual
problems. The cause of blurring of vision may
be corneal, lenticular, or retinal but if blurring of
vision is there, Timir is common term to describe
diminution of vision. Avyakta Darshana (blurring
of vision) is the first feature of Timir in eye disease
and ultimately resulted in complete loss of vision,
that is, Linganasha,[1]
if left untreated. Its literal
meaning is darkness. Etiological factors mentioned
for Timir in Ayurvedic classics are common causes
for all the eye diseases. Its clinical features are
based on involvement of Patalas (Layers/tunic/
covering) and vitiation of Doshas.[2]
When vitiated
Doshas present in first layer (Patala), the patients
complain of blurred vision for distant object.[3]
According to Vagbhatta, when Dosha presents in
First Patala then that person sees objects hazy and
sometimes clearly without any obvious cause.[4]
ISSN 2582 – 6050
Medha Lakra,
E-mail: medhalakra095@gmail.com

Agarwal, et al.: Congruity and incongruity between pratham patala gata timir and myopia
This is common complaint of myopia. Myopia is
the refractive condition of eye in which person
cannot see distant object clearly. In India, the
prevalence of myopia in the general population
has been reported to be only 6.9%. A latest survey
revealed that 26.6% of West Europeans 40 years or
above are having at least –1.00 Diopters of myopia
and 4.6% have at least –5.00 Diopters.[5]
The treatment of the Timir depends on the stage
and dominance of particular Doshas for which
local and systemic management has described
by Acharyas to treat different stages of Timir
(Diminution of vision).
Aim and Objective
This study aims to justify the correlation of
Pratham Patala Gata Timir described in Ayurveda
with myopia.
Various classical texts of Ayurveda, journals,
thesis, publications etc. available on Refractive
errors and Timir were explored to write this article
in its present form. Detailed review of classical
literature and ophthalmology were carried out at
fundamental level.
Etiology of Timir
This disease has been mentioned as a symptom or
sequel of many diseases in Ayurvedic texts. Thus,
Timir roga varies from symptom to a separate
disease. The etiological factors responsible for eye
diseases, which are also meant forTimir byAcharya
Charak are follows – as misuse, overuse, and
disuse of the senses and has regarded as “Volitional
transgression,” that is, excessive gazing at the
over brilliant object to see excessive use, avoiding
looking altogether is disuse and seeing too near,
too distant, fierce, frightful, wonderful, disliked,
disgusting, deformed, and terrifying objects is
perverted use of objects.[6]
Acharya Sushruta and
others have described the following causes for eye
diseases – taking cold water bath when body is
hot, see distant object continuously, alternation of
sleep pattern, excessive anger, grief, stress, due to
traumatic injury, and eating sour food item.[7]
Samprapti (Pathogenesis)
The pathological events of Timir begin with
the vitiation of Doshas at their respective sites.
Acharya Sushruta has clearly stated in reference
to Samprapti of Timir that when Doshas get
excessively vitiated internally, pervades the Siras
(vessels), and gets lodged in the first Patala of
Drishti, the patient sees all the objects as blurred.[8]
Dalhana opined that the word “Sira” represents
“Rupavaha Sira” and Drishti indicates inner
part of the Drishti.[9]
The presence of Doshas in
Patalas further prevents the functional capacity of
Patalas and leads to Avyakta Darshana or blurred
vision. It further inhibits the nutritional supply by
obstructing the channels responsible for it. The
involvement of second and third Patalas leads
to further deterioration of Drishti; whereas in
4th
Patala, affliction terminates into Linganasha or
loss of vision [Table 1].
Rupa (Clinical Features)
The actual diagnosis of the disease mainly depends
on the signs and symptoms. In case of Timir, the
signs and symptoms have been mentioned in two
ways – according to the involvement of Patalas and
vitiation of Doshas.
Table 1: Etiological factor for eye disease
Ayurveda aspects Modern aspects
Dureshanata To see distant object
Sukshmanirkshanata Observing the minute things
regularly
Abhighatada Due to traumatic injury
Swapnaviparayata Alteration of the pattern of sleep
Prasakta Sanrodana Continuous weeping
Kopha Excessive anger
Shoka Grief
Klesha Stress
Shuka‑arnala‑amla‑kulatha‑masha Sour food item intake
Dhoomnishevnata Smoking
Vashpagrhihata Suppressing the tears
Usnabhitaptasya‑Jala praveshata Sudden variation in the body
temperature

According to Dosha Involvement
Dominance of the particular Dosha in the
pathogenesis ofTimir also casts particular symptom
complex in this disease. The symptoms according
to predominant Dosha are as follows.
Vataja timir
The patients suffering from Vataja Timir see objects
as if they were moving, hazy, reddish in color, and
tortuous in shape.[10]
In Timir caused by Vata, the
person sees the objects as though covered with thin
cloth, unstable, grubby, reddish, sometimes and
some other times as clear and clean; sees webs,
hairs, mosquitos, and rays of light in front of his
eyes.[11]
Pittaja timir
In Pittaja Timir, the patient sees flashes of sun,
glow worm, rainbow, and the lightening. He views
bluish and blackish colors as variegated as the
feathers of peacock.[12]
In Timir, born from Pitta,
the person sees lightening (flashes of light), glow
warm and burning lamp, etc., objects appear as
deep blue in color like the feather of the peacock,
Tittiri (partridge).[13]
Kaphaja timir
In Kaphaja Timir, the person views all the objects
glossy and white like the colors of white “chamara”
or white clouds. The patient can see objects, which
are not excessively small and visualizes moving
clouds in the cloudless sky. All still objects appear
as if inundated in water.[14]
In general, in Kaphaja Timir, the person sees the
objects as unctuous (greasy), white, as that of a
conch shell, moon, flower of kunda (Jasmine)
and as though covered with kumuda (Petals of
Lilly).[15]
Raktaja timir
A patient of Raktaj Timir views all objects to be
variegated colors such as dark greenish, grayish or
blackish, and smoky all around.[16]
In Timir caused
by blood, the organ of vision is red and the person
sees objects as though in darkness.[17]
Sannipataja timir
In Timir due to vitiation of all Doshas together, the
person views all objects as of variegated colors,
scattered (spread out images), and as having
double or manifold images all around. All objects
appear to possess less or more than normal parts
or as luminous.[18]
In those Timir which are caused
by combination of two and three Doshas, the
symptoms of the Doshas involved are present, in
Timir, the objects are seen sometimes clear and
sometimes as covered.[19]
Patalagata Timir (Timir Affecting Layers of
Eye)
The clinical picture of Timir, when the Doshas are
vitiated in successive Patalas.
Doshas in 1st
patala
The only symptom produced when the vitiated
Doshas are present in the first Patala is Avyakta
Darshana. The patient is not able to appreciate
the exact nature of the object and there is slight
blurring of vision.[3]
Doshas in 2nd
patala
The main symptom when the Doshas are situated
in this Patala is Vihwala Darshana (vision full of
hollows). The clinical picture can be summarized
as follows – haziness of vision, visualization of
false images such as gnats, hairs, webs, circles,
flags, mirages, and ear rings, distant objects
appear to be near and near objects appears to be
far away. Pseudo-visualization like rain, cloud,
and darkness, unable to recognize the hole of
needle.[20]
Doshas in 3rd
patala
The third Patala is formed by Meda. The clinical
picture when Doshas are vitiated in the third
Patala includes visualization of objects situated
above and not below, objects appear as if covered
with cloths, details like ear/eyes are not visible
when looked at any face, coloring of Drishti
(discoloration of lens) called kancha[21]
(immature
cataract).

Doshas in 4th
patala
It is innermost Patala of eye and is formed byAsthi,
which is supportive in function. When Doshas are
vitiated in the fourth Patala, the clinical features
are complete loss of vision, Drishti Mandala
covered by vitiated Doshas, perception of bright
illuminations unless there is some gross pathology
in the eye.[1]
Management of Timir
In brief, the management essentially consists of the
avoidance of etiological factors (Nidan Parivarjana)
and specifically in detail it implies counteracting
the increased Vata and other Doshas. The treatment
of the Timir depends on the stage and dominance
of particular Dosha. In early stage of Timir, when
the symptoms of the vitiated Doshas have just
manifested but have not involved the whole eye,
these should be treated by Nasya, collyriums, and
other purification measures.
Samanya chikitsa (general treatment)
Oleation, bloodletting, Virechana, Nasya, Anjana,
Murdha Basti, Basti, Tarpan, Lepa, and Seka –
these therapies administered many times, suitable
to the Doshas is the mode of treatment.[22]
Preventive measures
The person who is regularly in habit of taking
old preserved Ghrita, Triphala, Shatavari, Patola,
Mudga, Amalaki, and Yava (barley) has no reason
to fear from even the severest form of Timir.[23]
Prophylactic measures
Payasa prepared from Shatavari or that prepared
similarly from Amalaki or else barley meal cooked
with sufficient quantity of Ghrita and the decoction
of Triphala are the prophylactic measures to
prevent Timir.[24]
Diets to improve eyesight
The cooked vegetables of Jivanti, Sunishannaka,
Tanduliya, good quantity of Vastuka, chili, and
madhuka and also the flesh of birds and of wild
animals are beneficial for eyesight. Patola,
karkotaka, karavellaka, brinjal, tarkari, karira
fruits, shigru, and artagala; all these vegetables
cooked with Ghrita promote eyesight.[25]
Curative Measures
Local measures
Local measures include Tarpan, Putapaka, Seka,
Aschyotana, and Anjana. These all together are
known as “Kriyakalpa”[26]
(Specialized therapeutic
procedure to treat ocular disease).[27]
Systemic measures
Shodhan chikitsa
Virechana (Purgation) is said to be ideal for
Anulomana of Doshas specially vitiated Pitta, as
eye is the sight of Pitta predominance.
In Vataja Timir, castor oil mixed with milk should
be taken at bed time, Triphala ghrita is a general
evacuativeparticularlyindiseasesofRaktaandPitta,
in Kaphaja type, Virechana with Ghee processed
with Trivrit is recommended while in Tridoshaja,
oil processed with the Trivrit is useful.[28]
Shaman chikitsa
Old ghee kept in iron container is beneficial in
Timir in all ways. Similarly, Triphala Ghrita and
Ghrita processed with fruits of Mesasringa are
useful. Triphala is said to be the drug of choice in
case of Timir with various Anupanas (vehicles)
according to the involvement of Doshas. In Pittaja
type mixed with plenty of Ghee regularly, similarly
in Vataja type, it should be taken with oil and in
Kaphaja one with plenty of honey properly.[29]
Sushruta and others indicate numbers of Nasya in
the management of Timir.
Contraindication of Timir
Raktamokhna (Bloodletting) should be avoided in
Kancha (Discolouration of lens) when colourised
as Dosha excited by the instrument destroys vision
immediately.[30]
Refractive error can be well correlated with Timir
of Ayurvedic Science, because both of these
conditions elicit similar/comparative clinical
features as evident from the Table 2.[31]

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