Prosiding Icpaps 2017

PROCEEDING
The 5th International Conference on

Pharmacy and Advanced Pharmaceutical Sciences
November 1 – 2, 2017 Yogyakarta, Indonesia
Editors:
Abdul Rohman
Susi Ari Kristina
Indonesia Published by:

Faculty of Pharmacy Universitas Gadjah Mada
Sekip Utara, Yogyakarta, 55281,
PROCEEDING
The 5th International Conference on

Pharmacy a nd Advanced Pharmaceutical Sciences
November 1 – 2, 2017 Yogyakarta, Indonesia
Editors:
Dr. Rina Kuswahyuning, M.Si., Apt.

Prof. Dr. Abdul Rohman, M.Si., Apt.
Dr. Fita Rahmawati, M.Si., Apt.
Dr. Ika Puspitasari, M.Si., Apt.
Dr. Silvia Utami Tanjung, M.Si., Apt.
Dr. Dwi Endarti, M.Kes., Apt.
Published by:
Indonesia
Pharmaceutical Scince & Clinical Pharmacy
Published by:
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ISSN : 2614-1779
First Edition, 2017

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Preface from Editor
Preface From Editor
On behalf of the Editors, I am deeply grateful to all the reviewers who have been working
th
very hard for reviewing manuscripts submitted during the 5 International Conference on
Pharmacy and Advanced Pharmaceutical Sciences" held in Sheraton Hotel Yogyakarta,
by the Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia on
November 1 - 2, 2017
We would like to acknowledge to keynote speakers and all the distinguished speakers for
their valuable contribution during this conference. Further more, we also thank the steering
committee for their advice and support. Finally, I would appreciate to all participants, paper
and poster presenters who participated in the conference as w ell as cordially contributed
by submitting their full manuscripts published in this proceeding.
Finally, we believe that the presence of this proceeding will significantly contribute to
the advance scientific research, especially in the field of Pharmaceutical Science and
Thecnology.
Yogyakarta, November 2017,

Chief
Rina Kuswahyuning
th
The 5 International Conference on Pharmacy and Advance Pharmaceutical Science
The 5th International Conference on Pharmacy and Advance Pharmaceutical Science
Table of Content
Preface from Editor
Table of Content
The Comparison of Sodium Alginate and Xanthan Gum on Captopril 1–9
Release Profile of Floating Drug Delivery System Effervescent Capsule
Adeltrudis Adelsa D., Zakinza Karina AP, Ratna Triana SGZ, Dahlia
Permatasari
Pharmacist’s Role In Individualising Amikacin Dosing In Severe Renal 10 – 14

Failure
Mochamad Djunaedi, Ab Fatah Ab Rahman
Observational Study of Analgesic and Pain Relief In Postoperative Patients 15 – 26

Budi Suprapti, Aisyah, Dewi Wara Shinta, Arga Patrianagara
Red Betel Leaves (Piper crocatum RUIZ & PAV) Extract Granule Formula 27 – 38
and In Vivo Antiinflammatory Activity Studies
Laksmitawati DR, Kusumaningsih DA, Fahleni, Arifin MF 1
Antidiabetic Activity and Phytochemical Analysis of Ethyl Acetate Fraction 39 – 48

of Dadangkak Roots (Hydrolea spinosa L) From South Kalimantan
Muhammad Zaini, Vivi Shofia, Amalia Ajrina
THE FORMATION OF INCLUSION COMPLEXES OF GLIMEPIRIDE- 49 – 55

BETACYCLODEXTRIN TO INCREASE SOLUBILITY AND DISSOLUTION RATE
Fitrianti Darusman, Ulfa Siti, Silviyaturrohmah
Utilization of Black Bali Rice (Oryza sativa L.) in Improving Insulin Activity 56 – 63
and Regeneration of Β-Cell Pancreas on White Diabetic Rat with Alloxan
Induced
Ketut Agus Adrianta, I Gusti Agung Ayu Kusuma Wardani
Toxicology of CR(III)- Glutamic Acid as Hypoglicemic Nutraceutical on 64 – 71

Streptozotocin-Nicotinamide Induced Diabetic Rats
Kun Sri Budiasih, Kartika Ratna Pertiwi, Rizqie Auliana
The Influence of Appearance Pharmacy And Drug Information Service to 72 – 76

Patient Satisfaction of Outpatient Program Jamkesda In H.Hasan Basry
Hospital at Kandangan City
Nita Pujianti, Aulia Azizah, Musafaah, Fauzie Rahman
The Effect of Keto-Acids Supplements on GFR Patients with Chronic Kidney 77 – 80

Disease in One of General Hospital in Jakarta
Putu Rika Veryanti, Yan Santosa
th
Health Related Quality of Life of Ischemic Stroke Patients in Yogyakarta 81 – 90
Measured With EQ-5D-5L
Muslimah, Tri Murti Andayani, Rizaldy Pinzon, Dwi Endarti
th
The Comparison Of Sodium Alginate And Xanthan Gum
THE COMPARISON OF SODIUM ALGINATE AND XANTHAN

GUM ON CAPTOPRIL RELEASE PROFILE OF FLOATING DRUG
DELIVERY SYSTEM EFFERVESCENT CAPSULE
Adeltrudis Adelsa D., Zakinza Karina AP, Ratna Triana SGZ, Dahlia
Permatasari
Pharmacy Study Program, Faculty of Medicine, Universitas Brawijaya, Jalan Veteran
65145 Malang, Indonesia
elsa.adam@ub.ac.id
ABSTRACT
Captopril is an antihypertensive therapy which also classified as BCS
(Biopharmaceutics Classification System) class III. It is mostly absorbed in the
stomach. The aim of this research was increasing the transit time of
captopril in stomach to improve permeability characteristics by comparing
two polymers, sodium alginate and xanthan gum. The chosen delivery
system is floating drug delivery system (FDDS) in capsule dosage.
Effervescent (sodium bicarbonate) was added to stimulate gas CO2 forming
and boost the floating. There are six formulas which made by wet
granulation method. The first three formula are using sodium alginate
percentage: F1 (5%), F2 (7,5%) and F3 (10%). The next three are designed in
captopril and xanthan gum ratio: F4 (50:21), F5 (50:42), and F6 (50:63). All
of the formulas have fullfiled the specification in flow characteristics, fines
percentages, homogeneity, organoleptic test, drug assay, weight diversity
and weight uniformity. The floating lag time takes less than 1 minute for all
of the formulas. We concluded F6 as the optimum formula. It has given the
long floating duration time and suitable with modified profile release
specification.
Keywords: captopril, sodium alginate, xanthan gum, release profile, floating,
capsule
INTRODUCTION
Captopril is one of antihypertensive choice classified as ACE
(Angiotensin Converting Enzyme) Inhibitor and often used as first line agent
on antihypertension therapy (Karakilic et al. 2012). Based on its
physicochemical characteristics, captopril is included in Class III BCS
(Biopharmaceutics Classification System). It has good solubility but low
permeability. The bioavailability of captopril is less than 90% (Shargel and Yu.
2005). In order to increase the permeability of captopril is increasing
retention time in gastric. The alternative modification is Gastro Retentive
Prooceding ICPAPS 2017 1

Adeltrudis Adelsa D
Drug Delivery System (GRDDS) (Bhowmik et al. 2012). These kind of systems
increase drug retention time in gastric. It prolongs the contact between
gastric and drug to give the enough time for drug permeability.
There are several types of GRDDS, but floating drug delivery system
(FDDS) effervescent eas chosen (Arora et al. 2005). This system works by
produce gases from effervescent reaction and generate low density system
to be floated on gastric fluid. The carbon dioxide gases was obtained due to
reaction of sodium bicarbonate, as gas generating agent, and HCl in gastric
fluid (Khan and Bajpai. 2010). This system is applied in capsule dosage form.
Capsule is one of the famous solid dosage form which is easy to swallow
because of its smooth and slippery surface. The bulk was tamped into
granules using wet granulation method. One of the reason of granulation
choice is to modify the release of captopril.
Polymer is best used in modified release system. Sodium alginat and
xanthan gum are natural polymer. It has swelling ability and forms gel to
entrapped drugs. The advantages of natural polymer are non toxic,
biodegradable, biocompatible, cheap, easy to obtain and not accumulated in
specific organ (Sachan et al. 2009). The higher of sodium alginate
concentration has been used, the lower of cumulative percentage of drug
release would be yielded until 12 hours (Kumar et al. 2014).
MATERIALS AND METHODS

Materials
The materials have been used in this research are captopril (PT
Pratapa Nirmala Jakarta), sodium alginate, xanthan gum, sodium
bicarbonate, amilum manihot, Avicel PH 101, talc, stearic acid, HCl 0,1 N, and
aquades.
The making of granules using wet granulation method

Captopril, polymer (sodium alginate/xanthan gum), sodium
bicarbonate and Avicel PH 101 were mixed for 10 minutes. This is called
internal phase. To make granules, we used 1% amilum paste. The mixture
was made using magnetic stirrer 350-700 rpm and temperature 120°C. The
amilum paste was added into internal phase until the dough became dull.
The dough was sieved using 10 mesh to obtain wet granules. They were
dried using oven for ± 45 – 60 minutes and the temperature was 50°C. Dry
granules were checked by In Process Control, including flowability, fines
percentage and homogeneity test. All of the tests were fullfiled according on
their specification. Dry granules were added with external phase (mixture of
amilum, talk and stearic acid). They were mixed for 2 minutes. Those final
2 Prooceding ICPAPS 2017

granules were ready to be filled in capsules. The formulas was attached in

Table 1.
Table 1. The Formulas of Captopril Floating Drug Delivery System Capsule

Material F1 (g) F2 (g) F3 (g) F4 (g) F5 (g) F6 (g)
Captopril 2,5 2,5 2,5 2,5 2,5 2,5
Sodium Bicarbonate 1,5 1,5 1,5 1,5 1,5 1,5
Sodium Alginate 7,5 11,25 15 0 0 0
Xanthan Gum 0 0 0 1,05 2,1 3,15
Amilum 0,9 0,9 0,9 0,5 0,6 0,5
Talc 0,3 0,3 0,3 6 6 6
Stearic Acid 0,3 0,3 0,3 6 6 6
Avicel pH 101 8,75 8,375 8 8,2 7,1 6
Flowability
In this research, flowability was tested using the determination of flow
velocity and angle of repose. The instrument we used was Flodex™. As much
as 10 grams of captopril granules were weighed and counted how much time
do they need to flow. The result is stated in g/second (USP, 2006). After
flowing from the Flodex, the granules has formed cone. We measured the
height (h) and radius (r) to calculate angle of repose (α)
tan α = h/r............................................................(1)
Fines Percentage
As much as 5 grams of captopril granules were placed on sieve shaker
mesh number 80. The instrument was running for 5 minutes in amplitude 60.
We calculated the weight of granules passed the sieve using the equation
(Khan et al. 2010).
(prior weight-final weight)
% fines= x 100..........................(2)
prior weight
Homogeneity Test of Captopril

The aim of this test are ensuring the homogeneity of captopril after
mixing and granulating process. We took sampling from the top, middle and
bottom part. Every sample was weighed as much as 300 mg (equal with 50
mg captopril) and dissoved in 0,1 N HCl until 50 ml. They were filtered and
the substrat was separated 1 ml to diluted until 10 ml. The sample was
measured to calculate the concentration (Garg and Gupta, 2015.

Adeltrudis Adelsa D
Organoleptic
The purpose of this test id identifying the physical appearance of FDDS
capsules (color, shape and odor).
Weight Uniformity
Randomly, 20 capsules were taken from each formula and weighed
respectively. The mean weight of 20 capsules were calculated. Deviation
percentage were calculated using this equation (Depkes RI, 1979):
(capsule weight – mean capsules weight)
% deviation = x 100
mean capsules weight
Weigh Diversity
As many as 10 capsules were weighed one by one. Then, capsules
were opened to pull out the granules. He empty capsules were weighed
thourougly The nett weight was calculated by substract capsule weight and
empty capsule weight. By the content uniformity (as stated in captopril
monography), we calculated captopril content on each capsule. The
assumption is that captopril is ditributed homogen (Depkes RI, 1995).
Drug Content
The granules were weighed as much as 300 mg (equal with 50 mg
captopril). The granules were mashed and dissolved in HCl 0,1N. The sample
was filtered and absorbance was measured using Spectrophotometer UV Vis
at maximum wavelength 201,8 nm. The absorbance was used to calculated
drug concentration using linear regression curve. The percentage of captorpil
are determined using this equation (USP, 2007):
(content measured)
% Drug Content = x 100 .....................................(3)
content on the label
Floating Lag Time

The dissolution apparatus 2 was used in this test. The medium was
900 ml solution of 0,1N HCl in 37°C ± 0,5° and 50 rpm paddle rotation. Each
vessel was placed with one capsule respectively and the time duration of
floating capsule was measured using stopwatch.
Floating Duration
This test was observed as long as the release profile test was run. The
observation was made on these interval time : minutes 60th, 240th, 360th,
dan 480th. The total duration of this observation was 7-8 hours.

Release Profile
This test used similar Apparatus 2 floating duration. The amount of
captopril released were determined by sampling on these interval times: at
0,25th; 0,5th; 0,75th; 1th; 2th; 3th; 6th; and 8th hour. The amount of drug release
was measured using Spectrophotometer UV-Vis at maximum wavelength
(13)
RESULTS AND DISCUSSION

The flowability of granules was determined by flow velocity and angle
of repose. All of the formulas have good flowability because the flow velocity
was more than 10 g/sec and angle of repose was less than 35°( USP, 2007).
The fines percentage were also good because they were less than 5% (Table
2) (Khan et al. 2010).
Table 2. Flow Velocity, Angle of Repose and Fines Percentage

Flow velocity Angle of Repose Fines
Formula
( g/sec ) ± SD (o) ± SD (%) ± SD
F1 15,3512 ± 1,692 28,3366 ± 1,4515 0.2489 ± 0,0044
F2 18,1714 ± 0.909 27,4160 ± 0,4681 0,9491 ± 0,1440
F3 14,6678 ± 1,339 34,5543 ± 2,4060 1,0304 ± 0,1326
F4 14,3221 ± 1,8286 28,3133 ± 1,1077 1,0638 ± 0,2879
F5 20,1951 ± 1,2888 26,1403 ± 1,7529 0,3128 ± 0,1516
F6 21,6153 ± 1,6598 27,2139 ± 1,7266 0,4675 ± 0,2354
Homogeneity
The datas shows that the drug content was suitable with the
spesification (not more than 98% and not less than 101,5%). The captopril
homogeneity was good because the RSD are less than 6% (BP, 2009).
Organoleptic
The capsules are ellipse, their color is white and blue. The surface of
capsule is clean, smooth and odorless.
Weight Uniformity
The capsules weight has uniformity. For capsules have mean weight
300mg or more, there were no 2 capsules which its deviation more than
7,5%

Adeltrudis Adelsa D
Weight Diversity
The weight diversity was suitable with the spesification. Their captopril
content not more than 98% and not less than 101,5%. The RSD are less than
6%.
Drug Content
Based on table 3, it can be concluded that all of the formulas
contained not more than 98% and not less than 101,5% captopril (Depkes RI,
1995).
Tabel 3. Drug Content Result
Formula Mean ± SD (%)

F1 98,4402 ± 0,2390
F2 98,5845 ± 0,4065
F3 100,6384 ± 0,1428
F4 100,6687 ± 0,1355
F5 98,2287 ± 0,2347
F6 99,7047 ± 0,5498
Floating Lag Time

All of the formulas have lag time less than 1 minute.
Floating Duration
From Table 4, it can be concluded than the higher concentration of
polymer, the longer FDDS capsule could float on the gastric fluid.
Tabel 4. Duration of Floating
Formula Mean (minutes)

F1 61.22
F2 245.89
F3 360.67
F4 120.0
F5 120.0
F6 480.0
Release Profile
According to Welling (1980), the release drug on the 2nd hours should
achieve 20-50%. At the 4th hours, the drug must 45-75%. Finally, at the 8th
hours, more than 80% drug has to be released. F3 and F6 have long floating

duration. They were also suitable with the specification of release profile.
But F6 has longer floating duration and at the 480th minutes, it has released
more than 80% of captopril (Table 5).
Table 5. Captopril Release Profile
Captopril Dissolved Percentage % (Mean ± SD)

Minutes
F1 F2 F3 F4 F5 F6
30 24,664 ± 23,918 ± 19,88 ± 59,3338 ± 37,7909 ± 37,2945 ±
0,087 0,087 0,046 1,4557 0,3435 0,0808
45 31,604 ± 31,162 ± 25,508 ± 70,480 ± 52,5198 ± 42,7582 ±
0,07 0,104 0,148 0,7186 0,1875 0,1513
60 43,697 ± 40,942 ± 29,497 ± 78,8680 ± 63,3459 ± 46,7469 ±
0.094 0,069 0,11 0,1069 0,1022 0,1067
120 54,867 ± 51,781 ± 40,286 ± 85,8704 ± 65,8627 ± 49,1619 ±
0.144 0,109 0,11 0,1910 0,1369 0,1879
180 60,639 ± 59,949 ± 51,246 ± 86,3672 ± 84,4666 ± 53,0229 ±
0.155 0,105 0,103 0,1943 0,1133 0,0899
240 71,103 ± 67,437 ± 60,946 ± 87,144 ± 85,3776 ± 57,5371 ±
0,11 0,094 0,088 0,0858 0,1059 0,5930
360 85,162 ± 80,134 ± 69,969 ± 91,055 ± 88,5291 ± 76,4350 ±
0,047 0,154 0,195 0,1060 0,1239 0,1275
480 91,265 ± 88,567 ± 78,333 ± 95,9767 ± 88,6724 ± 81,1160 ±
0,166 0,357 0,094 0,0867 0,1224 0,1380
Table 6. Regression Coefficinet Value of Drug Release
Zero Order First Order Higuchi Korsmeyer Peppas

R2 R2 R2 R2
F1 0,9612 0,9028 0,9903 0,9886
F2 0,9634 0,8999 0,9922 0,9896
F3 0,9720 0,9921 0,9967 0.9938
F4 0.8012 0.7534 0.8877 0.9394
F5 0.8254 0.7525 0.9124 0.9445
F6 0.9561 0.8898 0.9702 0.9655
Release Kinetics
Based on calculation of R2 value from linear regression, the highest R2
at Higuchi plot for sodium alginate and xanthan gum F6 (Table 6). F4 and F5
xanthan gum are following Korsmeyer Peppas model. The Higuchi model
means that most of drug release is controlled by diffusion process.

Adeltrudis Adelsa D
Meanwhile, the mechanism of Kormeyer Peppas can be observed using the n

value (n F4 = 0.2489, n F5 = 0,4504). It means that release mechanism of F4 is
using diffusion process and F5 is using the combination of erosion and
diffusion process.
CONCLUSION
It can be concluded F6 as the optimum formula. It has given the long
floating duration time and suitable with modified profile release
specification.
REFERENCES
American Pharmaceutical Association. 2007. USP 30-NF 25. The United States
Pharmacopeial Convention. USA.
Arora, S., Ali, J., Ahuja, A., Khar, R.K., dan Baboota, S. 2005. Floating Drug
Delivery Systems: A Review. AAPS PharmSciTech. 6(3): 372-390.
Bhowmik, D., Gopinath, H., Kumar, B.P., Duraivel, S., Sampath KP. 2012.
Controlled Release Drug Delivery Systems. The Pharma Innovation.
India.
British Pharmacopoeia. 2009. British Pharmacopoeia, Volume I & II.
Medicines and Healthcare Products Regulatory Agency (MHRA).
London.
Depkes RI. 1979. Farmakope Indonesia. Edisi III. Departemen Kesehatan RI.
Jakarta.
Depkes RI. 1995. Farmakope Indonesia. Edisi IV. Departemen Kesehatan RI.
Jakarta.
Karakilic, E., Buyukcam, F., Kocalar G., et al. 2012. Same Effect of Sublingual
and Oral captopril in hypertensive Crisis. Eur rev Med Pharmacoal Sci.
16:1642-1645
Khan, Azhar Danish, Meenakshi Bajpai. 2010. Floating drug delivery system:
An overview. International Journal of Pharmaceutical Technology
Research (2), 2497-2505.
Khan, AD, Bajpai, M. 2010. Floating Drug Delivery System: An Overview.
International Journal of PharmTech Research. 2(4): 2497-2505
Kumar, T.A., Velmurugan, S., Ravishankar, K., and Reddy, N. 2014.
Formulation and evaluation of flupirtine maleate sustain release
matrix tablets. Scholars Research Librar, Der Pharmacia Lettre. 6
(4):20-2
Sachan, N., Pushkar, S., Jha, A., Bhattcharya, A. 2009. Sodium alginate: the
wonder polymer for controlled drug delivery. Journal of Pharmacy
Research. India.

Shargel, L. dan Yu. 2005. Biofarmasetika dan Farmakokinetika Terapan. Edisi

Kedua. Airlangga University Press. Surabaya.
United States Pharmacopeia Convention. 2006. United States
Pharmacopoeia National Formulary, USP 30/NF 25. Twinbrook
Parkway: United States Pharmacopeial Convention

Mochamad Djunaedi
PHARMACIST’S ROLE IN INDIVIDUALISING AMIKACIN

DOSING IN SEVERE RENAL FAILURE
Mochamad Djunaedi1*, Ab Fatah Ab Rahman2
Community Pharmacy Faculty of Pharmacy (Universitas Airlangga) Jl. Darmawangsa
Dalam, Surabaya 60286, Indonesia
2.
Faculty of Pharmacy, Universiti Sultan Zainal Abidin, 22200 Besut, Terengganu,
Malaysia
ABSTRACT
Amikacin is an effective aminoglycoside commonly used in the
treatment of gram negative bacterial infections. Serum drug concentration
monitoring is used to guide dosing while achieving target concentrations.
The aim of this report is to describe the importance of properly performed
drug concentration monitoring in a patient on amikacin treatment. A 66-
year-old woman with chronic renal failure was treated with amikacin for
Acinetobacter infection. Initiation of amikacin loading dose of 700 mg
resulted in peak drug concentration of about 24.25 mg/L. Subsequent dosing
was administered with random drug concentration monitoring. Pharmacists
in therapeutic drug monitoring service should utilize individual
pharmacokinetic parameters and suggest appropriate dosing regimen.
Key words: Amikacin, Therapeutic Drug Monitoring, Random sampling, Renal

failure
INTRODUCTION
Amikacin is one of the most common aminoglycoside that may use in
combination with β-lactams due to effective for the treatment of systemic
infections caused by most gram negative bacteria (Avert, et al., 2011).
However, aminoglycoside has toxic properties if it is used imprecisely.
The most common clinical toxicities of aminoglycosides found such as
nephrotoxicity, ototoxicity and others. The risk factors of toxicity include:
disease state, concurrent drugs used and prolonged therapy. Many strategies
to reduce the risk of toxicity of Aminoglycosides had been performed as
reported by Prayle, et al. (2010), such as to manipulate dosage regimens
individually and adherence to the application of pharmacokinetic rules.
Large amount research had reported about the dosage regimen
manipulation of amikacin use. Amikacin can be administered by multiple
doses or simpler single-dose. However, both must be monitored for serum
levels (Abd-Elfattah, et al., 2017).

Pharmacist’s Role In Individualising Amikacin
An important reason so that a serum-level monitoring should be done

is the better strategy to ensure that amikacin administration can achieve a
therapeutic target level and avoid toxic effects. The method introduced by
Dijkstra, et.al. (2015) is called a Limited Sampling Strategy, it takes only twice
the measurement of serum levels after any dose given. Such monitoring
methods can ultimately reduce toxicity and maintain its effectiveness.
As amikacin has a narrow therapeutic index, therefore monitoring of
aminoglycoside absolutely needed. This monitoring is conducted in
Therapeutic Drug Monitoring (TDM) unit that established well in most of
hospitals and other health facilities around Malaysia in which a trained
Pharmacist is responsible to perform this task (Ab Rahman, et al., 2013).
TDM of amikacin may complementarily with monitoring of kidney and
auditory functions. An increase in the SrCl of 0.5 mg/dl within 3 days or less
indicates renal insufficiency, while an increase of the auditory threshold of
<15 dB indicates ototoxicity related aminoglycoside. Nevertheless, toxicities
are unpredictable, especially those with the existing risk factor (age) and
amikacin related administration. TDM of amikacin should pay attention that
parameters of pharmacokinetics may be altered due to pathological and
clinical condition (Sandu, et al., 2007; Oliveira, et al., 2006; Raveh, et al.,
2002)
The pharmacokinetics of amikacin is simple, so the characteristic of
serum concentration versus time can be derived from a linear one-
compartment kinetic model. However, the initial dose of amikacin prescribed
in various protocols, in practice, requires expertise for applying it (Roger, et
al., 2015).
The values of serum concentrations associated with therapeutic efficacy of
amikacin are:
Peak (µg/ml) Through (µg/ml)
Serious infection (15-25) <5
Life-threatening
(25-30) 4-8
infection
(White, et al., 2015; Blackburn, et al., 2015).
Amikacin is excreted unchanged in the urine (80-90) %. An increase in

concentration at the end of a dosing interval may indicate impairment in
renal function. Therefore, its use, especially in patients with renal failure
requires close monitoring of its concentration to avoid accumulation and
toxicity. The target trough concentration is usually 5<µg/ml (White, et al.,
2015).
In this article, we reported the use of random serum concentration
monitoring in a patient with renal failure.

Mochamad Djunaedi
CASE REPORT
A 66 year-old female (weight 70 kg) was treated at the Intensive Care
Unit of a General Hospital in Malaysia for suspected Acinetobacter infection.
Her current medical problems included diabetes mellitus, ischemic heart
disease, hypertension, dyslipidemia, and acute on chronic renal failure. Her
serum creatinine was 234 µmol/L (Creatinine clearance CrCL, was estimated
to be 22.3 mL/min).
Medications included digoxin, frusemide and ranitidine. Her antibiotics
were nystatin, metronidazole, ceftriaxone, and amikacin. Therapeutic drug
monitoring was requested for amikacin dosing. Following a 700 mg
intravenous loading dose, three more 500 mg intravenous doses were given
to this patient. Serum drug concentrations were measured randomly after
the doses were given.
The Figure below shows the concentration-time profile of amikacin.
Figure 1: Concentration versus time profile of amikacin
DISCUSSION
The elimination of amikacin would be expected to be very slow in
patients with renal impairment. While the target peak concentration may be
independent of the renal function, the target trough concentration on the
other hand, depends on the drug clearance. Therefore, the ability to predict
when it is safe to give the subsequent dose is important. In the absence of
computer software to predict the pharmacokinetic parameters of the drug,
the best approach would be to obtain two concentrations within an
appropriate interval and use those values to estimate a suitable time to give
the next dose. Pharmacokinetic parameters calculated using two
concentration data can also be used to estimate the volume of distribution,
which could be used to estimate a suitable dose for the patient to achieve
the desired peak concentration.

Pharmacist’s Role In Individualising Amikacin
A suitable time to give the next dose is when the trough concentration
of < 5 µg/L is achieved. In this patient, only one concentration was available
after the first loading dose was given. The second dose of 500 mg was
administered about 90 hours after the initial loading dose. However, it was
administered in the absence of suitable data that could be used to predict a
safe trough concentration.
Similarly, during the second and subsequent dosing intervals, only one
drug concentration value was available for each dosing interval. It is quite
difficult to predict how much dose is needed to achieve the target peak
concentration. The concentration-time profile shows that it was possible that
peak concentrations were not achieved during these dosing intervals. Renal
function in critically ill patients may change rapidly. As a result, drug
clearance which is dependent on renal function also changes rapidly.
Implementation of monitoring methods by the TDM service should give
meaningful and useful clinical information which can then be applied in the
management of drug dosing.
In this patient, monitoring of serum amikacin concentrations were
performed randomly and is unlikely to yield useful information. Although
several serum levels have been obtained from measurements from patients,
but planning in the routine procedure of amikacin administration is not
steady. In such patients, the need to quickly estimate a suitable
amikacin dosing regimen in order to achieve the desired therapeutic target is
very important.
CONCLUSION
The TDM was indicated in this patient but in the absence of suitable
pharmacokinetics computer software, the practice of random sampling
might not produce any suitable pharmacokinetic parameters, thus depriving
the patient of the benefits of TDM.
EKGNOWLEDGEMENT
I am grateful to all those who support this work as well to the Head of
Clinical Department, School of Pharmaceutical Sciences, Universiti Sains
Malaysia, Pulau Pinang Malaysia for facilities provided during the recording
of this case.
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& Salgado Filho, N. (2010). Monitoring renal function: measured and
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879x2010007500040
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7094-7096. doi: 10.1128/AAC.01032-15

Observational Study Of Analgesic And Pain Relief
OBSERVATIONAL STUDY OF ANALGESIC AND PAIN RELIEF

IN POSTOPERATIVE PATIENTS
Budi Suprapti13*, Aisyah1, Dewi Wara Shinta13, Arga Patrianagara23
1.
Faculty of Pharmacy Universitas Airlangga, Jalan Dharmawangsa Dalam, Surabaya,
Indonesia
2.
Faculty of Medicine Universitas Airlangga, Jalan Dr. Moestopo, Surabaya, Indoensia
3.
Universitas Airlangga Teaching Hospital, Jalan Mulyorejo, Surabaya, Indonesia
budiprapti@yahoo.co.id
ABSTRACT
The aim of this study was to observe the use of analgesic pattern and
pain intensity outcomes in postoperative patients. The study was conducted
on postoperative patients at Universitas Airlangga Teaching Hospital
Surabaya in the periode of April to Mei 2017. Recording the use of analgesics
and pain assessment was done during hospitalization, at early postsurgical
until the patients discharge. Results of 116 patients’ postoperative patients
showed the analgesics used were mefenamic acid, ketorolac, metamizole,
paracetamol and tramadol used as a single and analgesics combination.
Combination therapy was got by 45% of patients. Pain assesment showed
75% of patients without pain and mild pain, 24% with moderate pain, 2% got
severe pain at the early postsurgical. At discharge time 97% of patients
without pain and mild pain, 3% with moderate pain, and no patient with
severe pain. Inconclusion, nociceptic pain experienced by postoperative
patients and pain management has provided good outcomes, but there are
still 2% of patients with severe early postoperative pain requiring better
management from interprofessional health care.
Key words: Analgesic, postoperative pain, nociceptic pain, pain relief

INTRODUCTION
Postoperative pain is acute pain experienced after surgery and has a
rapid or sudden onset and in a short period of time. This is a predictable
condition caused by trauma and inflammatory processes, ie, tissue damage
that causes the body to produce pain mediators during the surgical
procedures including skin incision, tissue dissection, manipulation, and
traction. The type of postoperative pain is primarily nociceptive (Pogatzki-
zahn et al., 2017). Postoperative pain triggers a stress response, an
endocrine neuro response that affects mortality and various morbidities of
postoperative complications (Tennant, 2004).
The understanding of the mechanism of postoperative pain has
undergone considerable progress, but postoperative pain management has

Budi Suprapti
not been optimal (Apfelbaum and Chen, 2003). Globally, the prevalence of
postoperative pain ranges from 50% to 75% of total surgical patients (Philip
et al., 2007). More than 80% of patients undergoing surgical procedures
experience acute postoperative pain and about 75% of those reported
postoperative pain with severity ranging from moderate, severe or extreme
(Gan et al., 2014). Other studies have reported that 41% of patients
experience postoperative pain with moderate and severe pain levels on day
0. Even, the prevalence of moderate and severe pain was increased in the
type of abdominal surgery, extremity surgery, and back/spinal surgery
(Sommer et al., 2008).
Unresolved acute pain can provide significant psychological
consequences, starting from uncomfortable sleep to the stage of
development of Post-Traumatic Stress Disorder (PTSD) (Tennant, 2004).
Handling of inadequate pain therapy can have a negative effect on quality of
life, recovery of body function, risk of complications and postoperative
painful pain. In addition, the patient's rehabilitation process can be delayed,
resulting in longer hospitalization time (Morrison et al., 2003). Other effects
that may arise include increased risk of side-effects, such as the development
of chronic disease, suppression of immune cells, long wound healing
operations, and increased activation of adrenergic hormones and their risks
in the form of coronary heart disease or gastrointestinal cell damage,
difficulty in moving can trigger thromboembolism (Misiołek et al., 2014).
Analgesics are necessary for adequate postoperative pain control to avoid
postoperative complications and speed up the recovery process of patients
(Chaturvedi and Chaturvedi, 2007; Clark, 2002). To overcome pain
effectively, several factors need to be considered, from the cause of pain,
degree of pain, type selection and analgesic dosage to be used, route of
administration, and frequency of administration (Apfelbaum and Chen,
2003). The aim of this study is to observe the use of analgesic patterns and
pain intensity outcomes in postoperative patients.
MATERIAL AND METHODS

This study was observational prospective, conducted at Inpatient Care
Unit of Universitas Airlangga Hospital Surabaya, from April to May 2017. The
sample of this study is all patients who have undergone surgery during that
period. Inclusion Criteria include ≥ 17 year old adult patients undergoing
hospitalization, and using analgesics as pain therapy. Exclusion criteria
include inpatients due to trauma, patients with communicating disorders
such as epilepsy and seizures. The parameters observed were patient
characteristics, diagnosis & type of surgery, analgesic therapy, and pain
assessment right after surgery and before hospital discharge.

RESULT AND DISCUSSION

During the study period, 116 patients have been obtained as sample.
Patient characteristics data listed in Table 1. The number of female patients
was 62.9% and male patients was 37.1%. The age of the patients is divided
into 4 categories according to the MOH RI (2009). The patient's age ranges
from 17-70 years old. Most patients were early adult (26-35 years), as much
as 31.03%. The sample of patients in this study came from 8 surgical units,
with the big 3 groups of surgical units were general surgery 49.1%, obstetry
gynecology surgery 31.90%, and thoracic cardiovascular surgery 7.76%.
Table 1. Patient characteristic

Characteristic Number of patients (%)
Sex
Male 43 (37,1)
Female 73 (62,9)
Age (years)
17-25 17 (14,7)
26-35 36 (31,0)
36-45 20 (17,2)
46-55 21 (18,1)
56-65 15 (12,9)
>65 7 (6,0)
Surgery Unit
General surgery 57 (49,1)
Obstetry gynecology surgery 38 (32,8)
Thoracic Cardiovascular surgery 9 (7,8)
Orthopaedic surgery 5 (4,3)
Oral surgery 3 (2,6)
Neurosurgery 2 (1,7)
Urosurgery 1 (0,9)
Plastic surgery 1 (0,9)
Postoperative pain is an acute pain caused by surgery or tissue injury.

The intensity of this acute pain may be affected by the type of surgery /
surgical technique and / or patient conditions before surgery such as chronic
pain, depression, and anxiety that may affect the pain threshold (Pogatzki-
zahn et al., 2017). Appropriate analgesic selection becomes the main
foundation in the management of postoperative pain therapy in order to
improve the quality of life of the patient. The American Society of
Anesthesiologists recommend therapies for treating postoperative pain such
as NSAIDs, COXIB, and / or acetaminophen for mild to moderate

Budi Suprapti
postoperative pain, and parenteral ketorolac can be used for moderate to

severe pain. For moderate to severe postoperative pain should be preceded
by opiod analgesic therapy with or without NSAIDs (American Society of
Anesthesiologists Task Force on Acute Pain Management, 2012).
The analgesic type used for pain management in this study can be
seen in Table 2. From Table 2 it can be seen that single and combination
analgesics are used in postoperative patients. Acute pain caused by an
incision, will lead to the release of inflammatory mediators (prostaglandins,
cytokines, bradykinins) peripherally. This process is followed by a
transductions to the dorsal horn and to the brain, pain perception occurs and
then there is the process of modulating pain in the brain pathway to the
spinal cord that affects the intensity and duration of pain (Gupta, 2011).
Therefore, a multimodal analgesic therapy approach is required by
administering two or more types of analgesics through different mechanisms
of action. It is intended to overcome pain as an effective post-operative pain
management strategy without increasing the risk of side effects compared
with increasing the dosage of a single analgesic. For example, intravenous
opioid administration may be combined with NSAIDs (Chou et al., 2016).
In this study, the five most common types of analgesics used were
ketorolac 65.5%, mefenamic acid 46.5%, tramadol 31.9%, metamizole
31.03% and paracetamol 18.9%, (Figure 1). Ketorolac is a potent NSAIDs that
works by inhibiting the Cyclooxygenese (COX) enzyme that metabolizes
arachidonic acid into endoperoxide and prostaglandins that mediate pain
(Gopalraju et al., 2014). Adult dose of intravenous ketorolac is 15-30 mg
every 6 hours with a maximum dose of 120 mg/day. The dose of ketorolac
used in this study is accordance with the guideline (McEvoy, 2011).
Ketorolac can cause ulcer in gastrointestinal tract and bleeding.
Ketorolac has the highest GIT bleeding potential compared to other NSAIDs.
A study by Strom et al. (1996) suggests that the risk of gastrointestinal
bleeding increases in the administration of high dose ketorolac, elderly
patients, and more than 5 days (Strom et al., 1996). In addition, ketorolac
dose 3x10mg did not provide different analgesic effectiveness with a dose of
15 mg and 30 mg in overcoming moderate to severe pain without any
increased risk of side effects (Motov et al., 2017). Another study carried out
by Duttchen (2017) states that ketorolac 30 mg is no more superior than
ketorolac 15 mg iv in spinal surgery patients (Duttchen et al., 2017).
Therefore, the use of ketorolac should be limited to minimum dose and
duration, and at maximum of 5 days for oral and parenteral routes. In this
study the majority of ketorolac used in 1-2 days, no more than 5 days (Table
3).

Table 2. Analgesics type and administration as single and combination

therapy
Number of
Analgesik Type
patients (%)
Single analgesic
Mefenamic acid NSAIDs 48 (41,38)
Ketorolac NSAIDs 51 (43,97)
Metamizole NSAIDs 28 (24,14)
Paracetamol Non opioid 8 (6,90)
Tramadol Opioid 7 (6,03)
2 analgesics combination
Ketorolac + tramadol NSAIDs + opioid 25 (21,55)
Metamizole + tramadol NSAIDs + opioid 5 (4,31)
Ketorolac + paracetamol NSAIDs + non opioid 1 (0,86)
Ketorolac + mefenamic acid NSAIDs + NSAIDs 2 (1,72)
Ketorolac + metamizole NSAIDs + NSAIDs 4 (3,45)
Metamizole + paracetamol NSAIDs + non opioid 4 (3,45)
Tramadol + paracetamol Opioid + non opioid 4 (3,45)
Metamizole + mefenamic acid NSAIDs + NSAIDs 3 (2,59)
> 2 analgesics combination
Paracetamol + mefenamic acid + Non opioid + NSAIDs +
1 (0,86)
metamizole NSAIDs
Ketorolac + mefenamic acid + NSAIDs + NSAIDs + non
1 (0,86)
paracetamol opioid
Paracetamol + ketorolac + Non opioid + NSAIDs +
1 (0,86)
tramadol opioid
Metamizole + ketorolac + tramadol NSAIDs + NSAIDs +
1 (0,86)
+ mefenamic acid opioid + NSAIDs
Figure 1. The five most common types of analgesics used by postoperative

patients at the Inpatient Care Unit of Universitas Airlangga Hospital from
April to May 2017 (1 patient can obtain more than 1 analgesic during
hospitalization).

Budi Suprapti
Another common use of analgesics was oral mefenamic acid (46.55%)

with duration of administration 1 to 3 days, and metamizolee intravenously
(31.03%) with duration of administration 1 to 5 days (Table 3). The selection
of NSAIDs types is adjusted to the individual patient condition, including the
risk of side effects, contraindications, and available dosage forms (Misiołek et
al., 2014). Mefenamic acid has the same mechanism as ketorolac, while
metamizole provides a lower analgesic effect than other NSAIDs. At
Universitas Airlangga Hospital, metamizole is often used as single or
combination analgesic therapy in postoperative patients for moderate to
severe pain management. The most widely dose regimen of metamizole is
3x1 g iv. Metamizole has a special characteristic of low gastrointestinal side
effects and low toxicity in the kidney compared to other analgesics, but there
is also other potential risk of agranulocytosis (Nikolova et al., 2013, 2013).
Another nonopioid analgesics used in postoperative patients is oral
and intravenous paracetamol. Paracetamol is used for duration 1-5 day in
the following dose: 3-4 x 500-1000 mg orally, combination 500 mg
paracetamol and 200 mg n-acetylcysteine 3x1 oral tablet. Paracetamol is
recommended as a first choice analgesic for mild to moderate pain because
its lower postoperative GIT bleeding risks compared with NSAIDs (Chou et
al., 2016). Unlike NSAIDs that inhibit COX enzymes, Paracetamol works by
inhibiting the synthesis of prostaglandins in the central nervous system, and
inhibiting the activation of nociceptors in the periphery. In addition,
paracetamol also acts in inhibiting the raising the sensitivity of pain in the
spinal cord (Khalili et al., 2013). Dose recommendation of paracetamol is
325-1000 mg every 4-6 hours with a maximum dose of 3-4 g/day (McEvoy,
2011).
Intravenous paracetamol is used as an additional (extra) therapy for
patient who still feels pain. The given dose is 3x1 g. It is is an appropriate
therapy for mild and moderate postoperative pain, and may be used alone or
in combination with other analgesic drugs (Memis et al., 2010). It is also can
reduce the use of opioids, thereby decreasing the side effects of opioids such
as nausea and vomiting. Previous studies have suggested that when
paracetamol is given as prophylaxis, it can decrease the incidence of
Postoperative Nausea and Vomiting (PONV) (Apfel et al., 2013). The
advantage of intravenous paracetamol is the time for achieving the
maximum concentration (15 min after intravenous) much shorter than oral
or rectal route (> 45 min). Other benefits include improving pain relief,
improving patient satisfaction, accelerating rehabilitation and mobilization
and lowering health care costs (Pasero and Stannard, 2012).
Opioid analgesics used in postoperative patients were tramadol with
the most doses used were 3x100mg iv in NS 100cc (27.59%). Other doses are

2-3 x 30-50mg iv, and oral combination of tramadol 37.5 mg and

paracetamol tablets 325mg. The duration of tramadol administration in the
patients was an average of 1-4 days, but there was 1 patient who received
tramadol for 10 days ie patients with thrombectomy surgery (Table 3). There
is no specific maximum duration of tramadol administration. However, the
use of tramadol for 1-2 weeks needs dose reduction up to 20-25% every 1-2
days to reduce the risk of side effects and prevent withdrawal (Chou et al.,
2016). Tramadol is a weak opioid analgesic that effective for moderate pain
treatment. However, the use of opioids in postoperative patients may induce
nausea and vomiting, particularly in abdominal surgery (Spacek et al., 2003).
Slow intravenous injection will reduce the incidence of nausea and vomiting.
Therefore, tramadol is given as intermittent injection to reduce the incidence
of nausea and vomiting (Sim et al., 2007).
Table 3. Duration of analgesic therapy
Number of patients
Analgesic Regimentation
1 day 2 days 3 days 4 days 5 days 10 days
3x10mg iv 1
Ketorolac
3x30mg iv 60 12 2 1 1
3x30mg iv 1
3x50mg iv 1
3x100mg
Tramadol 26 6 1 1
intermittent iv
2x50mg iv 1
2x1tab oral 1
1x1g iv 7
2x1g iv 4
Metamizole
3x1g iv 9 10 1 1 1
3x1 tab oral 1
3x500mg oral 3 2 1
4x500mg oral 3 1 2
4x1000mg oral 1
Paracetamol 4x750mg
1
intermittent iv
3x1000mg
3 2
intermittent iv
Mefenamic 3x500mg PO 32 12 1
Fentanyl
1x12,5mg 1
patch

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Table 4. Initial & before hospital discharge postoperative pain intensity at

surgery units
Percentage (%) is counted based on 116 patient total; Pain intensity is

measured by Visual Analog Scale (VAS); No symptom: did not show pain
symptoms and/or VAS 0; Mild pain: VAS 1-3; moderate pain: VAS 4-6; Severe
pain: VAS 7-10
Analgesics were administered via intravenous, oral, and transdermal

routes (Table 3). Intravenous route is used at the beginning of postoperative,
it is expected that this route will provide rapid analgesic work (Shargel et al.,
2012). Oral route analgesics are used when the patient's pain has decreased
and the patient can perform swallowing activity. In this study, there was 1
patient receiving patch analgesic. This method of administration is less
precise. Patch analgesics are aimed in patients with chronic pain, whereas
postoperative pain is an acute pain (Chou et al., 2016; Wu and Raja, 2011).
Figure 2. Initial and before discharge Postopera Pain intensity in surgery units

Analgesic replacement occurs during hospitalization. two of the most

replacement are combination ketorolac 3x30mg IV and tramadol 3x100mg IV
to oral mefenamic acid 3x500mg, and replacement of single analgesic
ketorolac 3x30mg IV to oral mefenamic acid 3x500 mg.
Postoperative patients in each surgical unit have different pain
intensities according to the type of surgery. Observation of the intensity of
pain on a routine basis and the level of patient satisfaction that has
undergone surgery and during hospitalization are two essential points in
effective postoperative pain control management (Jawaid et al., 2009). In
acute pain management, pain intensity measurements should be performed
after 15-30 minutes in patients receiving parenteral route analgesic therapy,
and after 1-2 hours in patients with oral analgesics (Chou et al., 2016).
Examination of five vital signs at Universitas Airlangga Hospital which
includes body temperature, blood pressure, pulse rate, respiratory rate, and
pain score and patient complaints are routinely performed three times a day
(morning, noon, and night). This is supported by the literature that explains
that the assessment of pain, subjective patient complaints, patient response
to therapy and side effects that appear should be done every 4-8 hours
during the hospitalization. The evaluation was done by checking vital signs
and pain intensity before and after the administration of analgesic therapy
(Chou et al., 2016).
Common pain scales used to measure pain intensity are Visual Analog
Scale (VAS) and Numeric Rating Scale (NRS). VAS has several advantages over
other instruments, which are more commonly used in clinical practice,
simple to use and provide valid results, and also can be used to measure
other variables such as therapeutic side effects or decline pain (Hawker et
al., 2011; Jensen et al., 2003). According to WHO 3-Step ladder, pain
intensity is divided into three, ie mild pain (1-3 pain score), moderate pain
(pain score 4-6) and severe pain intensity (pain score 7-10).
Research data related to the intensity of postoperative early patient
pain showed variation of pain intensity in different surgical units, due to
different types of surgery as well as individual factors on the perception of
pain itself (Table 4; Figure 2). A total of 21.6% had no pain symptom and
78.42% of patients felt postoperative pain consisting of various intensities as
follow: mild pain (53.4%), moderate pain (23.7%), and severe pain (1.7%).
This data is supported by a previous study that stated that acute pain occurs
in more than 80% of patients who have undergone surgery (Gan et al., 2014).
Assessment of pain intensity before hospital discharge showed an
increase in treatment outcomes where 97.4% were in mild pain, 2.6% of
patients with moderate pain, and no patients with severe pain (Figure 2).

Budi Suprapti
CONCLUSION
In conclusion, postoperative pain management in Universitas Airlangga
Hospital has provided good outcomes, but there are still 2% of patients with
severe early postoperative pain requiring better management from
interprofessional health care.
ACKNOWLEDGEMENT
We are grateful to Universitas Airlangga Teaching Hospital for
permission doing this research.
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Pogatzki-zahn, E.M., Segelcke, D., Schug, S. a, 2017. Postoperative pain —
from mechanisms to treatment. PAIN Reports 2, e588.
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Pharmacokinetics, Sixth Edition, 6th ed. McGraw-Hill Education /
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sparing analgesia in major colorectal surgery. Color. Dis. 9, 52–60.
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of postoperative pain in a sample of 1490 surgical inpatients. Eur. J.
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and dipyrone (metamizol) versus tramadol alone. Acute Pain 5, 3–9.
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Kimmel, S., Carson, J.L., 1996. Parenteral Ketorolac and Risk of
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377, 2215–2225.

Red Betel Leaves (Piper crocatum RUIZ & PAV) Extract
RED BETEL LEAVES (Piper crocatum RUIZ & PAV) EXTRACT

GRANULE FORMULA AND IN VIVO ANTIINFLAMMATORY
ACTIVITY STUDIES
Laksmitawati DR 1*, Kusumaningsih DA 1, Fahleni1, Arifin MF1
1
Faculty of Pharmacy University of Pancasila Jalan Srengseng Sawah Jagakarsa,
Jakarta Selatan 12460
*Corresponding author
Author Correspondent Email : dian.ratih@univpancasila.ac.id
ABSTRACT
Red betel leaves (Piper crocatum Ruiz & Pav) contains flavonoid,
saponin, and tannin which have antiinflammatory activity against paw
edema with albumin as inducer. This research aims to determine the
optimum granule formula from red betel leaves dry extract which physically
and chemically stable and also effective as an antiinflammatory agent. This
study used 22 factorial design with 2 factors, red betel leaves extract and PVP
concentration as a binder. The evaluation result of physical appearance and
chemical properties were analyzed using Minitab 16 program then made
contour plots and contour plot superimposed. The optimum formula was
obtained from the contour plot superimposed on the levels of extract dose
2.55 gram and 1% PVP concentration. Furthermore, the optimum formula
was tested for antiinflammatory activity and showed edema inhibition
percentage of 44,65% against the negative group and no significance
difference with positive group, Na diclofenac 9mg/kgBB.
Keywords: Red betel leaves, antiinflammation, granule
INTRODUCTION
Inflammation is the local physiological response against tissue injury.
Arthritis gout is one example of disease that is accompanied by
inflammation. Arthritis gout is an inflammatory process caused by acid
crystalline desposition around the joints. Medication conducted for gout’s
patients were decreasing the production of uric acid serum with the xanthine
oxidase enzyme inhibitors as well as supressing the inflammatory response
with the antiinflammatory drugs. There are two classes of antiinflammatory
drugs i.e corticosteroids and Non Steroidal Antiinflammatory drugs
(NSAID’s). The use of these drugs are known cause adverse drug reaction,
such as gastric disorders. Therefore, treatment with herbal medicine could
be an alternative with fewer side effects1.

Laksmitawati DR
One of the herbal material that are commonly used as traditionally

drug is red betel leaves. Red betel leaves (Piper crocatum Ruiz & Pav)
contains secondary metabolites such as flavonoid, saponin, tannin, alkaloids,
and essential oils 2. Traditionally, people use decoction of the red betel
leaves for healthy treatment but that is not practical and also the bitter taste
and smell are not preferred. In addition, it must use a large dose of extract so
if it formulated into capsules or tablets it will make the difficulties for
consumer to take orally. In this study, red betel leaves dried extract will be
formulated into a sachet granule ready to drink, so it will make the consumer
easy to take this medicine.
The previous research showed that red betel leaves extract 200
mg/kg/BW has an antihyperurisemia effect on mice induced with potassium
oxonate crystal and inhibited edema (anti-inflammatory) on the paw of
albino rats induced by monosodium urate 3. In this research, we would like to
know whether the formula of red betel extract granules has an anti
infammatory effect. The aim of this research was to formulate a red betel
leaves dried extract into an instant granule in the tea bag pouch packaged
with sachet which have an antiinflammatory effects against paw edema on
rat with albumin as inducer.

Red betel leaves (Piper crocatum Ruiz & Pav) obtained from Balitro
Pascapanen Bogor and determinated in Herbarium Bogoriense, Indonesian
Institutes of Science (LIPI) Cibinong, West Java, ethanol 96%, maltodextrine,
lactose (Leprino Foods), PVP (PT Delta Chemical), aspartame (PT Sinosweet),
erytrosine, sodium benzoate, aerosil, aquadest, sodium diclofenac (PT Kimia
Farma), carboxy methylcellulose sodium (Na CMC), tea bag, standing pouch,
normal saline (NaCl 0,9%) (PT Otsuka), albumin, Sprague Dawley males rat.
Preparation of red betel leaves extract

A number of 2 kilograms red betel leaves simplisia powder maserated
with 96% ethanol as a solvent. Stirring done using kinetic maserator for 6
hours. Maserat obtained was then filtered using filter paper and then
evaporated with rotary evaporator until viscous. Extract was weighed and
stored in an airtight container.
Spray Drying Extract

A number of 100 mL red betel leaves extract diluted in aquadest and
maltodextrine, dried with spray dried methods using inlet temperature 170°C
and outlet temperature 90°C.

Phytochemical Screening Extract

Phytochemical screning was done for simplisia powder, viscous
extract, and dried extract using Phytochemical screening Farnsworth
methods. The aim was to identify the chemical compounds of extract and
also to ensure that the simplisia powder, viscous extract and dried extract
contains flavonoid, saponin and tanin which have antiinflammatory effect.
Red Betel Leaves Dried Extract Granule Formulation

This research used 4 formulas with factorial design 22. It was used 2
variations of extract dose, 2,28 grams and 2,85 grams and also 2 variations of
PVP concentration 0,5% and 2%. The composition of formula can be seen in
Table 1. Granules were made using wet granulation methods and tested
physical properties of granules such as appearance, moisture content, flow
properties, particle size distribution, dissolve time, and pH. The evaluation
result were analyzed using software Minitab 16 to get the optimum formula
and then tested for antiinflammatory activity. Granules were then packaged
with tea bag pouch.
Table 1. Red Betel Leaves Dried Extract Granule Formula
Formula (%)
No Materials
F1 F2 F3 F4
1 Red betel dried extract granule 2,28 g 2,85 g 2,28 g 2,85 g
2 PVP 0,5 0,5 2 2
3 Erythrosine 0,05 0,05 0,05 0,05
4 Aspartame 2 2 2 2
5 Na benzoate 0,1 0,1 0,1 0,1
6 Aerosil 0,5 0,5 0,5 0,5
7 Lactose ad 100 ad 100 ad 100 ad 100
Evaluation of Physical and Chemical Properties of Granules

1. Organoleptics
Organoleptics evaluation was determined by visual observation
included color, taste and smell.
2. Moisture Content
5 grams of wet granule were placed into petri disc and dried in the
oven temperature 40-60°C for 15 minutes. Granule was dried until constant
weight.

Laksmitawati DR
3. Flow Properties
a. Flow rate
The flow rate was determined by allowing 25 grams granules flow
through a funnel and fall freely onto a graph paper. The time of granule to
flow was measured using stopwatch.
b. Angle of Repose
The angle of repose was determined by allowing granules to flow
through a funnel and fall freely onto a graph paper on a horizontal surface.
The height and diameter of the resulting cone were measured and the angle
of repose is calculated from this equation:
Tan α =
α : angle of repose
h : granule height
r : radius of granule cone
4. Particle Size Distribution

The size and size distribution of the granules produced was
determined by agitation 100 grams granule for 10 min with a sieve shaker
fitted with a progression of standard sieves. From the weight retained on
each sieve, a particle size distribution graph was plotted from which the
median diameter was determined.
5. Dissolve Time
In vitro dissolve time was measured by pouring a tea bag granule in a
beaker containing 200 mL of water (temperature 40°±2,5°C) and stirred for
20 times. Dissolve time was measured using stopwatch.
6. pH
pH were tested using pH meter.
The Optimum Formula analysis

Granule evaluation result included moisture content, time flow, angle
of repose, dissolve time and pH were analyzed using Minitab 16 to
determine the interaction between factor and response. Each responses
were made contour plot and overlay plot (contour plot super imposed) to get
the optimum formula. The optimum formula was tested for in vivo
antiinflammatory activity.

In Vivo Antiinflammatory Study

Antiinflammatory activity was studied by albumin-induced paw
edema. Male mice (2,5-3 months) weighing between 130-150 grams used in
this studies. Before the studies, animals were adapted for a week and feed
with the standard feed BR 512 and water ad libitum. Before studies, the right
paw were measured using plethysmometer and noted as a baseline. Mice
were divided into 5 groups, each containing 5 animals. Group 1 was a control
group consist untreated normal and healthy rat, group 2-5 was rat with
albumin-induced hind paw edema treated with placebo granul, sodium
diclofenac (9mg/kgBB), optimum red betel granule formula (315mg/kgBB).
Thirty minutes after first measurement, the right hind paw was injected by
0,2 mL of 1% albumin intradermal subplantar. The volume of right paw was
measured using pletysmomether at the 1st, 2nd, 3rd, 4th, 5th, 24th and 25th
hours after induction. The data were analyzed by making the curve of time vs
edema volume and calculate the Area Under Curve using the trapezium
formula with the following equation :
[ ) ( )
Edema inhibition percentage = ( ( )
x
100%
Extraction of Red Betel Leaves

The plant used in this research was Piper Crocatum Ruiz & Pav leaves
from Piperaceae family. The extract was viscous with green and brownish
color, had a bitter taste and aromatic smell. The extraction yield was 12,63%
and pH 4,55, classified as acids because of the acidic properties of antocyanin
flavonoid. The extract could mix with distilled water with comparison (1:10)
and ethanol 96% (1:3).
Spray Dried Extract

Spray drying extract resulted a hygroscopic and voluminous dried
powder with green color and bitter taste. The moisture content of extract
was 4,98%, succesfully fulfill the requirements 4. The flow properties of dried
extract had not fulfill the requirement so it must be fixed with granulation.
Evaluation result can be seen on Table 2.

Laksmitawati DR
Table 2. Evaluation of Spray Dried Extract
Parameters Average Result

Mositure Content (%) 4,98 ± 0,03 Fulfill the requirement1
Flow Time (g/detik) 2,27 ± 0,18 Cohesive
Angle of Repose (°) 34,96 ± 1,02 Cohesive
Phytochemical Screening Result

The result of phytochemical screening showed that simplisia powder, viscous
extract and dried extract of red betel leaves positively contains flavonoid,
saponin, and tanin. Farnsworth methods.
Granule Formulation
Granule formulation were done using wet granulation methods. The
selection of this method is based on the properties of dried extract, which
had small density and voluminous properties, so the granulation were done
to increase the density. Granulation were also done to fix the the flow
properties of extract and reduce the dust formation. In a granulation, binder
played an important role as a material which had cohesive properties so that
capable to aglomerate dry powder particles forming a strong granule bond
after drying process 5.
Granule Evaluation Result
Table 3. Physical Appearance, Moisture Content, Flow Properties, Dissolve

Time and pH Granules
Parameters Formula I Formula II Formula III Formula IV

Color Red Red Red Red
Physical Smell aromatic aromatic aromatic Aromatic
Appearance Slightly Slighlty
Taste Bitter Bitter
bitter Bitter
Moisture Content (%) 2,42±0,12 3,15±0,06 2,75±0,08 3,96±0,13
Flow Time (g/s) 4,08±0,29 4,84±0,14 5,41±0,57 5,17±0,60
Flow
Angle of Repose
Properties 25,50±0,61 20,19±3,26 12,02±0,53 19,95±1,28
α (°)
Dissolve Time (minute) 3 min 50 s 2 min 09 s 7 min 08 s 9 min 17 s
pH 5,49±0,0416 4,94±0,0058 5,13±0,0153 4,78±0,02

Fig. 1 Particle Size Distribution Curve
Table 4. Average Diameter Particle Size of Granule
Formula Average Diameter Particle Size (µm)

I 425,34
II 369,01
III 371,94
IV 378,27
The evaluation toward physical and chemical properties granule aimed

to ensure the quality of resulted granules. The result of physical appearance
evaluation showed that all of the formula produced red color granule with an
aromatic smell. The taste of granule from formula II dan IV were more bitter
than formula I and III due to use of larger doses. The larger dose used in the
formula made the greater tanin compounds so it will enhance the bitter
taste. Evaluation of moisture content resulted that all of granule formula
succesfully fulfilled the requirements, which the requirement were 2-4% 6.
Moisture content granule formula II and IV were larger than formula I and III
due to use of larger doses. As mentioned above, the dried extract had a
hygroscopic characteristic so it had a tendency to absorb moist from the air.
The flow properties evaluation granule showed that the four formula
had a good flow characteristic so it can flow freely. The flow rate of granules
fulfilled the requirements ≤10g/sec and angle of repose were ≤ 25,50°. With
the ability of granules to flow, it will ease granule to flow in packing machine
so the accuracy of dose were more ensured. The dissolve time of granule
formula I and III fulfilled the requirements ≤5 minutes but formula II dan IV
had not fulfill the requrements. The difference between dissolve time due to
the use of PVP concentration in each formula. Formula II and IV used the

Laksmitawati DR
bigger concentration of PVP, which the concentration were 2%. The bigger
concentration of PVP will make the stronger bond between granule particles
so it needed the longer time for granule to dissolve.
Granule dissolve time were important to test because instant granule
expected to be perfectly dissolve in a short time, so it can be used
immediately and provide optimal effects. Further results from the evaluation
of pH granule showed that the four formula had an acidic pH. It was
complied to the literature that red betel leaves had an acidic pH because of
the flavonoid antocyanin in the extract which also an acidic.
Based on the result of particle size distribution evaluation on table IV,
it was showed that the range of average diameter particle size granule
formula I-IV between 369,01 µm – 425,34 µm. According to the literature,
granule with particle size ≥250 µm had free flowing properties 7 . It can
concluded that all of the formula had a good flow properties so it will freely
flow in the packing machine and ensure the accuracy of doses. A fine granule
also has a narrow particle size distribution and the amount of fines was not
more than 10%. The evaluation result showed that all of the formula has a
narrow particle size distribution and followed the normal curve as can be
seen in Fig. 1. Thus it can be concluded that the particle size distribution of
granules were distributed properly.
The Determination of Optimum Granule Formula

Optimum granule formula were determined by analyzing physical
properties data evaluation such as moisture content, flow rate, angle of
repose, dissolve time and pH using Minitab 16. The data were analyzed to
know the interaction between factors and effect. Picture of contour plot can
be seen in Figure 2-6.
Fig 2. Contour plot moisture content Fig 3. Contour plot flow rate vs PVP
vs PVP and extract concentration and extract concentration

Fig 4. Contour plot angle of repose vs Fig 5. Contour plot dissolve time vs
PVP and extract concentration PVP and extract concentration
Fig 6. Contour plot pH vs PVP and Fig 7. Contour plot super imposed
extract concentration
From the contour plots, it showed that the increasing of extract dose
will also increase the moisture content and granul dissolve time. It was
affected by the hygroscopic properties of dried extract. The increased of
extract dose will also lowering pH because of the flavonoid compounds
which classified as an acid. Beside the dose, increasing PVP concentration
will also increase moisture content, flow rate, and angle of repose. PVP will
form a strong bond between granule particles so it can enhance the cohesive
between particle and made a spheric granule. The spheric granule will
reduce particle friction so it will made a good flow rate. From each contour
plot then made the overlay contour plot or contour plot superimposed to get
the optimum formula. The white area in figure 1 determined the optimum
composition of formula. We choose red betel leaves dry extract at
concentration 2,55 grams and 1% of PVP as the optimum formula to be
tested its anti-inflammatory activity. Contour plot super imposed can be
seen in Figure 7.
In Vivo Antiinflammatory Studies

Inflammation is the local physiological response against tissue injury
caused by several cases for example physical stimulation, chemical agent

Laksmitawati DR
(antigen) and microbial infection. Inflammation on arthritis gout caused by

desposition of urid acid crystall around the joints. Red betel leaves extract
were used in this research for In vivo antiinflammatory studies using albumin
as an inducer. The result can be seen in table 5.
Table 5. Volume of paw edema (mL)
The average volume of paw edema (mL)

Group
0 hr 1 hr 2 hr 3 hr 4 hr 5 hr 24 hr 25 hr
I 1,48 1,48 1,48 1,48 1,48 1,48 1,48 1,48
(Normal control) ±0,21 ±0,21 ±0,21 ±0,21 ±0,21 ±0,21 ±0,21 ±0,21
II
1,65 2,60 2,47 2,62 2,59 2,54 2,27 2,15
(untreated /negative
±0,15 ±0,15 ±0,18 ±0,14 ±0,15 ±0,16 ±0,23 ±0,13
control)
III 1,39 2,01 1,97 2,13 2,13 2,08 1,86 1,70
(placebo) ±0,28 ±0,17 ±0,16 ±0,17 ±0,17 ±0,18 ±0,20 ±0,21
IV
(positive control) 1,37 2,17 2,09 2,03 1,90 1,79 1,47 1,38
Na diklofenac ±0,07 ±0,15 ±0,12 ±0,11 ±0,11 ±0,12 ±0,04 ±0,06
9mg/kgBB
V
(Optimum red betel 1,76 2,84 2,47 2,55 2,32 2,25 1,97 1,86
granule formula ±0,24 ±0,46 ±0,26 ±0,19 ±0,15 ±0,16 ±0,27 ±0,2
315mg/kgBB)
Fig. 8 Average edema volume (%)
The effect of albumin as an edema inducer can be seen at negative

control group. From Figure 8, we can seen that at the 1st hour after
induction, the volume of paw rats increased and decreased at the 2nd hour
and increased at the 3rd hour. The inflammation of paw rats caused by

albumin as an antigen. Arachidonic acid contained in albumin will released

chemical compounds such as hystamine, bradikinin, and prostaglandin. The
release of those compounds, in this case prostaglandin, will supress the
immune system and stimulate the growth of tumor cells so it can be used an
inflammation inducer 8. Each of placebo group, positive control group, and
treatment group has sucesfully decreased edema while occured at the 4th
hour until 25th hour, but the fastest edema decreased occured on positive
control group and treatment group.
The assesment of antiinflammatory agent effectivity can also be
concluded from the calculation of Area Under Curve (AUC) using edema
percentage. The greater value of AUC made the lower effectivity of an
antiinflammatory. The result of AUC calculation from each normal group,
negative control group, placebo group, positive control group and treatment
group were 0, 1164,06±336,24, 1087,56±371,08, 581,72±162,19,
644,251±168,64 %. hour.
Based on the statistical analysis showed that the use of sodium
diclofenac and optimum granule formula dose of 315mg/kgBB significantly
decreased volume paw edema which is characterized by a pvalue <0,05
compared with negative control group. The placebo group also proved to be
able decrease volume paw edema as compared with the negative control
group but the value were not significant. After that, the value of AUC then
used to calculate edema inhibition percentage with the following formula :
[ ) ( )
Edema inhibition percentage = ( ( )
x 100%
The result showed that edema inhibition percentage of placebo group

was 6,57%, positive control (sodium diclofenac 9mg/kgBB) was 50,02%, and
treatment group (optimum granule formula dose of 315 mg/kgBB) was
44,65%. The use of optimum granule formula significantly able inhibit paw
edema. It was caused by the chemical compounds contained in red betel
leaves extract such as flavonoids, saponin, and tanin. The mechanism of
flavonoids as an antiinflammation agent was by inhibit arachidonic acid
metabolism and secretion of lisosom enzyme from neutrofil cell and
endothelial cell 9. Flavonoid also inhibit neutrofil degradation so that directly
reduce the release of arachidonic acid from neutrofil and inhibit histamin
release from mast cells9. Saponin compounds worked as an antiinflammatory
by inhibite the release of inflammation mediators such as hystamine,
serotonin, or other mediators released during first phase of inflammation.
Further, tanin compounds also had an antiinflammatory activity but the
mechanism were not yet known clearly.

Laksmitawati DR
CONCLUSION
The optimum granule formula of red betel leaves dried extract were
obtained at the level of extract dose 2,55 grams and PVP concentration 1%.
These formula had an in vivo antiinflammatory activity against albumin-
induced rat paw edema with inhibition percentage of 44,65% at dose 315
mg/kg BW compared with control group and no significant difference with
the positive control sodium diclofenac (dose of 9mg/kgBW) which had
edema inhibition percentage of 50,02%.
REFERENCES
1.Pradhan, D., Suri, K. a, Pradhan, D. K. & Biswasroy, P. Golden Heart of the
Nature : Piper betel L .J. Pharmacogn. Phytochem. 2013,1, 147–167
2.Hainer BL, Matheson E, Wilkes T. Diagnosis, Treatment, and Prevention of
Gout. American Family Physician. 2014; Volume 90, No 12. p 831-836
3.Steven, Laksmitawati DR., Helisa N. Antigout Prospects of Ethanolic Extract
from Red Betel Leaf (Piper crocatum Ruiz & Pav) Through Anti-
hyperuricemic and Anti-Inflammatory Evaluations on Sprague Dawley
Rats. Proceeding Book The 2nd International Conference on
Pharmaceutical Nanotechnology/Nanomedicine 2015. Faculty of
Pharmacy University of Pancasila. 2015.p 91-98
4.Food and Drug Supervisory Agency of the Republic of Indonesia. Regulation
of the Head of the Food and Drug Supervisory Agency of the Republic
of Indonesia No. 12 concerning the quality requirements of Traditional
Medicine. Jakarta: Directorate General of Drug and Food Control;
2014. h. 12
5.Lachman L, Lieberman HA, Kanig JL. Teori dan Praktek Farmasi industri Ed
III Vol. 1. diterjemahkan oleh Siti Suyatmi. Jakarta: UI Press; 2007.
h.227-257
6.Voigt. Buku pelajaran teknologi farmasi. Diterjemahkan oleh Soendani N.
S., Yogyakarta: UGM Press; 1995, h. 171-73; 201-03
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Churchill Livingstone; 2007,
8. Senewe M, Yamlean P, Wiyono W. Uji efek antiinflamasi ekstrak etanol
daging buah labu kuning (Cucurbita moschata D.) terhap edema pada
telapak kaki tikus putih jantan galur wistar (Rattus novergicus).
Pharmacon Jurnal Ilmiah Farmasi. 2013; 2(01): h.75-80
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cancer and cardiovascular disease. Inﬂamm. Res. 2009; 58: p.537–55

Antidiabetic Activity And Phytochemical Analysis
ANTIDIABETIC ACTIVITY AND PHYTOCHEMICAL ANALYSIS

OF ETHYL ACETATE FRACTION OF DADANGKAK ROOTS
(HYDROLEA SPINOSA L) FROM SOUTH KALIMANTAN
Muhammad Zaini1*, Vivi Shofia2, Amalia Ajrina2
1.
Department of Pharmacy Jl. P. Hidayatulaah No. 10 RT. 14 Komplek Upik Futsal
Banjarmasin, 70239
2.
Department of Health Analyst Jl. P. Hidayatulaah No. 10 RT. 14 Komplek Upik
Futsal Banjarmasin, 70239
Zaini.apt@gmail.com
ABSTRACT
The root of Dadangkak (Hydrolea spinosa L) is a herbal plant that
commonly used by South Kalimantan people for antidiabetic. The main
purpose of this research are : to examine the activity of ethyl acetate fraction
from EtOH fraction of the roots of dadangkak and to identify the chemical
contents of the roots by using Thin Layer Chromatography (TLC). The extract
of ethanol from 10 grams of the roots is yielded from materation then
fractionation by ethyl acetate. Wistar male rats is divided into three groups
(five rats each groups ). The first group is given glibenclamide 0.45 mg/kgBW;
the second group is given aquades 2 ml/200 gBW; and the last group is given
100 mg/kgBW ethyl acetate fraction perorally. Each group deliberately made
suffered from diabetes by giving induction of 150 mg/kgBW Aloxan
intraperitoneally. The measurement of blood glucose was held at the 1st, 4th,
and 12th by using Gluco-DR. the assay treatment had been done for 7 days
(from the 5th until 11th day). The result then being analysed with SPSS by
confidence level 95%. The ethyl acetate fraction of the plants was being
identified by using reagent solutions and TLC. The result showed the decline
of blood glucose level after the suspention was given significantly (sig<0.05)
compared to the control group with blood glucose level 162 ± 8,631 mg/dL
(at the 12th day). The chemical content of the ethyl acetate fraction showed
positive result to the saponin triterpenoid with Lieberman Burchard (LB)
reagent by showing the brown ring. Then, TLC assay was done by using n-hex
: ethyl acetate (2 : 6) and showed 2 violet spots after being sprayed by LB
reagent (with Rf point : 0.5 and 0.69 ). From the TLC assay can be guessed
that the sample contained saponin triterpenoid.
Key words: Dadangkak Roots, Ethyl Acetate Fraction, Antidiabetic, Saponin

Triterpenoids

1
Muhammad Zaini
INTRODUCTION
Diabetes mellitus (DM) is a metabolic symptoms that appear on
someone caused by the increase of blood glucose consequence from the
damage or resistance of insulin (Scarano et al., 2006). The number of people
who suffer diabetes is increasing year by year. In 2000, the number of people
who suffer diabetes in Indonesia is 8,4 million people and estimated will
reach 21,3 million people in 2030. That case leads Indonesia to be the fourth
country with the highest number of diabetic sufferer after India, China, and
United States of America (Wild et al, 2004; For, 2008).
The high prevalence of diabetes mellitus makes people concern about
how to cure this disease. Concept of “back to nature-treatment” lately
become so famous and can be alternative of this treatment. Dadangkak
((Hydrolea spinosa L) is one of herbal plants that been used to cure DM in
South Kalimantan. the roots of Dadangkak is boiled with water and then the
water is drunk daily to decrease the blood glucose.
Experiment of using Dadangkak as antidiabetes before was only
observation datas (Widuri et al., 2004). The similar experiment was
conducted to evaluate the activity of ethyl acetate fraction of Chaenomeles
sinensis (Thouin) showed the ability to reduce cell damage caused by STZ
induction significantly (Sanchetti et al., 2017). Besides, the experiment of
Zanata et al. (2007) used the ethyl acetate fraction of Vitex megapotamica
(400 dan 800 mg / kg) leaves showed maximum hipoglicemic effect (each
28% and 20%) on mice that induced by Aloxan.
This experiment was conducted by examining the activity of roots of
Dadangkak as antidiabetes. The examination was counducted by giving the
ethyl acetate fraction from ethanol extract to Wistar diabetic male rats.
Induction of diabetes used 150 mg/kg of weights (i.p). Phytochemical
examination was conducted to identify the component of ethyl acetate
fraction. The main purposes of this experiment are to examine the activity
antidiabetes from ethyl acetate fraction of roots of Dadangkak and to
identify the chemical compenents of the ethyl acetate fraction that potential
as antidiabetes based on the Thin Layer Chromatoghraphy profiles.

Materials
Materials that have been used in this experiment are : Wistar male
rats, roots of Dadangkak, Aloxan, aquades, ethanol 70%, ethyl acetate,
methanol, Dragendorff reagent, Mayer reagent, sulfuric acid 98%, anhidrate
acetic acid, FeCl3, HCl, chloroform, and NaOH.

Instruments
The instruments that have been used are beaker glass, test tubes,
shelf test tube, Bunsen, tripod, analytical balance, Gluco-DR, strips of Gluco-
DR, materation vessel, vortex, waterbath, separation funnel, spuit, vacuum
rotary evaporator, volumetric pipette, drop pipette, and cage
Procedures
Simplisia Treatment
Dadangkak obtained from Marabahan, South Kalimantan. The
sampling is first conducted from whole part of the plant, then parted the
roots. the roots is brown with soft texture then washed by water. This was
held to wash-out the impurities on the roots.
Sample then cut and dried by wind automatically. This was held to
decrease the water content so that damage risk caused by microorganism
can be stopped. Dried sample was blended to be powder so that the
extraction process would be easier. The simplisia powder then saved in the
vacuum container.
Extraction and Fractination

Extraction method that used in this experiment is cold extraction
(materation). Simplisia powder is pondered 250 grams then put in the
materation vessel. Extraction was held 3 days using ethanol 70%. The extract
then emulsified with Vacuu, Rotary Evaporator and then suspensed with
aquades until dissolve. The next step was mixed the suspension with ethyl
acetate, then evaporated until dense.
Antidiabetes Activity
The examination of antidiabetes activity used Wistar male rats age 2-3
months with 200-250 grams weight. The rats was divided into 3 groups (each
5 rats) : 1. Glibenclamide 0,4525 mg/kgBW, 2. Aquades 2ml/200 gramBW, 3.
Ethyl acetats of roots of Dadangkak perorally.
Dosage fraction that been used based on the result of dosage
orientation. Before that, all of the male rats were fasting for 16 hours. All
groups wer given Aloxan 150 mg/kgBW at the first day to increase the blood
glucose. The examination of blood glucose was conducted by Gluco-DR. the
examination then was conducted again at the fourth day to check if the
blood glucose increased. If the blood glucose increased, then the giving of
sample held at 5th day until 11th . the examination then held again at the 12th
day. The blood glucose that have been obtained then analyzed with SPSS
(confidence level : 95%).

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Muhammad Zaini
Qualitative Assay of Chemical Contents

Qualitative assay of chemical content was conducted on alkaloids,
saponins, flavonoids, and tannin.
Alkaloid test :
Sample was added with HCl 2 ml, filtered, and then added with Mayer
reagent and dragendorf at separated test tube. Positive result if white or
yellow pale precipitation obtained and can be dissolved in methanol.
Saponin test :
Sample in test tube was added with aquadest 10 ml then mixed,
positive result if bubbles appear within ± 10 minutes. Sample was added with
2 ml of chloroform and LB reagent then appear brown ring so that positive
saponins.
Sample was added with LB reagent then change into red/purple so that
positive saponins.
Flavonoid Test :
Sample was addes with 2 ml aquadest and 10 drops of concentrated
HCl and 0.1 gram of Mg powder. If red color appear so positive flavonoids.
Sample was added with 2 ml of concentrate HCl and then heated for 15
minutes. Positive result was showed by liquid changing into orange.
Tannin Test :
Sample was added with FeCl3, if the solution change into green, blue,
or black so that contains tannin.
Thin Layer Chromatography Assay

Sample was dissoloved in pro analysis ethanol then spotted on TLC
plate. TLC plate then put into chamber filled with eluen. TLC plate was taken
after eluen arise until the line (0.5 cm from above). Spots that are obtained
then observed under UV lights with λ 254 dan 366 nm or sprayed with spray
reagents.
Rf value then calculated and compared with the reference value.

Extraction and Fractination
Roots of Dadangkak were being extracted by materation with 70%
ethanol. From the materation obtained concentrated extract 16.62 with
6.6%. fractionation from 10 grams ethanol extract was obtained 15.6%.
Antidiabetes Activity
This experiment was a Diabetes Type I that related with pancreas
damage caused by diabetogenic compounds. Aloxan can destroy β

Langerhans cell that cause leakage of lymphocyte to Langerhans. It indicates

that autoimmune happens (Nugroho, 2006).
Treatment to male rats was conducted to 3 groups with 5 rats each
group. Negative control was aquadest 2 ml/100 grBW and positive control
was glibenclamide 0.45 mg/kgBW. Dosage of roots of Dadangkak fraction
was used based on empirical dosage : ± 8 gram. Dosage for male rats was
obtained with converting the dosage with conversion factor 0,72 g/kgBW.
Based on average rendemen is 15%, so that obtained dosage fraction 108.6
mg/kgBW. Dosage fraction 100 mg/kgBW was determined as test dosage.
Aloxan 150 mg/kgBW was given as diabetes induction
intraperitoneally. Measurement of blood glucose was conducted at first,
fourth, and twelfth days. The giving of control and test groups was
conducted perorally everyday start from the 5th day until the 11th day. The
result of antidiabetes is the mean value of blood glucose, can be seen as
below (Table 1).
Table 1. mean value of blood glucose of rats
Mean value of blood glucose (mg/dL) Day :

No Treatments
1 4 12
1 Negative control 1 52.2 447.6
2 Positive control 2.4 85.6 140
Ethyl acetate fraction
3 7.6 70.6 162
100 mg/kgBW
Mean value of rats’ blood glucose at the first day shows normal
condition. At the fourth day shows that the blood glucose level reached the
DM range either on the test group or control group. The effect of giving the
sample and control at the 5th day until 11th day was evaluated from the
blood glucose level at the 12th day. On that day the blood glucose level
showed stabil increment at the negative control and decrement at the
positive and fraction groups.
The result of mean value of blood glucose level at the 12th day could
be seen at the diagram below.
The mean value of blood glucose level at the 12th day showed
significant differences, which negative control was still on DM range, in other
hand positive control and ethyl acetate fraction have an ability to decrease
blood glucose level.

1
Muhammad Zaini
Figure 1. Blood glucose level at the 12th day
Data analysis used SPSS program with confidence level 95%. The result
of normality test Kolmorgov-Smirnov showed that the datas are distributed
normally (sig>0,05) and the homogenity test Levene datas which were being
tested were homogeny (sig>0,05) so that the test are continued with One
Way ANOVA. The result of One Way ANOVA showed that there were
significant differences between control and treatment groups (sig<0,05). To
examine the differences this analysis were continued with Turkey HSD test as
shown table 2 below,
Table 2. Result of Turkey HSD Test
Groups Mean value of blood glucose level

Negative control 447,6 ± 9,53c
Positive control 140,0 ± 13,76a
Ethyl acetate fraction 100 mg/kgBW 162,0 ± 8,63b
Note: different notation showed that there were effects that significantly
different (p<0.05)
From the result above, known that blood glucose level at Male rats
control groups showed the lowest blood glucose level 140 ± 13,76 mg/dL.
Mean value of blood glucose level can be set as standart to examine the
increment and decline because the effect of treatment. Positive control and
ethyl acetate fraction showed the significant difference compared to
negative control (sig<0,05). This means that positive control and ethyl
acetate fraction could decrease the blood glucose level of Male rats. Ethyl
acetate fraction can decrease the blood glucose level until 162,0 ± 8,63
mg/dL although cannot defeat the effect of positive control (sig<0,05).

Chemical Contents Qualitative Assay

The analysis of chemical contents on alkaloids, flavanoids, tannins, and
saponins. Result of chemical contents could be seen as shown below.
Table 3. Chemical contents
No Compound Groups Reagent Test Result

Mayer (-)
1 Alkaloids
Dragendorff (-)
Mg powder + HCl (-)
2 Flavonoids
Conc HCl (-)
3 Tannins FeCl3 (-)
Bubble test (+)
4 Saponin Kloroform + LB (+)
LB (+)
Note : (+) : positive: negative
The result of chemical content test showed that the sample was positive
contains saponins.
Thin Layer Chromatography Profile

TLC profile was used as datas to emphasize the chemical content that
contained at the fraction which has ability as antidiabetes. TLC process was
done by several testing orientation to examine the eluen that can separate
the chemicals content perfectly.
The orientation was done to search the exact eluen composition for
separating and detecting the compound fraction based on qualitative assay
before. Orientation was done on n-hexane : ethyl acetate =
And chloroform : methanol : aquadest. The orientation result was
obtained that n-hexane : ethyl acetate = 2 : 6 could separate the spots well.
TLC plate then reacted with spray reagent to emphasize the spots at TLC
plate.
Spray reagents that have been used was suitable with qualitative
chemical content test that stated positive to saponins. Saponins could be
detected by using LB reagent and by heating at 110oC for 10 minutes and
obtained spots colored red/violet for tritepenoids and green for steroids
groups. The result with LB showed two spots colored violet and two spots
colored brown. Spots obtained then can be calculated Rf value. Rf value is
the comparison between spot distance and track line at TLC plate. TLC profile
of ethyl acetate shown at the figure below.
Detail detection of the spots was done at UV 254 nm and 366 nm. The
color that seem dimmed at UV 254nm showed the chromophore presence
and conjugated double bond at the compound. There were no saponins that

1
Muhammad Zaini
could be observed spesifically with UV 254 and 366 nm (Wagner, 1984). So

that spray reagents was specific way to detect the presence of saponins. The
result of TLC showed that there was an allegation of saponin triterpenoid
presence in ethyl acetate fraction at the two spots with Rf value : 0.50 and
0.69. this is was supported by the experiment before that stated if
triterpenoid was detected at the Rf range Rf : 0,5-0,89 (Stahl, 1973).
Note : (a) : UV 254 nm ; (b) : UV 366 nm ; (c) : LB ; (d) : illustration; Rf : 0,5 & 0,69 : (+) saponin
Figure 2. TLC Profile of Ethyl Acetate Fraction
Saponin in several experiments were found effective as antidiabetes

because can be an inhibitor to enzyme α-glukosidase. Enzyme α-glukosidase
was an enzyme that roled in changing carbohydrate into glucose. If work of
the enzyme was inhibited then the blood glucose would be decrease so that
the hypoglycemic effect would arise (Prashanth et al, 2001 ; Fiana & Dwita,
2016). Saponins were also reported in the severa experiments having
mechanism to increase the insulin plasma level by inducting insulin release,
inhibit the activity of diasaccharide, α-glucosidase and inhibit the expression
of mRNA from glycogen phosphorylase and glucose 6 phosphat (Lavle et al,
2016).
CONCLUSION
Ethyl acetate fraction could decrease the blood glucose levels
significantly (sig<0.05) compared to control groups and have potential to be
observed further as antidiabetes.ethyl acetate fraction gave positive result to
saponin triterpenoid with LB reagent by showing the brownish ring on the
solution. TLC profile with n-hexane : ethyl acetate (2:6) as eluent was
obtained two spots colored violet after sprayed with LB reagent. Rf value
was 0,5 and 0,69 and said that the sample were expected contain saponin

type triterpenoid.
ACKNOWLEDGEMENT
We gratefully acknowledge that we would like to say thank to
Kementerian Riset Teknologi and Pendidikan Tinggi for the grant
experimental funding so that this experiment could be done fluenty and on
time.
REFERENCES
For W.C. 2008. The role of nutrition in diabetes management: From basic to
recent advances. Paper presented at the meeting of Persada
Conference Plenary Lecture Session. Malang.
Fiana N and Oktaria D. 2016. Pengaruh Kandungan Saponin dalam Daging
Buah Mahkota Dewa (Phaleria macrocarpa) terhadap Penurunan
Kadar Glukosa Darah. Jurnal Majority, 5(4): 128-132.
Lavle N, Shukla P and Panchal A. 2016. Role of flavonoids and saponins in the
treatment of diabetes mellitus. J Pharm Sci Bioscientific Res. 6(4): 535-
541
Nugroho A.E. 2006. Animal models of diabetes mellitus: Pathology and
mechanism of some diabetogenics. Biodiversitas Journal of Biological
Diversity. 7(4).
Prashanth D, Amit A, Samiulla D.S, Asha M.K, Padmaja R. 2001. Alpha
Glucosidase Inhibitor Activity of Mangifera Indica Bark. Fitoterapia.
72(6):686-8.
Sancheti S, Sancheti S and Seo S.Y. 2013. Antidiabetic and
antiacetylcholinesterase effects of ethyl acetate fraction of
Chaenomeles sinensis (Thouin) Koehne fruits in streptozotocin-
induced diabetic rats. Experimental and Toxicologic Pathology, 65(1),
55-60.
Scarano W.R, Messias A.G, Oliva S.U, Klinefelter G.R and Kempinas W.G.
2006. Sexual behaviour, sperm quantity and quality after short-therm
streptozotocin-induced hyperglycaemia in rats. International Journal
Andrology. 29: 482-488.
Stahl. 1973. Drug Analisis By Chromatography. Transleted by Kosasih
Padmawinata and Soediro L. ITB-Press. Bandung
Wagner H, Bladt and Zgainski. 1984. Plant Drug Analysis. 225. Transleted by
Th. A. Scott. Springer-Verlag. Berlin
Wild S.H, Roglic, G, Green A, Sicree R and King H. 2004. Global prevalence of
diabetes: estimates for the year 2000 and projections for 2030:
response to Rathman and Giani. Diabetes care, 27(10), 2569-2569.

1
Muhammad Zaini
Zanatta L, De Sousa E, Cazarolli L.H, Junior A.C, Pizzolatti M.G, Szpoganicz B &
Silva F.R.M.B. 2007. Effect of crude extract and fractions from Vitex
megapotamica leaves on hyperglycemia in alloxan-diabetic
rats. Journal of ethnopharmacology. 109(1): 151-155.

Formation Of Inclusion Complexes Of Glimepiride-Betacyclodextrin
THE FORMATION OF INCLUSION COMPLEXES OF

GLIMEPIRIDE-BETACYCLODEXTRIN TO INCREASE SOLUBILITY
AND DISSOLUTION RATE
Fitrianti Darusman*, Ulfa Siti, Silviyaturrohmah
Departement of Pharmacy, MIPA, Universitas Islam Bandung,
Jl. Tamansari No.1 Bandung 40116, West Java, Indonesia
efit.bien@gmail.com
ABSTRACT
Glimepiride is a third-generation oral antidiabetic drug of sulfonylurea
group capable of lowering blood glucose levels with small hypoglycemia side
effects. However glimepiride including the Biopharmaceutical Classification
System (BCS) class II has a solubility practically insoluble in water so that the
effect on the dissolution rate and bioavailability. The efforts to increase the
solubility and dissolution rate of glimepiride by the method of formation of
inclusion complexes using betacyclodextrin compounds with co-grinding and
solvent evaporation technique in a 1:1, 1:2 and 2:1 mole ratio. Yield solids of
inclusion complexes glimepiride in betacyclodextrin in solubility test until it
reaches equilibrium at 37±5°C for 24 hours and the dissolution rate test
using USP II (paddle) with a stirring speed of 50 rotations per minute,
phosphate buffer pH 7.4 as medium, 900 mL at 37±5°C. The result of
solubility and dissolution rate which indicates the formation of inclusion
complexes of glimepiride-betacyclodextrin occurred in the 1:2 mole ratio, in
co-grinding and solvent evaporation techniques, characterized by increased
solubility and dissolution rate of glimepiride compared to pure glimepiride
and the physical mixture of both. However, significant effect on solvent
evaporation technique.
Key words : Glimepiride, inclusion complexes, betacyclodextrin, solubility,

dissolution rate.
INTRODUCTION
Glimepiride is a third-generation oral antidiabetic drug of sulfonylurea
group capable of lowering blood glucose levels with small hypoglycemia side
effects. However glimepiride including the Biopharmaceutical Classification
System (BCS) class II has a solubility practically insoluble in water so that the
effect on the dissolution rate and bioavailability (Kawabata, et.al., 2011).
One effort to increase the solubility of GMP is by forming inclusion
complex using cyclodextrin derivative compound that is betacylodextrin

Fitrianti Darusman
(BCD) which has hollow shape (toroidal) with the outside of the cavity is
hydrophilic so easily soluble in water and the inside is hydrophobic (Bekers
dkk., 1991).
BCD forms an inclusion complex by "capturing" drug molecules as a
guest into their sockets so as to alter the physicochemical properties of the
drug molecule particularly its solubility properties. The minimum
requirements that drug molecules must meet in order to form an inclusion
complex are the size and shape of the drug molecule entering or partially
entering into the BCD cavity and the inclusion complex formed is stabilized
by intermolecular forces, such as the van der Waals, hydrogen bonding,
hydrophobic interactions and high-energy water discharges (Frank, 1975,
Bekers dkk., 1991, Rajewski and Stella, 1996).
The successful formation of GMP inclusion complexes in BCD is seen
from the increase of GMP solubility by solubility testing conducted to reach
saturation condition and affect the percentage of GMP dissolved in unit time
by dissolution rate test.

Material
Glimepiride (PT. Kimia Farma, Tbk.), betacyclodextrine (PT. Sanbe
Farma), disodium hydrogen phosphate (Na2HPO4), potassium dihydrogen
phosphate (KH2PO4), methanol pro analisis and aquadest.
Methods
Manufacture of GMP-BCD inclusion complexes
Co-grinding Technique
Each GMP and BCD material is weighed based on a 1:1, 1:2 and 2:1 mole
ratio. Then both are mixed and milled manually with mortar and stamper for
30 minutes. Solids are collected in a glass tube, then stored in a desiccator.
Solvent evaporation Technique
Each GMP and BCD material is weighed based on a 1:1, 1:2 and 2:1 mole
ratio. Then the GMP is dissolved in methanol while BCD is dissolved in
aquadest. Both solutions were homogenized at constant stirring at 500 rpm
for 24 hours. This mixture is allowed at room temperature to evaporate the
solvent until a solid is obtained. Then mashed with a mesh screen number
20, to obtain the inclusion complex powder collected in a glass tube and
stored in a desiccator.
Solubility Test
The GMP-BCD inclusion complex powder previously produced from co-
grinding and solvent evaporation techniques in 1:1, 1:2 and 2:1 ratio is

weighed in excess, equivalent to 50 mg of pure GMP powder. Then put into a

glass vial containing a solution of phosphate buffer 7.4 as much as 10 ml. The
sample was stirred by using a waterbath shaker at a constant temperature of
37°C ± 0.5°C, a speed of 50 rpm. Stirring is done until equilibrium is reached.
The solution of the solution was filtered with Whatman filter paper, diluted
precisely. Then the GMP content in the pure form as well as in the form of
inclusion complexes was determined by UV spectrophotometer at a
maximum absorption wavelength of 228 nm.
Dissolution Rate Test

Powder of pure GMP, GMP-BCD physical mixture and GMP-BCD
inclusion complex were each weighed equivalent to pure GMP 5 mg, using a
USP II (paddle) with a stirring speed of 50 rpm, phosphate buffer pH 7.4 as
medium, 900 mL at 37±5°C. The sample solution was taken at 5, 10, 15, 20,
30, 40, 50 and 60 minutes intervals of 10 mL, then immediately replaced with
a dissolution medium of 10 mL at the same temperature. The sample
solution was filtered using Whatman filter paper, then measured uptake
using a UV spectrophotometer at a maximum absorption wavelength of 228
nm.

Manufacture of GMP-BCD inclusion complexes
Manufacture of GMP-BCD inclusion complexes based on 1:1, 1:2 and 2:1
mole ratios, as per table 1.
Table 1 GMP-BCD Mole Ratio
Weighing Based on mole ratio (g)

Pure Powder
1:1 1:2 2:1
Glimepiride (GMP) 0,491 0,491 0,981
Betacyclodextrin (BCD) 1,135 2,270 1,135
Notes : molecular weight of GMP = 490,62 g/mole; molecular weight of BCD
= 1135 g/mole
Selection of 1:1 mole ratio to see the ability to form inclusion complexes
between 1 mole of GMP with 1 mole of BCD to increase GMP solubility, 1:2
mole ratio to see the effect of BCD mole increase on GMP solubility and mole
ratio 2:1 to see the effect of decrease number of moles of BCD to GMP
solubility.
The formation of GMP-BCD inclusion complexes was performed by co-
grinding and solvent evaporation techniques.

Fitrianti Darusman
Co-grinding techniques can initiate the formation of hydrogen bonds

between guest molecules and host molecules due to the influence of
mechanical energy in the form of pressure and grinding causing molecular
breakdown, in addition to the reduction of particle size (Colombo. et al.,
2009). While the solvent evaporation technique the main mechanism of
inclusion complex is the dissolution process until it reaches the molecular
dispersed condition occurring in each guest molecule and host molecule in
its solvent, before mixing. The first stage begins with the cyclodextrin
molecular approach to the guest molecule, then the water structure breaks
inside the cyclodextrin ring and removes several water molecules from the
cyclodextrin ring, subsequent damage to the water structure around the
guest molecular part and the transfer of water molecules into the guest
solution so that the molecule guest can enter into cyclodextrin molecule. The
guest molecular interaction on the inside of the cyclodextrin is due to the
formation of hydrogen bonds between the guest and the cyclodextrin, and
ends with the reconstruction of the water structure around the guest part
after the inclusion process (Bekers, et al., 1991).
Solubility Test
The results of solubility test of GMP-BCD inclusion complexes in the 1:1,
1:2 and 2:1 mole ratios were compared with pure GMP powder and the
physical mixture both reached equilibrium conditions at time 24 are in Table
2 (Higuchi, 1965).
Table 2 Result of Solubility Test
Sample Solubility (mg/mL)

GMP 0,00937
Physical Mixtures 0,1111
Co-grinding :
(1:1) 0,1578
(1:2) 0,3605
(2:1) 0,0619
Solvent evaporation :
(1:1) 0.7750
(1:2) 0.7840
(2:1) 0,2469
Notes : molecular weight of GMP = 490,62 g/mole; molecular weight of BCD
= 1135 g/mole

Result of solubility test of GMP-BCD inclusion complex powder showed

an increase in GMP solubility when compared to pure GMP powder and a
mixture of both. Significant solubility improvement was seen in the inclusion
complexes of GMP-BCD mole ratio of 1:2, where in this ratio the mole of BCD
was greater than the number of moles of GMP. This proves that the more
mole of BCD in the inclusion complex will further increase GMP (Isadiartuti,
2005).
Dissolution Rate Test

The data and profile of the dissolution rate test result of GMP-BCD
inclusion complex powder of 1:1, 1:2 and 2:1 mole ratios in both techniques,
compared to pure GMP powder and physical mixture were both in Table 3
and Table 4 and Figure 1 and Figure 2.
Table 3 Result of Dissolution Test of Co-grinding Technique Inclusion

Complex
% Drug Release
Time in min
GMP PM 1:1 1:2 2:1
5 12,88 40,07 29,22 29,23 19,51
10 21,23 44,07 37,98 42,23 21,11
15 23,00 45,71 42,24 43,08 27,87
20 24,79 46,99 44,25 47,40 31,25
30 27,74 49,43 45,12 52,15 36,97
40 32,74 50,36 47,55 54,27 37,77
50 38,10 52,84 49,61 57,94 42,03
60 44,67 59,49 58,73 65,50 49,79
Figure 1. Dissolution Profiles by co-grinding technique : glimepiride (GMP),

physical mixtures (PM), inclusion complex 1:1, inclusion complex 1:2,
inclusion complex 2:1.

Fitrianti Darusman
Table 4 Result of Dissolution Test of solvent evaporation Technique Inclusion

Complex
% Drug Release
Time in min
GMP PM 1:1 1:2 2:1
5 12,88 59,22 59,23 70,07 49,51
10 21,23 67,98 72,23 74,07 51,11
15 23,00 72,24 73,08 75,71 57,87
20 24,79 74,25 76,99 77,40 61,25
30 27,74 75,12 79,43 82,15 66,97
40 32,74 77,55 80,36 84,27 67,77
50 38,10 79,61 82,84 87,94 72,03
60 44,67 88,73 89,49 95,50 79,79
Figure 2. Dissolution Profiles by solvent evaporation technique : glimepiride

(GMP), physical mixtures (PM), inclusion complex 1:1, inclusion complex 1:2,
inclusion complex 2:1.
Pure GMP showed the lowest dissolution profile when compared to

the physical mixtures and inclusion complexes of GMP-BCD in the 60th
minute of dissolution of 44.67%. The increased dissolution rate in the
physical mixture and GMP-BCD inclusion complexes is possible because the
GMP is complexed in a hydrophilic outer BCD matrix that will be easier to
wet and dissolve more quickly. Significant increases in dissolution rate were
seen in the inclusion complexes of GMP-BCD mole ratio of 1:2 in both
techniques, in the 60th minute deformed as much as 65.50% in co-grinding
technique and 95.50% in solvent evaporation technique.
CONCLUSION
Based on result of solubility and dissolution rate showing the inclusion
complexes of glimepiride-betacyclodextrin is in the mole ratio of 1:2 both co-

grinding and solvent evaporation techniques, which is characterized by

increased solubility and glimepiride disolution rate compared to pure
glimepiride and the physical mixture of both. However, significant effect on
solvent evaporation technique.
REFERENCES
Bekers, O., et.al., 1991, Cyclodextrin in Pharmaceutical Field, Drug Dev. Ind.
Pharm., 17 (11), 1503-1549.
Challa, R., Ahuja, A., Ali, J., Khar, and R.K., 2005, Cyclodextrin in drug delivery
: an updated review, AAPS PharmScitech, 6(2), E329-E357.
Chen HW, Lin AH, Chu HC, Li CC, Tsai CW, Chao CY, Wang CJ, Lii CK, Liu KL.
2011, Inhibition of TNF-α-induced inflammation by andrographolide
via down-regulation of the PI3K/Akt signaling pathway. J.Nat
Product. 74(11):2408-2413.
Colombo, I., Grassi, G., Grassi, M. (2009). Drug Mechanochemical Activation.
JPharmSci. 98(11): 3961-3986.
Frank, S.G., 1975, Inclusion Compounds, J.Pharm.Sci., 64(10), 1567.
Higuchi, T., and Connors, K.A., 1965, Advances in Analytical Chemistry and
Instrumentation, 4, 117, Interscience, New York.
Isadiartuti, Dewi, dkk., 2005, Pembentukan Kompleks Inklusi Fenobarbital
dengan Hidroksipropil-β-Siklodekstrin, Majalah Farmasi Indonesia
16(1), 28-37.
Kawabata, Y., Wada, K., Nakatani, M., Yamada, S., Onoue, S. (2011).
Formulation Design for Poorly Water-Soluble Drugs Based on
Biopharmaceutics Classification System: Basic Approaches and
Practical Applications. Int. J. Pharm. 420: 1-10.
Rajewski, R.A., and Stella, V.J., 1996, Pharmaceutical Application of
Cyclodextrine.2.In Vivo Drug Delivery, J.Pharm.Sci., 85(11), 1142-1169.

Ketut Agus Adrianta
UTILIZATION OF BLACK BALI RICE (Oryza sativa L.) IN

IMPROVING INSULIN ACTIVITY AND REGENERATION OF Β-
CELL PANCREAS ON WHITE DIABETIC RAT WITH ALLOXAN
INDUCED
Ketut Agus Adrianta, I Gusti Agung Ayu Kusuma Wardani
Akademi Farmasi Sarsawati Denpasar. Jalan Kamboja No. 11 A Denpasar, Pos Code
80236
adrianta@farmasisaraswati.ac.id
ABSTRACT
The development of antidiabetic treatment has been growing from
time to time, either with pharmacotherapy or herbal therapy using natural
ingredients to control blood sugar levels of patients and prevent diabetic
complications. Black sticky rice traditionally used as food in Bali (jaje bali) can
be an alternative treatment in diabetics. The highly dominant anthocyanin
contained in black glutinous rice is expected to improve the performance of
pancreatic beta cells in the production of insulin and increase the activity of
insulin work. The results showed that black sticky rice (Oryza sativa L.) dose
800 mg / Kg BW was effective for lowering blood glucose level. The
histopathology analysis on pancreatic β-pancreas cells can regenerate
pancreatic β-cells in alloxan induced diabetic white male rats (Rattus
norvegicus). Dose 800 mg / Kg BW is a dose that can regenerate the highest
β-cells of pancreas.
Key words: Diabetes mellitus, black sticky rice, anthocyanin
INTRODUCTION
Diabetes mellitus is a disease to watch out for, the prevalence of
diabetes for all age groups worldwide is estimated at 2.8% in 2000 and 4.4%
in 2030. The number of diabetics prevalence is 171 million in 2000 and 366
million in the year 2030. The latest data in 2015 shown by the Association of
Endocrinology (PERKENI) states that the number of diabetics in Indonesia has
reached 9.1 million people.
Different types of antidiabetic treatments have been used for
centuries to treat diabetes. The development of antidiabetic treatment has
progressed from time to time, either with pharmacotherapy or herbal
therapy using natural ingredients to control blood sugar levels of patients
and prevent complications of diabetes. Modern drugs used as antidiabetic
include insulin, sulfonylureas, biguanide and glitazon. The use of antidiabetic
drugs is often accompanied by adverse effects and toxicities such as nausea,

Utilization of Black Bali Rice (Oryza sativa L.)
vomiting, dermatological reactions, obstructive jaundice, and weight gain in

the use of sulfonylureas (Aru, 2009).
The use of natural ingredients in alternative medicine is already a
choice that has long been known to the public even long before the
introduction of chemicals. In addition to economic terms, the use of natural
ingredients provide a minimal side effects. Some natural ingredients that are
suspected to treat diabetes mellitus are Black glutinous rice (Oryza sativa L).
Black glutinous rice is a locally rich source of anthocyanin (Suhartatik, et al.,
2013). Consumption of anthocyanin in the diet proved to provide a
protective effect against cardiovascular disease, diabetes mellitus,
antioxidants, anti-inflammatory, and anticancer (Suhartatik et al., 2014). The
use of black sticky rice for Balinese people in general is often used for
traditional food or known as "jaje bali". Many potentials can be developed
from the use of black glutinous rice, but in practice there has not been much
research done. This is what lies behind the scientific research on the effect of
antidiabetes from black glutinous rice water extract (Oryza sativa L.). The
target outcome to be achieved in this research is a scientific publication on
the use of black glutinous rice extract (Oryza sativa L.) which has the
effectiveness in increasing the activity of insulin through the regeneration of
β-pancreatic cells in white rodents of diabetes mellitus induced aloxan.

The research design used in this study is a pure experimental
randomized pre-posttest control group design (Pocock, 2008). In the group
of research subjects will be carried out a random sample that meets the
inclusion requirements of the study. All male rats were divided into 4 groups:
1st Group is positive control group given glibenclamide 5 mg, 2nd group is
placebo-treated and 3rd Group treatment are given with 400 mg / KgBB
extract and the last group are given 800 mg / kg BW of black glutinous rice
extract (Oryza sativa L.) orally.
In preparing the Black sticky rice extract, first washed Black sticky rice,
then dried and then dried in a blender. Making water extracts is done by
adding boiling water into beaker glass that has contained powder of black
sticky rice. For Preliminary Blood Glucose Level is done by taking blood
venous through sinus orbitalis about 1 cc by using capillary micro tube, blood
is then checked in clinical laboratory by using glucose oxidase method: 1 ml
of white rat blood in centrifuge at 3000 rpm for 10 minutes then taken the
serum. Approximately 0.5 serum was inserted into the sample cup, then
inserted into the stardust and obtained blood sugar levels of mice with units
mg / dL.

The study was conducted through several stages, the first was the
selection of healthy mice, then all the rats were adapted for 30 days before
they were treated and on the 3rd day, the mouse was taken 1 ml through the
orbital sinus for blood glucose 2 hours post prandial before treatment.
Subsequently all the groups of mice were then given a single dose injection
of aloxan about 24 mg doses /200g intraperitoneally for 14 days.
Aloxan is a chemical used to induce experimental animals to produce
experimental diabetic conditions (hyperglycemic) rapidly. Hyperglycemic rats
can be produced by injecting 120-150 mg / Kg BW. The mechanism of action
of alloxan begins with the taking of alloxan into pancreatic β cells and this
rate of pickup will determine the alloxan diabetogenic properties. This stroke
may also occur in the liver or other tissues, but the tissue is relatively more
resistant than in pancreatic β cells. It is this property that protects tissue
against alloxan toxicity. The ability of alloxan to cause diabetes also depends
on the pathway induction, dose, compound, animal experiment and
nutritional status (Amma, 2009). Normal glucose levels in healthy mice are
between 50 mg / dL to 135 mg / dL. Like other mammals, these glucose
levels depend on the type of food consumed and the last meal time. Glucose
levels in mice can be said diabetes if glucose levels above 135mg / dL
(Ridwan, 2013).
All diabetic rats with 2 hours post prandial blood glucose level ≥ 135
mg /dL were then divided into 4 groups: group 1 as negative control group
(P1), group 2 as positive control group (P2), group 3 as treatment group with
a dose of 400mg /Kg BW (P3), group 4 as treatment group with dose 800
mg/Kg BW(P4). Subsequently treated for 14 days by giving the extract of
black glutinous rice and Aloxan. Blood sugar levels of rats were examined in a
clinical laboratory by the method of glucose oxidase, 1 ml of rat blood
centrifuged at 3000 rpm for 10 minutes then taken the serum.
Approximately half of the serum was inserted into a cup sample then
inserted into the stardust and obtained blood sugar levels of mice with mg /
dl, for further data analysis to compare the results. After taking blood, last
performed surgery and took pancreatic beta cells to be analyzed.


Table 1. Results Calculation Number of cells β- Pancreas
Examination of β- Average Three

pancreatic White Rats in Fields of View
No Treament Group
Three Fields of View
I II II Average
1. 24 27 29 26,66 26,81
2. 27 31 25 27,66
3. 31 24 28 27,66
4. Placebo (P1) 25 27 26 26
5. 27 26 25 26
6. 27 25 26 26
7. 31 24 28 27,66
8. 39 35 32 35,33 37,28
9. 37 40 38 38,33
10. 39 39 40 39,33
11. Positive control group (P2) 37 35 37 36,33
12. 39 36 31 35,33
13. 37 40 38 38,33
14. 37 39 38 38
15. 60 60 64 61,33 63,90
16. 70 59 66 65,00
17. Black Glutinous Rice Water 69 60 66 65,00
18. Extract 400mg/ KgBW 59 63 69 63,66
19. (P3) 71 59 67 65,66
20. 63 59 69 63,66
21. 60 61 68 63,00
22. 69 73 72 71,33 71,47
23. 71 71 73 71,66
24. Black Glutinous Rice Water 73 70 74 72,33
25. Extract 800mg/ KgBW 74 71 69 71,33
26. (P4) 69 72 72 71
27. 73 71 71 71,66
28. 70 71 72 71,00
Results of Histologic Analysis of Pancreatic Beta Cells

Here are the histopathologic results of pancreatic beta cells :

Fig.1 Histopatologic results of pancreatic Fig.2 Histopatologic results of
beta cells on placebo group, Beta cells pancreatic beta cells on group 2,
(1), and β cell necrosis (2) provision of glibenclamide: Beta cells
(1), and β cell necrosis (2).
Fig.3 Histopatologic results of Fig.4 Histopatologic results of

pancreatic beta cells on treatment pancreatic beta cells on treatment
group: Black Glutinous Rice Water group: Black Glutinous Rice Water
Extract 400mg / kgBB, Beta Cell (1), Extract 800mg / kgBB, Beta Cell (1),
and β cell necrosis (2) and β cell necrosis (2)
Observation of the histopathology of Langerhans Island in white

mouse pancreas, histopathology above showed that alloxan-induced
alteration-negative control group (P1) experienced fatty, cellular necrosis or
cell death that was reduced in the other three treatment groups.
The above test results show that:

1. The average number of β-pancreatic cells between the placebo group and
the positive control group that was significantly different with the value
of p = 0.001, the placebo group for the higher pancreatic beta cells.
2. Mean number of β-pancreatic cells between placebo group and group of
black glutinous rice infusion 400 mg / Kg BW that is giving significantly
different with value p = 0,001, black glutinous rice infuse treatment group
400mg / Kg BW more pancreatic beta cells high.

3. Mean number of β-pancreatic cells between placebo group and group of

black glutinous rice infusion of 800mg / Kg BW which is significantly
different with p = 0,001, black glutinous rice infuse treatment group
4. Mean number of β-pancreatic cells between positive control group and
group of black glutinous rice infusion 400mg / Kg BW that is significant
different with p = 0,001, black glutinous rice infuse treatment group
5. Mean number of β-pancreatic cells between positive control and group of
black glutinous rice infused rice 800mg / Kg BW is significantly different
with p = 0,001, black glutinous rice infusa treatment group 800mg / Kg
BW more pancreatic beta cells high.
6. Mean number of β-pancreatic cells between black-colored infuse
treatment group of 400 mg / Kg BW and group of black glutinous rice
infused at 800mg / Kg BW were significantly different with p = 0,001,
black glutinous rice infusa treatment group 800mg / Kg BW beta cell
number higher pancreas.
Table 2. Results Calculation Number of cells β- Pancreas
Group / subject Reference Group P values
Placebo Positive Control 0,001
Black Glutinous Rice Water 0,001
Extract 400mg/Kg BW
Extract 800mg/Kg BW
Kontrol Positif Black Glutinous Rice Water 0,001
Extract 400mg/Kg BW
Extract 800mg/Kg BW
Black Glutinous Rice Water Black Glutinous Rice Water 0,001
Extract 400mg/Kg BW Extract 800mg/Kg BW
Graph 1. of difference Average pre-post test of 2-hour post-prandial blood

sugar

Table3. Statistical test results of 2-hour post-prandial blood sugar levels
Group Reference Group p Value

Glibenklamid 0,000
Aquadest Black Glutinous Rice Water Extract 400mg/Kg BW 0,001
Black Glutinous Rice Water Extract 800mg/Kg BW 0,000
Aquadest 0,000
Glibenklamid Black Glutinous Rice Water Extract 400mg/Kg BW 0,006
Ekstrak 800 mg/kgBB 0,877
Aquadest 0,001
Water Extract Glibenklamid 0,006
400mg/Kg BW Water Extract 800mg/Kg BW 0,004
Aquadest 0,000
Water Extract Glibenklamid 0,877
800mg/Kg BW Water Extract 400mg/Kg BW 0,004
In the analysis, the extract of 800 mg / Kg BW with Glibenclamide

showed no difference, with p value of 0.877 where p> 0.05 so that there was
no significant difference between the treatment result of the extract of 800
mg / Kg BW with the result of glibenclamide treatment.
The Role of Secondary Metabolites Against Pancreatic-Cell Regeneration

An increase in the number of β-pancreatic cells with black glutinous rice
water extracts can be caused by bioactive compounds contained in black
glutinous rice water extract that can prevent damage to β-pancreatic cells
resulting in increased insulin secretion. Bioactive compounds in black
glutinous rice are alkaloids, flavonoids, triterpenoids, phenols and
anthocyanins that have been proven by Parisnawan's research (2015).
One of the chemical content contained in black glutinous rice is
anthocyanin which can lower blood glucose levels with its ability as an
antioxidant substance. The condition of hyperglycemia tends to increase the
formation of free radicals (ROS) such as hydrogen peroxide through the
glucose metabolism, antocyanin work as antioxidant is to bypass the free
radical chain oxidation reaction. Free radicals or ROS will receive electrons
from antioxidants, these compounds are not reactive anymore and do not
damage β-pancreatic cells that affect the secretion of insulin as a result of
the oxidation process has been disconnected, so that free radicals become
more stable compounds. Antioxidants can bind to free radicals thereby
reducing insulin resistance. With reduced insulin resistance, blood sugar
levels will decrease because insulin is working well.

CONCLUSION
Black glutinous rice water extract (Oryza sativa L.) has an influence on
regeneration β-pancreatic cells in white mice (Rattus norvegicus) male with
alloxan induced. Dose 800mg / Kg BW is dose which is capable of
regenerating β-pancreatic cells best demonstrated by the amount of β-
pancreas as indicator, so the higher the dose given the more number of cells
β-pancreas.
Black rice glutinous rice extract (Oryza sativa L.) has an effectiveness in
increasing insulin activity by lowering blood sugar levels 2 hours post
prandial white rat (Rattus norvegicus) males who are diabetic. Dose 800 mg
/ Kg BW is a dose that can lower blood sugar levels, so the higher the dose
given the greater the decrease in blood sugar levels.
ACKNOWLEDGEMENT
I would like to thank the parties who helped carry out this research.
Thanks to Kemenristek Dikti who has funded this research. Chairman of
Saraswati Academy of Higher Research Institute of Saraswati Ni Made
Dharma Shantini for her support and Researcher I Gusti Agung Ayu Kusuma
Wardhani who always petrified the completion of this research.
REFERENCES
Amma, N.R. (2009). Efek Hipoglikemik Ekstrak daun Murbei (Morus
multicaulis) Terhadap Kadar Glukosa Darah Tikus DM. Tesis. Bogor:
Program Studi Gizi Masyarakat dan Sumberdaya Keluarga IPB.
Aru W Sudoyo, Stiyohadi bambang, Alwi idrus et all 2009 Buku Ajar Ilmu
Penyakit Dalam Jilid I Interna Publishing, 885
Ditjen Bina Farmasi dan Alkes. (2005). Pharmaceutical Care untuk penyakit
Diabetes Mellitus. Jakarta: Departemen Kesehatan RI. Halaman 9, 29,
30, 32, 39, 43
Parisnawan. 2015. Identifikasi Senyawa Antosianin dan Metabolit Sekunder
dari Ekstrak Etanol Beras Ketan Hitam (Oryza Sativa L.) dalam
Pemanfaatannya sebagai ALternatif Pengobatan Demam Berdarah
Dengue. AKademi Farmasi Saraswati Denpasar. Bali
Pocock, S. 2008. Clinical Trials: A Practical Approach. Chichester: John Wiley
& Sons. p. 128 – 129.
Ridwan, 2013. Etika Pemanfaatan Hewan Coba dalam Penelitian Kesehatan.
Sandhar, H.K., Kumar, B., Prasher, S., Tiwari, P., Salhan, M., Sharma, P., 2011.
A revie of Phytochesmitry and Pharmacology of Flavonoid.
International Pharmaceutica Sciencia. 1(1) : 25-4

Kun Sri Budiasih
TOXICOLOGY OF CR(III)- GLUTAMIC ACID AS HYPOGLICEMIC

NUTRACEUTICAL ON STREPTOZOTOCIN-NICOTINAMIDE
INDUCED DIABETIC RATS
Kun Sri Budiasih, Kartika Ratna Pertiwi, Rizqie Auliana
Universitas Negeri Yogyakarta
kunsb@uny.ac.id
ABSTRACT
Cr-glutamic complex suplementation was conducted in pre-clinical
study as the hypoglicemic nutraceutical on nicotinamide-streptozotocin
induced diabetic Wistar rats. Three groups were examined on the effect of
Cr-glu [Cr(µ-OH)(glu)(OH)2]2·6H2O] (glu= glutamic) at dose (50, 150 and 300
µg/day). The remain groups are control (+) with chromium picolinate (CrPic),
control (-) diabetic group (DM) and non diabetic control (non DM) and
control group by glibenclamide. The toxicity of the compound was examined
by the liver and kidney function test on SGOT/SGPT, ureum and creatinine
determination. The result showed that the SGOT/SGPT was increased until
the 7th day, but decrease after treatment in 14 days. There was no significant
differences between the start and the end of the treatment (p>0.05).The
result was also found on the kidney’s function by BUN and creatinine
measurement. Cr (III)- glutamic acid is potentially developed as nutraceutical
product in the management of type-2 diabetes mellitus.
Keywords : Cr(III)-glutamic acid, hypoglicemic nutraceutical, toxicity,
INTRODUCTION
Supplement or nutraceutical is a part of the management of diabetes.
Diet, exercise, oral hypoglycemic agents and insulin endogen are other kind
of this . Nutraceuticals (often referred to functional foods) are natural
bioactive or chemical compounds that have health promoting, disease
preventing or medicinal properties[1]. This research is a part of application of
inorganic nutraceutical, an inorganic compound or metal-containing
medicinal product with special purpose as antiperglicemic agent.
Metal complex or organo-metallic compound as trivalent chroium has
been used in medicine in the management of diabetes mellitus. Intake of
chromium (III) complex showed considerable reduction in the glucose level
[2]
. Chromium works as a Glucose tolerance factor, by the interaction with
the insulin and its receptors on the first step in the metabolism of glucose
entry into the cell, and facilitates the interaction of insulin with its receptor
on the cell surface [3][4]. Chromium increases insulin binding to cells, insulin

Toxicology of CR(III)- Glutamic Acid as Hypoglicemic
receptor number as well as activates insulin receptor kinase leading to

increase sensitivity of insulin receptor. Studies in the activity of the Cr(III)
based supplement are urgently needed to find the optimum condition in d
the prevention and control of diabetes [5].
The amount of Cr(III) intake is about 200µgCr/ day. The well known
chromium supplement is chromium picolinate, Cr(pic)3. This compound has a
side effect in DNA damage [6], through the catalytic formation of reactive
oxygen species. Administration of the Cr(pic)3 to rats has demonstrated for
the first time that it can give rise to oxidative DNA damage in whole animals.
Some amino acids with Cr(III) act as a part of GTF (Glucose
Tolerance Factor). GTF is a low molecular weight Chromium (LMWCr), which
is, involved in the action of insulin in processing glucose into energy
(ochiaim 2008). GTF is an oligopeptide of molecular weight about 1400, and
consists of some amino acids : cysteine, glycine, glutamate, and aspartate.
It binds the molecule of Cr(III) by 1:4 ratio and acts in the hormonal action
of insulin[7].
It is a new chance in developig Cr(III) - amino acid compound as
antihiperglicemic supplements. Preparation of Cr-glutamate (Cr-Glu) was
reported in previous studies. The structure of the complex is [Cr(µ-
OH)(glu)(OH)2]2·6H2O][8].
The in vivo experiment was studied on Streptozotocin (Stz) –
nicotinamide induced diabetic albino rats. Collaboration of the two induction
agent according to the cytotoxicity of Streptozotocin (Stz) when given alone.
Nicotinamide-Stz induction is a new experimental diabetic model that mimic
some features of type 2 diabetes [9-10]. The induction models were applied on
some studies of natural product as antidiabetic agents[11-12]. Some previous
study also reported the application of Cr(III) based drug and supplement on
in vivo investigation[13-14].The histophatological studies on the effect of
alloxan [15], and nicotinamide-stz induction were reported [16].
Materials And Methods

The Cr(III) complex was produced from the previous study[19]. All
supplement samples were diluted in 0.2% sodium carboxy methyl cellulose
(CMC-Na). Nicotinamide (Sigma Aldrich) (E-Merck), Streptozotocin / Stz
(Sigma Aldrich). The control were prepared Na CMC. The subjects of the
study were 10 male Wistar albino rats ( ±8 weeks old, 200-290 grams). The
animals were kept and maintained with standard laboratory condition.
Feeding was done with standard laboratory diet and drinking was allowed
with water ad libitum.
The induction of diabetes was done by intraperitonial injection of
120mg/kg nicotinamide then followed 15 minutes later by 60 mg/kg

Kun Sri Budiasih
streptozotocin [13]. Streptozotocin was dissolved in citrate buffer (pH 4.5) and
nicotinamide was dissolved in NaCl 0.9%. Hyperglycemia was confirmed by
the elevated blood glucose levels at day 7 after injection. Blood sample was
collected from the eye vein. Measurement of blood glucose level was
conducted by using spectroscopic methods.
The Supplement in this work were synthesized in previous study[8]. The
formula is Cr-glutamate ([Cr(µ-OH)(glu)(OH)2]2·6H2O]). The supplement was
adiministered in 50,150 and 300 µg Cr/ day respectively, marked by Cr-AA1
(A), CrAA2 (B) and CrAA3 (C). The blood glucose level od diabetic subject is
126 mg/dL or more. Blood samples were taken and measured at H0
(start), H8 ( a week after induction) and H28 (4th week). The blood was
collected from the eye vein.
RESULT AND DISSCUSSION

The rats were inducted intraperitonially by nicotinamide and
streptozotocin. In this case, nicotinamide prevent the occurence of type 1
diabetes, by acting as a cytoprotectant against streptozotocin induced
diabetic damage in wistar rats brain. Collaboration of two induction agent in
this work give the most similar condition with type 2 diabetic subject.
The blood glucose level (in mg/dL) was measured during the
supplementation. At the day 8th (7 days after induction), all treatment
samples classified as diabetes with the blood glucose level minimum 126
mg/dL. Generally, the blood glucose level was decreased after treatment in
35 days in all groups except the control groups. Treatment in 5 weeks
showed that the glucose level were in the normal level[17].
The acute and sub chronical toxicity and the function of hepar
The diabetic rats were administered with oral suppementation of Cr-
AA, by 300 µg/day. CMC-Na was given to the control group. The treatment of
these subject were carried out in 5 weeks. The acute and sub chronical
toxicity and the the function of the hepar were measured by the value of
SGOT/SGPT, ureum, and creatinine.
The 1 st pre clinical test showed the potent of Cr(III)-glu as
hypoglicemic agent to the stz- nicotinamide diabetic rats(17). The effect of
supplementation showed that Cr-Glu give a better histophatological
performance of proximal tubules compared to standard oral therapy with
glibenclamide. The Cr-Glu groups also have the less degeneration and
necrosis, although still have a small part of congestion and blooding. The
dose of Cr-Glu 150 by µg/day was not give a significant effect in the
regeneration of diabetic subject in this research. It is necessary to pay
attention to the dose 200-300 µg/day, for futher research. It is also

important to to investigate the acyte toxicity of the highest dose, 300

µg/day. According to this result, the evaluation of the toxicity was carried
out at the highest dose. 300 µg/day(18).
Acute toxicity was investigated in 1-14 days. This aimed to khow the
general performance of he subject after administered by the supplement.
The specific organ chosen in the evaluation of the toxicity is the hepar,
based on the role of hepar as the center of the metabolism of human body.
It changes the lipophilic materials to hydrophilic so that can excreted by the
urine. The acute toxicity of the hepar is a response of the supplementation of
Cr(III)-glu in this research was determined by the investigation of the value of
SGOT- SGPT which is indicated the integration of the cells. The dose applied
in the test is 300 µg/ day, based on the previuous experiment of the 1st pre-
clinical test on the histopatology of the hepar.
The activity of Alanin Transaminase enzime / SGPT and Aspartat
Transaminase (AST) enzme / SGOT increaser if there are change in the
permeability of the cell wall. It indicated the disturbance in the cell integrity
(hepatocellular). SGOT ( Serum Glutamic Oxaloacetic Transaminase) is a
normal enzime that exist in the hepar cell and other organ. SGOT was
excreted when the hepar was disturbed. The level of the SGOT of the blood
then related to the abnormality of the hepar cell.
The SGOT and SGPT were investigated as the response of injury of the
hepatocite which excreted the Aspartat Transaminase (AST)/SGOT and
SGPT/ Alanin Transaminase ALT. The effect of acute supplementation of
Cr(III)-glu was expressed by the averafe value of the SGOT and SGPT of the
blood at the start (before induction, H0), after induction and the firts day of
supplementation (H8) and two weeks after (H14) as showed in Table 1.
Table 2. The SGOT and SGPT value in acute supplementation of Cr-Glu (in
U/I)*
Parameter Start (H0) Induction (H7) Acute suppl (H14) P**

SGOT/AST 162.42±2.87 276.2±0.0 164.3±0.0 0.142
SGPT/ALT 60.00±2.69 88.5±0.0 43.1±0.0 0.163
*average ± SD **Anova single factor (p<0.05)
The increasing of SGOT and SGPT indicated the damage in the cells of
the hepar. The normal SGOT and SGPT value in wistar albino rat are 30,2-
45,7 U/I and 2,1-23,8 U/I, respectivelly. As showed in Table 2, the average of
SGOT and SGPT of the treatment group by Cr(III)-glu (300 µg/ day ) was
increased until the 7th day. Supplementation in 7 days later decreased the
SGOT level to the value of the normal condition (starting time). The SGPT

Kun Sri Budiasih
decreased until lower level than the begining (H0). Statisctical analysis by
Anova single factor showed that there is no difference between the SGOT
level between non induced subject and after supplementation. In the other
word, the are a significant effect of the supplementation of Cr(III) in acute
interval (14 days) (p>0.05).
Kidney is also a target organ in the investigation of the acute toxicity
of Cr(III)-glu supplementation.The pre-clinical test of acute toxicity in kidney
was determined in the Blood Urea Nitrogen / BUN) and creatinine. Ureum is
is the residue of the protein metabolism which is toxic in the body. It must be
excreted by the activity of the kidney in urine. The incresing of the ureum
indicated the disturbance of the kidney’s function. Creatinine is a product
of the decomposition of the creatine, which is syntesyzed in the hepar as
(creatin phosphate, CP), as an energy storege. In the usage of teh energy, the
process produced creatinine, which is filtered by the glomerulus in the
kidney and excreted as urine. The amount of ureum and creatinine were
used in the assesment of the kidney function. The measurement of BUN-
creatinine of the treatment subject in this research was listed in table 2.
Table 2 . Blood Urea Nirogen (BUN) and creatinine by acute Cr-Glu (mg/dl)*
Parameter (H0) (H8) (H14) P**
BUN 35.00±5.80 37.2±0.00 33.60±0.00 0.109
creatinine 0.20±0.05 0.29±0.00 0.34±0.00 0.604
*average ± SD **Anova single factor (p<0.05)
The normal value of BUN and creatinine of albino rats are 13.9 – 28.3
mg/dl and 0,30-1.00 mg/dl respectively. The result of BUN and creatinine in
Table 2 showed the difference in trend. The highest BUN is in the 7th day, but
the highest creatinine is at 7th day. The BUN level then decreased until the
lower value than the day before induction. Statistical analysis showed that
there was no significant difference of both the BUN and creatinine between
before and after diabetic induction. It means, the diabetic condition
increased the BUN and creatinine level according to the disturbance of
kidney activity, but after supplementation of Cr-III)-glu, they came back to
the normal level. The increasing of BUN and creatinine of the diabetic subject
in this research was not sufficient high. Overall, the kidney was normaly
work during the supplementation of Cr-glu (300 µg/day).
Sub-chronical toxicity aimed to know the effect of the supplement to
the subject. The interval is about 10% of the lifetime (about 1-3 month). The
investigation of sub chronical toxicity was carried out during
supplementantion of Cr-glu in 4 weeks (28 days). The result was showed in
Fig 1.

Fig 1. SGOT and SGPT in supplementation of Cr-glu supplementation by 300

µg/day in 28 days
Fig. 1 indicated that Cr –glu tends to decerase the SGOT and SGPT
after increasing of both them according to the induction of diabetic by Stz-
nicotinamide. Sub-chronikal toxicity in kidney was observed by
determiantion of BUN) and creatinine until 28th day. The result showed in
Fig. 2 and Fig. 3.
Fig 2. BUN value in supplementation of Cr-glu (300 µg/day) in 28 days
Fig 3. Creatinine value in supplementation of Cr-glu (300 µg/day) in 28 days
The increasing of BUN and creatinine in 28 days supplementation

were also affected by the hypovolemic (dehidration) or the over protein

Kun Sri Budiasih
intake. It means that the increasing of the value was not the one and only
indicator of the damage in the kidney. As found in the previous research on
the histopatological performace if the kidney, the supplementation of Cr- glu
(300 µg/day) was not affected to the hepatotoxic and neufrotoxic and the
activity of the hepar dan kidney[18]. In the other word, the supplementation
of Cr(III)-glu is safely recomended.
CONCLUSSION
Cr (glu) complex is potentially as nutraceutical product to type 2
diabetes mellitus. Toxicity of this product has been evaluated to acute and
sub chronical interval. The supplementation of Cr(III)-glu is safely
recommended until 300 µg/day in 28 days. Chronical toxicity was needed to
investigate the further effect in toxicity.
ACKNOWLEDGMENT :
The research was funded by The Ministry of Research and Higher
Education, by “Hibah Bersaing” research scheme.
REFFERENCES
[1] Pandey, M., Vijayakumar., 2011, Nutraceutical Supplementation for
Diabetes : a Review, Int. J. Pharm. Pharmaceutical Sci., 3 (4), 33-40.
[2] Z Krejpcio, Essentiality of Chromium for Human Nutrition and Health,
Pol.J, Environ. Studies, 2001, 10 (6) 399-404.
[3] JB Vincent, (ed), The Nutritional Biochemistry of Chromium(III),
Elsevier,New York, 2007 : 139-151.
[4] RA Anderson., Chromium and the Prevention and Control of Diabetes,
Diabetes & Metabolism, 2007,vol.26, p. 22-27.
[5] D Boghchi, SJ Stohs, BW Downs, Cytotoxicity and Oxidative Mechanism
of Different Forms of Chromium Toxicol, 2002, No. 180 (1), 5-22.
[6] Tawkir, M., & Iqbal S.A., Synthesis, Characterization and Medical
Efficacy of Cr(III) Complexes of Sulphonil ureas as Oral Antidiabetics,
2012, Asian J, Pharm and Clin. Res,5(4).
[7] E.Ochiai, Bioinorganic Chemistry, John Willey & Sons, New York. 2008,
p.235.
[8] K.S. Budiasih, C.Anwar, S.J.Santosa, H.Ismail, 2013, Synthesis and
Characterization of Chromium (III) Complexes with L-Glutamic Acid,
Glycine and L-Cysteine, Waset Journal, 78, pp 1095-1909.
[9] EU Etuk, 2010, Animals Models for Studying Diabetes Mellitus, Agric.
Bio. J. of. N. Am., 2010:1 (2), 130-134.

[10] SS Ibrahim, SF Rizk, Nicotinamid: A cytoprotectant against

streptozotocin-induced diabetic damage in wistar rat brains, Afr.J.
Biochem.Res, 2008, 2 (8), pp.174-180.
[11] A Shirwaikar, K Rajendran, CD Kumar., R Bodla, Antidiabetic Actiivity
of Aqueous Leaf Extract of Anona Squamosa in Streptozotocin-
nicotinamide type 2 Diabetic Rats, J. Of. Etnopharmacology : 2004, 91 :
171-175.
[12] M Sharma, M. Siddique, M.W.., Shamim, A.M., Gyanesh, ., and K.K.
Pillai, Evaluation of Antidiabetic and Antioxidant Effects of
Seabuckthorn (Hippophaerhamnoides L.) in Streptozotocin-
Nicotinamide Induced Diabetic Rats , The Open Conference
Proceedings Journal, 2011, 2, 53-58.
[13] Selcuk MY.,, B Aygen, A Dogukan, Z Tuzcu, F Akdemir, J Komorowski, M
Atalay, K Sahin, Chromium Picolinate and Chromium Histidinate
Protects Against Renal Dysfinction by Modulation of NF-B pathway in
high-fat diet fed and Streptozotocin-induced Diabetic Rats , Nut. &
Met., 2012, 9:30.
[14] Ragavan,B., Krishnakumari .S., Effect of T Arjuna Stem Bark Extract on
Histopathology of Liver, Kidney And Pancreas Of Alloxan-Induced
Diebetic Rats, 2006, African J Biomed.Res, 9 : 189-197.
[15] Kante, K., Reddy, CS., Anti Diabetic activity of Dolichos Lablab (seeds)
in Sterptozotocin-nicotinamide induced diabetic rats, 2013, Hygeia
J.Diabetes.Med., 5 (1), 32-40.
[16] Madhavi, M., Kiran.S., Ramesh.D., Evaluation of antidiabetic,
Antihyperlipidemic and Antioxidant activities of Acacia leucophloea in
Sterptozotocin-Nicotinamide induced type II Diabetic in rats, 2014,
Global J. Pharm. 8 (1): 64-72.
[17] Budiasih ,KS, Pertiwi, KR.,Pre Clinical Study of Cr(III)-based
Hypoglicemic Supplement in –Type 2 Diabetic Rats, ICB-Pharma
International Conference, Universitas Muhammadiyah Surakarta, 31
Oktober 2015.
[18] Budiasih, KS. Pertiwi, KR., A Study on the Histopathology of Cr(III)-
glutamic acids Supplementation on Streptozotocin-Nicotinamide
induced Diabetic Wistar Rats, 6 Th Euchem Chemistry Congress, Seville,
Spain , 13-15 September 2016.

Nita Pujianti
THE INFLUENCE OF APPEARANCE PHARMACY AND DRUG

INFORMATION SERVICE TO PATIENT SATISFACTION OF
OUTPATIENT PROGRAM JAMKESDA IN H.HASAN BASRY
HOSPITAL AT KANDANGAN CITY
Nita Pujianti1 Aulia Azizah1, Musafaah1, Fauzie Rahman1
Public Health Study Program, Medical Faculty, Lambung Mangkurat University.
Jalan A. Yani KM. 36 Banjarbaru, Kalimantan Selatan 70714 Indonesia
nitapujianti@unlam.ac.id
ABSTRACT
Patient satisfaction is an affective and dynamic reaction associated
with a feeling of comfort, friendliness, speed of service and the provision of
information about health needs. Based on data from hospitals Brigjend H.
Hasan Basry Pharmaceutical care field shows the SME (Society Satisfaction
Index) in 2013 amounted to 64.75 with good service quality, in 2014
amounted to 54.43 with poor quality of service and in 2015 amounted to
55.6 with poor service quality. It is known that pharmaceutical IKM is below
standard and is the lowest index in the field of medical service. The aim of
research to explain to explain the influence of pharmaceutical care with
patient satisfaction level outpatient Jamkesda program. This study uses a
quantitative method with observational analytic design with cross-sectional
approach. This study population is outpatient program Jamkesda (132
people), sampling using purposive sampling with research instruments such
as questionnaires. The results showed five dimensions of quality
pharmaceutical services that significantly affect Appearance Pharmacy (p-
value = 0.0001) and Drug Information Service (p-value = 0.009). The
conclusion from this study is there is an influence of the 2 dimensions of
quality pharmaceutical care to patient satisfaction. Advice can be given that
the hospital could multiply seat waiting room pharmacy and the pharmacist
may become clear drug information slowly and clearly.
Keywords: Appearance Pharmacy, Drug Information Service, Patient
Satisfaction
INTRODUCTION
Pharmacy Installation is one of the health service facilities that handles
the distribution of drugs to patients, pharmacy supply line directly to the
community and pharmacy as a place of pharmacy service. Pharmaceutical
services are health services that have an important role in realizing quality

Influence of Appearance Pharmacy and Drug Information Service
health. Pharmacists as part of health personnel have the duty and

responsibility in realizing quality pharmaceutical services1.
Quality pharmaceutical installation service is a health service that can
satisfy every service usage in accordance with patient or consumer
satisfaction level, as well as its implementation in accordance with the code
of ethics and standard of service that has been set, because 25% patient
recovery is expected from comfort (Pusparia 2010). Pharmaceutical services
in addition to being a key to professionalism can also be seen as factors that
attract consumers to the purchase of drugs in pharmacies. Among them
include the appearance of pharmacies as well as drug information services.2,3
Based on the results of the initial survey conducted at the hospital.

Brigjend H. Hasan Basry Kandangan it is known that patients who seek
outpatient program Jamkesda less get good service due to insufficient
facilities available and waiting time to get a long service, so that patients are
not satisfied and can affect the process of service felt by patients in the
hospital. Based on data of RSUD Brigjen H. Hasan Basry in the field of
Pharmacy service showed IKM (Public Satisfaction Index) in the year 2013
amounted to 64.75 with good service quality, in 2014 54.43 with poor service
quality and in 2015 of 55.6 with poor service quality. It is known that the
pharmaceutical IKM is still below standard and is the lowest index in medical
service 2.4.
Based on these problems, it is necessary to study in-depth through
research to explain whether there is influence between the appearance of
pharmacies and drug information services with the level of outpatient
satisfaction Jamkesda program.

The design of this study is observational analytic, with cross sectional
approach. The population in this study is outpatient program Jamkesda, with
the number of samples as many as 132 people. Validity and reliability test
was conducted at Datu Sanggul Rantau Hospital as many as 30 respondents.

Influence Appearance Pharmacy Installation with the level of satisfaction
Based on table 1 it can be seen that from 35 respondents as many as
21 people (60.0%) who feel dissatisfied who feel dissatisfied in terms of bad
appearance pharmacy installation and from 97 respondents there are 8
people (8.2%) who feel dissatisfied from in terms of good pharmacy
appearance, and from 35 respondents assess the appearance pharmacy
installation is bad, there are 14 respondents (40.0%) who feel satisfied and

Nita Pujianti
from 132 respondents as many as 89 respondents said the appearance of

hospital pharmacy installation good and feel satisfied.
Table 1. The influences of appearance pharmacy with patient satisfaction

level in hospital pharmacy installation
appearance patient satisfaction

No Total p-value
pharmacy not satisfied satisfied
1 Less 21 (60,0%) 14 (40,0%) 35 (100%)
0,0001
2 Good 8 (8,2%) 89 (91,8%) 97 (100%)
Source: Primary data of 2016
The result of chi-square test with 95% confidence level, to see the
influence between appearance pharmacy installation to the satisfaction level
that p-value = 0,0001, from p value in statistical test result Ho decision was
rejected (p <0,05) which means there is a significant influence between the
appearance of pharmaceutical installation to the level of satisfaction means
the better the appearance of the pharmacy then the satisfaction of patients
using the services of pharmacies will be higher.
Based on the results of research from Ryu and Han (2010) comfort in
waiting is one of the factors that can affect patient satisfaction using the
services of pharmacies, and things that give comfort to the customer is an
attractive physical appearance and availability of supporting facilities, and
the appearance of a neat employee by using work uniform will give its own
characteristics as the image (image) about a service product that will be
given and sold to consumers.
Table 2. The influences of drug information service with patient satisfaction

level in hospital pharmacy installation
drug information patient satisfaction

No Total p-value
service not satisfied satisfied
1 Less 15 (37,5%) 25 (62,5%) 40 (100%)
0,009
2 Good 14 (15,2%) 78 (84,8%) 92 (100%)
Source: Primary data of 201
Influence of Drug Information Service with Patient Satisfaction Level

Based on table 5.9 from 40 respondents assessed information service
of hospital pharmacy installation is bad as much as 15 (37,5%) feel satisfied
though assessed bad information service of respondent stated that officer
attitude in explaining drug information make responder believe and no
doubt, and 92 respondent information service of hospital pharmacy

Influence of Appearance Pharmacy and Drug Information Service
installation is good, there are 14 responden (14,9%) who feel dissatisfied in

pharmacy installation because respondent rate that officer do not give
satisfactory drug information.
The result of chi-square test with 95% confidence level, to see the
influence of drug information service to satisfaction level that p-value value =
0,009, from p value in statistical test result Ho decision is rejected (p <0,05)
there is a significant influence between the drug information service on the
level of satisfaction.
The drug information service aims to let the patient know the use of
medication and can improve the healing rate of the illness suffered by the
patient it receives. Factors of drug information services can be assessed from
officers who provide drug information in an easily understandable language
and the officer provides information other than drugs associated with the
patient's illness.6
Research conducted by Sulistyawati, et al (2011), showed there was a
positive influence between drug information service on patient satisfaction
to buy drugs and research conducted by Ifmaily (2006), drug information
service will influence the interest of patient drug repurchase. Similarly,
research conducted by researchers where there is influence of drug
information services to the level of satisfaction1,7,8
CONCLUSION
Based on the result of the research, it can be seen that there is
influence between 5 dimension of pharmacy quality with patient satisfaction
level that is Pharmacy Appearance Appearance (p-value = 0.0001) anda Drug
Information Service -value = 0,009), The suggestions that can be given based
on the results of this study are: For the RSUD H. Hasan Basry Kandangan can
multiply the seats in the pharmacy waiting room so that patients can wait for
the medicine with relaxed and comfortable. For pharmacy installation
officers (pharmacies) can explain the drug information slowly and clearly, so
that patients can use drugs according to the rules.
ACKNOWLEDGEMENT
Many thanks to the RSUD Brig. H. Hasan Basry Kandangan who has
given permission in this research activity.
REFERENCES
1. Ifmaily. Analysis of the effect of perception of outpatient pharmacy service
service on the interest of drug buy back at RSI Pharmacy Installation.
Ibn Sina-Yarsi Padang Year 2006. Thesis. Semarang: Diponegoro
University, 2006.

Nita Pujianti
2. Pusparia L. Analysis of the relationship of outpatient satisfaction level to

the pharmacy installation service with the interest of the patient to
redeem the prescription in Pharmacy Installation of Budhi Asih
Hospital in 2010. Thesis. Depok: University of Indonesia, 2010.
3. Purwastuti C. Analysis of pharmaceutical service factors predicting drug
buying decision with perception approach of general clinic patient at
outpatient unit of Telogorejo Hospital Semarang. Thesis. Semarang:
Diponegoro University, 2005.
4. Muslichah. The influence of environmental factors, individual factors and
marketing communication factors on the decision to buy
pharmaceutical drugs between pharmacies in Sukoharjo regency and
pharmacies in the city of Surakarta. Thesis. Surakarta: University of
Muhammadiyah, 2005.
5. Abdullah N, Andrajati R, Supardi S. Knowledge, attitudes, and needs of
pharmacy visitors to drug information in the city of Depok. Health
Systems Research Bulletin 2010; 13 (4); 344-352.
6. Arimbawa P. Relationship of the pharmaceutical service with patient
satisfaction using the pharmacy service in Denpasar city. Thesis.
Denpasar: Udayana University, 2014.
7. Siregar, JP. Pharmacy Clinical Theory and Application. Bandung: EGC
Publisher, 2005.
8. Trimurthy, Iga. Analysis of Patient Perception Relationship on Quality of
Service with Interest of Re-Use of Outpatient Services Puskesmas
Pandanaran Semarang City. Thesis. Semarang: Diponegoro University,
2009.
9. Sulistyawati N, Nurdin P, Alimin M, et al. The relation of quality of
outpatient pharmacy service to satisfaction and decision to buy
medicine at IFRS Jala Ammari Makassar. Makassar: Hasanudin
University, 2010.

Effect of Keto-Acids on GFR Patients With CKD
THE EFFECT OF KETO-ACIDS SUPPLEMENTS ON GFR

PATIENTS WITH CHRONIC KIDNEY DISEASE IN ONE OF
GENERAL HOSPITAL IN JAKARTA
Putu Rika Veryanti1*, Yan Santosa2
1.
Department of Pharmacy, Institut Sains dan Teknologi Nasional, Jl. Moh. Kahfi II-
Jagakarsa, Jakarta, Indonesia. Pos Code : 12640
2.
Student of Pharmacy Department, Institut Sains dan Teknologi Nasional, Jl. Moh.
Kahfi II-Jagakarsa, Jakarta, Indonesia. Pos Code : 12640
Rika_veryanti@yahoo.co.id
ABSTRACT
Keto-acids are the nitrogen-free analogues of essential amino acids.
These amino acids therapy could be used as kidney protection by reduced
urea generation, delayed of uraemia and also reduced protein leaking into
urine. But there was a lack of study about the effectiveness of keto-acids
supplements in patients with Chronic Kidney Disease (CKD) in Indonesia. Aim
of this study is to evaluate the effect of keto-acid supplements on GFR
patients with CKD. A retrospective cohort study was conducted. Sixty two
patients with CKD divided into two groups. The trial group consist of 27
patients which treated by keto-acid supplements and the control group
consist of 35 patients without keto-acid supplements. The decrease of GFR
was measured in 3 month for CKD stage 5 and six month for CKD stage 4 and
3b. The decrease of GFR compared between two groups statistically using t-
test study. The results showed that there were no significant difference
between two groups baseline (p value gender = 0.64; p value age 0.74; p
value severity of CKD = 0.83). The decrease of GFR in trial group was lower
than in control group. In the trial group, the decreases of GFR in patient with
CKD stage 3b, 4 and 5 were -8.87±0.67, -4.11±2.29 and -1.40±1.03. While in
control group, the decrease of GFR value were -14.02±9.13 in stage 3b, -
4.47±4.45 in stage 4 and -1.60±1.01. But those difference in each stage of
patients were not statistically significant (p= 0.41 in stage 3b, p = 0.82 in
stage 4 and p= 0.72 in stage 5). We concluded that keto-acids supplement
has no significant effect on GFR patients with CKD in one of general hospital
in Jakarta.
Keywords: Keto-Acid, GFR, Chronic Kidney Disease, General Hospital, Jakarta
INTRODUCTION
Chronic Kidney Disease (CKD) is one of the high prevalence disease in
Indonesia. Indonesian Nephrology Association reported that the prevalence

Putu Rika Veryanti
of CKD in Indonesia is about 12.5% in 2006 (Kementerian Kesehatan RI,

2017).
Keto-acids were used worldwide since a long time ago in patients with
CKD (Bellizzi, 2013). Keto-acids are the nitrogen-free analogues of essential
amino acids. It has two advantages of using keto-acids in patient with CKD.
First, keto-acids could be used as renal protection by reduced urea
generation, delayed of uremia and also reduced protein leaking into urine.
The other advantage is keto-acids also could maintain the nutrition of
patients (Nitchwe, 2002).
A study about the effect of low protein diet supplements with keto-
acids on progression of CKD proved that the rate of CKD progression
revealed a 57% slower decline in renal function with the combination
between keto-acids and low protein diet compared to low protein diet only.
It also delaying dialysis for almost a year in stage 4 and 5 patients (Garnaeta
& Mircscu, 2013). There also the other study about the efficacy of the
essential amino acids and keto analogues on the CKD progression rate in real
practice in Rusia. The study showed that low protein diet combine with keto-
acids supplements lead to decrease of CKD progression both in well-designed
clinical study and in real nephrologist practice (Zemchenkov & Konakova,
2016).
While in Indonesia, there was a lack of study about the effectiveness
of keto-acids supplements in patients with CKD. So that, the aim of this study
is to evaluate the effect of keto-acids supplements on GFR patients with CKD
in one of general hospital in Jakarta.

This is an observational study and held in nephrology department in
one of general hospital in Jakarta. We use 62 out-patients with CKD in stage
3b, 4 and 5. They were divided into 2 groups. Trial group was patients with
low protein diet and also received keto-acid supplements and control group
was patients with low protein diet only. In the trial group there were 27
patients while in control group consist of 35 patients. Each group has 3 sub
groups (stage 3b, 4 and 5).
We collected data from medical records in January - December 2015.
The age of patients, gender, weight of body, and creatinin serum were
noted. Then we classified the stage of CKD and measured the decrease of
Glomerulus Filtration Rate (GFR) patients. We measured the decrease of GFR
patients in six months for CKD stage 3b and 4 patients and 3 months for
patients in stage 5. The effect of keto-acids supplements was analyzed by
compared the decrease of GFR patients in each sub groups statistically using
t-test study.

Effect of Keto-Acids on GFR Patients With CKD

CKD is one of degenerative disease. When people getting old, the
functions of kidney also decrease. This study found that the most patients
with CKD was > 55 years old. Indonesian Primary Health Study (2013)
reported that patient with CKD was higher in 35 - 44 years old compared to
25-34 years old (Kementerian Kesehatan RI, 2017). The decrease of kidney
function in productive age could be affected by the life style (Kementerian
Kesehatan RI, 2013).
Beside the age, gender is also one of the risk factors of CKD. Some
study shown that male has a higher risk of CKD than female. This study also
showed that male patients with CKD (53.23 %) were more than female
(46.77 %). This result linear to data from Indonesian Renal Registry (2014)
which reported that male patients with CKD was 55.77% and female 44.23%
(Perkumpulan Nefrologi Indonesia, 2014).
Table 1. Patients Characteristic Baseline
Patients Characteristic Trial Group Control Group p-value

Age (years old) 57.15±12.40 56.14±10.58 0.74
Gender (number of people): 0.64
Male 12 21
Female 15 14
Severity (number of
0.83
people):
Stage 3b 3 7
Stage 4 12 10
Stage 5 12 18
Table 1 showed that there were no significant difference between two

groups baseline in this study. Age, gender and severity of CKD were the same
in two groups (p>0.05). We measured GFR patients in different period.
Minimum measurement of GFR in patients with CKD stage 5 is 3 month and 6
months in patients with CKD stage 4 and 5. After measuring the GFR
patients, we found that the decrease of GFR in trial group was lower than in
control group (shown in table 2). But those difference in each sub groups of
patients were not statistically significant.
This result may be caused by the lack of this study. Retrospective
cohort design difficult to find information whether all patients obey to do the
low protein diet or not. Beside that, we could measured GFR patients only
one period a year in each sub groups. It was because of the serum creatinin

Putu Rika Veryanti
in the hospital was not consistently measured every month, so there were
some gaps in data which affect the GFR measurement.
Table 2. The Decrease of GFR patients in CKD
GFR Value
Stage p-value
Trial Group Control Group
3b -8.87±0.67 -14.02±9.13 0.41
4 -4.11±2.29 -4.47±4.45 0.82
5 -1.40±1.03 -1.60±1.01 0.72
In the next study, we suggest to evaluate prospectively the efficacy of

keto-acids supplements in patients with CKD. Data of serum creatinin
patients should be measured consistently at least every 3 month in CKD
stage 5 and 6 month in CKD stage 3b and 4.
CONCLUSION
We concluded that keto-acids supplement has no significant effect on
GFR patients with CKD in one of general hospital in Jakarta.
REFERENCES
Nitchwe. 2002. Dietary Protein Restriction in Chronic Renal Failure:
Nutritional Efficacy, Compliance, and Prognosis in Patient with Diabetic
Nephropathy. Kidney Int. 62: 220-28.
Bellizzi V. 2013. Low Protein Diet or Nutritional Therapy on Chronic Kidney
Disease. Blood Purif. 36: 41-46.
Garnaeta L, Mircscu G. 2013. Effect of Low Protein Diet Supplemented with
Keto Acid on Progression of Chronic Kidney Disease. J Renal Nutr. 23:
210-13.
Zemchenkov A, Konakova I N. 2016. Efficacy of the Essential Amino Acid and
Keto Analogues on the CKD Progression Rate in Real Practice in Russia
– City Nephrology Registry Data for Outpatient Clinic. BMC
Nephrology. 17: 62.
Kementerian Kesehatan Republik Indonesia. 2017. Situasi Penyakit Ginjal
Kronis. Jakarta: Pusat Data dan Informasi Kementerian Kesehatan RI.
Kementerian Kesehatan Republik Indonesia. 2013. Riset Kesehatan Dasar.
Jakarta: Kementerian Kesehatan Republik Indonesia.
Perkumpulan Nefrologi Indonesia. 2014. 7th Report of Indonesian Renal
Registry.

Health Related Quality Of Life
HEALTH RELATED QUALITY OF LIFE OF ISCHEMIC STROKE

PATIENTS IN YOGYAKARTA MEASURED WITH EQ-5D-5L
Muslimah1, Tri Murti Andayani2. Rizaldy Pinzon3. Dwi Endarti2
1.
Doctor in Pharmaceutical Sciences Program. Faculty of Pharmacy Universitas
Gadjah Mada.
Unit IX. Faculty of Pharmacy Universitas Gadjah. Sekip Utara. Sinduadi. Sleman.
Yogyakarta. 55281. Indonesia
2
. Faculty of Pharmacy Universitas Gadjah Mada. Sekip Utara. Sinduadi. Sleman.
Yogyakarta. 55281. Indonesia.
3.
Faculty of Medicine Universitas Kristen Duta Wacana. Doctoral Wahidin
Sudirohusodo Rd 5-25. Gondokusuman. Kota baru. Yogyakarta. 55224. Indonesia
mussaras250@gmail.com
ABSTRACT
A Stroke is the leading cause of death and disability, stroke recovery in
order to achieve a good quality of life need to the role as well as patients,
families, health workers and the surrounding community are integrated. The
purpose of this research is to know the characteristics of patients and
measure the utility value of the EQ-5D-5L and VAS symptoms of ischemic
stroke in Bethesda hospital Yogyakarta. Analytic observational research
methods design of cross-sectional based on patient interviews. Purposive
sampling technique has taken samples. Research subjects who meet the
inclusion criteria of 48 patients with the characteristics of the age, gender,
education, age, and occupation. Criteria for Inclusion include patient JKN, the
ischemic stroke of the first offensive, onset of fewer than 24 hours and none
of the references. The period of observation for 1 month with interviews
directly outpatient and inpatient with 3-month reminder systems
retrospectively given the State of the patient's medical condition. Health-
related quality of life was measured using the EQ-5D-5L questionnaire and
vase. The data collected are presented in the form of tables and charts were
analyzed using t-test with a 95% confidence level. Based on the results of the
statistical tests of the characteristics of the status, age, education, gender,
work, there were no significant influence (p > 0.05) against the value of the
utility of the EQ-5D-5L and VAS. Health status of hemiparesis has the lowest
utility value 0.592 and also the lowest VAS 65.06. Health status the highest
utility 0.887 on stage health face weakness and the tallest VAS 80.40 on
stage health paresthesia. The value of the utilities the EQ-5D-5L and the
VAS is not affected by patient characteristics factors but factors comorbid
and other complications which affected it.
Key words: Utilities, EQ-5D-5L, VAS, Ischemic Stroke

Muslimah
INTRODUCTION
Stroke became the cause of death tersering third after heart disease
and cancer and ranks first as a cause of disability (World Health Organization,
2015). The stroke also occupied the highest mortality rate in Indonesia
according to Riskesdas 2013. Treatment of stroke due to disability and
recurrent stroke, discomfort and dissatisfaction costs high enough to handle
the situation (Riskesdas, 2013). The prevalence of stroke sufferers in Asia 50-
400 people per 100,000 population per year (Bethesda Stroke Center, 2007).
A stroke is a clinical syndrome with symptoms in the form of impaired
brain function in focal and global that can cause death or disability who
settled more than 24 hours without any other cause except vascular
disorders. While the ischemic stroke is a stroke caused by a blockage of the
arteries that supply blood to the brain suddenly (World Health Organization,
2006).
Stroke is the biggest cause of the inability of the physical, emotional,
and social life in adults (BÁRTLOVÁ et al., 2007). Although stroke is a disease
that attacks the central nervous system, the resulting effect can affect the
entire body. Effects that may occur include paralysis, cognitive function
deficits, difficulty talking, emotional difficulties, problems in daily life, as well
as pain (NINDS, 2007). Stroke also is closely associated with depression.
Depression usually appears in the first two years after someone affected by
stroke (Lynch et al., 2008).
The inability of the physical, emotional, and social life of stroke
patients of course affect its social role. It gives a great influence towards the
health-related quality of life in stroke patients (Shofri, 2016). Measuring
health-related quality of life in stroke patients became common with the
recognition that the evaluation of stroke patient care must include the
quality at the same time the quantity of survival of the patient. These
measurements usually include elements of functional, physical,
psychological, and social of the patients (Almborg and Berg, 2009).
Measuring health-related quality of life in stroke patients are not only to
know the reaction of the patient against his illness and enhancing the efforts
of supportive care, but also to evaluate therapies that have been done (de
Haan et al., 1993).
The measurement of the quality of life of stroke patients is
indispensable to know the severity of the condition symptoms of ischemic
stroke. The measurement of the value of the utiltas patients there are
several types of EQ-5 d Questionnaire covers-1.5 l jar, EQ-5 d-3 l, Barthel
Index (BI), Study the SF-36 and the value of the Modified Ranking Scale
(mRs). Health-related quality of life was measured using a questionnaire the
Medical Outcomes Study SF-36 (SF-36). Health-related quality of life scores

on ischemic stroke patients the first attack is higher than the recurrent
attacks of ischemic stroke patients (mean ± standard deviation, ± 2238 399.7
with 1596 ± 554.2, P = 0.001). Also obtained meaningful differences between
the average score on health-related quality of life dimensions of physical
function (62 ± 24.8 with 25 ± 15.8, P = 0000), the role of the physical (23 ±
19.9 with 3 ± 8.8, P = 0.007), energy (75 ± 17.2 with 52 ± 17.7, P = 0.001)
(Yani, 2010).
The incidence of recurrent stroke often occurs among patients who
have recovered from a stroke. About 25% of patients will experience
recurrent stroke occurrence. Risk of death and disability after stroke is
increased by the presence of recurrent stroke events (NINDS, 2007). An
increase in the risk of the inability also showed an increase in the risk of a
decline in the quality of life in stroke patients.
The importance of measuring health-related quality of life in patients
of ischemic stroke and an increase in the risk of ischemic stroke patient
inability the attacks repeated pushing researchers to conduct research so
that the risk factors trigger the onset of strokes can be avoided and the early
symptoms of this disease can be immediately detected. The handling of this
disease therapy as soon as possible which will meminimalis the level of
disability and death. The purpose of this research is to know the
characteristics of patients and measure the utility value of the EQ-5 d.5 l jar
VASE and symptoms of ischemic stroke in bethesda hospital yogyakarta.

Analytic observational research methods design of cross sectional
based on patient interviews. Purposive sampling technique taken samples.
Research subjects who meet the inclusion criteria of 48 patients with the
characteristics of the age, gender, education, age and occupation. Criteria for
Inclusion include patient JKN, ischemic stroke of the first offensive, onset of
less than 24 hours and non of the references. The period of observation for 1
month with interviews directly outpatient and inpatient with 3 month
reminder systems retrospectively given the State of the patient's medical
condition. Research material in the form of EQ-5D-5L questionnaire VAS and
questionnaire data of the medical record of the patient. Health-related
quality of life was measured using the EQ-5D-5L questionnaire and VAS. The
data collected are presented in the form of tables and charts by using a value
of value sets of Thailand (Pattanaphesaj et al., 2014). The data were analyzed
using t test with a 95% confidence level.

Muslimah

The Utility And Value Of The VAS
Tabel 1. Utility value of the EQ-5D-5L and VAS Ischemic Stroke In Bethesda
Hospital Yogyakarta From 1 October 2015-30 September 2016
No Stage Health Utility Value VAS
1 Decreased Consciousness 0,752 72,19

2 Impaired Speaking (Aphasia) 0,863 75,33
Paralysis Of The Limbs And Face
3
(Hemipharesis) 0,592 65,06
4 Talk Pelo (Disartria) 0,885 77,17
5 Perot Faces (Facea Weakness) 0,887 76,33
6 Tingling (Paresthesia) 0,875 80,40
7 Eyesight (Blurred Views) 0,737 67,50
A stroke is a disease of the neurological deficit multi complex that

causes physical or mental disability can affect all aspects of life including the
quality of life of individual patients (Karim and Lubis, 2017). Based on the
results of the analysis in table 1, the average value of the utility of paralysis
limbs (hemipharesis) has the lowest utility value and also the lowest VASE
0.592 65.06. This fits with the theory that patients experience paralysis of
limbs then patients will experience a bit of difficulty to be able and capable
of doing your daily activities (house holding, world, self care) (Almborg and
Berg, 2009). The most high utility value utility 0.887 on stage health face
perot (facea weakness) and the tallest VASE 80.40 on stage health tingling
(paresthesia), determinants of high utility value, one of which can and are
able to do activities well everyday.
The Influence Of Characteristics Of Utility And VAS

Based on tables 3 and 4 show the results no significant difference
because p ≥ 0.05, which means that the deciding factor the value of utility
and a VASE from the symptoms of a stroke are not only determined by the
characteristic factor alone but rather a title such as komorbid and
complications join also the influence on quality of life of ischemic stroke
patients.

Tabel 3. Calculation of characteristic values of the utilities and EQ-5 d 1.5 l jar Vase Patients Ischemic Stroke In Bethesda
HOSPITAL Yogyakarta The period of October 1 to December 31, 2016
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Tabel 3. Calculation of characteristic values of the utilities and EQ-5 d 1.5 l jar Vase Patients Ischemic Stroke In Bethesda
HOSPITAL Yogyakarta The period of October 1 to December 31, 2016
Prooceding ICPAPS 2017

87
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CONCLUSION
Based on the research results based on the characteristics of
education, age, married status, gender and pekerjaa there is a significant
influence (p < 0.05) against the value of the utility of the EQ-5D-5L and VAS.
The utility value of paralysis limbs (hemipharesis) has the lowest utility value
and also the lowest VASE 0.592 65.06. The most high utility value utility
0.887 on stage health face perot (facea weakness) and the tallest VAS 80.40
on stage health tingling (paresthesia). Quality of life of stroke patients in
addition to the many factors that affect the characteristics of the patients
are also factors of complications and komorbid.onclusion is a brief summary
of findings and discussion. It is strongly recommended to avoid mere
repetitive statements from the previous sections.
REFERENCES
Almborg, A., Berg, S., 2009. Quality of life among Swedish patients after
stroke: Psychometric evaluation of SF-36. J. Rehabil. Med. 41, 48–53.
doi:10.2340/16501977-0287
Bethesda Stroke Center, 2007. RS Bethesda Jadi RS Pelopor Stroke Center di
DIY - Tribun Jogja [WWW Document]. URL
http://jogja.tribunnews.com/2017/09/05/rs-bethesda-jadi-rs-pelopor-
stroke-center-di-diy (accessed 10.6.17).
de Haan, R. d, Aaronson, N., Limburg, M., Hewer, R.L., Van Crevel, H., 1993.
Measuring quality of life in stroke. Stroke 24, 320–327.
Karim, U.N., Lubis, E., 2017. Kualitas Hidup Pasien Stroke dalam Perawatan
Palliative Homecare. J. Ners Dan Kebidanan Indones. 5, 42.
doi:10.21927/jnki.2017.5(1).42-50
Lynch, E.B., Butt, Z., Heinemann, A., Victorson, D., Nowinski, C.J., Perez, L.,
Cella, D., 2008. A qualitative study of quality of life after stroke: the
importance of social relationships. J. Rehabil. Med. Off. J. UEMS Eur.
Board Phys. Rehabil. Med. 40. doi:10.2340/16501977-0203
NINDS, 2007. NINDS Know Stroke Campaign - Know Stroke Home [WWW
Document]. URL https://stroke.nih.gov/ (accessed 10.6.17).
Pattanaphesaj, J., Thavorncharoensap, M., Teerawattananon, Y., Tongsiri, S.,
2014. Health-related Quality of Life Measure (EQ-5D-5L):
Measurement Property Testing and Its Preference-based Score in Thai
Population. Mahidol University.
Shofri, 2016. Difference in Anxiety between Left and Right Hemispheric
Lesions of Ischemia among Patients with Stroke at Dr. Moewardi
Hospital | Shofri | Indonesian Journal of Medicine [WWW Document].
URL

Muslimah
http://www.theijmed.com/index.php?journal=theijmed&page=article
&op=view&path%5B%5D=24 (accessed 10.6.17).
World Health Organization (Ed.), 2006. Neurological disorders: public health
challenges. World Health Organization, Geneva.
Yani, F.I.A., 2010. Perbedaan skor kualitas hidup terkait kesehatan antara
pasien stroke iskemik serangan pertama dan berulang. Universitas
Sebelas Maret.

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PROCEEDING

The 5th International Conference on

Indonesia Published by:

The 5th International Conference on

Dr. Rina Kuswahyuning, M.Si., Apt.

Dr. Dwi Endarti, M.Kes., Apt.

First Edition, 2017

Printed in Yogyakarta , Indonesia

Preface From Editor

Yogyakarta, November 2017,

Pharmacist’s Role In Individualising Amikacin Dosing In Severe Renal 10 – 14

Observational Study of Analgesic and Pain Relief In Postoperative Patients 15 – 26

Antidiabetic Activity and Phytochemical Analysis of Ethyl Acetate Fraction 39 – 48

THE FORMATION OF INCLUSION COMPLEXES OF GLIMEPIRIDE- 49 – 55

Toxicology of CR(III)- Glutamic Acid as Hypoglicemic Nutraceutical on 64 – 71

The Influence of Appearance Pharmacy And Drug Information Service to 72 – 76

The Effect of Keto-Acids Supplements on GFR Patients with Chronic Kidney 77 – 80

THE COMPARISON OF SODIUM ALGINATE AND XANTHAN

Prooceding ICPAPS 2017 1

MATERIALS AND METHODS

The making of granules using wet granulation method

2 Prooceding ICPAPS 2017

granules were ready to be filled in capsules. The formulas was attached in

Table 1. The Formulas of Captopril Floating Drug Delivery System Capsule

Homogeneity Test of Captopril

Prooceding ICPAPS 2017 3

Floating Lag Time

4 Prooceding ICPAPS 2017

RESULTS AND DISCUSSION

Table 2. Flow Velocity, Angle of Repose and Fines Percentage

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Tabel 3. Drug Content Result

Formula Mean ± SD (%)

Floating Lag Time

Tabel 4. Duration of Floating

Formula Mean (minutes)

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Table 5. Captopril Release Profile

Captopril Dissolved Percentage % (Mean ± SD)

Table 6. Regression Coefficinet Value of Drug Release

Zero Order First Order Higuchi Korsmeyer Peppas

Prooceding ICPAPS 2017 7

Meanwhile, the mechanism of Kormeyer Peppas can be observed using the n

8 Prooceding ICPAPS 2017

Shargel, L. dan Yu. 2005. Biofarmasetika dan Farmakokinetika Terapan. Edisi

Prooceding ICPAPS 2017 9

PHARMACIST’S ROLE IN INDIVIDUALISING AMIKACIN

Key words: Amikacin, Therapeutic Drug Monitoring, Random sampling, Renal

10 Prooceding ICPAPS 2017

An important reason so that a serum-level monitoring should be done

Amikacin is excreted unchanged in the urine (80-90) %. An increase in

Prooceding ICPAPS 2017 11

Figure 1: Concentration versus time profile of amikacin

12 Prooceding ICPAPS 2017

Prooceding ICPAPS 2017 13

14 Prooceding ICPAPS 2017

OBSERVATIONAL STUDY OF ANALGESIC AND PAIN RELIEF

Key words: Analgesic, postoperative pain, nociceptic pain, pain relief

Prooceding ICPAPS 2017 15

MATERIAL AND METHODS

16 Prooceding ICPAPS 2017

RESULT AND DISCUSSION

Table 1. Patient characteristic