Management of Acid Related Disease

:New Novel Proton Pump Down Regulator and inhibitor

of DLBS 2411
Ari Fahrial Syam MD,PhD, FINASIM, FACP, FACG
Division of Gastroenterology,Department of Intenal Medicine, University of Indonesia- Cipto
Mangunkusumo Hospital
Dean of Faculty of Medicine, Universitas Indonesia 2017-2025
www.dokterari.com @DokterAri arisyam91@yahoo.com

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GERD Dyspepsia IBS
functional dyspepsia Organic dyspepsia

Endoscopy normal Endoscopy abnormal

Erosive GERD, peptic ulcer,

esophagus Polyp, gaster,
duodenum, Cancer
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 Algorithm for the
management of dyspepsia

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Syam et al, PLOS ONE | DOI:10.1371/
November 23, 2015
 H. pylori (HP) Infection

• PUD is the most studied disease

related to HP infection.
• HP may also be involved in
GERD, certain lymphomas, iron
deficiency anemia, and skin
disorders
• Oral-oral and fecal-oral routes
are common methods of
transmission
• More common in developing
countries
1%-19% infected to
be Gastric cancer
Gastropathy
NSAIDs
• NSAIDs are taken intermittently by
approximately 13 million
Americans; 1% of population
daily.
• Risk factors of NSAID-induced
ulcers are often associated with:
• Advance age
• High NSAID dose
• History of PUD +/or GI bleeds
• Certain medications, i.e.
prednisone
Gastropathy NSAID
 Stress –related mucosal disease (SRMD):

 Is significant cause of morbidity and

mortality in critically ill patients in ICU

 Because upper gastrointestinal bleeding

is often an indicator of poor patient

 Evaluated the incidence of bleeding in Complication:

• Bleeding 20%
ICU: 48.5% mortality rate compared
• Perforation 5%
9.1% for other patient ( p< 0.001) • Obstruction 2%
*evaluable analysis

 In increase mortality can also lead to

prolonged length of hospital stay. ( 4 EM-0662 / August 2021

days-8 days )
( Cook, et al, 1994; Harris ,et al, 2014 )
 Pathophysiology of Peptic Ulcer
Shay and Sun’s Balance Theory

•Mucous blood
flow
•Surface ulcer Gastric acid
no
epithelial cell ulcer
Pepsin
•Prostaglandin
Bile reflux
•Phospholipid A Nicotine
•Mucus
NSAID
•Bicarbonate aggressive factors Corticosteroid
•Motility
Stress
•Intracellular
H pylori
pH regulation
D Free radicals

defensive factors

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 Peptic ulcer treatment

 Anti acid • Misoprostol

• Sucralphate 4x500 mg
 Mucoprotector • Teprenone 3x50 mg
H2 Antagonist
• Rebamipide 3x100 mg
 Cimetidine
 Ranitidine DLBS 2411?
 Roxatidine
 Famotidine ⚫ Proton Pump Inhibitor
 Nizatidine ⚫ Omeprazole
⚫ Lansoprazole ❑ Potassium-competitive acid
⚫ Rabeprazole blockers (P-CABs)
⚫ Esomeprazole  Vonoprazan (1 x 20 mg)
⚫ Pantoprazole  Tegoprazan (1 x 50 mg)
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 Challenges in the
management of hyperacidity
 How do we reduce the recurrent condition of
hyperacidity?
 In a condition of hyperacidity, is it enough to
inhibit proton pump?
 Do we need to also reduce the synthesis of
proton pump?

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 Hunt RH, Scarpignato C. Curr Treat Options
Gastroenterol. 2018 Dec;16(4):570-590

DLBS-2411 (Redacid®) is a natural PPI. It is a bioactive fraction

from Cinnamomum burmannii (Indonesian cinnamon, locally 14
known as kayu manis)
DLBS 2411 a plant-derived therapeutic
substance that inhibits the expression of
the proton pump messenger RNA in
parietal cells

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 Proton Pump Down Regulator
(Decreases Expression of H+/K+ ATPase)

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Gastroprotection effect of DLBS2411

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 Expression of H+/K+ ATPase
on HEK293 and gastric parietal cells

Tjandrawinata RR, Nailufar

F, Arifin PF. Int J Gen Med.
2013 Sep 23;6:807-15.

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 Inhibitory effect of DLBS2411 on
H+/K+ ATPase gastric parietal cells
in vitro

Tjandrawinata RR, Nailufar F, Arifin PF.

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Int J Gen Med. 2013 Sep 23;6:807-15.
 Activity of H+/K+ ATPase on various pHs
Concentration Enzyme Activity % at pH Enzyme Enzyme Activity
( μg/ml.) 7.4 Activity % at % at pH 2
pH 4
0 100.00 100.00 100.00
10 90.60 64.70 58.60
25 60.70 46.52 37.18
30 47.30 35.12 22.40
50 38.90 0.19 11.27
Enzy me Activ ity Assay at v arious pH

120.00

100.00

pH 7,4
80.00 Enzyme Activity % at pH 7.4

pH 4
Enzyme Activity % at pH 4

Enzyme Activity % at pH 2
60.00
Enzyme Activity (%of control)

40.00 pH 2

20.00

pH Enzyme
0.00

0 10 25 30 50
activity
Concentration

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Inhibitory effect of DLBs2411
on ulceration in vivo

Tjandrawinata RR, Nailufar

F, Arifin PF. Int J Gen Med.
2013 Sep 23;6:807-15.

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Inhibitory effect of DLBs2411 on H+/K+
ATPase gastric parietal cells ex vivo

Tjandrawinata RR, Nailufar

F, Arifin PF. Int J Gen Med.
2013 Sep 23;6:807-15.

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GASTROPROTECTION EFFECT OF DLBS2411

DLBS 2411

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DLBS2411 produces mucus
on gastric mucosal cells

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Gastroprotective Effect of DLBS2411 on Gastric
Damaged in Rats Induced by Indomethacin

Male wistar rats will be divided into 5 treatment groups

Group Treatment (Orally)

First Group Vehicle 1 mL

Second Group Indomethacin + Vehicle
1 mL
Third Group Indomethacin + DLBS2411 25 mg/kg
BW
Fourth Group Indomethacin + DLBS2411 50 mg/kg
BW
Fifth Group Indomethacin + Sucralfat 100 mg/kg BW

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 Ulcer Index between
DLBS2411 and Sucralfat

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Antioxidant Activity of DLBS2411

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 Pathology of rats’ stomachs after being induced with ethanol. (A) Normal control
group; (B) Negative control group; (C) Positive control group (100 mg/kg BW
sucralfate); (D) 25 mg/kg BW DLBS2411; (E) 50 mg/kg BW DLBS2411. The arrows (►)
show representative findings of gastric ulcers.

Tjandrawinata RR, Nailufar

F.. J Exp Pharmacol. 2020;12:87-
95.

Conclusion: This study showed that DLBS2411 at the dose of 50 mg/kg

BW was more effective in protecting the stomach lining than DLBS2411
at the dose of 25 mg/kg BW, as measured by percentage of ulceration
inhibition and the ulcerative lesion index.

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Clinical Trial of DLBS 2411:

Division of Gastroenterology
Department of Internal Medicine-
Faculty of Medicine, University of Indonesia ,
Cipto Mangunkusumo National General Hospital
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 Mean Gastric pH over 24 hours,
after a single dose administration

Mean pH over the first 15 hours :

DLBS2411 : 2.54  0.65 (* p = 0.043)
Placebo : 1.99  0.76

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Onset to reach
pH >4 and
pH > 6

Abudullah M, et al (DLBS2411-
0111) 2013

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Mean Gastric within the first hour after administration of
single dose DLBS2411 compare with placebo

Abdullah M, et al (DLBS2411-0111) 2013

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94% Subjects in DLBS2411 Groups versus 75% of
them in Placebo reaching pH > 4 within 12 hours

Abdullah M., et al (DLBS2411-0111)

36 2013
 Comparison with PPIs
Percent of time of 24-h period with intragastric pH > 4
after an oral single dose administration

D. Pantoflickova et al.
Aliment Pharmacol Ther
2003

Abdullah M, et al (DLBS2411-0111)
2013

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 Comparison with Omeprazole and Pantoprazole
(with similar study design):
Mean 24-h intragastric pH after an oral single dose

N = total number of subjects in all studies included

in the Meta analysis.

Murdani et al (DLBS2411-0111) 2013 38J. Kirchheiner et al. Eur J Clin Pharmacol 2009
 Good Safety Profile
DLBS2411 250 mg Placebo
p‡
Variables Visit (n = 17) (n = 17)
Mean SD Mean SD
Liver Function:
Alanine transaminase, ALT (U/L) Baseline 21,8 12,5 18,8 6,9 0,813
End of study 23,6 15,4 19,2 11,0 0,673
p† 0,350 0,776
Aspartate transaminase, AST (U/L) Baseline 21,1 6,4 19,9 4,8 0,740
End of study 24,5 13,8 19,5 6,0 0,643
p† 0,393 0,601
Gamma glutamyl transpeptidase (U/L) Baseline 28,5 20,1 22,8 9,8 0,416
End of study 30,5 21,5 23,6 10,1 0,700
p† 0,359 0,338
Total bilirubin (U/L) Baseline 0,63 0,23 0,65 0,23 0,909
End of study 0,66 0,23 0,72 0,25 0,694
p† 0,245 0,201
Renal Function:
Serum Creatinine (mg/dL) Baseline 0,86 0,11 0,85 0,12 0,553
End of study 0,84 0,14 0,84 0,09 0,709
p† 0,374 0,569

DLBS2411 did not affect liver and renal function

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 Good Safety Profile
DLBS2411 250 mg Placebo
p‡
Variables Visit (n = 17) (n = 17)
Mean SD Mean SD
Vital Signs:
Systolic Blood Pressure, SBP Baseline 114,4 5,6 117,4 7,1 0,143
Hour-24 112,9 4,7 114,1 6,2 0,570
Hour-48 113,2 4,7 115,3 6,2 0,406
End of study 117,1 4,7 112,6 5,6 0,056
p₣ 0,017 0,007
Diastolic Blood Pressure, DBP Baseline 73,2 5,8 75,8 5,2 0,503
Hour-24 73,2 4,3 75,3 4,8 0,403
Hour-48 75,2 4,7 76,2 6,5 0,851
End of study 75,9 4,8 74,7 6,0 0,629
p₣ 0,253 0,780
Pulse (beats per minute) Baseline 83,4 5,1 83,8 4,8 0,732
Hour-24 85,6 5,3 83,8 5,0 0,453
Hour-48 86,1 6,2 86,2 4,7 0,222
End of study 87,0 6,1 84,1 5,6 0,329
p₣ 0,011 0,202
DLBS2411 250 mg Placebo
Variables (n = 17) (n = 17) p€
n % n %
General Health Status - End of study Good 17 100% 17 100% 1,000
Physical examination - End of Study Normal 17 100% 17 100% 1,000
Urinalysis - End of Study Normal 17 100% 17 100% 1,000

DLBS2411 did not affect vital

40 signs nor health status
 Good Safety Profile DLBS2411 250 mg Placebo
p‡
Variables Visit (n = 17) (n = 17)
Mean SD Mean SD
Hematological Function:
Haemoglobin, Hb (g/dL) Baseline 14,5 1,2 14,4 0,9 0,620
End of study 14,9 1,3 14,8 0,9 0,864
p† 0,165 0,029
Hematocrit, Ht (%) Baseline 43,9 3,4 43,3 2,3 0,574
End of study 44,9 3,5 44,4 1,9 0,479
p† 0,070 0,037
Erythrocyte count (10^6/µL) Baseline 5,0 0,4 5,0 0,3 0,322
End of study 5,2 0,4 5,1 0,3 0,343
p† 0,016 0,032
Platelet count (10^3/µL) Baseline 285,1 63,5 268,9 65,9 0,682
End of study 288,1 62,2 266,2 62,8 0,523
p† 0,569 0,582
Leucocyte count (10^3/µL) Baseline 8,96 2,95 8,14 1,83 0,446
End of study 8,75 2,10 7,62 1,92 0,283
p† 0,647 0,27
Basophil (%) Baseline 0,53 0,35 0,48 0,23 0,334
End of study 0,44 0,15 0,35 0,27 0,010
p† 0,254 0,066
Eosinophil (%) Baseline 3,36 1,60 3,93 2,71 0,792
End of study 2,61 1,24 3,60 2,20 0,500
p† 0,044 0,493
Neutrophil (%) Baseline 57,7 6,5 56,3 7,8 0,062
End of study 59,0 8,1 56,5 6,7 0,166
p† 0,488 0,903
Monocyte (%) Baseline 5,78 1,58 5,34 0,98 0,477
End of study 5,64 1,14 5,33 1,26 0,493
p† 0,615 0,958
Lymphocyte (%) Baseline 30,38 5,78 31,28 6,44 0,254
End of study 29,88 7,14 31,91 5,94 0,445
p† 0,730 0,751

DLBS2411 did not affect41hematological function

 Adverse events

All adverse events were mild, resolved by the end of study, and unlikely
to have causal relationship with study product

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Efficacy and Safety of DLBS2411
in the Management of GERD

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DLBS2411 Treatment For
Functional Dyspepsia

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 Conclusions
 DLBS2411 is dual proton pump inhibitor & downregulator
 DLBS2411 has also gastroprotection effect to the gastric mucosa by
increasing mucous production and antioxidant effect
 DLBS2411 at the dose of 250 mg once daily is effective in increasing
intragastric pH (suppressing the intragastric acidity) and proven to
be safe and tolerable.
 A nightly dosing of the bioactive fraction is proposed to maintain
its effect over 24 hours.
 DLBS2411 is promising to be one of future treatment of GERD and
other acid related diseases

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