PRODUCT MONOGRAPH

PRODUCT MONOGRAPH

Overview of Digestion 1

Importance of enzymes in process of digestion 3

Digestive enzyme deficiency 5

Introduction to Dyspepsia 6
CONTENTS

Etiology and Pathophysiology of Dyspepsia 7

Overlap of dyspepsia and gastroesophageal reflux 9

Unmet needs in the management of Dyspepsia 10

Management options for Dyspepsia 11

Rationale and advantage of use of DGL + digestive enzymes 11

Introduction of Unienzyme XT 12

Clinical Evidence of Liquorice 15

Key Conclusion 21

Reference 22
 Overview of Digestion
The digestive system includes the digestive tract and its accessory organs, which process food
into molecules that can be absorbed and utilized by the cells of the body. Food is broken down, bit
by bit, until the molecules are small enough to be absorbed and the waste products are
eliminated.1

The digestive tract, also called the alimentary canal or gastrointestinal (GI) tract, consists of a long
continuous tube that extends from the mouth to the anus. It includes the mouth, pharynx,
esophagus, stomach, small intestine, and large intestine. The tongue and teeth are accessory
structures located in the mouth. The salivary glands, liver, gallbladder, and pancreas are major
accessory organs that have a role in digestion. These organs secrete fluids into the digestive tract.
1

Food undergoes three types of processes in the body:

Ÿ Digestion

Ÿ Absorption

Ÿ Elimination

Digestion and absorption occur in the digestive tract. After the nutrients are absorbed, they are
available to all cells in the body and are utilized by the body cells in metabolism (figure 1).
1

Figure 1: Parts of diges ve system

Organs of the Diges ve System

Mouth

Tongue Pharynx
Esophagus
Liver
Gallbladder Stomach

Pancreas Large intes ne

Small intesone
Rectum
Anus

1
The digestive system prepares nutrients for utilization by body cells through six activities, or
functions.

Ingestion

The first activity of the digestive system is to take in food through the mouth. This process, called
ingestion, has to take place before anything else can happen.

Mechanical Digestion

The large pieces of food that are ingested have to be broken into smaller particles that can be
acted upon by various enzymes. This is mechanical digestion, which begins in the mouth with
chewing or mastication and continues with churning and mixing actions in the stomach.

Chemical Digestion

The complex molecules of carbohydrates, proteins, and fats are transformed by chemical
digestion into smaller molecules that can be absorbed and utilized by the cells. Chemical
digestion, through a process called hydrolysis, uses water and digestive enzymes to break down
the complex molecules. Digestive enzymes speed up the hydrolysis process, which is otherwise
very slow.

Movements

After ingestion and mastication, the food particles move from the mouth into the pharynx, then into
the esophagus. This movement is deglutition, or swallowing. Mixing movements occur in the
stomach as a result of smooth muscle contraction. These repetitive contractions usually occur in
small segments of the digestive tract and mix the food particles with enzymes and other fluids. The
movements that propel the food particles through the digestive tract are called peristalsis. These
are rhythmic waves of contractions that move the food particles through the various regions in
which mechanical and chemical digestion takes place.

Absorption

The simple molecules that result from chemical digestion pass through cell membranes of the
lining in the small intestine into the blood or lymph capillaries. This process is called absorption.

2
Elimination

The food molecules that cannot be digested or absorbed need to be eliminated from the body. The
removal of indigestible wastes through the anus, in the form of feces, is defecation or elimination.

Importance of enzymes in process of digestion

The human pancreas has the largest capacity for protein synthesis of any organ in the human
body. Much of the capacity is devoted to synthesis of the digestive enzymes that are secreted in
the intestinal lumen. Table 1 lists the major proteolytic, amylolytic, lipolytic and nuclease digestive
enzymes.2,3 Some of the enzymes are present in more than one form (e.g., cationic trypsinogen,
anionic trypsinogen and mesotrypsinogen). Further, they are capable of digesting the cell and
causing significant damage. There are mechanisms to prevent these enzymes from potentially
digesting the pancreas including storage and packing in acidic zymogen granules to inhibit
activity; and synthesis and storage as inactive precursor forms. The lists in Table 1 show some of the
enzymes that are stored in the pancreas before secretion as inactive proenzymes. These
proenzymes are activated when they enter the duodenum. Activation of these enzymes takes
place in the surface of the duodenal lumen, where a brush-border glycoprotein peptidase,
enterokinase, activates trypsinogen by removing an N-terminal hexapeptide fragment of the
molecule. The active form, trypsin, then catalyzes the activation of the other inactive proenzymes.
3

Of note, many key digestive enzymes, such as α-amylase and lipase, are present in the pancreas
in their active forms (Table 1). Presumably, these enzymes would not cause pancreatic cellular
damage if released into the pancreatic cell/tissue because there is no starch, glycogen or
triglyceride substrate for these enzymes in pancreatic tissue.

Table 1: Diges ve proenzymes and enzymes in the pancreas. Diges ve enzymes are stored in the pancreas as
either inac ve proenzyme forms or ac ve enzymes.
PROENZYMES ENZYMES
Trypsinogens (1, 2, 3) α-Amylase
Chymotrypsinogen (A, B) Lipase
Procarboxypep dase A (1, 2) DNase
Procarboxypep dase B (1, 2) RNase
Prophospholipase (I, II)
Proelastase
Mesotrypsin

3
Another mechanism that the exocrine pancreas utilizes to prevent intracellular activation involves
the synthesis and incorporation of a trypsin inhibitor (pancreatic secretory trypsin inhibitor [PSTI])
into the secretory pathway and zymogen granule. PSTI is a 56-amino acid peptide that inactivates
trypsin by forming a relatively stable complex with the enzyme near its catalytic site. The function
5

of the inhibitor is to inactivate trypsins that are formed autocatalytically in the pancreas or
pancreatic juice, thus, preventing pancreatic digestion and resulting disorders, such as
pancreatitis. In the following paragraphs are descriptions of the functions of the major digestive
enzymes (Figure 2).6

Figure 2: Various types of pancrea c enzymes

Types of pancrea c enzymes

Protease
Amylase

Lipase

Amylase

It is secreted by both the pancreas and salivary glands, differing in molecular weight,
carbohydrate content and electrophoretic mobility.7 However, they have identical enzyme
activities. Salivary amylase initiates digestion in the mouth and may account for a significant
portion of starch and glycogen digestion because it is transported with the meal into the stomach
and small intestine, where it continues to have activity. Optimal enzyme activity occurs at neutral
pH. During a meal, gastric pH can approach neutrality despite gastric acid secretion because of
the buffering from molecules in the meal as well as alkaline secretions from the salivary glands
and gastric mucus. Salivary amylase can contribute up to 50% of starch and glycogen digestion
while pancreatic amylase contributes the remainder. The brush-border enzymes complete the
hydrolysis of the products of amylase digestion to glucose. The final product, glucose, is
transported across the intestinal absorptive epithelial cell by a Na+-coupled transport.
8

4
Lipases

They are secreted mainly by the pancreas in contrast to amylase where there is a significant
salivary contribution. There are lingual and gastric lipases but these contribute to fat digestion in
only a minor fashion. Major lipases secreted by the pancreas are lipase (or triglyceride lipase) and
prophospholipases.

Lipase binds to the oil/water interface of the triglyceride oil droplet, where it acts to hydrolyze the
triglyceride. Both bile acids and colipase are important for the full activity of lipase. Bile acids aid in
the emulsification of triglyceride to enlarge the surface area for lipase to act on, and they form
micelles with fatty acids and monoglyceride, which, in turn, remove these products from the
oil/water interface. Colipase is believed to form a complex with lipase and bile salts. These ternary
complex anchors lipase and allows it to act in a more hydrophilic environment on the hydrophobic
surface of the oil droplet.

Proteases

They are secreted by the pancreas are generally divided into two groups—the endopeptidases
and the exopeptidases. All are stored and secreted from the pancreas as inactive proforms that
are activated in the duodenum by trypsin. Trypsin, chymotrypsin and elastase are
endopeptidases that cleave specific peptide bonds adjacent to specific amino acids within a
protein. Exopeptidases include carboxypeptidases that cleave peptide bonds at the carboxyl
terminus of proteins.

Importantly, the combined actions of the pancreatic proteases and pepsin from the stomach
result in the formation of oligopeptides and free amino acids. The oligopeptides are further
digested by brush-border enzymes on the lumenal surface of the small intestine. Both free amino
acids and oligopeptides are transported across the intestinal mucosa by a group of Na+- and H+-
coupled transporters.

Digestive enzyme deficiency

Several factors cause enzyme inadequacy and deficiency. Impaired secretion meaning
dysfunction of digestive organs, mucosal disease, gastrointestinal surgery and nutritional
deficiency, Poor eating habits (inadequate chewing of food) “eating on the run,” or eating late in
the day could be some of the significant factors. Also, different dietary choices such as excessive
consumption of alcohol, refined carbohydrates and fat, as well as a high meat and cooked food

5
diets with few raw, enzyme-rich foods could also play a significant role. Aging alters digestive
enzyme secretion with linear decrease reported after 4th decade of life.

Aging leads to decrease in both basal and stimulated pepsin output. In elderly, pepsin output is
reduced by approximately 40%. In a study on pancreatic secretion in the elderly, it was found that
9

the concentrations of lipase, phospholipase and chymotrypsin decreased linearly from the 3rd
decade onwards.10 It is fairly common for elderly individuals to experience both a decrease in
hydrochloric acid production as well as a general decline in digestive enzyme secretion. With a
growing elderly population, unhealthy diets and stressful life styles, it is likely that healthcare
professionals will find more and more patients developing digestive problems. It is estimated that
58% of the population suffers from some type of digestive disorder. A lack of optimal digestive
function associated with enzyme inadequacy may lead to malabsorption and a host of related
conditions.

Introduction to Dyspepsia
The study of gastrointestinal problems in elderly is a priority for primary care physicians as they
constitute an ever-increasing part of the population. Over the years researchers have speculated
11

that functioning of the gastrointestinal tract declines with aging. It was hypothesized that the
efficiency of digestion and absorption declines with age which is now found to be true with rigorous
testing. Indigestion and its symptoms are associated with poor quality of life, increased
12

absenteeism from work, and also constitute a significant burden on the health care system.

Indigestion is very common in the community, with prevalence of 30% and above.13 Up to 40% of
patients will consult a primary care physician as a result. Dyspepsia is diagnosed in presence of
symptoms thought to originate from the gastro-duodenal region (early satiation, postprandial
fullness, epigastric pain or burning). Prevalence of dyspepsia is about 20-30% worldwide. 7.6 to
14

49% of Indian population report dyspeptic symptoms14. Dyspepsia is reported by almost one-third
of the population in Mumbai; significant symptoms occur in 12%. Forty percent of these subjects
receive treatment and only a small number undergo endoscopy or ultrasonography.
15

Patients who do not fit into the alarming criteria for dyspepsia classified as uncomplicated
dyspepsia need primary care management at the first instance.17

6
Common gastrointestinal complaints in elderly patients are indigestion, abdominal pain,
flatulence, GERD which affects more than 60% of the elderly population. These complaints have
multiple triggers like changing food habits, processed food items, improper food timings, multiple
medications, reduced production of digestive enzymes, recurrent abdominal infections, stress,
etc.18

Etiology and Pathophysiology of Dyspepsia

The etiopathology of dyspepsia is multifactorial. (figure 3, 4) Although the pathophysiology of
indigestion remains unclear, drastic reduction in digestive enzymes production, delayed gastric
emptying, impaired gastric accommodation, and visceral hypersensitivity have been suggested
as the underlying mechanisms. A study by Nakae et al. found significant dysbiosis in the gastric
19

fluid microbiota of patients with indigestion and considered it to be the underlying pathogenesis.
20

Therefore, an optimal balance between indigenous beneficial bacteria and potentially

pathogenic bacteria in the gut is essential for efficient digestion and nutrient absorption. Also,
various digestive enzymes, amylase, protease, and lipases act as a biological catalyst in the
process of digestion. Imbalances in this gastrointestinal milieu which occur due to aging can lead
to indigestion and other symptoms like abdominal pain and flatulence.21 Indigestion causes
malabsorption of nutrients and in turn malnutrition and breakdown of immune system in elderly
patients. Malnutrition is one of the most relevant conditions that negatively influence the health of
older people. The nutritional status of elderly has been shown to predict preterm death. Therefore,
22

maintaining a good GI/digestive health is of paramount importance and is the key to overall good
health.

Food ingestion plays an important role in the genesis of FD symptoms, although the mechanisms
remain to be elucidated. In a study, a standard solid meal was given to 218 tertiary care patients
with FD, and symptom severity was measured every 15 minutes for 4 hours.23 Even if patients failed
to recognize a relationship between eating and their symptoms, nearly 80% had increased
symptom intensity 15 minutes after the meal. Notably, the timing varied by symptom type, with
fullness occurring much earlier than pain after the meal. Interestingly, those patients with EPS were
also more likely to report a delayed peak in pain, suggesting they frequently have true meal-
induced symptomatology, but it often goes unrecognized.

7
 Figure 3: E ologies of dyspepsia

Dyspepsia pathophysiology

Lifestyle Medica on Diet Stress Post-Infec ous

Fundic Antrum Delayed Gastric Duodenal Sensi vity Immune

Accommoda on Distension Emptying to Acid Ac va on

Duodenal Visceral Duodenal Sensi vity

Eosinophilia Hypersensi vity to Lipids

Figure 4: Mul factorial pathophysiology of Dyspepsia

Psychological
Stress
Factors

Helicobacter
Pylori Inflamma on Stress Anxiety

Light to Moderate
Healthy Person Severe Dyspepsia
Dyspepsia

Environmental Gastrointes nal Soma za on

Depression
Factors infec on Disorder

Gene c >> Visceral

Factors Sensi vity

High-fat meals slow gastric emptying and can lead to dyspepsia, while moderate-to-fast eating
and irregular meals are also associated with dyspepsia.24,25 The role of disturbances in gut
hormones in FD postprandially is uncertain, although increased cholecystokinin and ghrelin have
both been implicated potentially.
26,27

8
Thus, in the pathogenesis of functional dyspepsia, gastric fullness, slow gastric emptying and
resultant slow digestion seems to be playing an integral part.

Overlap of dyspepsia and gastroesophageal reflux28

Figure 5: Overlap of Dyspepsia and GERD

Dyspepsia is defined as pain or discomfort centered in the upper abdomen. It has been suggested
that these symptoms differentiate dyspepsia from gastro-oesophageal reflux disease, where
heartburn is the predominant symptom. It has been suggested that a word-picture questionnaire
may help to improve the identification of dyspeptic patients with underlying heartburn.

The aims of this study were: (i) to assess the prevalence of dyspeptic symptoms with and without
overlapping reflux symptoms in the general population and their impact on daily life and on
healthcare utilization; and (ii) to compare symptom groupings in the general population to FD
patients.

2025 subjects were submitted to a questionnaire with validated questions on their dyspeptic and
reflux symptoms and with evaluators of impact on daily life and use of healthcare resources.

Significant dyspeptic symptoms were found in 417 (20.6%). Overlapping reflux symptoms were
present in 141 (33.8%). (Figure 6)

Dyspeptic symptoms are frequent in the general population, with overlapping reflux symptoms
and increased symptom burden in about a third.

9
 Figure 6: The pie chart on the le -hand side shows the propor on of subjects without and with dyspep c
symptoms. The pie chart on the right-hand side shows the overlap between dyspepsia and reflux symptoms
in those with self-reported dyspep c symptoms

141
(33.8%)

1608 417 4 (1.0%)

237
35
(56.8%)
(8.4%)

R0 D0: No symptoms during the last year

R– D+: Dyspep c symptoms, no reflux symptoms
R+ D+: Dyspep c and reflux symptoms
R+ D– : Reflux symptoms without dyspep c symptoms
R– D– : Indeterminate minimal symptom burden

In another prospective, pan-Indian multi-centric study, primarily aimed to evaluate clinical profile
of patients with IBS, 1364 of 2785 patients with IBS reported upper abdominal pain or discomfort,
which are the cardinal symptom for FD. This study suggested that frequency of overlap between FD
and IBS is high Indian population.
14

Unmet needs in the management of Dyspepsia

Digestive symptoms are common, affecting more than 60% of adults. Individuals with indigestion
suffer significant morbidity and expend significant resources through both direct and indirect
costs. The common symptoms of indigestion include abdominal pain, a feeling of undue fullness
29

after eating, loss of appetite, nausea, or vomiting and excessive. Age-related changes in the gut
microbiota are associated with the physiological changes in the GIT, as well as in dietary patterns,
with a concomitant decline in the normal function of the digestion leading to symptoms of
indigestion. Family physicians have a primary role in treating indigestion. Indigestion can be
30

treated initially by lifestyle changes. Lifestyle modifications include avoiding foods that trigger
indigestion, eating five or six small meals a day instead of three large meals, reducing or
eliminating the use of alcohol and caffeine, avoiding certain pain relievers, such as aspirin,
ibuprofen, and naproxen sodium, and controlling stress and anxiety. Definitive treatment includes
31

supplementation of digestive enzymes, acid suppressive therapy with proton pump inhibitors or

10
digestive enzymes, prokinetic agents, and 5-HT1 agonists.32 Limitations of these drugs include
incomplete cure, recurrence, relapse, and associated adverse drug reactions.

Therefore, there is a need for new therapy which can overcome the limitations of the current
therapy as well as provide an early and sustained symptomatic relief.

Management options for Dyspepsia

Treatment can be challenging, where the main aim is symptom control.33,34 Initial management
begins with an explanation of the diagnosis and discussing the patient's expectations for
treatment. If it is suspected, H. pylori eradication is recommended as the first treatment for all
patients with functional dyspepsia. This improves symptoms and decreases the risk of peptic
ulcers and gastric cancer. After this, treatment is a two-step process. The first-line treatment is
35,36

with a proton pump inhibitor or H2 receptor antagonist for at least four weeks. Then, if symptoms
persist, subsequent treatment with tricyclic antidepressants or prokinetic agents are pursued.37
Adjunctive or alternative non-pharmacologic therapies include psychotherapy, herbal
supplementation, lifestyle modification, dietary interventions, acupuncture, and electrical
stimulation.
38

These different therapy options are not satisfactorily efficacious. As compared to placebo,
prokinetics were able to provide 33% (95% CI: 18% to 45%) risk reduction were as H2 blockers
provided risk reduction of 23% (95% CI: 8% to 35%). Presently most commonly used therapy, proton
pump inhibitors provided mere 13% (95% CI: 4% to 20%) of risk reduction and bismuth salts 40%
(Marginally: 95% CI: -3 to 65%). Antacids and Sucralfate were found to be as good as placebo.39

Rationale and advantage of use of DGL + digestive enzymes

Digestive enzymes are often prescribed to patients with various dyspeptic complaints. Reports
suggested a beneficial role of enzyme preparations in dyspepsia. In addition to consuming
40

adequate levels of raw foods, a common approach to supporting the patient with digestive
enzyme inadequacy is oral enzyme replacement. A study pointed the role of pancreatic enzyme
supplementation in functional dyspepsia where the therapy significantly reduced the symptoms
of flatulence, bloating, belching, fullness and post-prandial distress.41

Mechanism of DGL shows that it is an antispasmolytic (i.e., helps to relax the intestinal wall) to
provide relief of indigestion symptoms, while it also repairs the mucosal lining of the digestive tract
to promote its overall integrity and the rationale for prescription of digestive enzymes is that

11
carbohydrates, proteins and fats are initially converted to smaller units by various digestive
enzymes and are then assimilated.

By aiding the digestive process, the dyspeptic symptoms would be ameliorated.

Hence, to assist the adequate digestion of every nutrient and symptomatic relief, a combination of
different enzymes and DGL supplementation must be given.

Introduction of Unienzyme XT
It is a dietary supplement that accelerates the digestion process and helps in the treatment of
indigestion, bloating, gas or any stomach discomfort. It acts as a natural pro-digestive enzyme
that helps in the breakdown of food into simpler compounds, thereby aiding the digestion process.

One of the integral component of Unienzyme XT is licorice which is also known as DGL licorice. DGL
stands for Deglycyrrhizinated licorice, which is a safer form of the natural digestive soothing
ingredient because it has less than 2% glycyrrhizin, which among other observed side effects, can
cause elevations in blood pressure with long-term use. This is the best DGL Licorice for medicinal
use.

Licorice is native to Europe (mostly Greece & Turkey) and Asia, where the plant is actually classified
as a weed. Growing to be three to seven feet in height, licorice has an extensive underground root
system, which grows horizontally. Licorice roots are brown on the outside and yellow on the inside.

Ancient cultures, especially early Egyptians, often used licorice root in tea as a general health
boost. Licorice later made its way to China where it became an important herb in Chinese
medicinal tradition.

Role of Liquorice

In traditional use, Licorice has been used more broadly for hormonal issues, gut and throat issues,
respiratory support, and fatigue. However, Licorice shines in particular for soothing inflammation in
the digestive tract and suppressing acid. Licorice (Glycyrrhiza glabra) has been used in food and
as medicine for thousands of years. Also known as "sweet root," licorice root contains a compound
that is about 50 times sweeter than sugar. (figure 7) Licorice root has been used in both Eastern
and Western medicine to treat a variety of illnesses ranging from the common cold to liver disease.
It acts as a demulcent, a soothing, coating agent, and as an expectorant, meaning it helps get rid
of phlegm. It is still used today for several conditions, although not all of its uses are supported by
scientific evidence.

12
 Figure 7: Liquorice

DGL Licorice has been well-studied to promote digestive comfort, and with strong results relative to
over-the-counter options. In particular, a 2018 observational study found that DGL was more
effective than acid-suppressive drugs. Scientific investigation into the mechanism of DGL shows
that it is an antispasmolytic (i.e., helps to relax the intestinal wall) to provide relief of indigestion
symptoms, while it also repairs the mucosal lining of the digestive tract to promote its overall
integrity.

Role of Fungal Diastase

Diastase enzyme can be found not just in malt, but also in barley seeds, plants, milk and our own
saliva. With standard diastase enzyme levels, carbohydrates in the human psyche are digestible
by transformation to sugars. Certainly, the enzymes detected in our saliva are glucoamylase and
amylase. Milk and honey are natural sources of diastase enzymes and will help to alleviate these
effects if you find that the body may not agree with the carbohydrates you have eaten. Diastase
enzyme is also present in supplementary form since many individuals are lactose-intolerant and
the absence of milk in their diet contributes to diastase deficiency. The entire aim of the enzymes,
whether normal or complemented, is to make sure that our body gets the most out of the food it
consumes.

It is an enzyme obtained from the growth of a strain of Aspergillus oryzae. It contains two types of
amylases namely, alpha amylase and beta amylase. These amylases have specific activity to
convert starch into dextrose, maltose. The amylolytic activity ratio of fungal diastase in tablets is
1:800. It means that, one part of fungal diastase digests 800 parts of cooked starch that is

13
consumed with meal. Fungal diastase also has some protease action and some lipase activity.
This means that some digestive action is seen on proteins and fats.

Role of papain

It is a proteolytic enzyme or mixture of enzymes, which have plant origin. Papain is prepared from
the juice of the unripe fruit of Carica Papaya. The enzyme consists chiefly of a mixture of papain
and chymopapain, which digest proteins to enzymes.

Papain is a plant proteolytic enzyme for the cysteine proteinase family cysteine protease enzyme
in which enormous progress has been made to understand its functions. Papain is found naturally
in papaya (Carica papaya L.) manufactured from the latex of raw papaya fruits. The enzyme is
able to break down organic molecules made of amino acids, known as polypeptides and thus
plays a crucial role in diverse biological processes in physiological and pathological states, drug
designs, industrial uses such as meat tenderizers and pharmaceutical preparations. The unique
structure of papain gives it the functionality that helps elucidate how proteolytic enzymes work
and also makes it valuable for a variety of purposes.

Papain has a proteolytic activity, which is like that of the natural enzyme pepsin. The advantage of
papain over pepsin is that it is active over a wide pH range of 3 to 10.5 as compared to pepsin
(which is not active above a pH of 4.5). Papain therefore is active in different pH value. Hence it is
useful even in conditions of achlorhydria or hypochlorhydria. It is thus used as one of the
ingredients in enzyme preparations to aid in protein digestion.

Role of Activated Charcoal

It is an enterosorbent. Specially prepared charcoal has high surface activity, adsorbs gases,
alkaloids, endo- and exotoxins and other chemical compounds. Activated charcoal in the
composition of Unienzyme XT acts as enterosorbent and detoxicant, provides adsorbtion of gas
and toxins, which occur under indigestion, adsorbs poorly soluble substances, reduces the volume
capacity of intestinal track, and thereby produces relief from symptoms of flatulence and
dyspepsia, acting complexly along with enzymes.

14
 Clinical Evidence of Liquorice
Objective:

Raveendra KR et al conducted a randomized, double-blind, placebo-controlled study using

Liquorice in patients with functional dyspepsia. Efficacy was evaluated in terms of change in the
severity of symptoms (as measured by 7-point Likert scale), the global assessment of efficacy,
and the assessment of quality of life using the short-form Nepean Dyspepsia Index.47

Method:

A randomized, double-blind, placebo-controlled study was conducted over a period of four

months.

After the diagnoses, 50 patients were randomly assigned to placebo (n = 25) and Liquorice (n =
25) groups.

Test medication was dispensed by the pharmacist in a container with 30 capsules on day 0 and
day 15.

The patients were instructed to take placebo or Liquorice (75 mg twice daily) with a glass of water
after food (one capsule morning and one in the night).

Patients were informed to visit the trial centers on day 15 and day 30 for follow-up. At each visit, the
investigators informed the patients to bring the capsule container, and remaining capsule
(unused) counts were performed.

Patient who took completely the issued capsules was considered to be compliant to the study
medication.

The primary outcome variables of the study were the change in the severity symptoms and the
global assessment of efficacy. The quality of life was evaluated as a secondary outcome measure.

15
 Figure 8: Flow chart of disposi on of pa ents

Randomized (ir = 50)

Placebo GutGard
Alloca on

Allocated to interven on (n = 25) Allocated to interve ion (n = 25)

Ÿ Received allocated interven on (n = 25) Ÿ Received allocated interven on (n = 25)
Ÿ Did not receive allocated interven on Ÿ Did not receive allocated interven on (give
(give reasons) (n = 0) reasons) (n = 0)

Follow up

Lost to followup (give reasons) (n = 0) Lost to followup (give reasons) (n = 0)

Discon nued interven on (give reasons) (it = 0) Discon nued interven on (give reasons) (it = 0)

Analysis

Analysed ( = 25) Analysed ( = 25)

Ÿ Excluded from analysis (give reasons) (n = 0) Ÿ Excluded from analysis (give reasons) (n = 0)

In comparison with placebo, Liquorice showed a significant decrease (P ≤ .05) in total symptom
scores on day 15 and day 30, respectively. (Figure 9) Similarly, Liquorice showed marked
improvement in the global assessment of efficacy in comparison to the placebo. The Liquorice
group also showed a significant decrease (P ≤ .05) in the Nepean dyspepsia index on day 15 and 30,
respectively, when compared to placebo. Liquorice was generally found to be safe and well-
tolerated by all patients. Liquorice has shown significant efficacy in the management of functional
dyspepsia. (figure 10).
47

Figure 9: Efficacy of Liquorice on improvement of total symptom scores and Nepean dyspepsia index

Day 15 Day 30 Day 15 Day 30

0

-5
-4.04
-5.08
-6.56
-10 -8.24
-11.32
-15 -12.08
-15.2
-20
Total symptom scores Nepean dyspesia index -19.56
(Change from baseline) (Change from baseline)
-25
Placebo Liquorice

16
 Figure 10: Efficacy of Liquorice on improvement of global assessment of efficacy

60%
56% 56%
50%
% of the total pa entes

44%
40%
36%
30%

20%

10% 4% 4%
0% 0% 0% 0%
0%
Symptom free Markedly Improved Moderately Not Changed Deteriorated
Improved
Liquorice Placebo

Laboratory Investigations

The blood parameters carried out on day 0 and day 30 in Liquorice and placebo groups were
within normal limits. There was no study medication-related adverse effect reported during the
complete intervention period and none of the patients in both groups complained deteriorated
condition. (Table 2)

Table 2: Results of laboratory blood parameters (mean ± SE)

parameters Day 0 Day 30
Placebo (n = 25) GutGard (n = 25) Placebo (n = 25) GutGard (n = 25)
Haemoglobin(g/d1) 13.30 ± 0.31 13.40 ± 0.33 13.37 ± 0.30 13.58 ± 0.28
Random blood sugar(mg/dL) 86.64 ± 2.76 103.6 ± 2.08* 91.44 ± 1.59 100.72 ± 2.30*
Serum crea nine(mg/dL) 0.93 ± 0.02 0.83 ± 0.03* 0.88 ± 0.02 0.88 ± 0.02
Serum glutamic oxaloace c transaminase (1U/1) 20.64 ± 1.56 20.50 ± 1.45 20.20 ± 1.08 17.28 ± 1.24
Serum glutamic pyruvic transaminase (U/L) 23.48 ± 1.73 28.03 ± 1.71 20.80 ± 1.07 23.20 ± 1.19
*P < .05 versus placebo.

Conclusion

The findings of the randomized double-blind, placebo-controlled, clinical trial revealed significant
decrease in symptoms scores in concordance with improvements in almost all individual
symptoms and found to be superior to placebo group in the management of functional
dyspepsia. The present study also exhibited significantly improved quality of life as evidenced by
improved NDI upon administration of the test substance at 75 mg twice daily for 30 days. Hence,

17
Liquorice supplementation can be considered as a safe and effective remedy for patients with
functional dyspepsia.

Numerous clinical studies over the years found DGL to be an effective antiulcer compound. DGL
was shown to be extremely effective in the treatment of gastric ulcers.

In one study, 33 gastric ulcer patients were treated with either DGL (760 mg, three times a day) or a
placebo for 1 month. There was a significantly greater reduction in ulcer size in the DGL group (78%)
than in the placebo group (34%). Complete healing occurred in 44% of those receiving DGL but only
in 6% of the placebo group.42

In several head-to-head comparison studies, DGL was shown to be more effective than cimetidine
(Tagamet), ranitidine (Zantac), or antacids in both short-term treatment and maintenance
therapy of peptic ulcers.43, 44, 45 For example, in a head-to-head comparison with Tagamet, 100
patients received either DGL (760 mg, three times a day between meals) or Tagamet (200 mg,
three times a day, and 400 mg at bedtime). The percentage of ulcers healed after 6 and 12 weeks
were similar in both groups. Although Tagamet is associated with some significant side effects,
DGL is extremely safe to use.

Gastric ulcers are often a result of using alcohol, aspirin, or other nonsteroidal anti-inflammatory
drugs, caffeine, and other factors that decrease the integrity of the gastric lining. Because DGL was
shown in human studies to reduce the gastric bleeding caused by aspirin, DGL is strongly indicated
for the prevention of gastric ulcers in patients requiring long-term treatment with ulcerogenic
drugs such as aspirin, nonsteroidal anti-inflammatory agents, and corticosteroids.46

Hajiaghamohammadi AA et al evaluate the effect of licorice in H. pylori eradication in patients

suffering from dyspepsia either with peptic ulcer disease (PUD) or non-ulcer dyspepsia (NUD) in
comparison to the clarithromycin-based standard triple regimen. In this randomized controlled
clinical trial, 120 patients who had positive rapid urease test were included and assigned to two
treatment groups: control group that received a clarithromycin-based triple regimen, and study
group that received licorice in addition to the clarithromycin-based regimen for two weeks. H.
pylori eradication was assessed six weeks after therapy. Data was analyzed by chi-square and t-
test with SPSS 16 software. Mean ages and SD were 38.8 ± 10.9 and 40.1 ± 10.4 for the study and
control groups, respectively, statistically similar. Peptic ulcer was found in 30% of both groups.
Response to treatment was 83.3% and 62.5% in the study and control groups, respectively. (Figure
11) This difference was statistically significant. Use of Licorice was associated with better
improvement in dyspepsia as well as H pylori resolution.48

18
 Figure 11: Frequency of response to treatment in the Liquorice and control groups

90.00% 85% 83.30%

82.40%
80.00%
% of the pa ent with

70.00% 67.50% 62.50%

symptom relief

60.00% 50%
50.00%
40.00%
30.00%
20.00%
10.00%
0.00%
Non-ulcer dyspepsia Pep c ulcer disease Total

Liquorice Placebo

Clinical evidence of efficacy and safety of oral enzymes supplement

Banka et al., evaluated the efficacy and safety of fungal diastase and papain in patients (n = 100)
of non-ulcer dyspepsia. Efficacy and tolerability were assessed at baseline, at day 7 and at day 14
of treatment.

Ÿ Significant improvement in frequency and severity of all symptoms of indigestion (fullness,

belching, bloating, flatulence and postprandial distress

Ÿ 67% and 29% of physicians rated excellent and good efficacy, respectively, in resolving
dyspeptic symptoms.

Ÿ 65% and 27% of patients rated excellent and good tolerability, respectively.

Ÿ Well tolerated with minor adverse effects (nausea and skin problems).40

A post-marketing surveillance study was conducted to evaluate the efficacy and tolerability of a
multienzyme preparation containing amylase, protease, lipase, lactase and alpha-
galactosidase. The FDC was given for 14 day.

Ÿ Significant reduction in frequency and severity of every abdominal symptom (flatulence,

bloating, belching, dyspepsia, feeling of fullness, abdominal discomfort, heart burn and
anorexia) (p <0.0001).

Ÿ 55% physicians rated the preparation as excellent and 41% as good.

Ÿ 51% rated the preparation as excellent and 44% rated it as good in terms of tolerability and
effectiveness.41

19
Ran et al. assessed patients (n=151, 18 to 75 years) diagnosed with chronic digestive diseases
presenting with two or more dyspepsia symptoms such as epigastric pain, abdominal distension,
epigastric burn, belching, diarrhea and constipation. The efficacy of an enzyme preparation
containing 24-mg enzyme extract of Aspergillus oryzae (cellulase, protease and amylase) and
220 mg pancreatin (lipase, proteinase and amylase) given post-meal (2 tablets), thrice a day was
assessed in these patients. Patients recruited included functional dyspepsia, GERD, a peptic ulcer
(without complications such as bleeding, perforation, stenosis and malignancy), chronic gastritis,
partial gastrectomy, small or large intestinal resection, diverticulosis, liver cirrhosis (without
serious complications), chronic biliary disease including cholecystitis, cholelithiasis, polyps of the
gallbladder, cholecystectomy, chronic pancreatic disease including chronic pancreatitis, chronic
pancreatic insufficiency, diabetes mellitus with dyspepsia symptoms and geriatric reduction of
digestive function.

Ÿ Compared with placebo, 2 weeks of enzymatic treatment decreased the severity index of
dyspepsia symptoms significantly.

Ÿ The efficacy rates of enzyme preparation and the placebo on dyspepsia were 90% and 22%,
respectively (P <0.01).
49

The study by Pawar D (2001) evaluated the efficacy and safety of fungal diastase and papain in
patients (n = 100) of non-ulcer dyspepsia. Efficacy and tolerability were assessed at baseline, at
day 7 and at day 14 of treatment.

Ÿ End of the 14-day treatment exhibit significant improvement in frequency and severity of all
symptoms of indigestion (fullness, belching, bloating, flatulence and postprandial distress).

Ÿ Physician rated excellent (67%) and good efficacy (29%) whereas patients rated excellent (65%)
and good tolerability (27%) in resolution of symptoms of functional dyspepsia.

The combination was well tolerated with minor adverse effects (nausea and skin problems).
50
Ÿ

A post-marketing surveillance study by Khandke D et al (2013) evaluated the efficacy and

tolerability of a multienzyme preparation containing amylase, protease, lipase, lactase and
alpha-galactosidase. The multienzyme preparation was given for 14 days.

Ÿ Treatment was associated with a significant reduction in frequency and severity of every
abdominal symptom (flatulence, bloating, belching, dyspepsia, feeling of fullness, abdominal
discomfort, heart burn and anorexia) (p <0.0001).

20
Ÿ In the overall assessment by physicians 55% rated the preparation as excellent and 41% as good.

Ÿ Assessment by patients in terms of tolerability and effectiveness was also carried out with 51%
rated the preparation as excellent and 44% rated it as good.41

Ahyani T (2016) conducted a randomized study 116 patients who fulfilled the Rome III criteria for
functional dyspepsia. Patients received either lactobacillus probiotics or placebo for 2 weeks. The
probiotics group had significantly reduced frequency of pain (P=0.0001), but no significant
differences in pain severity (P=0.08) or pain duration (P=0.091) compared to placebo after the end
of 2 weeks study period.

Ÿ In conclusion, authors found no significant differences in recovery from functional dyspepsia

but the probiotics group has significantly reduced frequency of pain compared to that of the
placebo group.51

Key Conclusion
Ÿ Dyspepsia is a common condition frequently found in individuals particularly with old ages

Ÿ Prevalence of dyspepsia is very common in India and it is associated with a common

symptom with a range of digestive diseases

Ÿ Presently, all the recommended medications have been shown to be mildly or moderately
effective in the management of dyspepsia

Ÿ Role of various digestive enzyme combinations have been suggested to be having an

important place in the management protocol of dyspepsia

Ÿ In various clinical studies also, the digestive enzyme combination has been proved to be
efficacious

Ÿ This digestive enzyme combination is shown to be equally efficacious to the other

pharmacological remedies with a greater safety profile

Ÿ Addition of DGL Liquorice makes the old and reliable Unienzyme combination further potent
and efficacious as well as relevant for the management of dyspepsia

21
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