Efficacy and acceptability of pomegranate effervescent granules in patients suffering from acid peptic disorders.

CONTEXT: Acid peptic disorders. AIMS: This study aimed to assess the efficacy and acceptability of pomegranate effervescent granules (PEGs) in dyspeptic patients. SETTINGS AND
DESIGN: It was a single-arm, open-labeled prospective multicentric clinical study, done at 3 centers: Vishwanand Kendra, Pune; Bharati Ayurved Hospital, Bharati Vidyapeeth, Pune, and M. A. Podar Medical Ayurved Hospital, Mumbai. The co-ordinating site was Interactive Research School for Health Affairs, Bharati Vidyapeeth, Pune.
MATERIALS AND METHODS: The granules, prepared from peel extract of pomegranate, were made available in sachets of 2.5 g with dose of, 1 sachet dissolved in 200 ml (1 cup) of water, twice a day after meals for 28 days. Gastrointestinal Symptom Rating Scale (GSRS) scores to assess symptoms of acid peptic disorders at day 0, 15, and 29 along with the taste of formulation were the main study outcomes. STATISTICAL ANALYSIS USED: Parametric data, presented as mean ± standard deviation, were analyzed using paired t-test, while nonparametric data presented as median (range) was analyzed using Wilcoxon rank-sum test. Categorical data were analyzed using Chi-square test.
RESULTS: The median GSRS score reduced from 14 on day 0-10 and then 5 on day 15 and day 29, respectively, with statistical significance. The formulation was found to taste good by ~80% of patients, while ~20% reported it to be palatable and none found it to be bad in taste.
CONCLUSION: PEGs proved to be palatable, patient-friendly, safe, and efficacious in resolving symptoms of dyspepsia in acid peptic disorders. CTRI Registration: The trial was registered retrospectively in the Clinical Registry of India [CTRI/2017/07/008999].

Introduction

Acid peptic disorders can be counted among the most common ailments occurring in daily life today due to stressful work environments, haphazard meal timings, increased intake of ready-to-eat foodstuffs, and lowered physical activity.[1] They influence the quality of life and productivity of afflicted patients along with morbidity and mortality of these patients.[2] There is a large population who frequently gulps down antacid medications for the same. Over the years, there has been a tremendous revolution in the treatment of acid peptic disorders with assured safety and efficacy which include histamine-2 receptor antagonists (H2RAs) and proton-pump inhibitors (PPIs).[2] However, most of these medications give only symptomatic relief. Further, H2RAs rapidly develop tolerance with repeat dosing, and exhibit an analgesic effect that may relieve heartburn while leaving the esophagus exposed to acid.[3] Short plasma half-life and necessity for preprandial dosing are significant problems with PPIs. Besides, long-term usage of high-dose PPIs is thought to affect the absorption of essential components such as calcium, magnesium, and Vitamin B12.[4] Thus, a prolonged duration of symptom control preventing symptom remission is an area wherein there is a need for new drugs.

Pomegranate (Punica granatum) has extensively been used as a traditional remedy against acidosis, dysentery, microbial infections, diarrhea, helminthic infections, hemorrhage, and respiratory pathologies.[5] Ayurveda has also described use of seeds, fruit peel, and fruit rind of pomegranate in various formulations. The fruit peels of pomegranate are a rich source of tannins.[6] They possess an ability to form a gastroprotective layer which is useful in amelioration of symptoms of gastritis.[7] One of the authors (PT) has demonstrated the anti-ulcerative potential of methanol extract of pomegranate fruit peel against ethanol, aspirin, and stress-induced ulceration in vivo.[8] PT has also reported safety of the extract up to the dose of 2000 mg/kg of body weight in Wistar rats. For clinical use, PT has developed user-friendly, palatable effervescent granule formulation of the same extract so as to achieve rapid and immediate alkalizing action.[9]

In the present study, the effervescent granules, thus developed, were evaluated for efficacy and acceptability in patients suffering from acid peptic disorders. Apart from the symptomatic relief, which is a conventionally used parameter for studies in acid peptic disorders, we additionally used GastroPanel, a panel of noninvasive tests to get a clear picture of a morphological and functional status of the gastric mucosa in a group of patients.[10]

Materials and Methods

Ethics

The study was conducted at three sites: Vishwanand Kendra, Pune; Bharati Ayurved Hospital, Bharati Vidyapeeth, Pune, and M.A. Podar Medical Ayurved Hospital, Mumbai. The study protocol was designed by the Interactive Research School for Health Affairs, Bharati Vidyapeeth, Pune that also co-ordinated and monitored overall conduct of the study. The study was initiated after obtaining permission of the Institutional Ethics Committee from all three sites and performed in compliance with the Declaration of Helsinki. It was registered retrospectively in the Clinical Registry of India (CTRI/2017/07/008999). Informed written consent was obtained from all participating individuals before screening and again before recruitment.

Study design

This was an open-label, prospective, multicentric clinical study.

Sample size

This was a proof of concept study, so a sample size of 150 completed patients was considered adequate. Ninety patients were recruited at Vishwanand Kendra, Pune, while 30 patients each were recruited at Bharati Ayurved Hospital, Pune, and M.A. Podar Ayurved Hospital, Mumbai.

Eligibility criteria

Individuals in the age group of 18–60 years of either sex, suffering from minimum five symptoms out of the various classical symptoms of acid peptic disorders, namely sour or pungent eructation/belching, retrosternal/throat burning, epigastric burning/pain, nausea, regurgitation, vomiting, unsatisfactory digestion, loss of appetite, heaviness in body, and tiredness in absence of physical activity, repetitively for at least once a week for the past 2 months, were recruited. The individuals on the prolonged treatment of NSAIDs for any other clinical condition were also included in the study.

Patients with an hemoglobin level of ≤7 mg%, those with a known history of carcinogenic pathology, and cases of per rectal bleed, coagulopathies, severe cardiac, renal, hepatic, pleural pathologies, were excluded from the study. Those having 2.5 times liver function test values than their upper normal limits, those who had participated in any clinical trial within the past 1 month, and pregnant and lactating females were also not considered for inclusion.

Study intervention

Pomegranate effervescent granules (PEGs), prepared from the peel extract of pomegranate, were made available in sachets of 2.5 g. The granules were developed at CU Shah College of Pharmacy, Mumbai, and manufactured by Amsar Goa Private Limited, Goa.

The patients were asked to drink a mixture prepared by dissolving 1 sachet of PEG in 200 ml (1 cup) of water twice a day after meals for a period of 28 days. The patients were advised to discontinue excessive spicy, heavy food along with observing moderate physical activity. They were asked to return the empty sachets at follow-up to ensure compliance.

Study conduct

All consecutive patients attending the OPDs of the three study sites and suffering from acid peptic disorders were screened for eligibility criteria. They were explained about the study and their detailed medical history was recorded along with demographic details. Their blood investigations, namely hemogram and liver function tests, were carried out and only the participants with test values within normal range were called for recruitment.

Written informed consent was again taken from the eligible patients for ensuring their willingness to continue their participation. On recruitment, per abdomen examination along with recording of vitals (pulse rate and blood pressure) was carried out. This was followed by baseline investigations which included bleeding time (BT), clotting time (CT), and GastroPanel tests. BT and CT were done to assess the signs of gastrointestinal bleeding seen in cases of peptic ulceration.[11] The GastroPanel consists of four tests, namely pepsinogen I (PgI), pepsinogen II (PgII), gastrin 17 (G17), and Helicobacter pylori antibodies (IgG). Pepsinogens (PgI and II) reflect the histological and functional status of stomach mucosa, particularly inflammation. G17 is the active and abundant form of gastrin and its secretion is influenced by acid concentration in the stomach. H. pylori antibodies denote the presence of H. pylori infection.[12] These tests were done only at Vishwanand Kendra, Pune, in randomly selected 20 patients.

The patients were then administered Gastrointestinal Symptom Rating Scale (GSRS), a standardized and validated tool for assessment of symptoms of acid peptic disorders.[13] It comprises 15 points such as abdominal pains, heartburn, acid regurgitation, sucking sensation in epigastrium, nausea and vomiting, borborygmus, abdominal distension, eructation, increased flatus, decreased/increased passage of flatus, stool consistency, urgency of defecation, and feeling of incomplete evacuation. The answer for each question is graded from 0 to 3, where 0 indicates normal physiological condition and 3 represents worsening of symptom. The minimum GSRS score that can be achieved is 0, while the maximum score is 45. Thus, lower scores denote mild symptomatology and improvement post treatment.

Following this, the sachets of PEG were administered to the patients along with a symptom relief record sheet and drug diary. The patients were expected to fill this sheet daily. This sheet contained information such as presence of symptomatic relief (yes/no), time to relieve symptoms after intake of study drug (categorized as <15 min/≥30 min – 1 h/>1 h), remission of symptoms (yes/no) and its duration (categorized as ≤6 h/≤3 days/≥7 days/≥12 days), need for other antacid (yes/no), and taste of PEG (categorized as good/palatable/bad).

The patients were asked to tick in drug diary daily after taking the study drug to keep an account of drug compliance.

The patients were asked to report the study site on day 15 and then on day 29 (i.e. after finishing the treatment). On both days 15 and 29, GSRS score compliance to treatment and symptom relief was assessed. The blood investigations were repeated only on day 29. At both the visits, empty drug sachets were collected back from the patients to ensure compliance.

Statistical analysis

The parametric data were presented as mean ± standard deviation and analyzed using paired t-test. The nonparametric data were presented as median (range) and analyzed using Wilcoxon rank-sum test. The categorical data were presented as numbers and analyzed using Chi-square test.

Results

A total of 206 patients were screened for eligibility criteria. Of these, 154 patients who fulfilled the criteria were recruited in the study. Sixteen patients dropped out of the study, while there were seven withdrawals. Thus, a total of 131 patients completed the study and were considered for analysis [Figure 1].

Figure 1

Participant flow

The mean age of the recruited patients was ~39 years. The male (n = 64)-to-female (n = 67) ratio was almost equal in the study population.

The median GSRS score was 14 on day 0, which was reduced to 10 on day 15 and further to 5 on day 29. The difference in GSRS score was statistically significant on both day 15 and 29 as compared to day 0. The difference between the median GSRS score on day 15 and day 29 was also statistically significant [Table 1].

Table 1

Effect of pomegranate effervescent granule on the resolution of symptoms of acid peptic disorder

Days	Median (range)
Day 0	14 (5-32)
Day 15	10 (0-25)***
Day 29	5 (0-12)***,###

***P<0.001 as compared to day 0 and, ###P<0.001 as compared to day 15 using Friedman’s test

While GSRS provided the idea about the effect of PEG on severity of symptoms, the symptom relief record sheet mainly assessed the time associated with action of PEG and its acceptability.

As compared to day 0, 119 patients showed symptomatic relief on day 15. On day 29, 127 patients showed relief from symptoms. There was no significant difference in the number of patients who reported symptomatic relief on day 29 as compared to day 15.

The duration in which symptoms got relieved after taking PEG was noted. There was an increase in the number of patients showing faster relief (i.e. <15 min) in the symptoms on day 29 as compared to day 15. However, the difference between days 15 and 29 was not significant statistically (P = 0.7059) [Table 2].

Table 2

Effect of pomegranate effervescent granule on number of patients with reference to duration of symptomatic relief and symptom remission

Duration of symptom relief	≤15 min	≥30 min	≥1 h	-
Day 15	34	47	50	-
Day 29	40	45	46	-
Duration of symptom remission	≤6 h	≤3 days	≥7 days	≥12 days
Day 15	20	31	31	49
Day 29	11	19	27	74*

*P<0.05 as compared to day 15 using Chi-square test

The number of patients showing remission (i.e. reoccurrence) of symptoms on day 15 (n = 123) significantly (P < 0.001) reduced on day 29 (n = 10). It was also observed that the duration of remission (i.e. period between 2 episodes of acute symptoms) was more than 12 days in 49 patients on day 15. This number significantly increased to 74 on day 29 [Table 2].

Only five patients reported the need for antacid medication other than PEG during the study period. There was no difference between the number of patients requiring antacid on day 15 and day 29. The formulation PEG was found to taste good by ~80% of patients in the study while ~20% reported it to be palatable. None of the patients reported taste of PEG as bad. The drug diaries revealed more than 95% compliance to PEG.

In case of hematological parameters, PEG significantly improved platelet count, while it significantly reduced BT. Although there was an increase in CT on day 29, it was not significant statistically. There was no significant difference seen in hemoglobin and LFT on day 29 as compared to day 0 [Table 3].

Table 3

Effect of pomegranate effervescent granule on hematological parameters

Parameter	Day 0	Day 29	P
Hemoglobin (g %)	13.31±1.90	13.36±1.99	0.5142
Platelet count (×103/cu mm)	276 (160-551)	296 (119-562)	0.0042*
Bleeding time (min)	2.30 (1.10-4.21)	2.05 (1.10-3.90)	0.0001#
Clotting time (min)	6.05 (2.40-8.30)	6.30 (2.50-8.55)	0.2780
Liver function tests
Bilirubin (mg/dl)	0.51 (0.16-2.20)	0.51 (0.09-2.50)	0.8300
SGOT (IU/L)	19.60 (11.00-44.00)	20.00 (2.00-38.90)	0.4626
SGPT (IU/L)	18.00 (6.00-41.80)	18.90 (6.10-45.50)	0.3475
Albumin (g/dl)	4.45 (2.90-5.10)	4.40 (2.70-5.30)	0.8898
Alkaline phosphatase (IU/L)	79.1 (42.50-150.00)	79.5 (40.40-148.00)	0.3186

*P<0.05 as compared to day 0, #P<0.001 as compared to day 0. SGOT=Serum glutamic oxaloacetic transaminase, SGPT=Serum glutamic pyruvic transaminase

GastroPanel tests were conducted in randomly selected 20 patients. There was no significant difference seen in any of the tests after treatment. The median values were within the normal range at both these time points [Table 4].

Table 4

Effect of pomegranate effervescent granule on stomach mucosa

Tests	Day 0	Day 29	P
PgI (µg/l)	56.20 (12.10-179.40)	63.80 (23.60-224.60)	0.6300
PgII (µg/l)	9.10 (1.02-24.70)	7.20 (2.20-21.30)	0.3279
G17 (pmol/l)	3.10 (0.30-18.30)	2.50 (0.90-51.3)	0.4834
IgG (EIU)	32.40 (12.40-441.20)	56.40 (10.80-370.00)	0.5992

PgI=Pepsinogen I, PgII=Pepsinogen II, G17=Gastrin 17

No adverse effects were reported during the study.

Discussion

The present study was conducted to evaluate the efficacy of effervescent granules made up of pomegranate (PEG), a new dosage form, in acid peptic disorders. We observed that PEG significantly reduced symptoms of acid peptic disorders and improved the time for remission. There were no adverse effects reported throughout the study, indicating the safety of the formulation.

P. granatum has been described in Ayurveda to have a range of medicinal properties.[14] An in vivo study highlighted its gastroprotective activity through an antioxidant mechanism.[15] Another in vivo study reported anti-ulcer activity of aqueous methanolic extract of P. granatum.[16] Dried peels of the fruit have been known to possess both astringent and germicidal properties and have been used for treating apthae and diarrhea in patients.[17] The fruit peels containing tannins, known to be anti-ulcer agents, were thus considered for formulating the study drug.

Effervescent preparations contain mixtures of medicinal agents with both acid substances and carbonates, which react rapidly in the presence of water to release carbon dioxide. The PEGs were prepared as per this principle to achieve antacid effect. There is buffering of the acidic environment present in the stomach by increasing the pH and neutralizing the same with release of carbon dioxide. It thus prevents degradation of active ingredient and facilitates maximum absorption of the same, thereby relieving the symptoms.[10] Similar studies describing the efficient potential of effervescent dosage form have been conducted in acid peptic disorders as well as other diseases.[1819] The effervescent granules thus would have proved beneficial in this study by providing immediate release of the extract. There are few studies on ayurvedic formulations/plant extracts showing amelioration of functional dyspeptic disorders[202122] which have reported symptomatic relief in the patients. However, these studies have employed traditional dosage forms. Thus, the application of new dosage form (effervescent granules) for a plant drug remains a unique feature of this study.

PEG significantly decreased the symptoms of acid peptic disorders during the study which was evident by scores obtained through GSRS. It efficiently provided symptomatic relief to ~95% of patients by the end of the study with increase in the number of patients reporting relief in <15 min after consumption of the same on day 29 as compared to day 15.

Relapse of symptoms is another issue with patients suffering from acid peptic disorders.[223] There was a significant decrease in the number of patients reporting remission on day 29 compared to day 15. Furthermore, a significant number of patients showed improvement in duration of remission at the end of the study compared to day 15 which meant that the symptoms did not majorly recur for many of the patients.

There were only five patients among 131 who admitted usage of alternate antacid medication during course of PEG therapy. The near absence of need for any other conventional antacid formulation during this study proves the potential of PEG in effective management of acid peptic disorders. PEG was found to be good in taste by a majority of patients, while the rest reported it to be palatable. This also explains the reason for an approximate 95% compliance rate toward PEG intake.

There was a significant increase in platelet count and decrease in BT along with slight improvement in hemoglobin post treatment indicative of hemostatic and hematinic properties of the granules. A similar hematinic effect of aqueous extract of P. granatum peel was observed in an in vivo study of lead-induced anemia.[24]

The GastroPanel tests revealed huge variation in the baseline values of all the tests. It would be a good idea to recruit the patients considering cutoff values of GastroPanel test and not merely on the basis of symptoms.

As stated before, Pgs are reflective of mucosal status of the stomach epithelium and their rate of secretion is strongly influenced by the amount of acid in the stomach.[25] A decrease in acid levels after treatment with PEG influenced the PG II levels too which decreased indicating a reduction in inflammation underlining the anti-inflammatory potential of P. granatum. There were two patients who had below normal range levels of PG I suggesting a reduced functional status of the stomach mucosa which improved post PEG treatment.

The levels of G17 were below the normal range in 6 patients prior to treatment which increased post treatment in all of them. As mentioned above, secretion of G17 is influenced by the pH of acid present in the stomach.[12] The increase in G17 levels indicates a decrease in acid secretion post PEG treatment, thereby regulating its mechanism. The six patients with hypochlorhydria had higher titers for H. pylori antibodies, too suggestive of presence of an active infection. Although the acid levels reduced, H. pylori antibody titer increased post treatment denoting possibility of antibacterial potential of PEG. Among 10 patients, having higher antibody titers for H. pylori at baseline, four patients had increased PG II levels too, which decreased after drug therapy.

Our study thus proved the efficacy of PEG in acid peptic disorders. It however has few limitations. There was no comparator and the assessments were mainly qualitative, which have left scope for bias. There was no follow-up assessment post completion of drug treatment posing question about the sustained effect of PEG. Although, PEG effectively showed a decrease in the number of patients reporting remission toward the end of the study and improvement in its duration, no data were collected over remission status after a certain duration post study completion.

Conclusion

PEGs, a novel dosage form, proved to be palatable, patient-friendly, safe, and efficacious in amelioration of symptoms of dyspepsia in acid peptic disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.