Interactions between Proton Pump Inhibitors and Clarithromycin:

A Preclinical Evaluation of Pharmacokinetic Properties and Antiulcer Activity in Healthy Rabbit and Wistar Albino Rats

Somasundaram Ramachandran¹, Chandravadivelu Gopi², AR Magesh³,

Alekkhya Veeramaneni⁴, Venkata Naga Koteswararao Nerella³,

Magharla Dasaratha Dhanaraju⁵

¹Department of Pharmacology, GIET School of Pharmacy,

Rajamahendravaram - 533296, Andhra Pradesh, India.

²Department of Pharmaceutical Chemistry, GIET School of Pharmacy,

Rajamahendravaram - 533296, Andhra Pradesh, India.

³Department of Pharmaceutical Analysis, GIET School of Pharmacy,

Rajamahendravaram - 533296, Andhra Pradesh, India.

⁴Department of Pharmacognosy, GIET School of Pharmacy,

Rajamahendravaram - 533296, Andhra Pradesh, India.

⁵Director, Research Lab, GIET School of Pharmacy, Rajamahendravaram - 533296, Andhra Pradesh, India.

*Corresponding Author E-mail: ramsnetin@yahoo.com, gopi@giet.ac.in, armagesh09@gmail.com, kotibobby66@gmail.com, alekhya.veramaneni@gmail.com, mddhanaraju@yahoo.com.

ABSTRACT:

The combination of Proton Pump Inhibitors and Clarithromycin is widely used to treat Helicobacter pylori-associated gastroduodenal ulcers. However, scientific evidence suggests potential pharmacokinetic interactions between these drugs. This preclinical study investigated the interactions between Rabeprazole/Pantoprazole and Clarithromycin in healthy rabbits and rats. Initially, rabbits were divided into 4 groups and performed a pharmacokinetic study. Furthermore, the anti-ulcer potential was assessed by Rabeprazole/Pantoprazole alone and co-administered with Clarithromycin using Wistar albino rats. The rats were divided into five groups and each group contained 6 animals, receiving water acted as a control (Group I), Rabeprazole (Group II), Pantoprazole (Group III), Rabeprazole with Clarithromycin (Group IV), and Pantoprazole with Clarithromycin(Group V) respectively. This interaction of proton pump inhibitor and Clarithromycin may enhance therapeutic efficacy and significantly increase proton pump inhibitor levels. Our study demonstrates pharmacokinetic interactions between Rabeprazole with Clarithromycin or Pantoprazole with Clarithromycin, which may impact clinical outcomes. These findings suggest beneficial drug interactions in treating Helicobacter pylori-induced ulcers but also warrant cautious consideration of potential adverse effects.

KEYWORDS: Helicobacter pylori, Proton pump inhibitors, Clarithromycin, Pharmacokinetic drug interaction.

INTRODUCTION:

Peptic ulcer is a prevalent gastrointestinal condition characterized by sores in the stomach and duodenum¹.

It arises from a disproportion between aggressive factors like stomach acid, pepsin, bile, and Helicobacter pylori infection and the body's defensive mechanisms, including gastric mucus, prostaglandins, bicarbonate secretion, nitric oxide, and mucosal blood flow². The development of peptic ulcers is multifaceted, involving psychological, hormonal, and vascular components³. Notably, H. pylori infection is a well-established primary cause of most duodenal ulcers and many gastric ulcers. Gastric acid secretion is pivotal in ulcer formation. Its regulation involves a complex interaction among histamine, acetylcholine (ACh), and gastrin⁴. These substances stimulate the proton pump (H+/K+ ATPase) in parietal cells, leading to acid production⁵. Histamine, acting through H₂ receptors, plays a central role, while ACh and gastrin indirectly influence acid secretion by promoting histamine release from enterochromaffin-like (ECL) cells⁶. The enteric nervous system (ENS) significantly influences gastric acid secretion⁷. Vagal nerve stimulation releases ACh, which activates ECL cells to release histamine and G cells to secrete gastrin⁸. Muscarinic receptors, particularly the M₁ subtype on ganglion cells and the M₃ subtype on parietal and ECL cells, mediate these vagal effects. Gastrin secretion is also modulated by antral pH, food components, and vagally mediated reflexes involving ENS ganglion cell⁹. Understanding these mechanisms is crucial for developing effective treatments for peptic ulcers. Antisecretory drugs, H₂ receptor antagonists and like proton pump inhibitors (PPIs) target specific receptors and enzymes involved in acid production. PPIs inhibit the proton pump directly, while H₂ receptor antagonists block histamine's action on parietal cells. Eradicating H. pylori infection is also essential, as it has been associated with a decreased risk of ulcer recurrence¹⁰. In summary, peptic ulcer disease is a complex disorder involving multiple factors, including gastric acid secretion, H. pylori infection and ENS regulation. Advancements in understanding its pathophysiology have led to effective treatments, notably the use of antisecretory drugs and antibiotic regimens targeting  H. pylori. Ongoing research into the molecular mechanisms of gastric acid secretion and ENS regulation may yield more targeted therapies in the future.

Proton Pump Inhibitors:

PPIs are highly successful medicines in controlling stomach acid discharge by irreversibly inhibiting the H+/K+ ATPase enzyme system in parietal cells, which is the final pathway for acid production. By covalently binding to this enzyme, PPIs suppress gastric acid secretion by up to 99%, surpassing the efficacy of H₂ antagonists. This substantial reduction in stomach acid facilitates the healing of duodenal ulcers and alleviates symptoms such as indigestion and heartburn¹¹.

Rabeprazole:

Rabeprazole is a PPI employed to treat problems like gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome and duodenal ulcers, which involves extreme stomach acid formation. It is also used along with antibiotics (e.g., Clarithromycin, Amoxicillin) to treat H. pylori-associated ulcers¹². Rabeprazole decreases stomach acid production by entering parietal cells and reducing the secretion of HCl. After absorption in the proximal small intestine, rabeprazole effectively reduces acid levels, alleviating symptoms and promoting healing. Pharmacokinetically, Rabeprazole has a bioavailability of approximately 52% and binds to plasma proteins at a rate of 96.3-97%. It has a biological half-life of about one hour, reaching maximum plasma concentration approximately 3.5 hours after oral administration. The liver extensively metabolizes rabeprazole, converting 90% of the drug into metabolites primarily through non-enzymatic reduction and the CYP2C19 and CYP3A4 bio-enzymes. These metabolites include thioether glucuronide, thioether carboxylic acid and sulfone. Only 10% of the dose is excreted in feces, with the remainder eliminated through renal excretion of metabolites.

Pantoprazole:

Pantoprazole is another PPI used to treat stomach ulcers, erosive esophagitis due to GERD, and Zollinger-Ellison syndrome. Common side effects are diarrhoea, headaches, vomiting, joint pain and abdominal pain¹³. More severe problems include atrophic gastritis, allergic reactions, Clostridium difficile colitis, vitamin B₁₂ deficiency and low magnesium levels,. Pantoprazole is generally considered safe during pregnancy. It manages acid secretion by inactivating the H+/K+ ATPase in the stomach, effectively alleviating symptoms and promoting healing. By covalently binding to this enzyme, pantoprazole prevents acid secretion for up to 24hours. The liver metabolizes pantoprazole via the cytochrome P450 system, primarily through CYP2C19 and CYP3A4, producing metabolites with no significant pharmacological effects. Due to irreversible binding, new proton pumps must be produced before acid production can resume. Pantoprazole has a plasma half-life of about two hours, reaching peak concentrations in 2-3hours, and is 98% protein-bound. Its inactivity in acidic environments necessitates co-administration with a prokinetic drug. This mechanism effectively suppresses acid secretion.

Clarithromycin:

Clarithromycin is a macrolide antibiotic employed to treat different bacterial infections, such as pneumonia, strep throat, Helicobacter pylori infection, skin infections and Lyme disease. It is available in oral and intravenous forms¹⁴. The general side effects such as diarrhoea, nausea and headaches,. Severe allergic reactions and liver problems are rare but have been reported. Clarithromycin works by inhibiting tthe bacterial protein synthesis through connecting to the 50S ribosomal subunit. It also inhibits the liver enzyme CYP3A4, which can lead to interactions with other medications. The drug is biotransformed in the liver, producing metabolites such as N-desmethylclarithromycin and 14-(R)-hydroxyclarithromycin, the latter being less potent against mycobacterial infections.

MATERIALS AND METHODS:

Materials:

Drugs and Chemicals:

The study examined two drug classes: PPIs (Rabeprazole and Pantoprazole) used for gastroesophageal diseases and peptic ulcers, and macrolide antibiotics (clarithromycin) used for respiratory and other infections. Additional chemicals included ether anesthesia, ethanol, HPLC-grade methanol, acetonitrile, methyl-tert-butyl ether and water.

Methods:

Preclinical Studies on Pharmacokinetic Drug Interactions:

Preclinical studies investigating pharmacokinetic drug interactions between proton pump inhibitors (PPIs) and Clarithromycin were conducted using rabbits. These studies aimed to elucidate potential interactions and their combined pharmacokinetic profiles¹⁵. Rabbits have a similar gastrointestinal anatomy and physiology to humans, making them a suitable model for studying drug absorption, distribution, metabolism and excretion (ADME). In addition to that, they are large enough for multiple sampling which is necessary for pharmacokinetic studies. They are well-established model in the scientific community.

Animal Selection and Ethical Approval:

The study utilized albino rats (150-250g) and rabbits (2-3 kg) of either sex, maintained under standard laboratory conditions. The rats were housed at 25-28°C with a 12-hour light-dark cycle and supplied with standard food. Prior to experimentation, animal ethical approval was acquired from the Institutional Animal Ethics Committee, recognized by the Government of India's CCSEA¹⁶.

Pharmacokinetic Study:

Nine rabbits were separated into three groups of three animals each, receiving the following oral administrations: Group 1: Rabeprazole (0.5mg/kg), Group 2: Pantoprazole (2mg/kg), Group 3: Rabeprazole (0.5mg/kg) along with Clarithromycin (15mg/kg), Group 4: Pantoprazole (2mg/kg) along with Clarithromycin (15mg/kg). Blood samples were withdrawn from the tail vein at 0, 1, 2, 3, 4, 5, and 6 hours post-administration. Samples were centrifuged, and serum was stored at -10°C for analysis. The pharmacokinetic profiles were evaluated using the HPLC method¹⁷ (Shimadzu-model-LL20AD).

Pyloric Ligation Method:

To assess pharmacokinetic drug interactions, peptic ulcers were induced in rats via pyloric ligation. The animals (n=6) were divided into four groups of six each and acclimatized for a week under standard conditions (25°C, 45-55% humidity, 12-hour light-dark cycle). The groups received the following oral doses: water (Group I), Rabeprazole (Group II), Pantoprazole (Group III), Rabeprazole with Clarithromycin (Group IV), and Pantoprazole with Clarithromycin(Group V) respectively. Prior to surgery, rats were denied food for 36 hours and were housed in raised mesh-bottomed cages. Under ether anaesthesia, the pyloric segment of the stomach was ligated, and the abdomen was sutured. Post-operatively, the animals were deprived of water and food  before being sacrificed¹⁸.

Gastric Acidity and pH Measurement:¹⁹

The pH of the gastric juice of the experimental animals was determined using pH strips (Glaxo India Limited). Free and total acidity were measured by titrating centrifuged gastric samples with 0.01 N NaOH using Topfer's reagent and a phenolphthalein indicator. Acidity was expressed as

· Total Acidity (mEq/L) = Quantity of NaOH x Normality x 100

· Ulcer Index (U.I.) = (Ulcer affected area/complete stomach area) x 100

· Percentage Ulcer Inhibition = [(U.I. in control - U.I. in test) x 100] / U.I. in control

Statistical Analysis:

Results are presented as mean±SEM. Statistical significance was determined using one-way ANOVA, followed by Dunnett's post hoc test for group comparisons, performed in SPSS version 21. A p-value of P<0.05 was considered statistically significant²⁰.

RESULT:

Pharmacokinetic parameters:

Pharmacokinetic factors were considered using a non-compartmental model, including peak concentration (Cmax), elimination rate constant (λ), time to peak (Tmax), elimination half-life (t_1/2), and area under the curve (AUC∞). Comparative analysis identified the optimal proton pump inhibitors combination with Clarithromycin, exhibiting the strongest synergistic effect. This combination of Rabeprazole (0.5mg/kg) along with Clarithromycin (15 mg/kg), Pantoprazole (2 mg/kg) along with Clarithromycin (15 mg/kg) exhibited peak concentration in the plasma of the rabbit at the different intervals when compared to the group treated with the Rabeprazole or Pantoprazole alone. There is a slight increase in Rabeprazole or Pantaprazole concentration at each time point when co-administered with Clarithromycin. The increase in AUC suggests Clarithromycin significantly enhances bioavailability compared to Rabeprazole or Pantaprazole alone treated. AUC values of co-administered Rabeprazole or Pantaprazole with Clarithromycin were consistently higher compared to Rabeprazole or Pantaprazole alone treated. The pharmacokinetic parameters of different groups are presented in Tables 1 and 2.

Pyloric Ligation Method:

The pH Measurement:

The study evaluated the effect of different treatments on pH levels (Eletronic India –model 112). The control group (Group I) exhibited the lowest pH (3.52±0.15). Rabeprazole alone (Group II) increased pH to 4.73±0.09, while pantoprazole alone (Group III) further elevated it to 4.95±0.14. Combining rabeprazole with clarithromycin (Group IV) resulted in a pH of 5.26±0.14. The highest pH (5.71±0.10) was observed in Group V, where pantoprazole was combined with Clarithromycin. These results suggest that both proton pump inhibitors increased pH, with pantoprazole being more effective, and the addition of clarithromycin further enhanced the effect. Measured gastric pH values in each group are presented in Table 3.

Table 1: Comparison of AUC of tested animal rats administered with Rabeprazole alone and Rabeprazole along with Clarithromycin

Time (hours)	Concentration of Rabeprazole (mg/L)	Δ AUC(mg.hr/L)	AUC (mg.hr/L)	Concentration of Rabeprazole along with Clarithromycin (mg/L)	Δ AUC(mg.hr/L)	AUC (mg.hr/L)
0	100	-	-	100	-	-
1	69	82.3	82.3	81	90.5	87.5
2	52	67.32	149.62	62	85.75	158.25
3	31	50.14	199.76	44	64.87	211.62
4	20	32.58	232.34	31	47.93	250.3
5	12	22.01	254.35	22	34.96	276.14
6	6	12.43	266.78	15	24.98	292.56

Table 2: Comparison of AUC of tested animal rats administered with Rabeprazole alone and Rabeprazole along with Clarithromycin

Time (hours)	Concentration of Pantoprazole (mg/L)	Δ AUC (mg.hr/L)	AUC (mg.hr/L)	Concentration of Pantoprazole (mg/L) along with Clarithromycin	Δ AUC (mg.hr/L)	AUC (mg.hr/L)
0	100	-	-	100	-	-
1	75	87.5	87.5	85	92.5	92.5
2	54	70.75	158.25	73	82.75	175.25
3	36	53-.37	211.62	52	67.37	242.62
4	24	38.68	250.3	45	56.18	298.8
5	13	25.84	276.14	39	47.59	346.39
6	7	16.42	292.56	26	36.79	383.18

Table 3: The anti-ulcer effect of proton pump inhibitors along with Clarithromycin on the pylorus ligation-induced ulcer Wistar albino rat model

Treatment	Gastric Volume (ml)	pH	Total acidity (mEq/l)	Free acidity (mEq/l)	Ulcer Index	Ulcer Index inhibition
Group I (Control)	8.27±0.24	3.52±0.15	132.38±2.35	97.45±2.35	3.86±0.07	-
Group II (Rabeprazole alone)	5.63±0.18	4.73±0.09	92.59±1.62	82.51±2.35	2.47±0.09	36.01
Group III (Pantoprazole alone)	5.52±0.26	4.95±0.14	88.72±1.48	80.63±2.82	2.25±0.15	41.70
Group IV (Rabeprazole + Clarithromycin)	4.51±0.09	5.26±0.14	81.68±2.67	74.72±2.41	1.92±0.10	50.25
Group V Pantoprazole + Clarithromycin	4.28±0.25	5.71±0.10	76.53±2.39	62.37±1.82	1.85±0.06	52.07

Group I (control): rats received only distilled water; Group II: rats received Rabeprazole 0.5mg/kg; Group III: rats received Pantoprazole 2mg/kg; Group IV: rats received Rabeprazole 0.5mg/kg + Clarithromycin 15 mg/kg which is dissolved in distilled water and given in a dose level; Group V: rats received Pantoprazole 2mg/kg + Clarithromycin 15mg/kg. n = 6/group. Values are expressed as mean±SEM (n = 6). ∗The P value is <0.001 versus control.

Gastric volume:

The study evaluated gastric volume across five treatment groups. The control group (Group I) had the highest gastric volume (8.27±0.24ml). Group II, receiving Rabeprazole alone, showed a reduction (5.63±0.18ml), while Group III, treated with pantoprazole alone, had a similar decrease (5.52±0.26ml). Combining Rabeprazole with Clarithromycin (Group IV) further reduced gastric volume (4.51±0.09ml). The lowest volume was observed in Group V (pantoprazole+clarithromycin) at 4.28±0.25ml. The secreted quantity of acids in each group is summarized in Table 3.

Total and free acidity determination:

A study evaluated the effects of different treatments on total and free acidity levels in experimental groups. The control group (Group I) exhibited the highest total acidity (132.38±2.35mEq/l) and free acidity (97.45±2.35 mEq/l). Rabeprazole alone (Group II) reduced total acidity to 92.59±1.62mEq/l and free acidity to 82.51±2.35mEq/l, while Pantoprazole alone (Group III) further lowered these levels to 88.72±1.48mEq/l and 80.63±2.82mEq/l, respectively. Combination therapy with Rabeprazole and Clarithromycin (Group IV) reduced acidity further. The Pantoprazole and Clarithromycin combination (Group V) showed the most significant reduction, with total acidity at 76.53±2.39 mEq/l and free acidity at 62.37±1.82mEq/l. These values were summarized in Table 3.

Ulcer Index and Ulcer Index inhibition:

The study evaluates the ulcer index and its inhibition across five groups. The control group (Group I) exhibited the highest ulcer index (3.86±0.07). Rabeprazole alone (Group II) reduced the ulcer index to 2.47±0.09, achieving 36.01% inhibition. Pantoprazole alone (Group III) showed a further reduction to 2.25±0.15, with 41.70% inhibition. Combining Rabeprazole with Clarithromycin (Group IV) significantly lowered the ulcer index to 1.92±0.10, achieving 50.25% inhibition. The most effective treatment was Pantoprazole with Clarithromycin (Group V), which reduced the ulcer index to 1.85±0.06, showing 52.07% inhibition. These results suggest enhanced ulcer protection with combination therapy. These values are summarized in Table 3.

Benefits:

· Eradication of H. pylori infection: This is the most preferred combination used in the treatment of    H. Pylori Infection and thereby reducing the risk of recurrent duodenal ulcers.

· Reduced risk of complications: Eradicating H. pylori infection reduces the risk of complications like gastric cancer, gastric ulcers and mucosa-associated lymphoid tissue lymphoma (MALT).

· Enhanced healing: PPIs promote healing of the stomach lining and reduce inflammation.

DISCUSSION:

Peptic ulcer disease is a prevalent gastrointestinal disorder characterized by sores in the stomach and duodenum. H. pylori infection is a major cause of duodenal and gastric ulcers. Understanding these mechanisms is essential for developing effective treatments for peptic ulcers. Proton pump inhibitors (PPIs) and H₂ receptor antagonists are widely used antisecretory drugs. PPIs, such as Rabeprazole and Pantoprazole, inhibit the proton pump directly. Eradicating H. pylori is crucial to reduce ulcer recurrence. The preclinical studies on pharmacokinetic drug interactions between PPIs and clarithromycin were conducted using rabbits. The pharmacokinetic profiles were analyzed to determine drug absorption and bioavailability in the rabbit. Co-administration of Rabeprazole (0.5mg/kg) or Pantoprazole (2mg/kg) with Clarithromycin (15mg/kg) significantly increased peak plasma concentrations and AUC, suggesting enhanced bioavailability compared to monotherapy. Tables 1 and 2 present the results.The pyloric ligation method was used in rats to assess ulcer inhibition using different drug combinations. The study evaluates the effects of different treatments on gastric volume, acidity, pH and ulcer index inhibition. The control group (Group I) exhibited the highest gastric volume (8.27±0.24ml), lowest pH (3.52±0.15), and highest acidity levels, resulting in the most severe ulceration (ulcer index: 3.86±0.07). Rabeprazole (Group II) and pantoprazole (Group III) alone significantly reduced gastric volume and acidity while increasing pH. Pantoprazole showed slightly better efficacy than rabeprazole, as reflected in a lower ulcer index (2.25±0.15 vs. 2.47±0.09) and higher ulcer inhibition (41.70% vs. 36.01%). This suggests pantoprazole may provide superior acid suppression when used alone. The combination of rabeprazole or pantoprazole with clarithromycin (Groups IV and V) further improved therapeutic outcomes. The pantoprazole along with clarithromycin group (Group V) demonstrated the most substantial reduction in gastric volume (4.28±0.25ml) and total acidity (76.53±2.39mEq/l), alongside the highest pH (5.71±0.10). It also achieved the greatest ulcer inhibition (52.07%), indicating a synergistic effect between the proton pump inhibitor and antibiotic therapy. The rabeprazole along with clarithromycin combination (Group IV) followed closely with a 50.25% ulcer index inhibition. Overall, while both proton pump inhibitors effectively reduce gastric acidity and ulcer severity, their combination with clarithromycin enhances efficacy. Pantoprazole along with clarithromycin demonstrated the most potent gastroprotective effects, making it a preferred treatment option for conditions like peptic ulcers and H. pylori infections.

CONCLUSION:

The present study demonstrates the significant impact of combining proton pump inhibitors (PPIs) with Clarithromycin on gastric acid secretion, pH levels, acidity, and ulcer inhibition in an experimental model. The findings highlight that Clarithromycin enhances the pharmacokinetics of proton pump inhibitors, leading to greater acid suppression and ulcer protection. The increased pH and reduced total and free acidity indicate the potential benefits of these combinations in managing gastric ulcers. Notably, Pantoprazole along with Clarithromycin exhibited superior efficacy in reducing gastric acidity and ulcer index, making it a promising therapeutic approach for optimizing ulcer treatment and gastric mucosal healing in H. pylori infections.

REFERENCES:

1. Mahurkar N, Sayeed ul hasan S.M. Synergistic Antiulcer Effect of Melatonin and Esomeprazole Combination in Pylorus Ligation, Ethanol, Aspirin induced Peptic Ulcers. Asian J. Pharm. Res., 2015; 5(1): 10-14. doi: 10.5958/2231-5691.2015.00002.7

2. Meshram N, Ojha M, Singh A, Alexander A, Ajazuddin, Sharma M. Significance of Medicinal Plant used for the Treatment of Peptic Ulcer. Asian J. Pharm. Tech., 2015; 5(1): 32-37. doi: 10.5958/2231-5713.2015.00007.0

3. Shanshal S.A, Noori A.S, Ghazi J.A, Dahham A.T, Saleh A.S.M, Al-Qazaz H.K. Impact of peptic ulcer disease on the quality of life: A Cross Sectional Study. RJPT., 2022; 15(7): 3267-3272. doi: 10.52711/0974-360X.2022.00548

4. Pandey A, Saraswat N, Wal P, Pal R.S, Wal A, Maurya D. A Detailed Review on: Recent Advances, Pathophysiological Studies and Mechanism of Peptic Ulcer. Res. J. Pharmacology and Pharmacodynamics. 2019; 11(4): 165-170. doi: 10.5958/2321-5836.2019.00029.6

5. Prinz C, Kajimura M, Scott D, Helander H, Shin J, Besancon M, Bamberg K, Hersey S, Sachs G. Acid secretion and the H,K ATPase of stomach. Yale J Biol Med. 1992; 65(6): 577-96. PMID: 1341065; PMCID: PMC2589780.

6. Shamburek RD, Schubert ML. Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors. Gastroenterol Clin North Am. 1992; 21(3): 527-50. PMID: 1355465.

7. Obata Y, Pachnis V. The Effect of Microbiota and the Immune System on the Development and Organization of the Enteric Nervous System. Gastroenterology. 2016; 151(5): 836-844. doi: 10.1053/j.gastro.2016.07.044

8. Chen D, Hagen SJ, Boyce M, Zhao CM. Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology. J Neuroendocrinol. 2023; 35(11): e13305. doi: 10.1111/jne.13305

9. Prerana Musale, S. D. Mankar. A Review on Polyherbal Formulation Used in the Treatment of Gastric Acidity. RJPP., 2023; 15(2): 173-8. doi: 10.52711/0975-4385.2023.00027

10. Labenz J. Consequences of Halicobacter pylori cure in ulcer patients. Best Practice and Research Clinical Gastroenterology., 2000; 14(1): 133-145. https://doi.org/10.1053/bega.1999.0064

11. Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages of Long-term proton pump inhibitor use. J Neurogastroenterol Motil 2018; 24(2): 182-196.  https://doi.org/10.5056/jnm18001

12. Gambaro C, Bilardi C, Dullbecco P, Iliritano E, Zentillin P, Mansi C, Usai P, Vigneri S, Savarino V. Comparable Helicobacter pylori eradication rates obtained with 4- and 7-day rabeprazole-based triple therapy a preliminary study. Dig Liver Dis., 2003; 35(11): 763-767. https://doi.org/10.1016/S1590-8658(03)00458-4

13. Aydin A, Onder G, Akarca U, Tekin F, Tuncyurek M, Ilter T. Comparision of 1- and 2- week pantoprazole –based triple therapies in clarithromycin-sensitive and resistant cases. Eur J Intern Med., 2007; 18(6): 496-500. https://doi.org/10.1016/j.ejim.2007.02.018

14. Tankovic J, Lamarque D, Lascals C, Soussy CJ, Delchier JC. Clarithromycin resistance of Helicobacter pyrlori has a major impact on the efficacy of the omeprazole-amoxicillin-clarithromycin therapy. Pathol Biol., 2001; 49(7): 528-533. https://doi.org/10.1016/S0369-8114(01)00209-7

15. Wedemeyer R.S, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf., 2014; 37(4): 201. https://doi.org/10.1007/s40264-014-0144-0.

16. Johnson D.B, Moganthan R, Swarnabala S. Evaluation of Anti Ulcer activity of Calycopteris floribunda Lams leaf extract in wistar rats. RJPPD., 2024; 16(4): 277-2. doi: 10.52711/2321-5836.2024.00048

17. Vijayaraj S, Singh A, Sampathkumar K.P.. Pharmacokinetic Study of Oxime Prodrug of Gliclazide by LC-MS/MS Method in Rabbit Plasma. Asian J. Research Chem., 2015; 8(5): 351-357. doi: 10.5958/0974-4150.2015.00058.9

18. Alumets J., Ekelund M., Håkanson R., Hedenbro J., Rehfeld J.F, F. Sundler, S. Vallgren. Gastric acid response to pylorus ligation in rats: is gastrin or histamine involved? J Physiol.,  1982; 323: 145. https://doi.org/10.1113/jphysiol.1982.sp014065

19. L.E. Borella, F. Herr. A new method for measuring gastric acid secretion in unanesthetized rats. Gastroenterol., 1971; 61(3): 345. https://doi.org/10.1016/S0016-5085(19)33532-2

20. O. Ahmed, T. Nedi, E.M. Yimer. Evaluation of anti-gastric ulcer activity of aqueous and 80% methanol leaf extracts of Urtica simensis in rats. Metab Open., 2022; 14: 100172. https://doi.org/10.1016/j.metop.2022.100172

Received on 06.03.2025      Revised on 05.07.2025

Accepted on 11.10.2025 Published on 03.04.2026

Available online from April 06, 2026

Research J. Pharmacy and Technology. 2026;19(4):1589-1594.

DOI: 10.52711/0974-360X.2026.00227

© RJPT All right reserved

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.