INTRODUCTION:

Proton-pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of acid production. Within the class of medications, there is no clear evidence that one agent works better than another.

They are the most potent inhibitors of acid secretion available. This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists.

PPIs are among the most widely sold drugs in the world, and the first one, omeprazole, is on the WHO Model List of Essential Medicines.

Due their effective acid suppressing effects, PPIs are approved for numerous indications, including short term management of gastroesophageal reflux disease, erosive esophagitis, H pylori and duodenal and gastric ulcers. Long term indications for PPIs include non-steroidal anti-inflammatory drug- associated gastric ulcers, hyper secretory conditions, and maintenance of healing erosive esophagitis.

PPIs bind to proton pumps in the stomach, blocking acid production, PPIs work by irreversibly blocking the H+/K+ATPase enzyme or the gastric proton pump, which is found within the parietal cells of the stomach and is the final step of acid production. Side effect profile is mild, and the most common adverse reactions reporter or headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence.

Proton pump inhibitors (PPIs) they clinically introduced more than 25 years ago and have since proven to be invaluable, safe and effective agents for the management of variety of acid related disorders. Although all members in these class act in similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism and food and drug administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflex disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individual, especially at night. Longer acting PPIs and technology to prolong conventional PPI activity have been developed specifically address these limitations and may improve clinical outcomes.

Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have steadily become the main stay in treatment of acid –related disorders. When compared with earlier agents such as hiatamine2-receptor antagonist(H2RAs), synthetic prostaglandin analogues, and anti-cholinergic, PPIs have demonstrated consistent patient tolerance, excellent safety, and generally superior acid suppressing capability then prior agents.

MECHANISM OF ACTION

Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ATPase, or, more commonly, the gastric proton pump) of the gastric cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. Decreasing the acid in the stomach can aid the healing of duodenal ulcers and reduce the pain from indigestion and heartburn. However, stomach acids are needed to digest proteins, vitamin B12, calcium, and other nutrients, and too little stomach acid causes the condition hypochlorhydria.

The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

USES:

These drugs are used in the treatment of many conditions, such as:

· Dyspepsia

· Peptic ulcer disease including after endoscopic treatment for bleeding

· As part of Helicobacter pylori eradication therapy

· Gastroesophageal reflux disease (GERD or GORD) including symptomatic endoscopy-negative reflux disease

· Barrett's esophagus

· Eosinophilic esophagitis

· Stress gastritis and ulcer prevention in critical care

^·Gastrinomas and other conditions that cause hypersecretion of acid including Zollinger–Ellison syndrome

PEPTIC ULCERS

Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, first part of the small intestine or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while that in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain or upper abdominal pain that improves with eating. With a gastric ulcer the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people have no symptoms. Complications may include bleeding, perforation and blockage of the stomach. Bleeding occurs in as many as 15% of people.

Treatment includes stopping smoking, stopping NSAIDs, stopping alcohol and giving medications to decrease stomach acid. The medication used to decrease acid is usually either a proton pump inhibitor (PPI) or an H2 blocker with four weeks of treatment initially recommended. Ulcers due to H. pylori are treated with a combination of medications such as amoxicillin, clarithromycin and a PPI. Antibiotic resistance is increasing and thus treatment may not always be effective. Bleeding ulcers may be treated by endoscopy, with open surgery typically only used in cases in which it is not successful.

Peptic ulcers are present in around 4% of the population. New ulcers were found in around 87.4 million people worldwide during 2015. About 10% of people develop a peptic ulcer at some point in their life. They resulted in 267,500 deaths in 2015 down from 327,000 deaths in 1990. H. pylori was first identified as a causing agent for peptic ulcers

SIGNS AND SYMPTOMS

· Abdominal pain, classically epigastric strongly correlated to mealtimes. In case of duodenal ulcers, the pain appears about three hours after taking a meal

· Bloating and abdominal fullness

· Water brash (rush of saliva after an episode of regurgitation to dilute the acid in esophagus - although this is more associated with gastroesophageal reflux disease)

· Nausea and copious vomiting

· Loss of appetite and weight loss

· Hematemesis (vomiting of blood), this can occur due to bleeding directly from a gastric ulcer, or from damage to the esophagus from severe/continuing vomiting.

· Melena (tarry, foul-smelling feces due to presence of oxidized iron from hemoglobin)

· Rarely, an ulcer can lead to a gastric or duodenal perforation, which leads to acute peritonitis, extreme, stabbing pain and requires immediate surgery.

Burning or gnawing feeling in the stomach area lasting between 30 minutes and 3 hours commonly accompanies ulcers. This pain can be misinterpreted as hunger, indigestion or heartburn. Pain is usually caused by the ulcer but it may be aggravated by the stomach acid when it comes into contact with the ulcerated area. The pain caused by peptic ulcers can be felt anywhere from the navel up to the sternum, it may last from few minutes to several hours and it may be worse when the stomach is empty. Also, sometimes the pain may flare at night and it can commonly be temporarily relieved by eating foods that buffer stomach acid or by taking anti-acid medication.^[27]

CAUSES

· H. pylori

Helicobacter pylori is one of the major causative factors of peptic ulcer disease. It secretes urease to create an alkaline environment which is suitable for its survival. H. pylori secretes certain products that inhibit hydrogen potassium ATPase, activate calcitonin gene-related peptide sensory neurons which increases somatostatin secretion to inhibit acid production by parietal cells, and inhibit gastrin secretion. This reduction in acid production causes gastric ulcers. On the other hand, increased acid production at the pyloric antrum is associated with duodenal ulcers in 10 to 15% of the H. pylori infection cases.

· NSAIDs

Taking nonsteroidal anti-inflammatory drugs (NSAID) and aspirin can increase the risk of getting peptic ulcer disease by four times when compared to non-users. The risk of getting peptic ulcer is two times for aspirin users.

· Stress

Stress due to serious health problems such as those requiring treatment in an intensive care unit is well described as a cause of peptic ulcers, which are also known as stress ulcers.

· Diet

Dietary factors such as spice consumption, were hypothesized to cause ulcers, but have been shown to be of relatively minor importance.^[28] Caffeine and coffee, also commonly thought to cause or exacerbate ulcers. Similarly, while studies have found that alcohol consumption increases risk when associated with H. pylori infection.

· Other

Other causes of peptic ulcer disease include: gastric ischemia, drugs, metabolic disturbances, cytomegalovirus (CMV), upper abdominal radiotherapy, Crohn's disease, and vasculitis. Gastrinomas (Zollinger–Ellison syndrome), rare gastrin-secreting tumors, also cause multiple and difficult-to-heal ulcers.

COMPLICATIONS

· Gastrointestinal bleeding is the most common complication. Sudden large bleeding can be life-threatening. It is associated with 5% to 10% death rate.

· Perforation (a hole in the wall of the gastrointestinal tract) following a gastric ulcer often leads to catastrophic consequences if left untreated.

· Erosion of the gastro-intestinal wall by the ulcer leads to spillage of the stomach or intestinal content into the abdominal cavity.

· Perforation at the anterior surface of the stomach leads to acute peritonitis, initially chemical and later bacterial peritonitis. The first sign is often sudden intense abdominal pain such as Valentino's syndrome. Posterior wall perforation leads to bleeding due to the involvement of gastroduodenal artery that lies posterior to the first part of the duodenum. The death rate in this case is 20%.

· Penetration is a form of perforation in which the hole leads to and the ulcer continues into adjacent organs such as the liver and pancreas.

· Gastric outlet obstruction is a narrowing of the pyloric canal by scarring and swelling of the gastric antrum and duodenum due to peptic ulcers. The person often presents with severe vomiting.

· Cancer is included in the differential diagnosis (elucidated by biopsy), Helicobacter pylori as the etiological factor making it 3 to 6 times more likely to develop stomach cancer from the ulcer.

MATERIALS AND METHODS:

EXPERIMENTAL ANIMALS

Male wistar rats weighing between 100 and 150 gm were used for present study. Animals were procured from Sainath agencies, Musheerabad, Hyderabad. The animals were randomly grouped in cages with paddy husk as bedding. Animals were housed at a temperature of 24±2˚C and relative humidity of 30-70%. All the animals were allowed to free access to water and fed with pellets. The study was approved by institutional animal ethics committee (IAEC) before the commencement of the experiment.

DRUGS AND CHEMICALS

Omeprazole was obtained as a gift sample from DR. REDDY’S laboratories, Nalgonda. All the other drugs and chemicals were obtained commercially and were of analytical grade.

PREPARATION OF SOLUTION OF OMEPRAZOLE FOR FURTHER BIOCHEMICAL STUDIES

Omeprazole powder was suspended in 1% acacia solution and was used for the study.

EXPERIMENTAL PROCEDURE

The animals were weighed and marked. The animals were divided in to three groups of six animals in each group. Group I served as control and Group II rats served as test and Group III served as standard. A one-week acclimation period was allowed before initiation of the experiment.

On the day of experiment omeprazole obtained was dissolved in 1% acacia solution. Group 1 animals were treated with normal saline or water (5ml/kg body weight) and pellet feed daily for 14 days, Group 2 animals were treated with high dose of omeprazole (100mg/kg bodyweight) for 14 days, Group 3 animals were treated with a standard drug silymarin (25mg/kg bodyweight) for 14 days through oral routes. The experiment was terminated on the 14^th day. The blood samples were collected through retro orbital puncture for estimating biochemical parameters like SGOT, SGPT, ALP, total protein, Bilirubin. The liver of each animal was promptly removed and preserved in formalin for histopathological studies.

STATISTICAL ANALYSIS

The statistical analysis was performed using analysis of variance (ANOVA). The results are expressed as mean ± standard error mean (SEM). The 0.05 level of probability was used as criterion of significance for experimental groups.

TEST PRINCIPLES

a. ALANINE AMINOTRANSFERASE (ALT)

As a group, the transaminases catalyze the interconversion of amino acids and α-keto acids by transferring the amino groups. The enzyme ALT been found to be in highest concentration in the liver, with decreasing concentrations found in kidney, heart, skeletal muscle, pancreas, spleen, and lung tissue. Alanine aminotransferase measurements are used in the diagnosis and treatment of certain liver diseases (e.g., viral hepatitis and cirrhosis) and heart diseases. Elevated levels of the transaminases can indicate myocardial infarction, hepatic disease, muscular dystrophy, or organ damage. Serum elevations of ALT activity are rarely observed except in parenchymal liver disease, since ALT is a more liver-specific enzyme than asparate aminotransferase (AST).^[54]

b. ALKALINE PHOSPHATASE (ALP)

Increased ALP activity is associated with two groups of diseases: those affecting liver function and those involving osteoblastic activity in the bones. In hepatic disease, an increase in ALP activity is generally accepted as an indication of biliary obstruction. An increase in serum phosphatase activity is associated with primary hyperparathyroidism, secondary hyperparathyroidism owing to chronic renal disease, rickets, and osteitis deformans juvenilia due to vitamin D deficiency and malabsorption or renal tubular dystrophies. Increased levels of ALP are also associated with Von Recklinghausen's disease with bone involvement and malignant infiltrations of bone. Low levels are associated with hyperthyroidism, and with the rare condition of idiopathic hypophosphatasia associated with rickets and the excretion of excess phosphatidyl ethanolamine in the urine.^[55]

c. ASPARTATE AMINOTRANSFERASE (AST)

As a group, the transaminases catalyze the interconversion of amino acids and α-keto acids by transferring the amino groups. The enzyme AST has been demonstrated in every animal and human tissue studied. Although the enzyme is most active in the heart muscle, significant activity has also been seen in the brain, liver, gastric mucosa, adipose tissue, skeletal muscle, and kidneys of humans. AST measurements are used in the diagnosis and treatment of certain types of liver and heart disease. AST is present in both the cytoplasm and mitochondria of cells. In cases involving mild tissue injury, the predominant form of serum AST is from the cytoplasm, with smaller amounts from the mitochondria. Severe tissue damage results in more of the mitochondrial enzyme being released. Elevated levels of the transaminases can signal myocardial infarction, hepatic disease, muscular dystrophy, or organ damage.^[56]

d. ALBUMIN

Albumin constitutes about 60% of the total serum protein in normal, healthy individuals. Unlike most of the other serum proteins, albumin serves a number of functions which include transporting large insoluble organic anions (e.g., long-chain fatty acids and bilirubin), binding toxic heavy metal ions, transporting excess quantities of poorly soluble hormones (e.g., cortisol, aldosterone, and thyroxine), maintaining serum osmotic pressure, and providing a reserve store of protein. Albumin measurements are used in the diagnosis and treatment of numerous diseases primarily involving the liver or kidneys.^[57]

e. TOTAL BILIRUBIN

Total bilirubin is coupled with diazonium salt DPD (2,5-dichlorophenyldiazonium tetrafluoroborate) in a strongly acidic medium (pH 1-2). The intensity of the color of the azobilirubin produced is proportional to the total bilirubin concentration and can be measured photometrically. Bilirubin is an organic compound formed by the reticuloendothelial system during the normal and abnormal destruction of red blood cells. Elevated levels are associated with hemolytic jaundice, paroxysmal hemoglobinuria, pernicious anemia, polycythemia, icterus neonatorum, internal hemorrhage, acute hemolytic anemia, malaria, and septicemia. Low bilirubin levels are associated with aplastic anemia, and certain types of secondary anemia resulting from toxic therapy for carcinoma and chronic nephritis.^[58]

f. TOTAL PROTEIN

In alkaline solution, a colored chelate forms between cupric ions and compounds containing at least two -CONH₂, -CSNH₂, -CH₂NH₂ or similar groups, joined directly or through a carbon or nitrogen atom. In proteins, the chelate is formed between one cupric ion and about six nearby peptide bonds. The intensity of the color is proportional to the total number of peptide bonds undergoing reaction and thus to the total amount of protein present. This is similar to the biuret reaction. Although compounds undergoing the biuret reaction give colors ranging from pink to purple, the violet colors given by serum albumins and globulins are essentially the same. Serum proteins perform a number of different functions in the body. In addition to being major structural components of cells, proteins are involved in transport, enzymatic catalysis, homeostatic control, hormonal regulation, blood coagulation, immunity, growth and repair, and heredity. Total protein measurements are used in the diagnosis and treatment of a variety of diseases involving the liver, kidney, or bone marrow, as well as other metabolic or nutritional disorders.^[59]

g. CREATININE :

This method, which uses the Jaffe reaction, is based on the work of Popper, Seeling, and Wuest. In an alkaline medium, creatinine forms a yellow-orange-colored complex with picric acid. The rate of color formation is proportional to the concentration of creatinine present and may be measured photometrically. Creatinine measurement serves as a test for normal glomerular filtration. Elevated levels are associated with acute and chronic renal insufficiency and urinary tract obstruction. Levels below 0.6 mg/dL are of no significance.^[60]

RESULTS:

BIOCHEMICAL PARAMETERS

Table 1: Showing Biochemical Parameters of Omeprazole

TESTS	Control group (normal negative goup,5ml/kg normal saline-orally)	Test group (omeprazole, 0.625 ml)	Standard group (omeprazole + silymarin)
SGOT	36.00±0.707	217.4±0.927^***	26.20±1.463^***
SGPT	40±0.707	76.64±0.715^***	36.20±2.154
ALP	112.6±3.326	354.6±2.40^***	97.60±0.273^**
TP	6.540±0.092	3.380±0.363^*	6.440±0.150
TB	0.640±0.172	5.280±0.3216^***	0.680±0.168
SC	0.60±0.141	0.780±0.135	0.760±0160

The values are expressed as mean ± SEM,

When compared to Test and Standard, results were analyzed using one-way ANOVA, followed by Dunnets test where,

***P < 0.001, **P < 0.01 and *P < 0.05 was considered statistically significant.

DISCUSSION:

There was a significant decrease in the level of TP and increase in the level of biochemical parameters that includes SGOT, SGPT, ALP, TB, Renal parameters- serum creatinine in test when compared to control and standard.

Graphical representation showing effect of omeprazole on SGOT levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on SGOT Levels

Graphical representation showing effect of omeprazole on SGPT levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on SGPT Levels

Graphical representation showing effect of omeprazole on ALP levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on ALP Levels

Graphical representation showing effect of omeprazole on TP levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on TP Levels

Graphical representation showing effect of omeprazole on TB levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on TB Levels

Graphical representation showing effect of omeprazole on SC levels in comparison to control and standard groups.

Graphical Representation of Omeprazole on SC Levels

HISTOPATHOLOGICAL EVALUATION OF LIVER

(A) Liver Section of Control Group

Fig.A: Represents the liver section of control group showing normal hepatocytes, portal triads, central veins and sinusoids.

(B) Liver Section of Standard Groups

Fig B: Represents the liver section of standard group showing less damage of hepatic architecture in the presence silymarin

(C) Liver Section of Test Group

Fig.C: Represents the liver section of omeprazole treated group showing congestion of central veins and sinusoids with focal

periportal aggregation of lymphocytes.

CONCLUSION:

The present thesis entitled “Biochemical estimation of high dose of omeprazole in experimental rodents” deals with the exploration of biochemical parameters such as liver and kidney.

The liver and kidney disorders are world problems. Despite its frequent occurrence, high morbidity and mortality, its medical management is currently inadequate, no therapy has successfully prevented the liver and kidney disorders.

The present was carried out to evaluate the biochemical parameters of the effect of omeprazole at high concentrations (0.625ml)

A total of 18 albino wistar rats were used for the study. The animals were divided into three groups, each group consisting of 6 animals. Group 1 animals were treated with normal saline or water 5ml/kg body weight daily for 14 days. Group 2 animals were treated with high dose of omeprazole (0.625ml) for 14 days. Group 3 animals were treated with a standard drug silymarin 25mg/kg bodyweight. The blood samples were used for the estimation of various biochemical parameters including SGOT, SGPT, ALP, TP, TB and Serum creatinine. Histopathological studies were carried out for the liver.

In the present investigation it was observed that the animals treated with the high dose of omeprazole showed significant hepatic damage as shown by the elevated levels of serum markers. These changes in the marker levels will reflect in hepatic structural integrity.

The rise in the SGOT, is usually accompanied by an elevation in the levels of SGPT which play a vital role in the conversion of amino acids to keto acids.

In standard group (omeprazole + silymarin) there is a normalization of serum markers. Increase in the serum level of ALP and bilirubin is due to increased synthesis in the presence of increase in biliary pressure. The biochemical alterations were corelated by histological findings of liver i.e.; congestion of central veins and sinusoids with focal periportal aggregation of lymphocytes.

It can be concluded that the high dose of omeprazole showed significant elevation levels of hepato parameters.

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53. Procedural insert: Hitachi 917 ALT/IFCC. Indianapolis: Roche Diagnostics.

54. Procedural insert: Hitachi 917 Alk Phos/AMP. Indianapolis: Roche Diagnostics.

55. Procedural insert: Hitachi 917 AST/IFCC. Indianapolis: Roche Diagnostics.

56. Procedural insert: Hitachi 917 Albumin/BCP. Indianapolis: Roche Diagnostics.

57. Procedural insert: Hitachi 917 Bilirubin/DPD. Indianapolis: Roche Diagnostics.

58. Procedural insert: Hitachi 917 Total Protein/Biuret. Indianapolis: Roche Diagnostics.

59. Procedural insert: Hitachi 917 Creatinine. Indianapolis: Roche Diagnostics.

Received on 20.04.2019 Modified on 30.04.2019

Res. J. Pharmacology and Pharmacodynamics.2019; 11(2):67-75 .

DOI: 10.5958/2321-5836.2019.00012.0