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Entasafe, A Necessary Adjuvant To Long-term Use Of PPI In GI Compromised COVID-19 Patients

Author: Dr. Sudhir Maharishi

DM Gastroenterology, Associate professor, SMS Hospital and Medical College, Jaipur

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Proton pump inhibitors are one of the most widely used classes of drugs, especially for long-term treatment, and are often prescribed and used under inappropriate conditions. Much attention has been paid to a wide range of adverse events in recent years, and although potential biological mechanisms are reliable, clinical data on adverse events are often insufficient. Several long-term side effects have been investigated, including drug interactions, increased risk of infection, decreased intestinal absorption of vitamins and minerals. Entasafe is a combination of multivitamin, multiminerals, and pre-probiotics that help reduce the risk of serious side effects from long-term use of PPIs.

Keywords: Proton pump inhibitors, Self-medication, Adverse effects, COVID-19, Entasafe



Proton pump inhibitors (PPIs) are essentially H+-K+-ATPase (Hydrogen Potassium ATPase) inhibitors that inhibit gastric acid secretion. These drugs are commonly used to treat acid-related diseases such as peptic ulcer (PU), gastroesophageal reflux disease (GERD), gastrointestinal bleeding and Helicobacter pylori infection, or to prevent stomach ulcers in patients taking monstrous inflammatory drugs (NSAIDs), glucocorticosteroids (GCs) and anticoagulants (figure 1) [1].


Figure 1: Percentage of various PPIs among the co-prescription drugs


The main PPIs currently on the market are omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole (table 1) [2]. The first PPIs approved by the FDA in the United States in 1989 were omeprazole, followed by lansoprazole in 1995, rabeprazole in 1999, pantoprazole in 2000, and esomeprazole in 2001. Proton pump inhibitors are the standard for the treatment of gastroesophageal reflux disease (GERD). The increasing prevalence of GERD is a major driver of market growth [3].

Table 1: Comparison of the Pharmacokinetic Parameters of Various PPIs








Bioavailability, %







Time to peak plasma level (tmax, hr)




1-2, 4-5



Protein binding (%)







Half-life (hr)







Primary excretion







Liver metabolism










Global Proton Pump Inhibitors (PPIs) Market Outlook

They are now one of the most commonly prescribed and used drugs in the world. For example, in the UK, around 59 million PPIs are distributed annually, with total usage doubling since 2007 [4]. One of the largest hospitals in southwest China has noticeably increased PPI use between 2004 and 2013, about 10.4 times. At the same time, there are growing concerns about the abuse of PPIs. It is estimated that 25 to 70% of PPI prescriptions in the United States are unconfirmed. The Proton Pump Inhibitors market was valued at $275 million in 2020 and is projected to reach $3585 million by 2026. By 2021-2026, during the forecast period, the CAGR is expected to reach nearly 4.5% [5]. In India, the current 12 monthly value sale is estimated at 6000 crores with a growth of 15%.


Prescription Behavior of Practitioners

PPIs have been one of the most frequently prescribed drugs for approved and off-label use in recent years. In fact, with annual sales of $13.6 billion, it was the third most popular drug class in the United States (figure 2). There is growing concern that PPIs are being overwritten globally in primary and secondary care. Among hospital patients in Australia, Ireland and the United Kingdom, 63%, 33% and 67% of PPI patients did not meet their national drug intake standards [6-7]. Additionally, 35.59% of patients received PPI and 57% were asymptomatic. The overuse of PPIs in clinical settings is often the result of pressure sores (SUP) prevention in non-ICU patients and the inability to discontinue this treatment before discharge, even in the absence of indications for treatment. Despite its apparent safety and reasonable cost, excessive use of PPIs can lead to serious health risks such as gastrointestinal discomfort, indigestion, and more elevated liver transaminase, allergic reactions, visual abnormalities, osteoporosis, hypomagnesemia, community-acquired pneumonia, as well as Clostridium difficile colitis [8].


Figure 2: Prescription number of different proton pump inhibitors (PPIs) with approved indications


Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use

PPIs are the most potent gastric acid secretion inhibitors available and, as mentioned above, block the acid pump itself. The superior biochemical effect compared to H2RA (H2 receptor antagonist) is based on its ability to stably maintain intracellular pH > 4 between 15-21 hours per day, compared to 8 hours for H2RA [9]. In addition to a longer surgical duration, more effective PPI and nocturnal control of intravenous pH in work branding are clinically important for some patients [10]. The effects of PPIs are also long lasting without the need to increase the dose. However, tachycardia with H2RA can develop rapidly within 3-5 days with regular use [11]. Although the short-term effect of this difference is not significant, continued use of H2RA for several weeks to months can nearly halve the acid-suppressing effect [12]. Clinical trials consistently show higher healing of gastroduodenal ulcers with PPI treatment than with H2RA [13]. Several high-quality publications, including the Maastricht Consensus Report and the recent Cochrane Systematic Review, suggest that the inclusion of a PPI and two (triple therapy) or three antibiotics (quadruple therapy) provides a synergistic effect in eradicating H. pylori. PPI is more effective in this role than H2RA. Although Zollinger Ellison Syndrome associated gastric hypersensitivity can be effectively managed with PPIs, studies with large numbers of patients are rare due to the rare nature of this disease [14]. Normal doses of PPIs are very effective in inducing symptomatic relief in most patients and treating erosive esophagitis [15]. Most side effects related to acid suppression occur during long-term PPI treatment, whereas side effects not related to acid suppression follow in patients on long-term and short-term treatment (table 2) [16].

Table 2: List of adverse event related and unrelated to acid inhibition

Adverse events unrelated to acid inhibition

Adverse events related to acid inhibition

  • Allergic reaction to drug chemicals
  • Collagenous colitis
  • Acute interstitial nephritis
  • Chronic kidney disease
  • Drug interaction
  • Dementia
  • Cerebral ischemic disease
  • Ischemic cardiac disease
  • Pneumonia
  • Gastrointestinal infection
  • Gastric carcinoid tumor
  • Gastric fundic mucosal hypertrophy
  • Changes in gut microbiome
  • Small intestinal bacterial overgrowth
  • Iron deficiency
  • Bone fracture
  • Vitamin B12 deficiency
  • Hypomagnesemia
  • Gastric fundic gland polyps
  • Colon cancer
  • Spontaneous bacterial peritonitis
  • Hepatic encephalopathy
  • Drug interaction


Unsafe Trends of Self-medication of PPIs

The increasing prevalence of GERD along with increasing risk factors is likely to increase the demand for proton pump inhibitors, which in turn will stimulate the market. The increasing shift from prescription to over-the-counter drugs is also driving the proton pump inhibitor market [17].

Several countries have reported a multiple increase in the number of PPI prescriptions between 2001 and 2015. Some of the important factors leading to the abuse of PPIs may include the availability of inexpensive generic PPIs [18-19].


PPIs: Considerations with Long-Term Use (Regulation Caution of the Long Term Use of PPI)

Since 2010, the FDA has issued various warnings about the potential long-term consequences of PPI use, including fracture risk, hypomagnesemia, Clostridium difficile-associated diarrhea, vitamin B12 deficiency, acute interstitial nephritis (AIN), intestinal lupus, and systemic erythema phenomenon (figure 3) [20].


Figure 3: PPIs Therapeutic effects versus Adverse effects


A study published in JAMA 2006 found that "long-term PPI treatment, especially at high doses, is associated with an increased risk of hip fracture”. Several studies since 2006 have linked this substance to fractures. Available evidence suggests that the drug reduces bone density and increases the risk of osteoporosis. Since 2010, the FDA has mandated all PPIs to warn them about the risk of spinal, wrist, and hip fractures. The FDA has found that this risk is highest in people taking high doses for a long time [21]. In 2011, the FDA issued a warning on drug labels about the risk of low magnesium levels (hypomagnesemia). Low magnesium levels can cause irregular heartbeats (arrhythmias). Patients do not always show symptoms. The FDA warned in 2014 that patients taking PPIs for three years or more are at risk of vitamin B12 deficiency. Dementia can be a sign of low vitamin B12 levels. Long-term use of these drugs can cause kidney disease, injury, and disability. It can also lead to heart attacks, cancer and fractures. Other side effects range from vitamin B12 deficiency and low magnesium levels to pneumonia and lupus erythematosus. A new study also linked long-term use with chronic kidney disease (CKD) [22]. The FDA has warned manufacturers not to add CKD warnings to drug labels. Although several studies have found a link between the drug and acute interstitial nephritis, the FDA did not require manufacturers to add in warnings to labels until 2014. In 2012, the FDA published a safety report indicating that the use of PPIs may increase the risk of C. difficile infection. In addition, the FDA said in 2014 that some manufacturers would add hazard warnings to their labels [23-24].


Proton Pump Inhibitors and COVID-19

Proton pump inhibitors (PPIs) did not significantly increase the risk of death or COVID-19 abduction, but did increase the risk of serious illness. Fecal analysis showed the presence of gastrointestinal disease in patients with COVID-19. Since PPIs decrease the production of gastric acid, the microbial composition of the gut changes, and increases the infection risk for Campylobacter, Salmonella, and Clostridium difficile species [25].


Necessity of Entasafe Rx in COVID-19 Medication

Imbalances in the type and volume of bacteria found in the gut may be associated with the risk of 'long COVID', the symptoms of which last for weeks or months beyond the initial illness, variety of bacteria in the gut, known as the microbiome, may influence the severity of COVID-19 as well as the level of the immune system response to the infection. In addition, other nutrients (example zinc, iron, selenium, magnesium and copper) are inadequate [26]. Several studies have shown that cathelicidin inactivation is a potential mechanism for inducing the protective effect of vitamin D against respiratory infections, and vitamin D plays a key role in other important functions, such as musculoskeletal activity. COVID-19 infection appears to have long-term adverse effects on the anatomy and physiology of the gastrointestinal tract, and thus the gut microbiota. Probiotics have strong antibacterial properties against several pathogens. Over the past two decades, probiotics have been proposed as antimicrobial agents against viruses that cause respiratory infections. Entasafe is a dietary supplement specifically designed to help maintain the balance of vitamins, minerals and intestinal flora, typically affected by the prolonged use of proton pump inhibitors (PPIs) [27].



PPIs are used for the prevention and treatment of acid-related disorders. PPI is indicated for relatively short-term use, up to 8 weeks for gastric ulcer disease, gastroesophageal reflux disease (GERD) and erosive esophagitis, and up to 2 weeks for clearance of heartburn and Helicobacter pylori. PPI users' efficiency, availability, and friendliness have made them overused for outpatient and inpatient care. However, Pneumonia, C. difficile diarrhea, fracture risk, hypomagnesemia, thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis, AIN, intestinal infections and neoplasms is seen in some cases. PPIs are commonly used, and rare side effects can affect many people. This is partly due to the availability of PPIs in retail stores. Patients self-medicate indefinitely for suspicious symptoms without being aware of the potentially serious side effects of these medications. PPI is associated with an increased risk of vitamin and mineral deficiencies that affect the metabolism of vitamin B12, vitamin C, calcium, iron, and magnesium. For long-term treatment, multivitamin, minerals, and pre-probiotics may be administered with PPIs to reduce the potential risk of vitamin and mineral deficiencies. Entasafe contains novel forms of highly soluble calcium and iron, whose absorption does not depend on the gastric pH, which guarantees its bioavailability, even under conditions of gastric acid lack. The proprietary blend or probiotics contained in Entasafe helps maintain a digestive balance, which may be disturbed by the regular use of Proton Pump Inhibitors. Entasafe also contains vitamin D3 and vitamin K2, which works to increase bone density and reduce the risk of osteoporosis due to calcium deficiency. Therefore, Entasafe capsules are a good nutritional supplement to treat these side effects associated with long-term use of PPIs. As more patients hospitalized with COVID-19 receive inappropriate antibiotics, complications can be expected. More antibiotic use may translate into higher rates of AAD (Antibiotic Associated Diarrhoea), so Entasafe may be one of the choice for the prevention of AAD in COVID-19 treatment.



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