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Advances in Therapy Jun 2023Since their approval by the Food and Drug Administration (FDA) in 1989, proton pump inhibitors (PPIs) have become one of the most highly utilized drugs in the United... (Review)
Review
Since their approval by the Food and Drug Administration (FDA) in 1989, proton pump inhibitors (PPIs) have become one of the most highly utilized drugs in the United States, assuming a position as one of the top 10 most prescribed medications in the country. The purpose of PPIs is to limit the amount of gastric acid secreted by the parietal cells via irreversible inhibition of the H+/K+-ATPase pump, therefore maintaining an elevated gastric acid pH of greater than 4 for 15-21 h. Even though PPIs have many clinical uses, they are not without their adverse effects, mimicking achlorhydria. Besides electrolyte abnormalities and vitamin deficiencies, long-term use of PPIs has been linked to acute interstitial nephritis, bone fractures, poor COVID-19 infection outcomes, pneumonia, and possibly an increase in all-cause mortality. The causality between PPI use and increased mortality and disease risk can be questioned since most studies are observational. Confounding variables can greatly affect an observational study and explain the wide-ranging associations with the use of PPIs. Patients on PPIs are generally older, obese, sicker with a higher number of baseline morbidities, and on more medications than the compared PPI non-users. These findings suggest that PPI users are at a higher risk of mortality and complications based on pre-existing conditions. This narrative review aims to update readers on the concerning effects that proton pump inhibitor use can have on patients and give providers a resource to create informed decisions on appropriate PPI use.
Topics: Humans; Proton Pump Inhibitors; COVID-19; Fractures, Bone; Kidney; Observational Studies as Topic
PubMed: 37140707
DOI: 10.1007/s12325-023-02476-3 -
CPT: Pharmacometrics & Systems... Jun 2023Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility...
Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling in the prediction of gastric pH-mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle-out manner from a stepwise in vitro-in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole-induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH-mediated exposure observed in the clinical investigation. Based on the model-based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH-mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH-mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.
Topics: Humans; Itraconazole; Achlorhydria; Prospective Studies; Reproducibility of Results; Hydrogen-Ion Concentration
PubMed: 36967484
DOI: 10.1002/psp4.12959 -
Endocrine Journal Jun 2023Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea,...
Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.
Topics: Female; Humans; Middle Aged; Vipoma; Multiple Endocrine Neoplasia Type 1; Vasoactive Intestinal Peptide; Pancreatic Neoplasms; Diarrhea
PubMed: 36889692
DOI: 10.1507/endocrj.EJ22-0578 -
Digestive and Liver Disease : Official... Sep 2023Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in...
BACKGROUND
Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in hypo-achlorhydria and hypergastrinemia, which exerts a proliferative effect on the gastric mucosa.
AIMS
We investigate the incidence of gastric polyps in CAAG patients.
METHODS
This is a single-center retrospective study examining patients with confirmed CAAG from January 1990 until June 2022. Demographic, clinical, biochemical, and serological data were collected for each included patient. The histopathological characteristics of the detected polyps were recorded.
RESULTS
A total of 176 CAAG patients were included. Eighty-nine (50.5%) had 163 incidental polyps. Seventy-six patients (85%) had 130 non-endocrine lesions, among which 118 (90.7%) were inflammatory, 6 (4.6%) adenomatous, and 4 (3%) fundic; 33 patients (37%) had gastric neuroendocrine neoplasms (gNENs), and 21 (23.6%) both; one had MALToma and one gastric adenocarcinoma. Higher circulating levels of gastrin and chromogranin A were observed among patients with polyps (median 668 vs 893 pg/ml p = 0.0237, 146 vs 207 ng/ml p = 0.0027, respectively).
CONCLUSION
CAAG implies a high incidence of gNENs and exocrine lesions. Gastrin plays a possible trophic role on the mucosa. Further evidence is needed to validate its predictive role for increased polyp risk in CAAG.
Topics: Humans; Gastrins; Retrospective Studies; Autoimmune Diseases; Gastritis; Gastritis, Atrophic; Gastric Mucosa; Stomach Neoplasms; Precancerous Conditions; Polyps
PubMed: 36858908
DOI: 10.1016/j.dld.2023.02.008 -
Digestive Diseases (Basel, Switzerland) 2023Chronic atrophic gastritis (CAG) alone is a precancerous condition for gastric cancer. Achlorhydria plays an important role in the formation of a class I carcinogen,...
BACKGROUND
Chronic atrophic gastritis (CAG) alone is a precancerous condition for gastric cancer. Achlorhydria plays an important role in the formation of a class I carcinogen, acetaldehyde. L-cysteine has been claimed to bind acetaldehyde covalently. Symptoms are present in 55% of CAG patients, of whom 70% have upper gastrointestinal complaints. The aim of this study was to investigate the properties of L-cysteine in the modification of symptom patterns in CAG patients.
METHODS
Consecutive patients with histological diagnosis of CAG (OLGA ≥1 with gastric corpus involvement) were evaluated with serological determination of gastric function, clinical assessment of symptoms using the visual analog score (VAS) and the global symptomatic score (GSS), and considered for therapy with L-cysteine, 300 mg daily. Data regarding symptoms were collected at enrollment and after 3, 6, 12, 18, and 24 months, with an ultimate follow-up of 2 years.
RESULTS
A total of 330 patients with CAG were divided in group 1 (77 patients treated with L-cysteine) and group 2 (50 patients who received no specific treatment - control group). A statistically significant improvement in the VAS score (7.8 at baseline vs. 4.5 after 24 months; p < 0.01) was observed in patients treated with L-cysteine, while no significant changes in symptom pattern/intensity were recorded in the 2-year follow-up of untreated patients with CAG.
CONCLUSIONS
Long-term treatment with L-cysteine provides symptom improvement in CAG patients and might be proposed as maintenance therapy in such patients.
Topics: Humans; Gastritis, Atrophic; Cysteine; Stomach Neoplasms; Acetaldehyde; Helicobacter pylori; Gastric Mucosa
PubMed: 36423587
DOI: 10.1159/000528168 -
Current Opinion in Gastroenterology Nov 2022Autoimmune gastritis is characterized by atrophy of acid secreting parietal cells resulting in achlorhydria. Upper gastrointestinal symptoms are common in autoimmune... (Review)
Review
PURPOSE OF REVIEW
Autoimmune gastritis is characterized by atrophy of acid secreting parietal cells resulting in achlorhydria. Upper gastrointestinal symptoms are common in autoimmune gastritis and frequently result in prescriptions for acid suppressant medications despite the inability of the stomach to secrete acid. Evidence-based recommendations for management of gastrointestinal symptoms in autoimmune gastritis are lacking.
RECENT FINDINGS
The most common symptoms in patients with autoimmune gastritis are dyspepsia, heartburn, and regurgitation. Gastroesophageal reflux should be confirmed by pH-impedance testing and is typically weakly acid or alkaline. Therapy for reflux focuses on mechanical prevention of reflux (i.e., elevation of the head of the bed and alginates) or when severe, antireflux surgery. The etiology of dyspepsia in autoimmune gastritis is unclear and largely unstudied. In the first half of the 20th century, oral administration of acid to "aid digestion" was widely used with reported success. However, randomized, placebo-controlled trials are lacking. Here, we provide suggestions for attempting gastric acidification therapy.
SUMMARY
Upper GI symptoms are common in autoimmune gastritis. Their pathogenesis and therapy remain incompletely understood. Acid suppressant medications are useless and should be discontinued. A trial of acid replacement therapy is recommended especially in the form of placebo-controlled trials.
Topics: Alginates; Dyspepsia; Gastritis; Gastroesophageal Reflux; Heartburn; Humans
PubMed: 36165039
DOI: 10.1097/MOG.0000000000000878 -
BMJ Open Gastroenterology Aug 2022We aimed to study the prevalence of achlorhydria (AC) in a large Asian population.
OBJECTIVE
We aimed to study the prevalence of achlorhydria (AC) in a large Asian population.
DESIGN
Medical records of patients who underwent oesophagogastroduodenoscopy (OGD) with Congo red staining method at the Vichaiyut Hospital from January 2010 to December 2019 were retrospectively reviewed.
RESULTS
A total of 3597 patients was recruited; 223 were excluded due to concurrent use of proton pump inhibitors. Eighteen from 3374 patients (0.53%) had AC. Seven patients were presented with permanent AC (5F, 2M) (median age=69 years; range 58-92). Among 11 patients with temporary AC (5M, 6F: mean age 73.4 years; SD 13.2 years), all had gastrointestinal bacterial infection and were over 45 years old. After successful treatment for , AC was absent among patients with temporary AC. If counting only patients over 45 years of age, the prevalence of AC was 0.68% (18/2614). No adverse events arising from Congo red occurred.
CONCLUSION
AC is relatively rare. Permanent and temporary AC were found only when they were over 55 and 45 years old, respectively. Staining Congo red on gastric mucosa can be safely and routinely incorporated into the OGD procedure for early detection of AC. We recommended a low-cost screening test such as serum vitamin B levels for screening only in patients aged 50 and over.
Topics: Achlorhydria; Aged; Aged, 80 and over; Congo Red; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; Prevalence; Retrospective Studies; Staining and Labeling
PubMed: 36008085
DOI: 10.1136/bmjgast-2022-000976 -
AACE Clinical Case Reports 2022To describe a case of composite vasoactive intestinal peptide (VIP)-secreting pheochromocytoma and review literature to provide insight into the various presentations...
OBJECTIVE
To describe a case of composite vasoactive intestinal peptide (VIP)-secreting pheochromocytoma and review literature to provide insight into the various presentations and potential management of these rare tumors.
CASE REPORT
A 64-year-old male patient presented with hypertensive emergency and coronary demand ischemia with development of watery diarrhea, hypokalemia, and achlorhydria syndrome. Serum and urine studies demonstrated elevated metanephrine and VIP levels. Definitive surgical resection resolved symptoms and normalized laboratory values. Pathologic examination of the specimen revealed pheochromocytoma with a Pheochromocytoma of the Adrenal gland Scaled Score of 4 and patchy expression of VIP.
DISCUSSION
Given the different actions of hormones that can be secreted by these composite tumors, we suggest that pheochromocytomas with diversified secretory capabilities may be an underrecognized clinical entity. Localized disease is often amenable to surgical resection, although management of metastatic disease is not well established due to the rarity of these tumors and lack of randomized trials.
CONCLUSION
In patients presenting with diarrhea of unclear etiology or the suggestion of secondary hypertension, assessment for a possible neuroendocrine tumor may be prudent. If an adrenal mass is discovered but the patient exhibits atypical symptoms of catecholamine excess, a diagnosis of composite pheochromocytoma with multisecretory properties should be considered.
PubMed: 35959082
DOI: 10.1016/j.aace.2022.03.003 -
Drug Development and Industrial Pharmacy Mar 2022Development and optimization of orally administered drug products often require bio-predictive tools to help with informing formulation and manufacturing decisions.... (Review)
Review
Development and optimization of orally administered drug products often require bio-predictive tools to help with informing formulation and manufacturing decisions. Reliable bio-predictive dissolution toolkits not only allow rational development of target formulations without having to conduct excessive studies but also help in detecting critical material attributes (CMAs), critical formulation variables (CFVs), or critical process parameters (CPPs) that could impact a drug's performance. To provide early insights for scientists on the development of a bio-predictive method for drug product development, this review summarizes current phase-appropriate bio-predictive dissolution approaches applicable to address typical concerns on solubility-limited absorption, food effect, achlorhydria, development of extended-release formulation, clinically relevant specification, and biowaiver. The selection of an method which can capture the key rate-limiting step(s) of the dissolution and/or absorption is considered to have a better chance to produce a meaningful correlation (IVIVC) or relationship (IVIVR).
Topics: Administration, Oral; Delayed-Action Preparations; Dosage Forms; Drug Development; Solubility
PubMed: 35786119
DOI: 10.1080/03639045.2022.2098315