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Toxicological studies on omeprazole
Abstract
As part of the safety evaluation of the gastric antisecretory drug, omeprazole, toxicological studies have been performed in several species of animals. The acute toxicity after oral administration to rodents was low. The oral LD50 value was above 4 g/kg. The general toxicity after repeated administration has been studied in rats and dogs. No clinical signs of adverse reactions were seen. Some minor changes in hematology parameters were observed. In rats and mice decreases in the erythrocyte count, hematocrit and hemoglobin have occasionally been found at doses of 125 mumol/kg/day and more. Hyperplasia of oxyntic mucosal cells, concomitant with increases in stomach weight, oxyntic mucosal thickness and folding, has been observed in the species investigated, the dog, rat and mouse. In addition, slight chief cell atrophy and eosinophilia of the chief cell granules were observed in rats. The oxyntic mucosal effects were reversible upon treatment being discontinued. In the oncogenicity studies, gastric carcinoids occurred in the rat but not in the mouse. Investigations of the carcinoids showed that the vast majority of the endocrine cells could be characterised as ECL-cells. The hyperplasia of oxyntic mucosal cells, including hyperplasia of endocrine ECL-cells and development of gastric carcinoids in rats, is attributable to the pronounced hypergastrinemia produced as a secondary effect of almost complete inhibition of acid secretion by the large doses of omeprazole used in the toxicity studies. In agreement with this hypothesis, the hyperplasia of the oxyntic cells was prevented by antrectomy. The reproduction studies performed in rats and rabbits showed no sign of fetal toxicity or teratogenic effect. The results of the short-term mutagenicity tests, Ames test, the micronucleus test in mice and the mouse lymphoma test were all negative.
... Similarities between the gastric mucosal effects of chronic hypergastrinemia in ZES and in animal studies include a number of observations. In dog, rat, and mouse, long-term PPI treatment resulted in an increase in oxyntic mucosal thickness and folding [203], similar to that seen in both groups of ZES patients. With animal studies, the degree of the chronic hypergastrinemia induced by PPIs, other anti-secretory drugs, or other methods, correlated directly with the extent of the ECL cell changes, as it does in both sporadic ZES and MEN1/ZES patients [25,56,61,62,204]. ...
... With animal studies, the degree of the chronic hypergastrinemia induced by PPIs, other anti-secretory drugs, or other methods, correlated directly with the extent of the ECL cell changes, as it does in both sporadic ZES and MEN1/ZES patients [25,56,61,62,204]. Long-term treatment in rats with either PPIs or the insurmountable H 2 antagonist, loxtidine, resulted in advanced ECL changes and gastric carcinoids [203,205], whereas in mice, chronic PPI treatment caused advanced ECL changes, but no gastric carcinoids [203], similar to that seen in sporadic ZES. In contrast, long-term loxtidine treatment in mice caused both advanced ECL changes and the development of gastric carcinoids [206]. ...
... With animal studies, the degree of the chronic hypergastrinemia induced by PPIs, other anti-secretory drugs, or other methods, correlated directly with the extent of the ECL cell changes, as it does in both sporadic ZES and MEN1/ZES patients [25,56,61,62,204]. Long-term treatment in rats with either PPIs or the insurmountable H 2 antagonist, loxtidine, resulted in advanced ECL changes and gastric carcinoids [203,205], whereas in mice, chronic PPI treatment caused advanced ECL changes, but no gastric carcinoids [203], similar to that seen in sporadic ZES. In contrast, long-term loxtidine treatment in mice caused both advanced ECL changes and the development of gastric carcinoids [206]. ...
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
... [31][32][33][34][35][36] However, theoretical mechanisms are not necessarily applicable to animals and humans, and preclinical studies did not suggest teratogenicity of PPIs, even at doses 56 times higher than that recommended for humans, although dose-related fetal deaths in pregnant rats and rabbits were reported. [37][38][39] Likewise, the findings of the present study also suggested no meaningful increase in the risk of malformations. The latest meta-analysis 12 of 18 observational studies reported that PPI use during pregnancy was associated with a 28% increase in the risk of overall malformations. ...
... Earlier studies 4,5 that excluded a large increase in the risk of malformations associated with maternal PPI use have generally focused on omeprazole based on dose-related mortality observed in animal studies. 37,39 To our knowledge, only 1 study 6 to date has investigated PPIs both as a class and as individual agents; that study included omeprazole and other PPIs, finding no associations with overall malformations. Our study, based on more recent data, further adds to the literature and provides evidence on the fetal safety of PPIs. ...
Importance:
Proton pump inhibitors (PPIs) are increasingly used during pregnancy; however, several observational studies have raised concerns about an increased risk of specific types of congenital malformations.
Objective:
To examine the association between PPI exposure during early pregnancy and the risk of congenital malformations.
Design, setting, and participants:
This population-based cohort study used data from the National Health Insurance Service-National Health Information Database of South Korea (2010-2020); sibling-controlled analyses were conducted to account for familial factors. A total of 2 696 216 pregnancies in women aged 19 to 44 years between June 1, 2011, and December 31, 2019, and their live-born infants were identified. Pregnant women who were exposed to known teratogens or who delivered infants with chromosomal abnormalities or genetic syndromes were excluded. Data on participant race and ethnicity were not collected because the National Health Information Database does not report this information.
Exposures:
Proton pump inhibitor use during the first trimester.
Main outcomes and measures:
Primary outcomes were major congenital malformations, congenital heart defects, cleft palate, hydrocephalus, and hypospadias. The subtypes of major congenital malformations and congenital heart defects were evaluated as exploratory outcomes. Propensity score fine stratification was used to control for potential confounders, and a weighted generalized linear model was used to estimate relative risks with 95% CIs.
Results:
Of 2 696 216 pregnancies (mean [SD] maternal age, 32.1 [4.2] years), 40 540 (1.5%; mean [SD] age, 32.4 [4.6] years) were exposed to PPIs during the first trimester. The absolute risk of major congenital malformations was 396.7 per 10 000 infants in PPI-exposed pregnancies and 323.4 per 10 000 infants in unexposed pregnancies. The propensity score-adjusted relative risks were 1.07 (95% CI, 1.02-1.13) for major congenital malformations, 1.09 (95% CI, 1.01-1.17) for congenital heart defects, 1.02 (95% CI, 0.72-1.43) for cleft palate, 0.94 (95% CI, 0.54-1.63) for hydrocephalus, and 0.77 (95% CI, 0.51-1.17) for hypospadias. In the sibling-controlled analyses, no associations were observed between PPI use and primary outcomes, including major congenital malformations (odds ratio, 1.05; 95% CI, 0.91-1.22) and congenital heart defects (odds ratio, 1.07; 95% CI, 0.88-1.30). A range of sensitivity analyses revealed results that were similar to the main findings.
Conclusions and relevance:
In this cohort study, the use of PPIs during early pregnancy was not associated with a substantial increase in the risk of congenital malformations, although small increased risks were observed for major congenital malformations and congenital heart defects; findings from sibling-controlled analyses revealed that PPIs were unlikely to be major teratogens. These findings may help guide clinicians and patients in decision-making about PPI use in the first trimester.
... 15 In the present study, no used this controversial and costly Somatostatin, but have used Omeprazole, the longest used safe Proton pump inhibitor, which is easily available and cheap and whose safety profile is known. It is also found to be safe for high up to 60mg 6hourly dose for a longer period 1-43months as in case of Zollinger Ellison syndrome with no evidence of hematologic, biochemical, or gastric toxicity 16,17,18 Omeprazole 60 mg 12hourly used per enteral route for 8 weeks and usual dose 20mg 12hourly for another 4weeks continuously without any side effect. However, it was repeated in a few cases after an interval. ...
... This overuse is estimated between 40% to 80% in different countries [2,3]. Fortunately, they are very well tolerated, but the initial phase of omeprazole development was stopped when it was shown that carcinoids (ECLome) developed in the oxyntic mucosa in rodents [4]. Nevertheless, in the last decade, growing concerns have emerged regarding their safety, with a large number of studies reporting long-term toxicity, including cancer (of gastric, pancreatic, liver and biliary tract location) [5]. ...
Multikinase inhibitors (MKIs), and particularly tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs), are currently some of the major breakthroughs in cancer treatment. Proton pump inhibitors (PPIs) revolutionised the treatment of acid-related diseases, but are frequently overused for epigastric pain or heartburn. However, long-term acid suppression from using PPIs may lead to safety concerns, and could have a greater impact in cancer patients undergoing therapy, like bone fractures, renal toxicities, enteric infections, and micronutrient deficiencies (iron and magnesium). Moreover, acid suppression may also affect the pharmacokinetics of drugs (at least during acid suppression) and decrease the absorption of many molecularly-targeted anticancer therapies, which are mostly weak bases with pH-dependent absorption. This type of drug-drug interaction may have detrimental effects on efficacy, with major clinical impacts described for some orally administrated targeted therapies (erlotinib, gefitinib, pazopanib, palbociclib), and conflicting results with many others, including capecitabine. Furthermore, the long-term use of PPIs results in severe alterations to the gut microbiome and recent retrospective analyses have shown that the benefit of using CPIs was suppressed in patients treated with PPIs. These very expensive drugs are of great importance because of their efficacy. As the use of PPIs is not essential, we must apply the precautionary principle. All these data should encourage medical oncologists to refrain from prescribing PPIs, explaining to patients the risks of interaction in order to prevent inappropriate prescription by another physician.
... These A-SA are commonly available for the treatment of functional gastrointestinal disorders and acid-related diseases, such as peptic ulcers and reflux esophagitis. However, long-term use of PPIs causes a number of adverse effects, including bone fracture [6], Clostridium difficile infection [7], pneumonia [8], and atrophic gastritis [9], and has the potential to cause gastric cancer [10] or gastric carcinoid [11] due to hypergastrinemia. Furthermore, PPI use causes various endoscopic gastric mucosal changes, such as fundic gland polyps (FGP) [12], white flat elevated mucosa [13], black spot [14], gastric cobblestone-like mucosa (GCSM), and gastric cracked mucosa (GCM) [15] because of parietal cell degeneration. ...
White globe appearance (WGA) is defined as a microendoscopic white lesion with a globular shape underlying the gastric epithelium and is considered a marker of gastric cancer. We recently reported that endoscopically visualized white spot (WS) corresponding to WGA appeared on the nonatrophic mucosa of patients with acid-suppressing agents (A-SA) use. We evaluated patients undergoing routine esophagogastroduodenoscopy and divided the patients into an A-SA group (n = 112) and a control group (n = 158). We compared the presence of WS in both groups. We also compared WS-positive- (n = 31) and -negative (n = 43) groups within the A-SA group regarding these patients’ backgrounds and serum gastrin concentrations. Comparing the A-SA group with controls, the prevalence of WS was significantly higher (31/112 vs. 2/158; p < 0.001). The number of patients with high serum gastrin concentrations was significantly higher in the WS-positive group (18/31) vs. the WS-negative group (5/43) (p < 0.001). Within the A-SA group, the prevalence of WS was also significantly higher in patients taking potassium-competitive acid blockers vs. proton-pump inhibitors (21/31 vs. 10/31, p < 0.001). The WS-positive group had a significantly greater percentage of patients, with a high serum gastrin level (p < 0.001). WS may be associated with hypergastrinemia and potassium-competitive acid blockers.
... 15 In the present study, no used this controversial and costly Somatostatin, but have used Omeprazole, the longest used safe Proton pump inhibitor, which is easily available and cheap and whose safety profile is known. It is also found to be safe for high up to 60mg 6hourly dose for a longer period 1-43months as in case of Zollinger Ellison syndrome with no evidence of hematologic, biochemical, or gastric toxicity 16,17,18 Omeprazole 60 mg 12hourly used per enteral route for 8 weeks and usual dose 20mg 12hourly for another 4weeks continuously without any side effect. However, it was repeated in a few cases after an interval. ...
Introduction: Pancreatic fistula is a serious complication after pancreatic and peripancreatic
organ surgery. No clear management modality is fool proof. Increased Gastrin level is
known to reduce Secretin. Omeprazole is the first proton pump inhibitor and in use since
in the last 40years. Thus, a high dose of Omeprazole is likely to suppress the Secretin and
likely to reduce the fistula output and thus improve the healing.
Materials and methods: Confirmed pancreatic fistula patients as defined by an international
consensus group were included in this prospective study. Patients with ascites and fistula
healing in five days were excluded. Bacterial culture positive drain fluid patients were not
excluded. All received 60mg of Omeprazole 12hourly and continued for 2months after the
closure of fistula. The drain fluid volumes were measured daily and amylase periodically
during the follow up.
Result: There were 39 cases in 13years (2005 to 2017) with 35 males and 4 females. All the
fistulae closed in 7-24days (mean 11.777 SD +/- 3.882). One case developed a pseudocyst
after early stoppage of Omeprazole, but it, resolved with another course. Second end PF
required elective fistulo-enterostomy for recurrent fistula.
Conclusion: High dose Omeprazole hastens up the healing of pancreatic fistula. Further
studies are needed.
Keywords: pancreatic fistula, high dose omeprazole, open main pancreatic duct,
postoperative pancreatic fistula, end duct fistula
... 15 In the present study, no used this controversial and costly Somatostatin, but have used Omeprazole, the longest used safe Proton pump inhibitor, which is easily available and cheap and whose safety profile is known. It is also found to be safe for high up to 60mg 6hourly dose for a longer period 1-43months as in case of Zollinger Ellison syndrome with no evidence of hematologic, biochemical, or gastric toxicity 16,17,18 Omeprazole 60 mg 12hourly used per enteral route for 8 weeks and usual dose 20mg 12hourly for another 4weeks continuously without any side effect. However, it was repeated in a few cases after an interval. ...
Patients having pancreatic fistula ( post tube drain, pancreatic injury, necrosectomy) were given Omeprazole 60 mg tice daily and observed. Most of the fistula got healed. It is compaired with the published literatures using various methods of treatment for the same condition. This study is safe, effective and heals the fistula in an average time of 11.88 days.
... Rodents are susceptible to development of hyperplasia and neoplasia in endocrine target organs when faced with excessive chronic hormonal trophic stimulation. Examples of this phenomenon in rats include thyroid hyperplasia and neoplasia in response to chronic TSH stimulation (6,22) and development of hyperplasia and neoplasia of gastric enterochromaf n cells associated with excessive chronic gastrin stimulation (12). ...
This study assessed the effects of raloxifene, a selective estrogen receptor modulator (SERM), on ovarian morphology and circulating hormone levels in rats. Female Fischer-344 rats (65/group) were given dietary raloxifene for 6 months at average daily doses of 0, 15, 75, and 365 mg/kg. Morphologic evaluation of ovaries was conducted on 25 rats/group at the end of the treatment period and from 20 rats per group after 1 and 3 months withdrawal from treatment. Plasma hormone analyses were conducted on 10 rats per group at the end of the treatment period and after each withdrawal period.
Treatment with raloxifene for 6 months resulted in disruption of the hypothalamic-pituitary-ovaria n axis, manifested by increased plasma concentrations of luteinizing hormone (LH) and estradiol-17 β (E2), and failure of ovulation, manifested by ovarian follicular prominence (retained anovulatory follicles), lack of corpora lutea (CL), and depressed plasma progesterone (P4). Many (56% to 80%) rats in all raloxifene treated groups had focal, minimal to slight hyperplasia of granulosa cells within individual retained follicles. A few treated rats in the mid- and high-dose groups (2 of 25 and 3 of 25, respectively) had more extensive focal proliferation of granulosa cells. These foci were approximately 3 to 6 mm in overall size and were characterized by moderate papillary proliferation of large granulosa cells associated with cystic spaces, often with hemorrhage. In 4 of the 5 rats with this focal cystic granulosa cell hyperplasia, the remainder of the involved ovary and the contralateral ovary were atrophic.
After 1 or 3 months of drug withdrawal, most previously treated rats examined had morphologic evidence of ovarian cyclic changes, including developing follicles, various stages of CL, and normal plasma levels of LH, E2, and P4. Continued lack of cyclic changes was limited to 4 of 20 rats from the low-dose group after 1 month of recovery and to 1 low dose rat after 3 months. Intrafollicular granulos a cell hyperplasi a was not seen in rats in the reversibility phase. Areas of prior focal cystic granulosa cell hyperplasia were represented by focal sclerosis that included hemorrhage and/or hemosiderin. The foci of sclerosis were associated with cystic spaces after 1 month and were solid after 3 months.
A granulosa cell tumor, approximately 12—13 mm diameter, was present in a high-dose rat in the 3-month reversibility group. This tumor effaced 1 ovary and was characterized by proliferative granulosa cells, usually in papillary formations and cords within cystic spaces. This rat had atrophy of the uninvolved ovary, excessive plasma levels of E2 and prolactin, and high P4 levels considering the absence of CL.
The results of this study indicate that ovarian granulos a cells in rats are susceptibl e to proliferative changes when stimulated chronicall y with excessive trophic hormones. Most of these proliferative changes were reversible upon cessation of the hormonal stimulation. However, the proliferative lesion in one treated rat progressed to apparent autonomous (neoplastic) growth.
... Extensive rodent studies have demonstrated that hypergastrinemia induced by continuous treatment of acidsuppressing drugs, including PPIs and H 2 histamine receptor antagonists, results in mucosal hyperplasia and ECL cell hyperplasia. In rare cases, ECL cell neuroendocrine tumors (NETs) might develop although these generally remain benign (126,127). However, Mastomys, a hypergastrinemic rodent model that is genetically susceptible to spontaneous formation of gastric NETs, can develop gastric carcinoid tumor in the presence of normal serum gastrin levels, likely through the constitutive activation of CCK2R (128,129). ...
The structurally-related peptides, gastrin and cholecystokinin (CCK), were originally discovered as humoral stimulants of gastric acid secretion and pancreatic enzyme release, respectively. With the aid of methodological advances in biochemistry, immunochemistry, and molecular biology in the past several decades, our concept of gastrin and CCK as simple gastrointestinal hormones has changed considerably. Extensive in vitro and in vivo studies have shown that gastrin and CCK play important roles in several cellular processes including maintenance of gastric mucosa and pancreatic islet integrity, neurogenesis, and neoplastic transformation. Indeed, gastrin and CCK, as well as their receptors, are expressed in a variety of tumor cell lines, animal models, and human samples, and might contribute to certain carcinogenesis. In this review, we will briefly introduce the gastrin and CCK system and highlight the effects of gastrin and CCK in the regulation of cell proliferation and apoptosis in both normal and abnormal conditions. The potential imaging and therapeutic use of these peptides and their derivatives are also summarized.
... These toxicity data indicate a wide and adequately safe therapeutic index for oral administration. 7 Neuroinflammation is the first response of the neuronal immune system soon after the invasion of a foreign particle, thus occurring as a signal of infection or irritation. 8 It consists of a protective mechanism that isolates damaged brain tissue from the uninjured area, and destroys the affected (damaged, impaired) cells, causing repair of the extracellular matrix. ...
... These toxicity data indicate a wide and adequately safe therapeutic index for oral administration. 7 Neuroinflammation is the first response of the neuronal immune system soon after the invasion of a foreign particle, thus occurring as a signal of infection or irritation. 8 It consists of a protective mechanism that isolates damaged brain tissue from the uninjured area, and destroys the affected (damaged, impaired) cells, causing repair of the extracellular matrix. ...
... These toxicity data indicate a wide and adequately safe therapeutic index for oral administration. 7 Neuroinflammation is the first response of the neuronal immune system soon after the invasion of a foreign particle, thus occurring as a signal of infection or irritation. 8 It consists of a protective mechanism that isolates damaged brain tissue from the uninjured area, and destroys the affected (damaged, impaired) cells, causing repair of the extracellular matrix. ...
Our study aimed to analyze the effect of ouabain (OUA) administration on lipopolysaccharide (LPS)-induced changes in hippocampus of rats. Oxidative parameters were analyzed in Wistar rats after intraperitoneal injection of OUA (1.8 µg/kg), LPS (200 µg/kg), or OUA plus LPS or saline. To reach our goal, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), in addition to levels of reduced glutathione (GSH), protein carbonyl (PCO) and lipid peroxidation (LPO) were evaluated. We also analyzed the membrane lipid profile and some important lipids for the nervous system, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphati-dylinositol (PI), phosphatidic acid and sphingomyelin. The group that received only LPS showed increased oxidative stress, as evidenced by an increase in LPO (about twice), PCO (about three times) levels, and CAT activity (80%). Conversely, administration of LPS decreased GSH levels (55%), and GPx activity (30%), besides a reduction in the amount of PI (60%) and PC (45%). By other side, OUA alone increased the amount of PI (45%), PE (85%), and PC (70%). All harmful effects recorded were attenuated by OUA, suggesting a protective effect against LPS-induced oxidative stress. The relevance of our results extends beyond changes in oxidative parameters induced by LPS, because nanomolar doses of OUA may be useful in neurodegenerative models. Other studies on other cardenolides and substances related issues, as well as the development of new molecules derived from OUA, could also be useful in general oxidative and/or cellular stress, a condition favoring the appearance of neuronal pathologies. K E Y W O R D S hippocampus, lipopolysaccharide, membrane lipids, ouabain, oxidative stress J Cell Biochem. 2018;1-11. wileyonlinelibrary.com/journal/jcb
... Recent studies show an important effect of PPIs on the microbiome, with a potentially bigger impact on population-level compared to antibiotics, [14][15][16][17] and there is increasing evidence linking long-term PPI use with other diseases although the evidence remains uncertain [18,19]. Coherence and experimental studies, already during the 1980s evidence emerged from animal studies indicating potential carcinogenic and teratogenic effects of PPI use [20][21][22][23][24]. Analogy, as some other studies have indicated, antibiotic use may also be associated with an increased cancer risk (with studies on colorectal and breast cancer), with dysbiosis of the microbiota as one of the proposed mechanisms; yet to our knowledge, no evidence has thus far been published on oesophageal cancer [25][26][27]. ...
... single dose of 120 mg [16]. It is a safe drug and in an animal study of omeprazole toxicity, the oral dose of LD 50 value was above 4 G/Kg [17]. Omeprazole is now the drug of choice in patients with ZES and is safe for long-term treatment of up to 4 yr. ...
Most of pain-relieving agents in chronic pancreatitis are nonspecific and unpredictable. Omeprazole induces hypergastrinemia due to reduced gastric acidity. Raised serum gastrin, in turn, modulates to reduce secretin level. Secretin is responsible for secretion of almost 80 % bicarbonate-rich pancreatic juice from the ductular epithelium without affecting enzyme output. It is a prospective randomized study in patients with CT-confirmed chronic pancreatitis. The control group got the standard care and 60 mg of omeprazole twice daily was added to the test group. Absence of pain relief at 14 days was considered as failure. Pain relief, weight gain and any toxic effect of omeprazole were reviewed at 12 months. One hundred thirty-seven cases were included, with an age range of 19 to 72 years. (mean 42.67). The majority of them were alcoholic males. At 2 weeks, pain relief was noted in 47/69(68.1 %) and 63/65(96.96 %) in the control and omeprazole group, respectively. At the end of 1 year, the omeprazole group had greater weight gain (95 %) than the control group (69.5 %). All the pseudocysts in the omeprazole group and most in the control group resolved. No side effect of omeprazole was seen. The high-dose omeprazole (HDO) group of patients had significantly better pain relief in chronic pancreatitis than those treated with conventional therapy. A high number of cases gained weight in the HDO group than the controlled group. No patient had clinical, endoscopic, biochemical, or haematological toxicity of HDO. More studies are necessary.
... We found that both groups of HK −/− mice had increased volume density of antral G-cells and decreased volume density of D-cells compared with PAI-1 +/+ /HK +/+ , which is compatible with previous findings in rats given a proton pump inhibitor [29] , whereas the PAI- 1 genotype did not influence G-cell and D-cell number or volume density significantly. It is well known that hypergastrinemia induced by long-term inhibition of gastric acid secretion increases corpus proliferation rates [3] and mucosal thickness [15,30]. We found an increased number of Ki-67 positive cells in PAI-1 −/− /HK −/− mice compared with PAI-1 +/+ /HK −/− mice, whereas the density of proliferating cells did not differ. ...
... [25] There have been claims that the rat is rather special since PPI was not reported to give ECL cell tumors in the dog [26] or the mouse. [27] However, since the pivotal part of the pathogenesis of these tumors is reduction of gastric acidity and secondary hypergastrinemia, studies with doses of PPI not affecting gastric acidity in species where these compounds have low potency like the mouse, [28] are irrelevant to the question of whether PPIs may increase the risk of ECL cell tumors. The role of gastrin in gastric carcinogenesis has also been shown in the rodent Mongolian gerbils infected with Helicobacter pylori, [29] and the Japanese cotton rats where mainly females spontaneously develop gastropathy with destruction of oxyntic glands making the animals hypoacidic and hypergastrinemic. ...
Objective:
Since the description of ECL cell-derived tumors in rodents after long-term profound acid inhibition inducing hypergastrinemia, there has been concern that proton pump inhibitors (PPIs) could also do that in man. The recent description of a Spanish family with gastric ECL cell tumors at the age of about 30 years secondary to a defect in the proton pump due to mutation in the ATP4A gene clearly shows that hypergastrinemia alone also is sufficient to induce ECL cell neoplasia in man. The present review aims to evaluate the risk of gastric neoplasia secondary to gastric acid inhibition.
Methods:
Literature (MEDLINE) was searched for the role of the ECL cell in gastric carcinogenesis in animals and man in general and particularly secondary to long-term inhibition of acid secretion.
Results:
An important proportion of patients treated with PPI develops hypergastrinemia causing ECL cell hyperplasia and the first descriptions of ECL cell carcinoids secondary to PPI have been reported. The role of the ECL cell has hitherto been under estimated in gastric carcinogenesis in man where for instance the signet ring cell type of gastric carcinoma seems to originate from the ECL cell.
Conclusions:
The first two of three steps in rodent ECL cell carcinogenesis (hyperplasia, carcinoid, and carcinoma) secondary to PPI dosing, have been described for man. It is every reason to believe that the final step, gastric carcinoma, will develop also in man. Clinical decisions should be based not only on so-called evidence based medicine, but also on physiological knowledge and animal studies.
... single dose of 120 mg [16]. It is a safe drug and in an animal study of omeprazole toxicity, the oral dose of LD 50 value was above 4 G/Kg [17]. Omeprazole is now the drug of choice in patients with ZES and is safe for long-term treatment of up to 4 yr. ...
... In acute experiments a single dose of omeprazole and SCH28080 were administrated by the intravenous injection through the jugular vein. Omeprazole was dissolved in 40% polyethylene glycol (PEG 400) [32] and SCH28080 was dissolved in 0.4% methylcellulose-saline suspension [33]. The doses were chosen according to the previous studies and injected two hours before collecting pancreatic secretion [33,34]. ...
The mechanism by which pancreas secretes high HCO3- has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3- from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised.
... As phase III trials were underway, rats, but not mice or dogs, developed ECL cell carcinoid tumors, halting the clinical PPI trials, which the involved scientists were convinced was an effect of hypergastrinemia and not primarily drug dependent, supported by data generated by a Hässle team led by Enar Carlsson, which was sufficient to re-start the clinical trials. A key experiment used to support the hypergastrinemia hypothesis was that rats treated with high-dose H 2 RA also developed ECL tumors [33]. In contrast to rats, the ECL cell is terminally differentiated in humans, explaining why ECL tumors have not been described in humans receiving long-term, high-dose PPI therapy. ...
... The hyperplasia of gastric endocrine cells and development of carcinoid-like neoplasms was first reported in the stomach of rats treated with omeprazole over 20 years ago (Ekman et al., 1985;Havu et al., 1990). Omeprazole inhibits gastric acid secretion by blocking the enzyme H+, K+-ATPase, the proton pump of the parietal cells. ...
This article addresses a number of concepts related to the selection and modelling of carcinogenicity data for the calculation of a Margin of Exposure. It follows up on the recommendations put forward by the International Life Sciences Institute - European branch in 2010 on the application of the margin of exposure (MoE) approach to substances in food that are genotoxic and carcinogenic. The aims are to provide practical guidance on the relevance of animal tumour data for human carcinogenic hazard assessment, appropriate selection of tumour data for benchmark dose modelling, and approaches for dealing with the uncertainty associated with the selection of data for modelling and, consequently, the derived point of departure (PoD) used to calculate the MoE. Although the concepts outlined in this article are interrelated, the background expertise needed to address each topic varies. For instance, the expertise needed to make a judgement on biological relevance of a specific tumour type is clearly different to that needed to determine the statistical uncertainty around the data used for modelling a benchmark dose. As such, each topic is dealt with separately to allow those with specialised knowledge to target key areas of guidance and provide a more in-depth discussion on each subject for those new to the concept of the margin of exposure approach.
Background
Proton pump inhibitors (PPIs) are widely used to treat a number of gastroesophageal disorders. PPI-induced elevation in intra-gastric pH may alter gastrointestinal physiology. The tight junctions (TJs) residing at the apical intercellular contacts act as a paracellular barrier. The TJ barrier dysfunction is an important pathogenic factor in Inflammatory Bowel Disease (IBD). Recent studies suggest that PPI may promote disease flares in IBD patients. The role of PPI in intestinal permeability is not clear.
Aim
The aim of the present study was to study the effect of PPI on the intestinal TJ barrier function.
Methods
Human intestinal epithelial cell culture and organoid models and mouse IBD models of Dextran sodium sulfate (DSS) and spontaneous enterocolitis in IL-10 -/- mice were used to study the role of PPI in intestinal permeability.
Results
PPI increased TJ barrier permeability via an increase in a principal TJ regulator, myosin light chain kinase (MLCK) activity and expression, in a p38MAPK dependent manner. PPI-induced increase in extracellular pH caused MLCK activation via p38MAPK. Long term PPI administration in mice exaggerated increase in intestinal TJ permeability and disease severity in two independent models of DSS colitis and IL-10 -/- enterocolitis. The TJ barrier disruption by PPI was prevented in MLCK -/- mice. Human database studies revealed increased hospitalizations associated with PPI use in IBD patients.
Conclusions
Our results suggest that long term use of PPIs increases intestinal TJ permeability and exaggerates experimental colitis via increase in MLCK expression and activity.
There is a significant inverse relationship between intragastric acidity and plasma gastrin concentration. All generally available gastric acid antisecretory drugs induce a release of gastrin into the circulation. The more potent the gastric antisecretory dosage regimen or drug, the greater the rise of plasma gastrin concentration. The drug-induced rise of plasma gastrin concentration is of no direct clinical concern, although it may be partly responsible for the phenomenon of tolerance to H2-blockade. Drug-induced hypergastrinemia could stimulate the proliferation of certain cell lines associated with the gastrointestinal tract, for example, the gastric epithelium, ECL cells, or colonic neoplasms.
Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H⁺K⁺-ATPase, the proton pump of the parietal cell.
Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H⁺K⁺-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs.
Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H⁺K⁺-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.
Realizando a ponte entre a farmacologia homeopática (princípio da similitude) e a farmacologia moderna, encontramos uma infinidade de relatos, tanto em compêndios farmacológicos como em experimentos e ensaios clínicos publicados em periódicos científicos, que descrevem uma reação do organismo oposta e secundária a uma ação primária da droga, confirmando a teoria hahnemanniana. Essa ação secundária do organismo, no sentido de manter a homeostase orgânica, é denominada de efeito rebote ou reação paradoxal segundo a racionalidade científica moderna, sendo usada pela homeopatia como resposta terapêutica.
Building a bridge between homeopathic pharmacology (principle of similitude) and modern pharmacology, one can find countless reports in pharmacological compendia and clinical and experimental trials published in the scientific media describing the secondary reaction of the organism opposed to the primary action of the drug, which confirm Hahnemann’s theory. Such secondary action of the organism to preserve organic homeostasis is known in modern science as rebound effect or paradoxical reaction, being used by homeopathy as a therapeutic response.
Targeting ribosome biogenesis, a cellular process frequently upregulated in cancer, with the novel Pol I transcription inhibitor CX-5461 is highly efficacious in pre-clinical models of solid and haematological cancers, which lead to the commencement of clinical trials. However, as is common with single agent therapies in the mouse models (similar to challenges with treating human patients), the mice eventually succumb to disease, highlighting the need for a combination therapy approach. Based on the strong link between altered ribosome biogenesis and metabolism in cancer it was hypothesised that targeting these two processes in combination would prove efficacious in cancer, and acute myeloid leukaemia (AML) was chosen to test this as it is an aggressive malignancy with poor therapeutic options. In order to address this hypothesis In vitro drug synergy testing in AML cell lines was performed to identify promising combinations (Chapter 3), these were then tested for efficacy in in vivo transplant models of AML (Chapter 4). Finally, in vitro mechanistic analysis of the most promising drug combination was performed in order to understand the mechanisms of synergy (Chapter 5). In vitro testing of CX-5461 in combination with 10 clinically-approved metabolism-modifying drugs confirmed that orlistat, dichloroacetate (DCA), ritonavir, omeprazole and chloroquine act synergistically with CX-5461 to reduce cell viability in multiple AML cell lines. Three such combination therapies were evaluated in a syngeneic mouse AML model. Neither orlistat nor DCA improved survival in combination with CX-5461 compared to CX-5461 alone, however synergy was observed with the autophagy inhibitor chloroquine. Interestingly, the combination of CX-5461 and chloroquine had limited efficacy in human cell line xenograft mouse models, despite strong in vitro results. As the dosing of CX-5461 and chloroquine could not be increased due to toxicity, mechanistic analysis was performed in order to identify an alternative to chloroquine with reduced toxicity, and potentially improved efficacy. CX-5461 and chloroquine were found to synergise through cell cycle arrest and cell death in all four cell lines tested. Metabolic flux analysis revealed that the combination of drugs significantly affected mitochondrial activity, indicating that the combination of CX-5461 and chloroquine is placing the cells in mitochondrial stress. Therefore, direct targeting of the mitochondria was identified as a promising approach in combination with ribosome biogenesis inhibition with CX-5461, and various clinically-approved drugs that target mitochondria were identified for future combination testing.
Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.
Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.
Hypergastrinemia is a very important clinical condition for the reason that a growing body of evidence obtained from animal and human experiments has revealed gastric carcinoids induced by hypergastrinemia. We investigated 35 patients with Basedow's disease (BD) to elucidate the mechanism of hypergastrinemia associated with BD as well as the relationship between type A gastritis and BD. Fasting serum gastrin levels in BD (296.1±251.4pg/ml; mean±S.D.) were significantly (p<0.001) higher than those in age-matched 27 healthy subjects (106.1±69.2), and in the BD group, significant positive correlation was detected between fasting serum gastrin levels and thyroid hormones (i.e. T3 and free T4). In the hyperchlorhydria group in BD with hypergastrinemia, the levels of fasting serum gastrin were normalized after euthyroidism was attained due to antithyroidal drugs. On the other hand, in the achlorhydria group in BD significant hypergastrinemia was persisted in spite of normalization of thyroid function. Twenty % of the BD patients had histologically proved type A gastritis with achlorhydria, and all patients with type A gastritis were older than 60 years old. Endoscopic examination revealed that one patient with type A gastritis had an early gastric cancer. However, no gastric carcinoids were demonstrated in this study. In conclusion, the results described as above suggested, 1) hypergastrineumia observed in patients with BD may be induced by gastrin hypersecretion due to hyperthyroidism as well as type A gastritis, 2) BD patients with type A gastritis were recommended to undertake regular endoscopic examination for detecting gastric cancers as well as gastric carcinoids.
Carcinomas of the gastrointestinal (GI) tract and pancreas account for more than 222,500 new cases of cancers and cause the death of 125,000 patients yearly in the United States (1). Treatment of patients with these cancers relies heavily on adequate surgical resection. This is effective only when a localized tumor is present. There are no effective systemic treatments for metastatic colon, stomach, or pancreatic cancers.
Long-term toxicological experiments with inhibitors of acid secretion were found to induce hyperplasia and eventually carcinoid tumors of the enterochromaffinlike cells of the oxyntic mucosa. To evaluate the effects of 6 months' treatment with omeprazole in humans, the oxyntic endocrine cells were morphometrically investigated at the ultrastructural level in five patients with active duodenal ulcer. No omeprazole-induced changes were found in the volume density of the total endocrine cell population and specific cell types (including the enterochromaffinlike cell) as well as in the other cytological parameters investigated (number of cell profiles per unit area, mean cross-sectional area of cell profiles, nuclear-cytoplasmic ratio, and density of cytoplasmic secretory granules). Both pretreatment and posttreatment values in our patients with duodenal ulcer significantly differed from those of a previous investigation of healthy volunteers with regard to the volume density of enterochromaffinlike cells and nongranulated cells, which increased, and of D cells, which markedly decreased. The latter result may provide a cellular basis for impairment in the paracrine release of fundic somatostatin in peptic ulcer disease. Finally, morphometric data on endocrine cell volume density provided by electron microscopy were found to correlate with those obtained in the same patients using light microscopy techniques (Grimelius silver impregnation and chromogranin A immunostaining). It is concluded that 6 months' treatment with pharmacological doses of omeprazole is devoid of appreciable trophic effect on endocrine cells of human oxyntic mucosa.
There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e., alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of > 50 endpoint-specific control compounds was identified. For further test development, an additional “test” set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the > 100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.
If a chronic duodenal ulcer perforates, the choice of operation will depend on the patient's condition. Preoperative shock, concurrent medical diseases, severe generalized peritonitis, or the presence of an intra-abdominal abscess are contraindications to a definitive ulcer operation; hence, simple closure or omental patch closure is performed. Omeprazole can then be used to heal the ulcer in the early postoperative period, with long-term H2-blocker therapy to follow. The patient without a contraindication to a definitive operation should have a proximal gastric vagotomy in addition to an omental patch closure of the perforation. The addition of this procedure does not change the operative mortality rate in properly selected patients, does not cause the gastrointestinal sequelae associated with truncal vagotomy and pyloroplasty or resection, and has a low rate of recurrent ulcer in experienced hands. The presence of a synchronous posterior "kissing" duodenal ulcer would prompt some to choose a vagotomy and pyloroplasty in preference to a proximal gastric vagotomy. The appropriate operation to perform after perforation of an acute duodenal ulcer in a patient with any of the contraindications listed above is simple closure or omental patch closure. In the stable nonseptic patient, the choice is not as clear. Boey and associates noted cumulative recurrent ulcer rates of 37% and 31% at 3 years in separate studies in which omental patch closure was used for perforated acute duodenal ulcers. This may reflect the asymptomatic nature of chronic duodenal ulcers in some patients prior to perforation, the failure of the surgeon to recognize the extent of periduodenal scarring at operation, or differences in the length of postperforation follow-up in series reporting perforations of acute or chronic ulcers. Jordan has suggested that all stable patients with perforated duodenal ulcers should undergo a proximal gastric vagotomy in addition to omental patch closure. In his hands, the addition of proximal gastric vagotomy has an operative mortality rate of 0 to 1%, a recurrent ulcer rate of 3% to 5%, and no adverse postoperative sequelae. He has noted that "this operation gives protection from further ulcer disease to those who need it and will produce no harm to the unidentifiable patients that might not have benefited from definitive surgery." Boey and Wong suggested that omental patch closure is indicated for "acute ulcers associated with drug ingestion or acute stress" in addition to those that occur in patients who are considered to be poor risk, while proximal gastric vagotomy should be added in the remaining patients with perforations of acute ulcers.(ABSTRACT TRUNCATED AT 400 WORDS)
There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e., alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of > 50 endpoint-specific control compounds was identified. For further test development, an additional "test" set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the > 100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.
In rats, hypergastrinemia due to achlorhydria produced by antisecretory drugs or resection of the gastric fundus leads to enterochromaffinlike (ECL) cell hyperplasia and gastric carcinoids. In humans, achlorhydria due to pernicious anemia may also lead to ECL cell hyperplasia and multicentric gastric carcinoids in as many as 5% of cases. To examine the apparent gastrin dependence of gastric ECL carcinoids, three patients were studied (2 men aged 59 and 73 years; 1 woman aged 45 years) who had pernicious anemia, serum gastrin concentrations of >1000 ng/L (>1000 pg/mL), and multicentric gastric carcinoids. Antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6–16 weeks. In each of the three patients, a focus of microcarcinoid was found at 12–18 months. Further follow-up in each of the three patients 21–30 months after antrectomy again showed no carcinoids or ECL cell hyperplasia. It is concluded that multicentric ECL gastric carcinoids in patients with pernicious anemia and achlorhydria appear to be gastrin dependent and disappear after normalization of serum gastrin by antrectomy. Antrectomy rather than total gastrectomy may be the most appropriate treatment for this condition.
Evidence has accumulated in recent years from animal experiments that drugs inhibiting acid secretion can stimulate the growth of gastric mucosa. This was first shown in our laboratories, when rats were treated with high doses of metiamide, a precursor of cimetidine1–3. It was later confirmed with cimetidine4 and was subsequently also observed with prolonged antacid treatments5. In all these studies a hyperplasia of the parietal cells was observed. The functional correlate was an acid rebound following discontinuation of drug therapy1,3. It is likely that this trophic effect is mediated by gastrin, the established trophic hormone of the gastrointestinal tract6, since in the rat every high dose of a histamine H2-antagonist or antacid leads to a transient gastrin releasel.
Cancer is a complex, multistage, multimechanism phenomenon. Despite this, long-term rodent carcinogenicity studies have been the principal means used to assess the potential carcinogenic effect of compounds. Unfortunately, decades of carcinogenicity testing have failed to provide an unequivocal set of guidelines that determines the true carcinogenic potential of a compound in laboratory animals or humans. Furthermore, there is often considerable debate over what is a biologically significant finding in an individual study. A statistical evaluation helps in assessing the probability that a finding is treatment related, but numerous other factors have an impact on that determination. The data must be evaluated separately and collectively to determine whether the change in question is real.
Symptoms of several human diseases are manifested as increased salivation (e.g., Parkinson’s disease) or decreased salivation (e.g., xerosis). Studies to find and to evaluate sialagogues, such as substance P and its synthetic derivatives, as well as to search for salivation inhibitors are necessary. Saliva excretion is greatly influenced by anesthetics. Wagner et al (1991) proposed a simple method to study saliva secretion in conscious rats and to evaluate sialagogues and sialagogue antagonists.
Gastroesophageal reflux disease (GERD), the most common disorder of the esophagus, is extremely variable in its presentations and clinical course. It is known from epidemiological studies that many people complain of typical reflux symptoms, including heartburn and regurgitation, but only few request medical investigation. About 20%–40% of the world’s population has symptoms suggestive of GERD; an exact estimate is difficult because of the way the disease presents [1]. In 1985, Castell [2] described GERD as an iceberg, with a large base indicating patients with slight and episodic symptoms without need of medical assistance, a smaller portion of patients with moderate and recurrent symptoms and, at the top, patients with severe and persistent symptoms requiring special care (Fig. 1). Furthermore, a number of patients with atypical symptoms, such as refractory asthma, recurrent hoarseness, chronic unexplained cough or non-cardiac chest pain, are later discovered as having GERD. Thus, it seems evident that this disease is frequently underdiagnosed.
So far, all speakers in this symposium have focussed mainly on the harmful effects of gastric acidity on the gastric and duodenal mucosa. On the other hand, the assumed pathogenicity of Campylobacter pylori has opened a new perspective in the treatment of peptic ulcer disease. It may well be that the combined treatment of gastric acidity of C. pylori-colonization will display a synergistic effect in ulcer healing. However, since all the following presentations will give more details about C. pylori-colonization and eradication, we feel it is still necessary to highlight briefly the hitherto and conventional treatment of peptic ulcer disease.
Originally Gosh and Schild (1958) introduced a method for the continuous recording of gastric acid secretion in the stomach lumen-perfused anesthetized rat. In this model gastric acid secretion can be stimulated by histamine, carbachol, or gastrin. Stimulated gastric acid secretion is inhibited by test drugs with antisecretory potential.
In 1955 Zollinger and Ellison described two patients with recurrent peptic ulceration, a marked increase in gastric acid secretion, and islet cell tumors. This triad of findings became known as the Zollinger-Ellison syndrome (ZES). Zollinger and Ellison (1955) suggested that this syndrome was caused by a circulating hormone released from the tumor, which also caused gastric acid hypersecretion. Subsequent studies showed large amounts of the hormone gastrin in the serum and in tumors of patients with ZES (Gregory et al. 1969; MCGuigan and Trudeau 1969; Stremple and Meade 1968). Because these tumors synthesize and release large amounts of gastrin they have been called gastrinomas.
This chapter deals with the digestive system. The major and minor salivary glands and their secretions also represent and integral part of the protective mechanism of the oral cavity, and derangement of saliva production may lead to loss of integrity of the oral mucosa. Drug-induced abnormalities of taste sensation are also well-described phenomena occurring in man although human studies are necessary for the detection of these effects. Inflammation of the oral cavity may involve the buccal mucosa, the gingiva (gingivitis), the tongue (glossitis), and the peridontal tissues (peridontitis). Therapeutic agents can induce inflammatory lesions in the tongue. Moreover, a protective layer of mucus, a visco-elastic material containing high molecular weight glycoproteins produced by the major and minor salivary glands, covers the stratified squamous mucosa of the oral cavity. Salivary secretions also possess digestive enzyme activity although in herbivores and carnivores, it is usually low in contrast to high digestive enzyme activity in omnivorous species.
The chapter elaborates on the drug-induced changes in the urinary tract. Many therapeutic and diagnostic agents used in humans have the potential to cause renal damage. Hospital-based series have suggested that life-threatening nephrotoxicity that cause admission to a hospital is relatively uncommon as compared to adverse gastrointestinal effects. Among laboratory animals, there are species and probably also strain differences in the sensitivity of renal tissue to the effects of drugs. The main structural and functional unit of the kidney is the nephron, which is composed of the glomerulus and the renal tubule. Urine formation commences in the glomerulus with the elaboration of an ultrafiltrate across the walls of the glomerular capillaries. Fatty acids and acetoacetate have been shown to be the main exogenous fuels of respiration in the rat kidney cortex when available in physiological concentrations. A variety of polypeptide and protein antigens can be used as immunocytochemical markers in the assessment of renal damage. The glomerulus is the site of a number of spontaneous degenerative, inflammatory, and immune-mediated disorders in both laboratory animals and humans, and it is also the target for damage by drugs and chemicals. Findings show that morphological changes are accompanied by functional alterations as well as notably increased glomerular basement membrane permeability and the loss of selectivity.
J.1 Salivary glandsJ.1.0.1 Measurement of salivationPURPOSE AND RATIONALESymptoms of several human diseases are manifested as increased salivation (e.g., Parkinson's disease) or decreased salivation (e.g., xerosis). Studies to find and to evaluate sialagogues, such as substance P and its synthetic derivatives, as well as to search for salivation inhibitors are necessary. Saliva excretion is greatly influenced by anesthetics. Wagner et al. (1991) proposed a simple method to study saliva secretion in conscious rats and to evaluate sialagogues and sialagogue antagonists.PROCEDUREFed, male Sprague-Dawley rats (200–300 g) are weighed and distributed randomly into groups of 6 animals. Conscious rats are injected i.v., via the lateral tail vein, with either the vehicle or the sialagogue, e.g., substance P (0.3–3 μg/kg in 1 ml saline/kg). The rat's oral cavity is swabbed immediately after i.v. injection by placing and holding a pre-weighed, absorbent foam cube (e.g., 5/16″, ...
Salivary GlandsMeasurement of SalivationPurpose and RationaleSymptoms of several human diseases are manifested as increased salivation (e. g., Parkinson's disease) or decreased salivation (e. g., xerosis). Studies to find and to evaluate sialagogues, such as substance P and its synthetic derivatives, as well as to search for salivation inhibitors are necessary. Saliva excretion is greatly influenced by anesthetics. Wagner et al. (1991) proposed a simple method to study saliva secretion in conscious rats and to evaluate sialagogues and sialagogue antagonists.ProcedureFed, male Sprague‐Dawley rats (200–300 g) are weighed and distributed randomly into groups of 6 animals. Conscious rats are injected i.v., via the lateral tail vein, with either the vehicle or the sialagogue, e. g., substance P (0.3–3 µg/kg in 1 ml saline/kg). The rat's oral cavity is swabbed immediately after i.v. injection by placing and holding a pre-weighed, absorbent foam cub ...
An 84-year-old man who was being treated for aseptic necrosis of the left femoral head was referred to our department for evaluation of epigastralgia, nausea and loss of appetite. Upper gastrointestinal endoscopy revealed duodenal ulcers on the anterior and posterior walls of the duodenal bulb. He was treated with omeprazole. About 8 weeks after the initiation of omeprazole therapy, he developed pain in both breasts. A physical examination revealed gynecomastia, which disappeared after administration of omeprazole was discontinued. Although the patient was positive for hepatitis C virus antibody, his liver function was fairly well preserved during his clinical course. Serum levels of luteinizing hormone, follicle stimulating hormone and human chorionic gonadotropin were elevated, and levels of testosterone and dehydroepiandrosterone-S were decreased. These hormonal abnormalities persisted even after discontinuance of omeprazole therapy, suggesting that they represented age-related hormonal changes. Our findings suggest that gynecomastia was induced by omeprazole.
Abstract We evaluated the efficacy of omeprazole (OPZ) for the treatment of upper gastrointestinal (UGI) lesions in rheumatoid arthritis (RA) patients. Fourteen RA patients with H2 receptor antagonist- (H2RA-) resistant UGI lesions (1 stomal, 11 gastric, and 2 esophageal with reflux esophagitis ulcers) were treated with OPZ at 20 mg/day (study A). New untreated UGI lesions (1 stomal and 12 gastric ulcers) were treated with OPZ (study B). Three patients who showed renal dysfunction during H2RA treatment for UGI lesion were treated with OPZ (study C). Nonsteroidal antiinflammatory drugs (NSAIDs) were not discontinued. The stage of each ulcer was determined by gastrointestinal fiberscopy (GIF). In study A, during the first 8 weeks of OPZ treatment, 1 esophageal and 7 gastric ulcer patients were completely cured. Six patients showing partial response were treated further with OPZ for another 8 weeks. During this second period, 1 stomal and 3 gastric ulcer patients were completely cured, and 1 gastric and 1 esophageal ulcer patient showed only partial response. In study B, after an 8-week OPZ treatment, all except 2 patients showed complete healing. One patient developed mild eruption at 4 weeks and was shifted to H2RA. One patient showed complete healing after 4 weeks. No patient in study C showed renal dysfunction with OPZ. Our results suggest that OPZ is an effective treatment for UGI lesions in RA patients using NSAIDs.
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