-
Archives of Pharmacal Research Jan 2024Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison...
Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison syndrome (ZES). Pantoprazole is mainly metabolized by cytochrome P450 (CYP) 2C19, converting to 4'-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the genetic polymorphism affects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populations with various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases was conducted to collect the clinical pharmacogenomic data, physicochemical data, and disposition properties of pantoprazole, and the collected data were used for model establishment. The model was evaluated by comparing the predicted plasma concentration-time profiles and/or pharmacokinetic parameters (AUC and C) with the clinical observation results. The predicted plasma concentration-time profiles in different CYP2C19 phenotypes properly captured the observed profiles. All fold error values for AUC and C were included in the two-fold range. Consequently, the minimal PBPK model for pantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokinetics of pantoprazole in different CYP2C19 phenotypes. The present model can broaden the insight into the individualized pharmacotherapy for pantoprazole.
Topics: Cytochrome P-450 CYP2C19; Genotype; Pantoprazole; Phenotype; Polymorphism, Genetic; Humans
PubMed: 38150171
DOI: 10.1007/s12272-023-01478-7 -
Supportive Care in Cancer : Official... Nov 2019The aim of the present study was to evaluate the potential uroprotective effect of pantoprazole (PPZ) in a mouse model of cyclophosphamide (CP)-induced hemorrhagic...
PURPOSE
The aim of the present study was to evaluate the potential uroprotective effect of pantoprazole (PPZ) in a mouse model of cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) due to its antioxidant and anti-inflammatory properties.
METHODS
Balb/c mice received a single intraperitoneal (i.p.) injection of CP (300 mg/kg) to induce HC. PPZ (20, 50, and 100 mg/kg/day;i.p.) was administered for 3 consecutive days before the induction of HC. Mesna (30 mg/kg;i.p.) was administered 20 min before, 4 and 8 h after CP injection to compare the protective effects of PPZ. After 24 h of HC induction, the bladders were removed for functional studies, biochemical analyses, and histopathological examination.
RESULTS
In vitro contractility studies demonstrated that CP-induced HC decreased the responsiveness of detrusor muscle strips to acetylcholine (ACh), which was reversed by PPZ pretreatment at all doses tested. However, mesna treatment was not able to improve responsiveness to ACh. Biochemical analyses showed that CP caused significant elevation of malondialdehyde (MDA), reduction of total glutathione (GSH), and increment of proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) level, which were measured in bladder homogenates. PPZ pretreatment at three doses found to be effective in reducing the CP-induced elevation of MDA and TNF-α levels. The highest dose of PPZ (100 mg/kg) caused a significant increase in GSH level. CP induced severe HC with marked bladder edema and histological disturbances which were partially abolished by PPZ pretreatment.
CONCLUSIONS
Our results indicate that PPZ pretreatment could attenuate CP-induced HC by interfering with oxidative stress and modulating proinflammatory cytokines.
Topics: Animals; Cyclophosphamide; Cystitis; Disease Models, Animal; Immunosuppressive Agents; Male; Mice; Pantoprazole; Proton Pump Inhibitors
PubMed: 30874926
DOI: 10.1007/s00520-019-04731-2 -
The Oncologist Jul 2018Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short-term endpoints, it was... (Randomized Controlled Trial)
Randomized Controlled Trial
Pantoprazole, an Inhibitor of the Organic Cation Transporter 2, Does Not Ameliorate Cisplatin-Related Ototoxicity or Nephrotoxicity in Children and Adolescents with Newly Diagnosed Osteosarcoma Treated with Methotrexate, Doxorubicin, and Cisplatin.
LESSONS LEARNED
Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short-term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin-associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient-reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring "at least rarely" after cycle 1, prior to objective high-frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long-term toxicity are needed.
BACKGROUND
Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFR) in patients receiving cisplatin with and without pantoprazole.
MATERIALS AND METHODS
Cisplatin (60 mg/m × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6-19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle.
RESULTS
Pantoprazole had no impact on decrements in hearing threshold at 4-8 kHz, post-treatment elevation of urinary AKI biomarkers, or GFR (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died.
CONCLUSION
Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFR and increase in N-acetyl-ß-glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.
Topics: Acute Kidney Injury; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Cross-Over Studies; Doxorubicin; Female; Hearing; Hearing Loss; Humans; Kidney; Male; Methotrexate; Organic Cation Transporter 2; Osteosarcoma; Pantoprazole; Young Adult
PubMed: 29445029
DOI: 10.1634/theoncologist.2018-0037 -
Biomedicine & Pharmacotherapy =... Aug 2018Proton pump inhibitors (PPIs) are effective antagonists of gastric acid secretion used to treat a number of gastro-esophageal disorders. The present study investigated...
BACKGROUND AND AIMS
Proton pump inhibitors (PPIs) are effective antagonists of gastric acid secretion used to treat a number of gastro-esophageal disorders. The present study investigated the effect of Pantoprazole on vascular relaxation in-vitro and ex-vivo and its effect on blood coagulation in an animal model.
MAIN METHODS
Isolated mouse arterial rings were pre-contracted in-vitro with phenylephrine and concentration-response curves to the acetylcholine relaxing effect were constructed in the presence of escalating concentrations of pantoprazole. In another set of experiments, male albino mice weighing ∼25 g were administered a daily dose of pantoprazole (0.4 mg by oral gavage) for four consecutive weeks; a vehicle control group was run in parallel. At the end of the treatment period, thoracic aorta was isolated for the assessment of vascular function ex-vivo. Blood samples were also collected to evaluate the effect of chronic pantoprazole therapy on coagulation parameters, namely, prothrombin time (PT) and activated partial thromboplastin time (aPTT).
KEY FINDINGS
Vascular responsiveness to acetylcholine demonstrated a reduced relaxation of the arterial ring from baseline in the presence of different concentrations of pantoprazole (1 μM: 54.69 ± 1.42%, 10 μM: 34.64 ± 0.90% and 100 μM: 31.50 ± 0.67% vs. control 74.39 ± 1.426%, p < 0.001). Furthermore, acetylcholine-induced relaxation of the aorta was significantly diminished after four weeks of administrating pantoprazole to mice (37.12 ± 2.50%) compared with the control group (72.47 ± 1.68%, p < 0.001). This, however, wasn't accompanied by significant changes in the phenylephrine-induced vasoconstriction. Animals that received pantoprazole daily for four weeks also exhibited increased blood coagulation time in comparison to the vehicle control group (PT 45.30 ± 3.52 s vs. 15.30 ± 0.70 s, p < 0.05; aPTT 96.1 ± 4.62 s vs. 48 ± 1.97 s, p < 0.05, respectively).
SIGNIFICANCE
The results of the present investigation suggest that pantoprazole reduces arterial relaxation and interferes with blood coagulation. Additional studies are warranted to assess the clinical implications of such observations.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Acetylcholine; Animals; Aorta; Blood Coagulation; Disease Models, Animal; Male; Mice; Mice, Inbred BALB C; Pantoprazole; Partial Thromboplastin Time; Phenylephrine; Vasodilation; Vasodilator Agents
PubMed: 29803168
DOI: 10.1016/j.biopha.2018.05.084 -
Biomedicine & Pharmacotherapy =... Dec 2019Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H-K-ATPase...
Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H-K-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; KB Cells; Mice; Mice, Inbred BALB C; Mouth Neoplasms; Pantoprazole; Phosphatidylinositol 3-Kinases; Signal Transduction; TOR Serine-Threonine Kinases; Vincristine
PubMed: 31568987
DOI: 10.1016/j.biopha.2019.109478 -
Clinical Drug Investigation 2007The efficacy of pantoprazole as on-demand therapy for the long-term management of patients with mild gastro-oesophageal reflux disease (GORD) has been demonstrated in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The efficacy of pantoprazole as on-demand therapy for the long-term management of patients with mild gastro-oesophageal reflux disease (GORD) has been demonstrated in clinical studies. In this study, the efficacy of pantoprazole 20mg and esomeprazole 20mg as on-demand therapy for relief of symptoms of mild GORD was compared.
METHODS
Patients with reflux oesophagitis grade A or B (Los Angeles classification) or endoscopy-negative reflux disease (enGORD) were treated with pantoprazole 20mg once daily for 28 days during the acute phase (AP, n = 236). Patients without heartburn during the final 3 days of the AP entered the long-term phase (LTP, n = 199) and were randomised to either pantoprazole 20mg or esomeprazole 20mg as on-demand treatment for 6 months. Antacids were provided as rescue medication during this phase. The mean intensities of the symptoms of heartburn, acid eructation and pain on swallowing, both separately and as a combined symptom score, together with the mean duration of these symptoms during on-demand treatment, were compared between the two treatment groups. The number of tablets taken was also compared.
RESULTS
After 4 weeks of treatment with pantoprazole, 87.3% of patients had relief from heartburn, 74.1% from epigastric pain and 80.8% from acid eructation, according to the investigator assessment. A total of 236 patients were eligible for the on-demand phase. Based on patient diary data, on-demand treatment with pantoprazole resulted in significantly lower mean intensity of heartburn compared with that in the esomeprazole group (1.12 for pantoprazole and 1.32 for esomeprazole, respectively [p = 0.012], in the intention-to-treat [ITT] population). The mean symptom intensities of acid eructation and pain on swallowing, together with the duration of these symptoms, were comparable in the two treatment groups. The combined symptom score of the three symptoms heartburn, acid eructation and pain on swallowing was numerically lower in the pantoprazole group compared with the esomeprazole group (1.72 vs 1.99, respectively, in the ITT population). Tablet intake was comparable in both groups. Relief of symptoms in Helicobacter pylori-positive and -negative patients was also similar in both treatment groups. Both treatments were well tolerated with a good safety profile.
CONCLUSION
On-demand therapy with either pantoprazole 20mg or esomeprazole 20mg is a comparably effective treatment strategy for the long-term treatment of non-erosive and mild GORD. However, the mean intensity of heartburn was significantly lower with pantoprazole treatment.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Female; Gastroesophageal Reflux; Humans; Male; Middle Aged; Pantoprazole; Treatment Outcome
PubMed: 17358101
DOI: 10.2165/00044011-200727040-00008 -
Intensive Care Medicine May 2019In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was...
PURPOSE
In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was interaction (P = 0.049) suggesting increased mortality in patients allocated to pantoprazole as compared with placebo. We aimed to explore this further.
METHODS
The SUP-ICU trial allocated acutely admitted adults at risk of gastrointestinal bleeding to pantoprazole vs placebo. In this post hoc study, we repeated all the preplanned analyses of SUP-ICU in patients with baseline SAPS II > 53.
RESULTS
A total of 1140 patients had a complete SAPS II > 53 and were included. At 90 days, 272/579 patients (47%) assigned to pantoprazole had died, as compared with 229/558 patients (41%) assigned to placebo [relative risk 1.13; 95% confidence interval (CI) 1.00-1.29]. This was supported by sensitivity analyses adjusted for risk factors and those in the per-protocol population. When accounting for patients with incomplete SAPS II in two additional analyses, the relative risk was 1.08; 95% CI 0.96-1.22 and 1.10; 95% CI 0.97-1.25. This was also observed for the secondary outcome days alive without life support. There were no differences between the intervention groups in the other secondary outcomes.
CONCLUSIONS
In this post hoc analysis of patients with high disease severity included in the SUP-ICU trial, we observed higher 90-day mortality and fewer days alive without life support with pantoprazole vs placebo. Some of this may have been explained by missing SAPS II data, but further research is needed to draw firm conclusions. CLINICALTRIALS.GOV: ClinicalTrials.gov No. NCT02467621.
Topics: Adult; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Mortality; Pantoprazole; Patient Acuity; Placebos; Pre-Exposure Prophylaxis; Simplified Acute Physiology Score; Treatment Outcome
PubMed: 30863936
DOI: 10.1007/s00134-019-05589-y -
JAMA Oct 2022In arthroscopic knee and shoulder surgery, there is growing evidence that opioid-sparing protocols may reduce postoperative opioid consumption while adequately... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of a Postoperative Multimodal Opioid-Sparing Protocol vs Standard Opioid Prescribing on Postoperative Opioid Consumption After Knee or Shoulder Arthroscopy: A Randomized Clinical Trial.
IMPORTANCE
In arthroscopic knee and shoulder surgery, there is growing evidence that opioid-sparing protocols may reduce postoperative opioid consumption while adequately addressing patients' pain. However, there are a lack of prospective, comparative trials evaluating their effectiveness.
OBJECTIVE
To evaluate the effect of a multimodal, opioid-sparing approach to postoperative pain management compared with the current standard of care in patients undergoing arthroscopic shoulder or knee surgery.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial was performed at 3 clinical sites in Ontario, Canada, and enrolled 200 patients from March 2021 to March 2022 with final follow-up completed in April 2022. Adult patients undergoing outpatient arthroscopic shoulder or knee surgery were followed up for 6 weeks postoperatively.
INTERVENTIONS
The opioid-sparing group (100 participants randomized) received a prescription of naproxen, acetaminophen (paracetamol), and pantoprazole; a limited rescue prescription of hydromorphone; and a patient educational infographic. The control group (100 participants randomized) received the current standard of care determined by the treating surgeon, which consisted of an opioid analgesic.
MAIN OUTCOMES AND MEASURES
The primary outcome was postoperative oral morphine equivalent (OME) consumption at 6 weeks after surgery. There were 5 secondary outcomes, including pain, patient satisfaction, opioid refills, quantity of OMEs prescribed at the time of hospital discharge, and adverse events at 6 weeks all reported at 6 weeks after surgery.
RESULTS
Among the 200 patients who were randomized (mean age, 43 years; 73 women [38%]), 193 patients (97%) completed the trial; 98 of whom were randomized to receive standard care and 95 the opioid-sparing protocol. Patients in the opioid-sparing protocol consumed significantly fewer opioids (median, 0 mg; IQR, 0-8.0 mg) than patients in the control group (median, 40.0 mg; IQR, 7.5-105.0; z = -6.55; P < .001). Of the 5 prespecified secondary end points, 4 showed no significant difference. The mean amount of OMEs prescribed was 341.2 mg (95% CI, 310.2-372.2) in the standard care group and 40.4 mg (95% CI, 39.6-41.2) in the opioid-sparing group (mean difference, 300.8 mg; 95% CI, 269.4-332.3; P < .001). There was no significant difference in adverse events at 6 weeks (2 events [2.1%] in the standard care group vs 3 events [3.2%] in the opioid-sparing group), but more patients reported medication-related adverse effects in the standard care group (32% vs 19%, P = .048).
CONCLUSIONS AND RELEVANCE
Among patients who underwent arthroscopic knee or shoulder surgery, a multimodal opioid-sparing postoperative pain management protocol, compared with standard opioid prescribing, significantly reduced postoperative opioid consumption over 6 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04566250.
Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Anti-Ulcer Agents; Arthroscopy; Clinical Protocols; Drug Therapy, Combination; Female; Humans; Hydromorphone; Knee Joint; Male; Naproxen; Ontario; Pain, Postoperative; Pantoprazole; Patient Education as Topic; Postoperative Care; Shoulder Joint
PubMed: 36194219
DOI: 10.1001/jama.2022.16844 -
Cellular and Molecular Neurobiology Nov 2018Gastric H/K-ATPase or vacuolar-ATPases (V-ATPases) are critical for the cancer cells survival and growth in the ischemic microenvironment by extruding protons from the...
Gastric H/K-ATPase or vacuolar-ATPases (V-ATPases) are critical for the cancer cells survival and growth in the ischemic microenvironment by extruding protons from the cell. The drugs which inhibit V-ATPases are known as proton pump inhibitors (PPIs). In the present study, we aimed to evaluate the anticancer efficacy of pantoprazole (PPZ) and its consequences on NF-κB signaling in glioma cells. We have used MTT and clonogenic assay to show PPZ effect on glioma cell growth. Propidium iodide and rhodamine 123 staining were performed to demonstrate cell cycle arrest and mitochondrial depolarization. TUNEL staining was used to evidence apoptosis after PPZ treatment. Immunoblotting and immunofluorescence microscopy were performed to depict protein levels and localization, respectively. Luciferase assay was performed to confirm NF-κB suppression by PPZ. Our results revealed PPZ treatment inhibits cell viability or growth and induced cell death in a dose- and time-dependent manner. PPZ exposure arrested G0/G1 cyclic phase and increased TUNEL positivity, caspase-3 and PARP cleavage with altered pro and anti-apoptotic proteins. PPZ also induced ROS levels and depolarized mitochondria (Δψm) with increased cytosolic cytochrome c level. Further, PPZ suppressed TNF-α stimulated NF-κB signaling by repressing p65 nuclear translocation. NF-κB luciferase reporter assays revealed significant inhibition of NF-κB gene upon PPZ treatment. PPZ exposure also reduced the expression of NF-κB-associated genes, such as cyclin-D1, iNOS, and COX-2, which indicate NF-κB inhibition. Altogether, the present study disclosed that PPZ exerts mitochondrial apoptosis and attenuates NF-κB signaling suggesting PPZ can be an effective and safe anticancer drug for glioma.
Topics: Animals; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioma; Humans; Membrane Potential, Mitochondrial; Mitochondria; NF-kappa B; Pantoprazole; Poly(ADP-ribose) Polymerases; Rats; Reactive Oxygen Species; Signal Transduction; Time Factors; Transcription Factor RelA; Tumor Necrosis Factor-alpha
PubMed: 30302629
DOI: 10.1007/s10571-018-0623-4 -
International Journal of Molecular... Nov 2022Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal...
Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal models. However, since PPIs can induce microbiota modulation despite the absence of a high-fat diet or weight gain, it is an interesting model to correlate microbiota modulation with the establishment of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of pantoprazole treatment on TLR4 signaling and liver histology in C57BL/6J mice for 60 days, trying to correlate microbiota modulation with some aspects of liver injury. We performed glucose (GTT) and insulin (ITT) tolerance tests, serum lipopolysaccharide (LPS) dosage, liver histology, liver and intestine extraction for Western blot and qPCR. Fecal microbiota were investigated via metagenomics. Chronic treatment with pantoprazole induced microbiota modulation and impaired ileum barrier integrity, without an association with insulin resistance. Furthermore, increased circulating LPS and increased Toll-like receptor 4 (TLR4) and TGFβ downstream signaling may have an important role in the development of the observed liver microvesicular steatosis and fibrosis. Finally, this model of PPI-induced changes in microbiota might be useful to investigate liver microvesicular steatosis and fibrosis.
Topics: Mice; Humans; Animals; Toll-Like Receptor 4; Gastrointestinal Microbiome; Pantoprazole; Proton Pump Inhibitors; Lipopolysaccharides; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Fibrosis
PubMed: 36430244
DOI: 10.3390/ijms232213766