The Development of Foveolar-type Gastric Adenocarcinoma during Maintenance Therapy of Vonoprazan for Reflux Esophagitis

We herein report the first case of foveolar-type gastric adenocarcinoma that developed after the initiation of vonoprazan (VPZ). A 51-year-old man had heartburn at the first visit and reflux esophagitis endoscopically, so he started taking VPZ. An approximately 5-mm-sized reddish polyp with a raspberry-like morphology was detected at the anterior wall of the upper body of the stomach 156 weeks after starting maintenance therapy with VPZ 10 mg/day. It was diagnosed as foveolar-type gastric adenocarcinoma based on a biopsy. Another approximately 4-mm-sized foveolar-type gastric adenocarcinoma was also detected at the posterior wall of the middle body of the stomach.     

The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine

Summary In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3- (IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7–17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10g/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150g/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1–5.0g/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.     

Immunomodulatory effect of candesartan on indomethacin-induced gastric ulcer in rats

Non steroidal anti-inflammatory drugs (NSAIDs) induce gastric mucosal lesions in part by induction of oxidative stress as well as the activation of inflammatory cells and the production of proinflammatory cytokines. In this study, we examined the protective effect of candesartan (2 and 5?mg/kg) on indomethacin-induced gastric mucosa damage. Pretreatment with candesartan for 10 days reduced significantly the ulcer index induced by indomethacin injection. The preventive index of 2?mg/kg (76.74%) was higher than that of 5?mg/kg (65.11%). Both doses of candesartan were able to reduce significantly the stomach malondialdehyde content compared to indomethacin-treated group. Myeloperoxidase, tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant gastric levels were significantly reduced by 2?mg/kg of candesartan more than 5?mg/kg. The Th1 cytokine interferon γ was also significantly reduced by both doses of candesartan compared to indomethacin injected group. On the other hand, indomethacin significant decreased the anti-inflammatory cytokine IL-10 gastric level. Pretreatment with candesartan (2 and 5?mg/kg) reversed this effect. In conclusion, the present study indicates that pretreatment with candesartan, can protect against the stomach injury induced by indomethacin through its antioxidant and immunomodulatory effects.     

A multifaceted approach to calcium channel blocker overdose: a case report and literature review

Calcium channel blocker toxicity can be devastating. Initial therapy with fluid, calcium, and adrenoreceptor agonists should be prompt and novel therapies can be added if no response. Determining cardiogenic shock versus vasoplegia with echocardiogram or other hemodynamic monitoring may guide treatment options.     

From the Cover: Molecular determinants of Hv1 proton channel inhibition by guanidine derivatives

The voltage-gated proton channel Hv1 plays important roles in proton extrusion, pH homeostasis, and production of reactive oxygen species in a variety of cell types. Excessive Hv1 activity increases proliferation and invasiveness in cancer cells and worsens brain damage in ischemic stroke. The channel is composed of two subunits, each containing a proton-permeable voltage-sensing domain (VSD) and lacking the pore domain typical of other voltage-gated ion channels. We have previously shown that the compound 2-guanidinobenzimidazole (2GBI) inhibits Hv1 proton conduction by binding to the VSD from its intracellular side. Here, we examine the binding affinities of a series of 2GBI derivatives on human Hv1 channels mutated at positions located in the core of the VSD and apply mutant cycle analysis to determine how the inhibitor interacts with the channel. We identify four Hv1 residues involved in the binding: aspartate 112, phenylalanine 150, serine 181, and arginine 211. 2GBI appears to be oriented in the binding site with its benzo ring pointing to F150, its imidazole ring inserted between residue D112 and residues S181 and R211, and the guanidine group positioned in the proximity of R211. We also identify a modified version of 2GBI that is able to reach the binding site on Hv1 from the extracellular side of the membrane. Understanding how compounds like 2GBI interact with the Hv1 channel is an important step to the development of pharmacological treatments for diseases caused by Hv1 hyperactivity.The Hv1 voltage-gated proton channel (also known as HVCN1 or voltage-sensor–only protein) regulates the production of superoxide and other reactive oxygen species by NADPH oxidase (NOX) enzymes in a variety of cell types, including microglial cells (1) and leukocytes (2). NOX activity causes membrane depolarization and intracellular accumulation of protons. Hv1 allows sustained NOX activity by repolarizing the membrane and extruding excess protons from the cell (3–5).Hv1 has been shown to enhance brain damage in a mouse model of ischemic stroke through its NOX-modulating activity (1). The channel was also found overexpressed in many B-cell malignancies (6) and breast and colorectal cancer tissues (7, 8). High Hv1 activity was shown to increase invasiveness of breast cancer cells and be associated with shorter overall and recurrence-free survival in breast cancer patients (7). These findings highlight that excessive activity of the Hv1 channel can have serious pathological consequences in ischemic stroke and cancer and that small-molecule inhibitors targeting Hv1 could lead to the development of new neuroprotective or anticancer drugs.The Hv1 protein is made of four membrane-spanning segments (S1–S4) (9, 10), and it is related to the voltage-sensing domains (VSDs) of other voltage-gated ion channels (11) and voltage-sensitive phosphatases (VSPs) (12). The inner end of the S4 segment is connected to a coiled-coil domain responsible for protein dimerization (13, 14). As a result, the channel is made of two VSD subunits, each containing a gated proton pore (15–17).The block of voltage-gated sodium, potassium, and calcium channels by small molecules has been studied for decades. Its mechanism has been elucidated for many drugs, and in the majority of cases, the inhibitors were found to bind to different regions of the pore domain (18, 19). With the exception of peptide toxins (20, 21), not much is known about compounds interacting with VSDs (22), and only recently have there been successful attempts to produce small-molecule drugs that specifically target these domains in voltage-gated ion channels (23, 24).We have recently shown that some guanidine derivatives have the ability to inhibit Hv1 activity and that one of these compounds, 2-guanidinobenzimidazole (2GBI), binds the channel''s VSD only in the open conformation (25). We have also found that the binding site is within the proton permeation pathway and faces the cytoplasm.Here, we explore the chemical space available to guanidine derivatives for Hv1 binding. We then use a mutation cycle analysis approach to identify the residues in the channel that contribute to the binding environment of 2GBI and establish the overall orientation of the blocker within the VSD in the open conformation. Our results suggest that residues D112, F150, S181, and R211 are located close to each other deep within the membrane and in the proximity of the intracellular vestibule of the VSD, where they can interact with the blocker. We discuss our binding model in the context of a recent crystal structure of the channel (26).