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Frontiers in Cellular and Infection... 2024Azole resistance has been increasingly reported and become an issue for clinical managements of invasive mycoses. New strategy with combination therapy arises as a...
INTRODUCTION
Azole resistance has been increasingly reported and become an issue for clinical managements of invasive mycoses. New strategy with combination therapy arises as a valuable and promising alternative option. The aim of the present study is to investigate the combinational effect of proton pump inhibitors (PPIs) and azoles against pathogenic fungi.
METHODS
interactions of PPIs including omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN), and rabeprazole (RAB), and commonly used azoles including itraconazole (ITC), posaconazole (POS), voriconazole (VRC) and fluconazole (FLC), were investigated via broth microdilution chequerboard procedure adapted from the CLSI M27-A3 and M38-A2. A total of 67 clinically isolated strains, namely 27 strains of spp., 16 strains of spp., and 24 strains of dematiaceous fungi, were studied. (ATCC 22019) and (ATCC 204304) was included to ensure quality control.
RESULTS
PPIs individually did not exert any significant antifungal activity. The combination of OME with ITC, POS, or VRC showed synergism against 77.6%, 86.6%, and 4% strains of tested pathogenic fungi, respectively, while synergism of OME/FLC was observed in 50% strains of spp. Synergism between PAN and ITC, POS, or VRC was observed against 47.8%, 77.6% and 1.5% strains of tested fungi, respectively, while synergism of PNA/FLC was observed in 50% strains of spp. Synergism of LAN with ITC, POS, or VRC was observed against 86.6%, 86.6%, and 3% of tested strains, respectively, while synergism of LAN/FLC was observed in 31.3% strains of spp. Synergy of the combination of RAB with ITC, POS, or VRC was observed against 25.4%, 64.2%, and 4.5% of tested strains, respectively, while synergism of RAB/FLC was observed in 12.5% of spp.. Among PPIs, synergism was least observed between RAB and triazoles, while among triazoles, synergism was least observed between VRC and PPIs. Among species, synergy was much more frequently observed in spp. and dematiaceous fungi as compared to spp. Antagonism between PPIs with ITC or VRC was occasionally observed in spp. and dematiaceous fungi. It is notable that PPIs combined with azoles showed synergy against azole resistant , and resulted in category change of susceptibility of ITC and POS against spp.
DISCUSSION
The results suggested that PPIs combined with azoles has the potential to enhance the susceptibilities of azoles against multiple pathogenic fungi and could be a promising strategy to overcome azole resistance issues. However, further investigations are warranted to study the combinational efficacy in more isolates and more species, to investigate the underlying mechanism of interaction and to evaluate the potential for concomitant use of these agents in human.
Topics: Humans; Azoles; Proton Pump Inhibitors; Fungi; Antifungal Agents; Triazoles; Voriconazole; Fluconazole; Candida; Aspergillus; Candida parapsilosis; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 38304196
DOI: 10.3389/fcimb.2024.1296151 -
International Journal of Pharmaceutics Mar 2024Multidrug therapeutic hybrids constitute a promising proposal to overcome problems associated with traditional formulations containing physical mixtures of drugs,...
Multidrug therapeutic hybrids constitute a promising proposal to overcome problems associated with traditional formulations containing physical mixtures of drugs, potentially improving pharmacological and pharmaceutical performance. Indomethacin (IND) is a non-selective non-steroidal anti-inflammatory drug (NSAIDs) that acts by inhibiting normal processes of homeostasis, causing a series of side effects, such as gastrointestinal symptoms. Proton pump inhibitors, such as omeprazole (OME), have been used to treat such gastrointestinal tract symptoms. In this work, two new multidrug therapeutic hybrids were prepared (an IND:OME salt and an IND:OME co-amorphous system) by ball mill grinding crystalline IND and OME under different conditions, i.e., liquid assisted grinding (LAG) with ethanol and dry grinding, respectively. The crystalline salt returned to a neutral state co-amorphous system when submitted to ball mill grinding in the absence of solvent (dry grinding), but the reverse process (LAG of the IND:OME co-amorphous system) showed partial decomposition of OME. The IND:OME co-amorphous system showed a higher physical stability than the neat IND and OME amorphous materials (with an amorphous stability longer than 100 days, compared to 4 and 16 h for the neat amorphous drugs, respectively, when stored at dry conditions at room temperature). Furthermore, OME presented a higher chemical stability in solution when dissolved from a salt form than from the pure crystalline form. The dissolution studies showed a dissolution enhancement for IND in both salt (1.8-fold after 8 h of dissolution) and co-amorphous (2.5-fold after 8 h of dissolution) forms. Anti-inflammatory activity using a mice paw oedema model showed an increase of the pharmacological response to IND at a lower dose (∼5mg/kg) for both IND:OME salt (2.8-fold) and IND:OME co-amorphous system (3.2-fold) after 6 h, when compared to the positive control group (IND, administered at 10 mg/kg). Additionally, the anti-inflammatory activity of both salt and co-amorphous form was faster than for the crystalline IND. Finally, an indomethacin-induced gastric ulceration assay in mice resulted in a higher mucosal protection at the same dose (40 mg/kg) for both IND:OME salt and IND:OME co-amorphous system when compared with crystalline OME.
Topics: Mice; Animals; Indomethacin; Omeprazole; Drug Stability; Crystallization; X-Ray Diffraction; Anti-Inflammatory Agents, Non-Steroidal; Sodium Chloride; Solubility
PubMed: 38281693
DOI: 10.1016/j.ijpharm.2024.123857 -
PloS One 2024The objectives of the present study were to evaluate the acute toxicity, gastroprotective, therapeutic, anti-inflammatory and anti H. pylori activities of T. vulgaris...
The objectives of the present study were to evaluate the acute toxicity, gastroprotective, therapeutic, anti-inflammatory and anti H. pylori activities of T. vulgaris total plant extract against ethanol-induced gastric ulcers in Sprague Dawley rats. Animals were divided into five groups i.e G-1 (Normal Control), Group 2 (ulcer control) were administered orally with 0.5% Carboxymethylcellulose (CMC), Group 3 (omeprazole treated) was administered orally with 20 mg/kg of omeprazole and Groups 4 and 5 (Low dose and High dose of the extract) were administered orally with 250, and 500 mg/ kg of Thymus vulgaris extract, respectively. After 1 hour, the normal group was orally administered with 0.5% CMC (5 ml/kg), whereas absolute alcohol (5ml/ kg) was orally administered to the ulcer control group, omeprazole group, and experimental groups. Stomachs were examined macroscopically and microscopically. Grossly, rats pre-treated with T. vulgaris demonstrated significantly decreased ulcer area and an increase in mucus secretion and pH of gastric content compared with the ulcer control group. Microscopy of gastric mucosa in the ulcer control group showed severe damage to gastric mucosa with edema and leukocytes infiltration of the submucosal layer. However, rats pretreated with omeprazole or Thyme vulgaris exhibited a mild to moderate disruption of the surface epithelium and lower level of edema and leukocyte infiltration of the submucosal layer. The T. vulgaris extract caused up-regulation of Hsp70 protein, down-regulation of Bax protein, and intense periodic acid Schiff uptake of the glandular portion of the stomach. Gastric mucosal homogenate of rats pre-treated with T. vulgaris exhibited significantly increased superoxide dismutase (SOD) and catalase (CAT) activities while malondialdehyde (MDA) level was significantly decreased. Based on the results showed in this study, Thymus vulgaris extract can be proposed as the safe medicinal plants for use and it has considerable gastroprotective potential via stomach epithelium protection against gastric ulcers and stomach lesions.
Topics: Rats; Animals; Rats, Sprague-Dawley; Stomach Ulcer; Thymus Plant; Ulcer; Ethanol; Plant Extracts; Gastric Mucosa; Omeprazole; Antioxidants; Anti-Ulcer Agents; Edema
PubMed: 38271407
DOI: 10.1371/journal.pone.0287569 -
Gels (Basel, Switzerland) Jan 2024Topical and transdermal drug delivery are advantageous administration routes, especially when treating diseases and conditions with a skin etiology. Nevertheless,... (Review)
Review
Topical and transdermal drug delivery are advantageous administration routes, especially when treating diseases and conditions with a skin etiology. Nevertheless, conventional dosage forms often lead to low therapeutic efficacy, safety issues, and patient noncompliance. To tackle these issues, novel topical and transdermal platforms involving nanotechnology have been developed. This review focuses on the latest advances regarding the development of nanoemulgels for skin application, encapsulating a wide variety of molecules, including already marketed drugs (miconazole, ketoconazole, fusidic acid, imiquimod, meloxicam), repurposed marketed drugs (atorvastatin, omeprazole, leflunomide), natural-derived compounds (eucalyptol, naringenin, thymoquinone, curcumin, chrysin, brucine, capsaicin), and other synthetic molecules (ebselen, tocotrienols, retinyl palmitate), for wound healing, skin and skin appendage infections, skin inflammatory diseases, skin cancer, neuropathy, or anti-aging purposes. Developed formulations revealed adequate droplet size, PDI, viscosity, spreadability, pH, stability, drug release, and drug permeation and/or retention capacity, having more advantageous characteristics than current marketed formulations. In vitro and/or in vivo studies established the safety and efficacy of the developed formulations, confirming their therapeutic potential, and making them promising platforms for the replacement of current therapies, or as possible adjuvant treatments, which might someday effectively reach the market to help fight highly incident skin or systemic diseases and conditions.
PubMed: 38247768
DOI: 10.3390/gels10010045 -
Scientific Reports Jan 2024Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the...
Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03-1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81-1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS.
Topics: Humans; Clopidogrel; Proton Pump Inhibitors; Cohort Studies; Omeprazole; Platelet Aggregation Inhibitors; Ticlopidine; Retrospective Studies; Ischemic Stroke; Acute Coronary Syndrome; Drug Interactions
PubMed: 38242975
DOI: 10.1038/s41598-024-51682-8 -
Scientific Reports Jan 2024In recent times, the methods used to evaluate gastric ulcer healing worldwide have been based on visual examinations and estimating ulcer dimensions in experimental...
In recent times, the methods used to evaluate gastric ulcer healing worldwide have been based on visual examinations and estimating ulcer dimensions in experimental animals. In this study, the protective effect of rhodanine and 2,4-thiazolidinediones scaffolds compared to esomeprazole was investigated in an ethanol model of stomach ulcers in rats. Pretreatment with experimental treatments or esomeprazole prevented the development of ethanol-induced gastric ulcers. The severity of the lesions and injuries was significantly lower than that of vehicle (10% Tween 80) treated rats. Significant and excellent results were obtained with the compound 6 group, with inhibition percentage and ulcer area values of 97.8% and 12.8 ± 1.1 mm, respectively. Synthesized compounds 2, 7 and 8 exhibited inhibition percentages and ulcer areas of 94.3% and 31.2 ± 1.1 mm, 91. 3% and 48.1 ± 0. 8 mm, 89. 5% and 57. 6 ± 1. 2 mm, and 89. 1% and 60.3 ± 0. 8 mm, respectively. These biological outcomes are consistent with the docking studies in which Compounds 7 and 8 showed remarkable binding site affinities toward human H+/K+-ATPase α protein (ID: P20648), rat H+/K+-ATPase α protein (ID: P09626), and Na+/K+-ATPase crystal structure (PDB ID:2ZXE) with binding site energies of - 10.7, - 9.0, and - 10.4 (kcal/mol) and - 8.7, - 8.5, and - 8.0 (kcal/mol), respectively. These results indicate that these test samples were as effective as esomeprazole. Likewise, immunohistochemical staining of antiapoptotic (BCL2) and tumor suppressor (P53) proteins showed strong positive marks in the10% Tween 80- treated group, opposing the mild staining results for the esomeprazole-treated group. Similarly, the staining intensity of the group treated with Compounds 2-8 was variable for both proteins.
Topics: Humans; Rats; Animals; Esomeprazole; Rhodanine; Tumor Suppressor Protein p53; Gastric Mucosa; Anti-Ulcer Agents; Ulcer; Polysorbates; Thiazolidinediones; Stomach Ulcer; Plant Extracts; Ethanol; Proto-Oncogene Proteins c-bcl-2; Adenosine Triphosphatases
PubMed: 38242960
DOI: 10.1038/s41598-024-51446-4 -
Inflammopharmacology Apr 2024Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were...
AIMS
Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model.
MAIN METHODS
In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 μg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day.
KEY FINDINGS
NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin.
SIGNIFICANCE
In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.
Topics: Animals; Male; Rats; Acetates; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Gastric Mucosa; Glutathione; Indomethacin; Ketorolac; Neuropeptides; NF-kappa B; Omeprazole; Peroxidase; Rats, Sprague-Dawley; Signal Transduction; Stomach Ulcer; Ulcer
PubMed: 38227096
DOI: 10.1007/s10787-023-01403-w -
Trials Jan 2024Treating Helicobacter pylori is becoming increasingly difficult with the development of bacterial resistance to many established treatment regimens. As a result,...
Efficacy of a 2-week therapy with levofloxacin concomitant versus a levofloxacin sequential regimen for Helicobacter pylori infection in the Syrian population: a study protocol for randomized controlled trial.
BACKGROUND
Treating Helicobacter pylori is becoming increasingly difficult with the development of bacterial resistance to many established treatment regimens. As a result, researchers are constantly looking for novel and effective treatments. This trial aims to establish the efficacy of levofloxacin-based sequential treatment regimen and concomitant levofloxacin-based regimen as empirical first-line therapy in the Syrian population.
METHOD
This is an open-label, prospective, single-center, parallel, active-controlled, superiority, randomized clinical trial. The recruitment will target Helicobacter pylori-positive males and females between the ages of 18 and 65 to evaluate the efficacy of empirical first-line therapy in the Syrian population. We are planning to recruit up to 300 patients which is twice the required sample size. One hundred fifty individuals will be randomly assigned to undergo either a sequential levofloxacin-based treatment regimen or a concomitant levofloxacin-based regimen. High-dose dual therapy (proton-pump inhibitor and amoxicillin) will be the rescue therapy in the event of first-line failure. The first-line eradication rate in both groups is the primary outcome, and one of the secondary outcomes is the overall eradication rate of high-dose dual therapy in the event of first-line treatment protocol failure. Intention-to-treat analysis and per-protocol analysis will be used to evaluate the eradication rates of Helicobacter pylori for first-line treatment protocols.
DISCUSSION
For the first time in the Syrian population, this randomized controlled trial will provide objective and accurate evidence about the efficacy of a sequential levofloxacin-based treatment regimen.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06065267 . Registered on October 3, 2023. Prospective registered. Enrollment of the first participant has not started yet.
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Anti-Bacterial Agents; Clinical Protocols; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Levofloxacin; Metronidazole; Prospective Studies; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Syria; Treatment Outcome; Equivalence Trials as Topic
PubMed: 38225650
DOI: 10.1186/s13063-024-07906-3 -
ACS Omega Jan 2024The present study was carried out to investigate the antioxidant effect of ascorbic acid on omeprazole (O.P.)-induced acute kidney infection (AKI). Design of experiment...
Design, Synthesis, Evaluation, and Molecular Docking Study of Ascorbic Acid Dual-Coated Omeprazole Pellets and the Antioxidative Effect of Ascorbic Acid on Omeprazole-Induced Renal Injury in an Animal Model.
The present study was carried out to investigate the antioxidant effect of ascorbic acid on omeprazole (O.P.)-induced acute kidney infection (AKI). Design of experiment (DoE) was employed to fabricate formulations (P1-P8) by the extrusion spheronization technique, and they were evaluated using various analytical techniques. P1-P8 formulations have % drug loading ranging from 56.34 ± 1.10 to 98.67 ± 1.05%, encapsulation efficiency from 70.98 ± 0.96 to 98.67 ± 1.05%, percentage drug release varying from 36.56 ± 1.34 to 93.45 ± 1.45%, Hausner's ratio ranging from 1.026 ± 0.05 to 1.065 ± 0.02%, and Carr's index varying from 2.3 ± 0.07 to 6.1 ± 0.06 g/mL. The optimized formulation (P6) was dual-coated with Eudragit L-100 (5% w/v) and ascorbic acid (2% w/v). A smooth uniform morphology was found after coating, and particle size nonsignificantly changed from 85.31 ± 77.43 to 101.99 ± 65.56 μm. IR spectra showed omeprazole characteristic peaks confirming drug loading, and peaks at 1747.40 and 1611.51 cm confirmed ascorbic acid and Eudragit L-100 coating. X-ray diffraction (XRD) analysis confirmed the crystalline nature, and thermal degradation studies until 500 °C demonstrated increased stability after coating. Cytotoxicity analysis with 97% cell viability revealed the nontoxic behavior of pellets. dissolution studies of coated pellets showed <20% drug release at pH 1.2 and 99.54% at pH 6.8. Animal studies showed that pure omeprazole showed a nonsignificant decrease in weight, urine output, and fecal output compared to rodents on ascorbic acid pellets. Increased uric acid and creatinine levels in the group on pure omeprazole indicated AKI. Histopathological studies of renal cells also supported these results. The integration of experimental pellet formulation with molecular docking simulations has unveiled the potential of ascorbic acid and omeprazole as highly promising therapeutic agents for addressing oxidative stress and inflammation.
PubMed: 38222658
DOI: 10.1021/acsomega.3c07396 -
Clinical Nephrology. Case Studies 2024Drug-induced hypomagnesemia is an adverse effect with the potential for serious and fatal outcomes. Although rare, chronic use of proton pump inhibitors (PPIs) can cause...
Drug-induced hypomagnesemia is an adverse effect with the potential for serious and fatal outcomes. Although rare, chronic use of proton pump inhibitors (PPIs) can cause hypomagnesemia due to impaired intestinal absorption, mainly attributed to reduced transcellular transport of magnesium via transient receptor potential melastatin 6 (TRPM6) and 7 (TRPM7) channels. However, a reduction of magnesium paracellular absorption due to the downregulation of intestinal claudins has also been reported. PPI-induced hypomagnesemia can trigger other concomitant electrolyte derangements, including hypokalemia, hypocalcemia, hypophosphatemia, and hyponatremia. Here we report two cases of multiple electrolyte disorders associated with PPI-induced hypomagnesemia, the clinical manifestations of which were cardiac arrhythmia, cognitive changes, and seizure crisis. These cases illustrate the need to monitor serum magnesium levels in patients on long-term PPI use, especially in the elderly and those with malabsorptive bowel syndromes or taking loop diuretics and thiazides.
PubMed: 38222324
DOI: 10.5414/CNCS111284