-
ACS Infectious Diseases Mar 2023Leishmaniasis is an infectious disease responsible for a huge rate of morbidity and mortality in humans. Chemotherapy consists of the use of pentavalent antimonial,... (Review)
Review
Leishmaniasis is an infectious disease responsible for a huge rate of morbidity and mortality in humans. Chemotherapy consists of the use of pentavalent antimonial, amphotericin B, pentamidine, miltefosine, and paromomycin. However, these drugs are associated with some drawbacks such as high toxicity, administration by parenteral route, and most seriously the resistance of some strains of the parasite to them. Several strategies have been used to increase the therapeutic index and reduce the toxic effects of these drugs. Among them, the use of nanosystems that have great potential as a site-specific drug delivery system stands out. This review aims to compile results from studies that were carried out using first- and second-line antileishmanial drug-carrying nanosystems. The articles referred to here were published between 2011 and 2021. This study shows the promise of effective applicability of drug-carrying nanosystems in the field of antileishmanial therapeutics, with the perspective of providing better patient adherence to treatment, increased therapeutic efficacy, reduced toxicity of conventional drugs, as well as the potential to efficiently improve the treatment of leishmaniasis.
Topics: Humans; Pharmaceutical Preparations; Antiprotozoal Agents; Leishmaniasis; Pentamidine; Paromomycin
PubMed: 36795604
DOI: 10.1021/acsinfecdis.2c00632 -
Nature Communications May 2024Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two...
Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.
Topics: Trypanosoma brucei brucei; Aquaglyceroporins; Cryoelectron Microscopy; Molecular Dynamics Simulation; Melarsoprol; Pentamidine; Biological Transport; Trypanocidal Agents; Protozoan Proteins; Humans
PubMed: 38734677
DOI: 10.1038/s41467-024-48445-4 -
Frontiers in Immunology 2023Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses...
Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses the blockade of immune checkpoint markers, such as program cell death-1 (PD-1) or its cognate ligand PD-L1, has been the basis for developing clinically effective anticancer therapies. We identified pentamidine, an FDA-approved antimicrobial agent, as a small-molecule antagonist of PD-L1. Pentamidine enhanced T-cell-mediated cytotoxicity against various cancer cells by increasing the secretion of IFN-γ, TNF-α, perforin, and granzyme B in the culture medium. Pentamidine promoted T-cell activation by blocking the PD-1/PD-L1 interaction. administration of pentamidine attenuated the tumor growth and prolonged the survival of tumor-bearing mice in PD-L1 humanized murine tumor cell allograft models. Histological analysis of tumor tissues showed an increased number of tumor-infiltrating lymphocytes in tissues derived from pentamidine-treated mice. In summary, our study suggests that pentamidine holds the potential to be repurposed as a novel PD-L1 antagonist that may overcome the limitations of monoclonal antibody therapy and can emerge as a small molecule cancer immunotherapy.
Topics: Mice; Animals; Pentamidine; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Immunotherapy; Neoplasms
PubMed: 37205112
DOI: 10.3389/fimmu.2023.1145028 -
Indian Journal of Ophthalmology Apr 2024This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical... (Review)
Review
This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical features, diagnosis, medical and surgical therapy, as well as outcomes of Acanthamoeba keratitis (AK). AK is a significant cause of ocular morbidity, and early diagnosis with timely institution of appropriate therapy is the key to obtaining good outcomes. The varied presentations result in frequent misdiagnosis, and co-infections can increase the morbidity of the disease. The first line of therapy continues to be biguanides and diamidines, with surgery as a last resort.
Topics: Humans; Acanthamoeba Keratitis; Pentamidine; Biguanides
PubMed: 38454853
DOI: 10.4103/IJO.IJO_2627_23 -
Biomedical Chromatography : BMC Jul 2023Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to... (Review)
Review
Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic (PK) analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphotericin B, miltefosine, paromomycin, pentamidine, and pentavalent antimonials in human matrices. The applicability of the assays for leishmaniasis clinical trials as well as their relevance to PK studies with emphasis on the choice of matrix, calibration range, sample volume, sample preparation, choice of internal standards, separation, and detection was discussed for each antileishmanial drug. Given that no published bioanalytical methods included multiple antileishmanial drugs in a single assay although antileishmanial shortened combination regimens currently were under investigation, it was recommended to combine various drugs in a single bioanalytical method. Furthermore, bioanalytical method development regarding target site matrix as well as applying microsampling strategies was recommended to optimize future clinical PK studies in leishmaniasis.
Topics: Humans; Antiprotozoal Agents; Pentamidine; Leishmaniasis; Amphotericin B
PubMed: 36208186
DOI: 10.1002/bmc.5519 -
Cancer Science Jul 2023Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug...
Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.
Topics: Humans; Mice; Animals; Glioblastoma; Pentamidine; Brain Neoplasms; Cell Proliferation; Cell Line, Tumor; Glioma; Apoptosis; Xenograft Model Antitumor Assays
PubMed: 37142416
DOI: 10.1111/cas.15827 -
International Journal of Molecular... Jan 2023This in vivo study in mice addresses the relationship between the biodiversity of the microbiota and the levels of S100B, a protein present in enteroglial cells, but...
This in vivo study in mice addresses the relationship between the biodiversity of the microbiota and the levels of S100B, a protein present in enteroglial cells, but also in foods such as milk. A positive significant correlation was observed between S100B levels and Shannon values, which was reduced after treatment with Pentamidine, an inhibitor of S100B function, indicating that the correlation was influenced by the modulation of S100B activity. Using the bootstrap average method based on the distribution of the S100B concentration, three groups were identified, exhibiting a significant difference between the microbial profiles. Operational taxonomic units, when analyzed by SIMPER analysis, showed that genera regarded to be eubiotic were mainly concentrated in the intermediate group, while genera potentially harboring pathobionts often appeared to be more concentrated in groups where the S100B amounts were very low or high. Finally, in a pilot experiment, S100B was administered orally, and the microbial profiles appeared to be modified accordingly. These data may open novel perspectives involving the possibility of S100B-mediated regulation in the intestinal microbiota.
Topics: Mice; Animals; Gastrointestinal Microbiome; Pentamidine; Microbiota; Biodiversity; RNA, Ribosomal, 16S; S100 Calcium Binding Protein beta Subunit
PubMed: 36768570
DOI: 10.3390/ijms24032248 -
International Immunopharmacology Sep 2023Interferon-gamma (IFN-γ) is a type II interferon produced primarily by T cells and natural killer cells. IFN-γ induces the expression of inducible nitric oxide...
High throughput screening identifies auranofin and pentamidine as potent compounds that lower IFN-γ-induced Nitric Oxide and inflammatory responses in mice: DSS-induced colitis and Salmonella Typhimurium-induced sepsis.
Interferon-gamma (IFN-γ) is a type II interferon produced primarily by T cells and natural killer cells. IFN-γ induces the expression of inducible nitric oxide synthase (NOS2) to catalyze Nitric Oxide (NO) production in various immune and non-immune cells. Excessive IFN-γ-activated NO production is implicated in several inflammatory diseases, including peritonitis and inflammatory bowel diseases. In this study, we screened the LOPAC® library in vitro on the H6 mouse hepatoma cell line to identify novel non-steroidal small molecule inhibitors of IFN-γ-induced NO production. Compounds with the highest inhibitory activity were validated, which led to identifying the lead compounds: pentamidine, azithromycin, rolipram, and auranofin. Auranofin was the most potent compound determined based on IC and goodness of fit analyses. Mechanistic investigations revealed that majority of the lead compounds suppress the IFN-γ-induced transcription of Nos2 without negatively affecting NO-independent processes, such as the IFN-γ-induced transcription of Irf1, Socs1 and MHC class 1 surface expression. However, all four compounds lower IFN-γ-induced reactive oxygen species amounts. In addition, auranofin significantly reduced IFN-γ-mediated NO and IL6 production in resident as well as thioglycolate-elicited peritoneal macrophages (PMs). Finally, in vivo testing of the lead compounds in the pre-clinical DSS-induced ulcerative colitis mice model revealed pentamidine and auranofin to be the most potent and protective lead compounds. Also, pentamidine and auranofin greatly increase the survival of mice in another inflammatory model: Salmonella Typhimurium-induced sepsis. Overall, this study identifies novel anti-inflammatory compounds targeting IFN-γ-induced NO-dependent processes to alleviate two distinct inflammatory models of disease.
Topics: Mice; Animals; Interferon-gamma; Nitric Oxide; Salmonella typhimurium; Auranofin; Pentamidine; High-Throughput Screening Assays; Nitric Oxide Synthase Type II; Colitis; Sepsis
PubMed: 37392571
DOI: 10.1016/j.intimp.2023.110569 -
Pharmacogenomics Oct 2023Intravenous pentamidine is used for prophylaxis against pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially...
Intravenous pentamidine is used for prophylaxis against pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by , which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as pneumonia prophylaxis. The primary objective was the association between phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and pneumonia infection rates were low.
Topics: Humans; Pentamidine; Pneumonia, Pneumocystis; Antifungal Agents; Retrospective Studies; Cytochrome P-450 CYP2C19; Pneumocystis carinii; Drug-Related Side Effects and Adverse Reactions; Phenotype
PubMed: 37846549
DOI: 10.2217/pgs-2023-0093 -
BMC Women's Health Nov 2022Pentamidine has been reported to have many pharmacological effects including anti- protozoal, anti-inflammatory, and anti-tumor activities. The aim of this study is to...
BACKGROUND
Pentamidine has been reported to have many pharmacological effects including anti- protozoal, anti-inflammatory, and anti-tumor activities. The aim of this study is to investigate the potential therapeutic role of Pentamidine and molecular mechanisms of Pentamidine on PI3K/AKT signaling pathway underlying the anti-tumor properties in endometrial cancer.
METHODS
Our study was carried out in the central laboratory of Harbin Medical University from 2019 to 2021. Human endometrial cancer cell lines Ishikawa and HEC-1A were treated with Pentamidine. The proliferation ability of cells was investigated by MTS and colony formation assays. The cell cycle distribution was detected by flow cytometry. Cell migration and invasion were analyzed by using the wound healing assay and Transwell assay. Western blotting was performed to measure the levels of AKT, p-AKT, MMP-2, and MMP-9.
RESULTS
Our results revealed that treatment of Pentamidine inhibited proliferation, migration and invasion of Ishikawa and HEC-1A endometrial cancer cells. Mechanistic investigation showed that Pentamidine inhibited PI3K/AKT signaling pathway and also reduced the expression of MMP-2 and MMP-9. In addition, co-treatment with PI3K kinase inhibitor LY294002 and Pentamidine leaded to increased repression of cell viability and the protein expression of p-AKT in Ishikawa cells.
CONCLUSIONS
Pentamidine suppresses PI3K/AKT signaling pathway, and inhibits proliferation, migration and invasion of EC cells. These findings suggested that Pentamidine might be a potential candidate for treating EC through PI3K/AKT pathway.
Topics: Female; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pentamidine; Cell Proliferation; Signal Transduction; Endometrial Neoplasms
PubMed: 36434592
DOI: 10.1186/s12905-022-02078-1