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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 -
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 -
Antibiotics (Basel, Switzerland) Jul 2023The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against larvae infected with an MDR strain of and...
Combination Therapy with Ciprofloxacin and Pentamidine against Multidrug-Resistant : Assessment of In Vitro and In Vivo Efficacy and the Role of Resistance-Nodulation-Division (RND) Efflux Pumps.
The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against larvae infected with an MDR strain of and (ii) determine if pentamidine acts as an efflux-pump inhibitor. Resistant clinical isolates, mutant strains overexpressing one of three RND efflux pumps (MexAB-OprM, MexCD-OprJ, and MexEF-OprN), and a strain with the same three pumps deleted were used. MIC assays confirmed that the clinical isolates and the mutants overexpressing efflux pumps were resistant to ciprofloxacin and pentamidine. The deletion of the three efflux pumps induced sensitivity to both compounds. Exposure to pentamidine and ciprofloxacin in combination resulted in the synergistic inhibition of all resistant strains in vitro, but no synergy was observed versus the efflux-pump deletion strain. The treatment of infected larvae with the combination of pentamidine and ciprofloxacin resulted in enhanced efficacy compared with the monotherapies and significantly reduced the number of proliferating bacteria. Our measurement of efflux activity from cells revealed that pentamidine had a specific inhibitory effect on the MexCD-OprJ and MexEF-OprN efflux pumps. However, the efflux activity and membrane permeability assays revealed that pentamidine also disrupted the membrane of all cells. In conclusion, pentamidine does possess some efflux-pump inhibitory activity, in addition to a more general disruptive effect on membrane integrity that accounts for its ability to potentiate ciprofloxacin activity. Notably, the enhanced efficacy of combination therapy with pentamidine and ciprofloxacin versus MDR strains in vivo merits further investigation into its potential to treat infections via this pathogen in patients.
PubMed: 37627656
DOI: 10.3390/antibiotics12081236 -
Journal of Orthopaedic Translation Mar 2024Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in...
BACKGROUND
Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in the experimental setting to prevent adhesions, clinical application is limited due to the complexity of application and delivery in clinical translation.
METHODS
In this study, optimal dosages of gelatin and pentamidine were validated by gelatin concentration test. Following cell viability, cell migration, live and dead cell, and cell adhesion assay of the Turkey tenocytes, a model of Turkey tendon repair was established to evaluate the effectiveness of the Pentamidine-Gelatin sheet.
RESULTS
Pentamidine carried with gelatin, a Food and drug administration (FDA) approved material for drug delivery, showed good dynamic release, biocompatibility, and degradation. The optimal dose of pentamidine (25ug) was determined in the in vivo study using tenocyte viability, migration, and cell adhesion assays. Further biochemical analyses demonstrated that this positive effect may be due to pentamidine downregulating the Wnt signaling pathway without affecting collagen expression.
CONCLUSIONS
We tested a FDA-approved antibiotic, pentamidine, for reducing adhesion formation after flexor tendon repair in both in vitro and in vivo using a novel turkey animal model. Compared with the non-pentamidine treatment group, pentamidine treated turkeys had significantly reduced adhesions and improved digit function after six weeks of tendon healing.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
This study for the first time showed that a common clinical drug, pentamidine, has a potential for clinical application to reduce tendon adhesions and improve tendon gliding function without interfering with tendon healing.
PubMed: 38511123
DOI: 10.1016/j.jot.2023.10.007 -
Drug Delivery Dec 2023Topical drug delivery is preferable route over systemic delivery in case of (CL). Among the available agents, amphotericin B (AmB) and pentamidine (PTM) showed...
Topical drug delivery is preferable route over systemic delivery in case of (CL). Among the available agents, amphotericin B (AmB) and pentamidine (PTM) showed promising result against CL. However, monotherapy is associated with incidences of reoccurrence and resistance. Combination therapy is therefore recommended. Thin film hydration method was employed for amphotericin B-pentamidine loaded niosomes (AmB-PTM-NIO) preparation followed by their incorporation into chitosan gel. The optimization of AmB-PTM-NIO was done via Box Behnken Design method and in vitro and ex vivo analysis was performed. The optimized formulation indicated 226 nm particle size (PS) with spherical morphology, 0.173 polydispersity index (PDI), -36 mV zeta potential (ZP) and with entrapment efficiency (EE) of 91% (AmB) and 79% (PTM), respectively. The amphotericin B-pentamidine loaded niosomal gel (AmB-PTM-NIO-Gel) showed desirable characteristics including physicochemical properties, pH (5.1 ± 0.15), viscosity (31870 ± 25 cP), and gel spreadability (280 ± 26.46%). In vitro release of the AmB and PTM from AmB-PTM-NIO and AmB-PTM-NIO-Gel showed more prolonged release behavior as compared to their respective drug solution. Higher skin penetration, greater percentage inhibition and lower IC50 against the promastigotes shows that AmB-PTM-NIO has better antileishmanial activity. The obtained findings suggested that the developed AmB-PTM-NIO-Gel has excellent capability of permeation via skin layers, sustained release profile and augmented anti-leishmanial outcome of the incorporated drugs.
Topics: Humans; Pentamidine; Amphotericin B; Leishmaniasis, Cutaneous; Combined Modality Therapy; Skin
PubMed: 36722301
DOI: 10.1080/10717544.2023.2173335 -
Human Molecular Genetics Feb 2024GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the...
GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease.
Topics: Humans; Central Nervous System; Mutation; Protein Domains; Receptors, Glutamate
PubMed: 37944084
DOI: 10.1093/hmg/ddad188 -
Proceedings of the National Academy of... Apr 2024Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully...
Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully understood. In this study, we investigated the role of MUC1, a mucin protein overexpressed in pancreatic cancer, in regulating polyamine metabolism. Utilizing pancreatic cancer patient data, we noted a positive correlation between MUC1 expression and the expression of key polyamine metabolism pathway genes. Functional studies revealed that knockdown of spermidine/spermine N1-acetyltransferase 1 (), a key enzyme involved in polyamine catabolism, attenuated the oncogenic functions of MUC1, including cell survival and proliferation. We further identified a regulatory axis whereby MUC1 stabilized hypoxia-inducible factor (HIF-1α), leading to increased SAT1 expression, which in turn induced carbon flux into the tricarboxylic acid cycle. MUC1-mediated stabilization of HIF-1α enhanced the promoter occupancy of the latter on promoter and corresponding transcriptional activation of , which could be abrogated by pharmacological inhibition of HIF-1α or CRISPR/Cas9-mediated knockout of . knockdown caused a significant reduction in the levels of SAT1-generated metabolites, N1-acetylspermidine and N8-acetylspermidine. Given the known role of MUC1 in therapy resistance, we also investigated whether inhibiting SAT1 would enhance the efficacy of FOLFIRINOX chemotherapy. By utilizing organoid and orthotopic pancreatic cancer mouse models, we observed that targeting SAT1 with pentamidine improved the efficacy of FOLFIRINOX, suggesting that the combination may represent a promising therapeutic strategy against pancreatic cancer. This study provides insights into the interplay between MUC1 and polyamine metabolism, offering potential avenues for the development of treatments against pancreatic cancer.
Topics: Mice; Animals; Humans; Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Polyamines; Signal Transduction; Acetyltransferases; Mucin-1
PubMed: 38547055
DOI: 10.1073/pnas.2315509121 -
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 -
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037