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Tropical Biomedicine Dec 2022The present study compares the in vitro effects of nanoparticles loaded pentamidine drug and conventional pentamidine on Leishmania tropica. Herein, pentamidine-loaded...
The present study compares the in vitro effects of nanoparticles loaded pentamidine drug and conventional pentamidine on Leishmania tropica. Herein, pentamidine-loaded chitosan nanoparticles (PTN-CNPs) have been synthesized through an ionic gelation method with sodium tripolyphosphate (TPP). Next, the physical characteristics of PTN-CNPs were determined through the surface texture, zeta potential, in vitro drug release, drug loading content (DLC), and encapsulation efficacy (EE) and compared its efficacy with free pentamidine (PTN) drug against promastigotes and axenic amastigotes forms of L. tropica in vitro. The PTN-CNPs displayed a spherical shape having a size of 88 nm, an almost negative surface charge (-3.09 mV), EE for PTN entrapment of 86%, and in vitro drug release of 92% after 36 h. In vitro antileishmanial activity of PTN-CNPs and free PTN was performed against Leishmania tropica KWH23 promastigote and axenic amastigote using 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyletetrazolium bromide (MTT) assay. It was observed that the effect of PTN-CNPs and free PTN on both forms of the parasite was dose and time dependent. Free PTN presented low efficacy even at higher dose (40 µg/ml) with 25.6 ± 1.3 and 26.5 ±1.4 mean viability rate of the promastigotes and axenic amastigotes, respectively after 72 hrs incubation. While PTN-CNPs showed strong antileishmanial effects on both forms of parasite with 16 ± 0.4 and 19 ± 0.7 mean viability rate at the same higher concentration (40 µg/ml) after 72 hrs incubation. Half maximal inhibitory concentration (IC50) values of PTN-CNPs toward promastigotes and amastigotes were obtained as 0.1375 µg/ml and 0.1910 µg/ml, respectively. In conclusion, PTN-CNPs effectively inhibited both forms of the L. tropica; however, its effect was more salient on promastigotes. This data indicates that the PTN-CNPs act as a target drug delivery system. However, further research is needed to support its efficacy in animal and human CL.
Topics: Animals; Humans; Pentamidine; Leishmania tropica; Chitosan; Antiprotozoal Agents; Drug Delivery Systems; Nanoparticles
PubMed: 36602209
DOI: 10.47665/tb.39.4.003 -
PLoS Neglected Tropical Diseases Apr 2021Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the...
BACKGROUND
Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10-100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations.
METHODOLOGY
To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation in vitro, quantified pentamidine CNS delivery of a sub-set of formulations in vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using an in vivo single dose brain penetration study.
PRINCIPAL FINDINGS
Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2 receptor. The reduction in insulin secretion in MIN6 β-cells by pentamidine may be secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect in vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine.
SIGNIFICANCE
These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.
Topics: Animals; Blood-Brain Barrier; Female; Humans; Male; Mice; Mice, Inbred BALB C; Neglected Diseases; Pentamidine; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African; Tsetse Flies
PubMed: 33857146
DOI: 10.1371/journal.pntd.0009276 -
Clinical and Experimental Dermatology Jul 2023There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety...
There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety of pentamidine over a 10-year period. Every child seen in French Guiana between 2010 and 2020 with proven CL and treated with pentamidine was included. In total, 55 children met the inclusion criteria - 23 girls and 32 boys. There were 38 patients (38/55, 69%) with a > 50% improvement at 1 month after pentamidine treatment and a complete cure at 3 months; 16 children had a < 50% improvement at 1 month and were given a second dose. Of these 16, 8 showed a complete cure at 3 months, 5 were lost to follow-up and 3 showed therapeutic failure at 3 months. The overall cure rate was 84% (46/55) after one or two doses. In terms of the safety of pentamidine, no severe adverse events (grade ≥ 3) were reported.
Topics: Male; Female; Humans; Child; Pentamidine; Antiprotozoal Agents; French Guiana; Leishmaniasis, Cutaneous; Injections, Intramuscular
PubMed: 37075241
DOI: 10.1093/ced/llad146 -
Frontiers in Cellular and Infection... 2022Fungal infection is a serious global health issue, causing approximately 1.5 million mortalities annually. However, clinically available anti-fungal drugs are limited,...
Fungal infection is a serious global health issue, causing approximately 1.5 million mortalities annually. However, clinically available anti-fungal drugs are limited, especially for multidrug-resistant fungal infections. Therefore, new antifungal drugs are urgently needed to address this clinical challenge. In this study, we proposed two non-antifungal drugs, auranofin and pentamidine, in combination to fight against multidrug-resistant . The insufficient antifungal activity of anti-rheumatic drug auranofin is partially due to fungal membrane barrier preventing the drug uptake, and anti-protozoal drug pentamidine was used here to improve the permeability of membrane. The auranofin/pentamidine combination displayed synergistic inhibitory effect against both drug-susceptible and drug-resistant , as well as biofilm, and significantly reduced the minimum inhibitory concentration of each drug. At non-antifungal concentration, pentamidine can disrupt the membrane integrity and increase membrane permeability, leading to enhanced cellular uptake of auranofin in . This repurposing strategy using the combination of non-antifungal drugs with complementary antifungal mechanism may provide a novel approach for discovery of antifungal drugs to fight against multidrug-resistant fungal infections.
Topics: Antifungal Agents; Candida albicans; Pentamidine; Auranofin; Drug Repositioning; Microbial Sensitivity Tests
PubMed: 36590591
DOI: 10.3389/fcimb.2022.1065962 -
Frontiers in Medicine 2022Human African Trypanosomiasis (HAT) is caused by unicellular flagellated protozoan parasites of the genus . The subspecies is mainly responsible for mostly chronic... (Review)
Review
Human African Trypanosomiasis (HAT) is caused by unicellular flagellated protozoan parasites of the genus . The subspecies is mainly responsible for mostly chronic anthroponotic infections in West- and Central Africa, accounting for roughly 95% of all HAT cases. results in more acute zoonotic infections in East-Africa. Because HAT has a two-stage pathogenesis, treatment depends on clinical assessment of patients and the determination whether or not parasites have crossed the blood brain barrier. Today, ultimate confirmation of parasitemia is still done by microscopy analysis. However, the introduction of diagnostic lateral flow devices has been a major contributor to the recent dramatic drop in HAT. Other techniques such as loop mediated isothermal amplification (LAMP) and recombinant polymerase amplification (RPA)-based tests have been published but are still not widely used in the field. Most recently, CRISPR-Cas technology has been proposed to improve the intrinsic diagnostic characteristics of molecular approaches. This will become crucial in the near future, as preventing the resurgence of HAT will be a priority and will require tools with extreme high positive and negative predicted values, as well as excellent sensitivity and specificity. As for treatment, pentamidine and suramin have historically been the drugs of choice for the treatment of blood-stage gambiense-HAT and rhodesiense-HAT, respectively. For treatment of second-stage infections, drugs that pass the blood brain barrier are needed, and melarsoprol has been effectively used for both forms of HAT in the past. However, due to the high occurrence of post-treatment encephalopathy, the drug is not recommended for use in HAT. Here, a combination therapy of eflornithine and nifurtimox (NECT) has been the choice of treatment since 2009. As this treatment requires IV perfusion of eflornithine, efforts were launched in 2003 by the drugs for neglected disease initiative (DNDi) to find an oral-only therapy solution, suitable for rural sub-Saharan Africa treatment conditions. In 2019 this resulted in the introduction of fexinidazole, with a treatment regimen suitable for both the blood-stage and non-severe second-stage infections. Experimental treatment of HAT has now been initiated as well.
PubMed: 36405602
DOI: 10.3389/fmed.2022.1037094 -
International Journal of Pharmaceutics Sep 2019Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine...
Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine isethionate. The interaction between the anionic hyaluronic acid and the cationic pentamidine resulting in the formation of polyelectrolyte complexes was firstly studied. Then, nanoparticles made of hyaluronic acid and polyarginine loaded with pentamidine were developed. These drug delivery systems consist of a monodisperse population of negatively charged pentamidine-loaded nanoparticles with a high drug encapsulation rate (80%). Such high encapsulation efficiency coming from ion exchange was confirmed by measurements of the counterion isethionate released from pentamidine during nanoparticles formation. Besides, freeze-dried pentamidine-loaded nanoparticles kept their integrity after their reconstitution in water. In vitro studies on human lung (A549) and breast (MDA-MB-231) cancer cell lines showed that pentamidine-loaded nanoparticles were more cytotoxic in comparison to the free drug, suggesting an enhanced internalization of encapsulated drug by cancer cells.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Drug Liberation; Drug Stability; Freeze Drying; Humans; Hyaluronic Acid; Nanoparticles; Pentamidine; Peptides; Solubility
PubMed: 31323370
DOI: 10.1016/j.ijpharm.2019.118526 -
ACS Chemical Biology Nov 2022Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest...
Most Gram-positive-selective antibiotics have low activity against Gram-negative bacteria due to the presence of an outer membrane barrier. There is, therefore, interest in developing combination therapies that can penetrate the outer membrane (OM) with known antibiotics coupled with membrane-active sensitizing adjuvants. However, two unanswered questions hinder the development of such combination therapies: the sensitization spectrum of the sensitizer and the mechanism of antibiotic-sensitizer mutual potentiation. Here, with pentamidine as an example, we screened a library of 170 FDA-approved antibiotics in combination with pentamidine, a compound known to disturb the OM of Gram-negative bacteria. We found that four antibiotics, minocycline, linezolid, valnemulin, and nadifloxacin, displaced enhanced activity in combination with pentamidine against several multidrug-resistant Gram-negative bacteria. Through a descriptor-based structural-activity analysis and multiple cell-based biochemical assays, we found that hydrophobicity, partial charge, rigidity, and surface rugosity were key factors that affected sensitization via a cooperative membrane damage mechanism in which lipopolysaccharides and phospholipids were identified as sites of synergy. Finally, experiments showed that the linezolid-pentamidine combination slowed the generation of drug resistance, and there was also potent activity in experiments. Overall, our results highlight the importance of the physicochemical properties of antibiotics and cooperative membrane damage for synergistic pentamidine-antibiotic drug combinations.
Topics: Anti-Bacterial Agents; Pentamidine; Linezolid; Gram-Negative Bacteria; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests
PubMed: 36269311
DOI: 10.1021/acschembio.2c00613 -
Tropical Medicine and Infectious Disease May 2023With more than 12 million cases worldwide, leishmaniasis is one of the top 10 neglected tropical diseases. According to the WHO, there are approximately 2 million new... (Review)
Review
With more than 12 million cases worldwide, leishmaniasis is one of the top 10 neglected tropical diseases. According to the WHO, there are approximately 2 million new cases each year in foci in around 90 countries, of which 1.5 million are cutaneous leishmaniasis (CL). Cutaneous leishmaniasis (CL) is a complex cutaneous condition that is caused by a variety of species, including () , () () , () () , and () . The disease imposes a significant burden on those who are affected since it typically results in disfiguring scars and extreme social stigma. There are no vaccines or preventive treatments available, and chemotherapeutic medications, including antimonials, amphotericin B, miltefosine, paromomycin, pentamidine, and antifungal medications, have a high price tag, a significant risk of developing drug resistance, and a variety of systemic toxicities. To work around these limitations, researchers are continuously looking for brand-new medications and other forms of therapy. To avoid toxicity with systemic medication use, high cure rates have been observed using local therapy techniques such as cryotherapy, photodynamic therapy, and thermotherapy, in addition to some forms of traditional therapies, including leech and cauterization therapies. These CL therapeutic strategies are emphasized and assessed in this review to help with the process of locating the appropriate species-specific medicines with fewer side effects, lower costs, and elevated cure rates.
PubMed: 37235323
DOI: 10.3390/tropicalmed8050275 -
Human Molecular Genetics Jan 2023DNA drug molecules are not only widely used in gene therapy, but also play an important role in controlling the electrical properties of molecular electronics. Covalent...
DNA drug molecules are not only widely used in gene therapy, but also play an important role in controlling the electrical properties of molecular electronics. Covalent binding, groove binding and intercalation are all important forms of drug-DNA interaction. But its applications are limited due to a lack of understanding of the electron transport mechanisms after different drug-DNA interaction modes. Here, we used a combination of density functional theory calculations and nonequilibrium Green's function formulation with decoherence to study the effect of drug molecules on the charge transport property of DNA under three different binding modes. Conductance of DNA is found to decrease from 2.35E-5 G0 to 1.95E-6 G0 upon doxorubicin intercalation due to modifications of the density of states in the near-highest occupied molecular orbital region, δG = 1105.13%. Additionally, the conductance of DNA after cis-[Pt(NH3)2(py)Cl]+ covalent binding increases from 1.02E-6 G0 to 5.25E-5 G0, δG = 5047.06%. However, in the case of pentamidine groove binding, because there is no direct change in DNA molecular structure during drug binding, the conductance changes before and after drug binding is much smaller than in the two above cases, δG = 90.43%. Our theoretical calculations suggest that the conductance of DNA can be regulated by different drug molecules or switching the interaction modes between small molecules and DNA. This regulation opens new possibilities for their potential applications in controllable modulation of the electron transport property of DNA.
Topics: DNA; Electron Transport
PubMed: 35771227
DOI: 10.1093/hmg/ddac147 -
The European Journal of Neuroscience Apr 2020Pentamidine, diminazene and 4',6-diamidino-2-phenylindole (DAPI) are antiprotozoal diarylamidine compounds. In the present work, we have studied their action on native...
Pentamidine, diminazene and 4',6-diamidino-2-phenylindole (DAPI) are antiprotozoal diarylamidine compounds. In the present work, we have studied their action on native N-methyl-D-aspartate (NMDA) receptors in rat hippocampal pyramidal neurons. All three compounds inhibited NMDA receptors at -80 mV holding voltage with IC of 0.41 ± 0.08, 13 ± 3 and 3.1 ± 0.6 μM, respectively. The inhibition by pentamidine was strongly voltage-dependent, while that of DAPI was practically voltage-independent. Inhibition by diminazene had both voltage-dependent and voltage-independent components. Diminazene and DAPI demonstrated tail currents and overshoots suggesting "foot-in-the-door" mechanism of action. In contrast, pentamidine was partially trapped in the closed NMDA receptor channels. Such difference in the mechanism of action can be explained by the difference in the 3D structure of compounds. In the pentamidine molecule, two benzamidine groups are connected with a flexible linker, which allows the molecule to fold up and fit in the cavity of a closed NMDA receptor channel. Diminazene and DAPI, in contrast, have an extended form and could not be trapped.
Topics: Animals; Aspartic Acid; Benzamidines; Cells, Cultured; Hippocampus; N-Methylaspartate; Pyramidal Cells; Rats; Receptors, N-Methyl-D-Aspartate
PubMed: 31605636
DOI: 10.1111/ejn.14589