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British Medical Journal (Clinical... Feb 1983
Topics: Animals; Drug Combinations; Female; Humans; Infant; Male; Pentamidine; Pneumonia, Pneumocystis; Rats; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 6402123
DOI: 10.1136/bmj.286.6364.499 -
Molecules (Basel, Switzerland) Jun 2019Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis...
Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine's effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC) value of ~3.6 μM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.
Topics: Blood Coagulation; Blood Coagulation Tests; Factor VIIa; Factor XIIa; Factor XIa; Factor Xa; Fibrinolysis; Humans; Partial Thromboplastin Time; Pentamidine; Prothrombin Time; Thrombin; Thrombin Time; Thrombosis
PubMed: 31174390
DOI: 10.3390/molecules24112146 -
Frontiers in Immunology 2019Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the genus, is a major cause of... (Review)
Review
Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the genus, is a major cause of mortality and morbidity in animals and man. Human African trypanosomiasis (HAT), or sleeping sickness, results from infections with or with accounting for over 95% of infections. Historically there have been major epidemics of the infection, followed by periods of relative disease control. As a result of concerted disease surveillance and treatment programmes, implemented over the last two decades, there has been a significant reduction in the number of cases of human disease reported. However, the recent identification of asymptomatic disease carriers gives cause for some concern. The parasites evade the host immune system by switching their surface coat, comprised of variable surface glycoprotein (VSG). In addition, they have evolved a variety of strategies, including the production of serum resistance associated protein (SRA) and -specific glycoprotein (TgsGP) to counter host defense molecules. Infection with either disease variant results in an early haemolymphatic-stage followed by a late encephalitic-stage when the parasites migrate into the CNS. The clinical features of HAT are diverse and non-specific with early-stage symptoms common to several infections endemic within sub-Saharan Africa which may result in a delayed or mistaken diagnosis. Migration of the parasites into the CNS marks the onset of late-stage disease. Diverse neurological manifestations can develop accompanied by a neuroinflammatory response, comprised of astrocyte activation, and inflammatory cell infiltration. However, the transition between the early and late-stage is insidious and accurate disease staging, although crucial to optimize chemotherapy, remains problematic with neurological symptoms and neuroinflammatory changes recorded in early-stage infections. Further research is required to develop better diagnostic and staging techniques as well as safer more efficacious drug regimens. Clearer information is also required concerning disease pathogenesis, specifically regarding asymptomatic carriers and the mechanisms employed by the trypanosomes to facilitate progression to the CNS and precipitate late-stage disease. Without progress in these areas it may prove difficult to maintain current control over this historically episodic disease.
Topics: Animals; Antiprotozoal Agents; Blood-Brain Barrier; Brain; Delayed Diagnosis; Humans; Incidence; Neglected Diseases; Pentamidine; Severity of Illness Index; Suramin; Treatment Outcome; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 30740102
DOI: 10.3389/fimmu.2019.00039 -
Biomolecules Dec 2022The S100A1 protein in humans is a calcium-binding protein. Upon Ca binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with...
The S100A1 protein in humans is a calcium-binding protein. Upon Ca binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with target proteins. RAGE consists of three domains: the cytoplasmic, transmembrane, and extracellular domains. The extracellular domain consists of C1, C2, and V domains. V domains are the primary receptors for the S100 protein. It was reported several years ago that S100A1 and RAGE V domains interact in a pathway involving S100A1-RAGE signaling, whereby S100A1 binds to the V domain, resulting in RAGE dimerization. The autophosphorylation of the cytoplasmic domain initiates a signaling cascade that regulates cell proliferation, cell growth, and tumor formation. In this study, we used pentamidine and a newly synthesized pentamidine analog (WLC-4059) to inhibit the S100A1-RAGE V interaction. H-N HSQC NMR titration was carried out to characterize the interaction between mS100A1 (mutant S100A1, C86S) and pentamidine analogs. We found that pentamidine analogs interact with S100A1 via H-N HSQC NMR spectroscopy. Based on the results, we utilized the HADDOCK program to generate structures of the mS100A1-WLC-4059 binary complex. Interestingly, the binary complex overlapped with the complex crystal structure of the mS100A1-RAGE-V domain, proving that WLC-4059 blocks interaction sites between S100A1 and RAGE-V. A WST-1 cell proliferation assay also supported these results. We conclude that pentamidine analogs could potentially enhance therapeutic approaches against cancers.
Topics: Humans; Calcium; Magnetic Resonance Spectroscopy; Neoplasms; Pentamidine; Protein Binding; Signal Transduction
PubMed: 36671465
DOI: 10.3390/biom13010081 -
British Medical Bulletin 2012The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from... (Review)
Review
BACKGROUND
The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.
SOURCES OF DATA
PubMed.
AREAS OF AGREEMENT
There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.
AREAS OF CONTROVERSY
Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.
GROWING POINTS
There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.
AREAS TIMELY FOR DEVELOPING RESEARCH
Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.
Topics: Administration, Oral; Africa; Amphotericin B; Antiprotozoal Agents; Benzamides; Boron Compounds; Chagas Disease; Drug Therapy, Combination; Humans; India; Leishmaniasis; Nitroimidazoles; Pentamidine; Triazoles; Trypanosomiasis, African
PubMed: 23137768
DOI: 10.1093/bmb/lds031 -
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 -
World Journal of Transplantation Mar 2016Despite advances in transplantation techniques and the quality of post-transplantation care, opportunistic infections remain an important cause of complications.... (Review)
Review
Despite advances in transplantation techniques and the quality of post-transplantation care, opportunistic infections remain an important cause of complications. Pneumocystis jirovecii (P. jirovecii) is an opportunistic organism, represents an important cause of infections in heart transplantation patients. Almost 2% to 10% of patients undergoing cardiac transplantation have Pneumocystis pneumonia. Prophylaxis is essential after surgery. Various prophylaxis regimes had been defined in past and have different advantages. Trimethoprim/sulfamethoxazole (TMP/SMX) has a key role in prophylaxis against P. jirovecii. Generally, although TMP/SMX is well tolerated, serious side effects have also been reported during its use. Pentamidine is an alternative prophylaxis agent when TMP/SMX cannot be tolerated by the patient. Structurally, pentamidine is an aromatic diamidine compound with antiprotozoal activity. Since it is not effectively absorbed from the gastrointestinal tract, it is frequently administered via the intravenous route. Pentamidine can alternatively be administered through inhalation at a monthly dose in heart transplant recipients. Although, the efficiency and safety of this drug is well studied in other types of solid organ transplantations, there are only few data about pentamidine usage in heart transplantation. We sought to evaluate evidence-based assessment of the use of pentamidine against P. jirovecii after heart transplantation.
PubMed: 27011917
DOI: 10.5500/wjt.v6.i1.193 -
Archives of Biochemistry and Biophysics Sep 2020Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a...
Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a significant role in the metastasis of cancer. Tumor suppressor p53 is one of the S100A4's main targets. Previous reports show that through p53, S100A4 regulates collagen expression and cell proliferation. When S100A4 interacts with p53, the S100A4 destabilizes wild type p53. In the current study, based on H-N HSQC NMR experiments and HADDOCK results, S100A4 interacts with the intrinsically unstructured transactivation domain (TAD) of the protein p53 and the pentamidine molecules in the presence of calcium ions. Our results suggest that the p53 TAD and pentamidine molecules share similar binding sites on the S100A4 protein. This observation indicates that a competitive binding mechanism can interfere with the binding of S100A4-p53 and increase the level of p53. Also, we compare different aspects of p53 activity in the WST-1 test using MCF 7 cells. We found that the presence of a pentamidine molecule results in higher p53 activity, which is also reflected in less cell proliferation. Collectively, our results indicate that disrupting the S100A4-p53 interaction would prevent cancer progression, and thus S100A4-p53 inhibitors provide a new avenue for cancer therapy.
Topics: Antineoplastic Agents; Binding Sites; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; MCF-7 Cells; Pentamidine; Protein Binding; Protein Multimerization; S100 Calcium-Binding Protein A4; Tumor Suppressor Protein p53
PubMed: 32649952
DOI: 10.1016/j.abb.2020.108442 -
Pharmaceutics Mar 2018The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach...
The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach the brain through intranasal delivery. Mucoadhesive properties and stability testing in various environments were evaluated to examine the potential of these formulations to be effective drug delivery vehicles for intranasal delivery to the brain. Samples were prepared using thin film hydration method. Changes in size and ζ-potential of coated and uncoated niosomes with and without loading of pentamidine in various conditions were assessed by dynamic light scattering (DLS), while size and morphology were also studied by atomic force microscopy (AFM). Bilayer properties and mucoadhesive behavior were investigated by fluorescence studies and DLS analyses, respectively. Changes in vesicle size and ζ-potential values were shown after addition of chitosan glutamate to niosomes, and when in contact with mucin solution. In particular, interactions with mucin were observed in both drug free and pentamidine loaded niosomes regardless of the presence of the coating. The characteristics of the proposed systems, such as pentamidine entrapment and mucin interaction, show promising results to deliver pentamidine or other possible drugs to the brain via nasal administration.
PubMed: 29565809
DOI: 10.3390/pharmaceutics10020038 -
Biochimie Jul 2008Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and... (Review)
Review
Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.
Topics: Animals; Antiparasitic Agents; DNA, Protozoan; Drug Delivery Systems; Eukaryota; Heterocyclic Compounds; Humans; Models, Molecular; Nucleic Acid Conformation; Pentamidine
PubMed: 18343228
DOI: 10.1016/j.biochi.2008.02.017