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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 -
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 -
Thorax Jun 1990An estimate of the absolute pulmonary deposition of nebulised pentamidine isethionate was obtained in nine patients with AIDS. Two nebuliser systems were compared,... (Clinical Trial)
Clinical Trial
An estimate of the absolute pulmonary deposition of nebulised pentamidine isethionate was obtained in nine patients with AIDS. Two nebuliser systems were compared, System 22 Mizer (Medic-Aid) and Respirgard II (Marquest), with 50 and 150 mg doses of pentamidine in a 3 ml solution driven by an air flow of 6 l/min with the patient in the sitting position. The 50 mg pentamidine dose was repeated with a 6 ml fill with both devices. The nebuliser cloud was labelled with technetium-99m human serum albumin (Ventocol) and lung deposition was measured with a gamma camera. Of the two nebulisers studied, System 22 Mizer delivered more drug to the lungs as a whole and to each individual lung region, including the peripheral and upper zones. For the 50 mg dose the mean (SEM) total pulmonary deposition with the 3 and the 6 ml fill respectively was 2.63 (0.34) and 3.71 (0.41) mg for the System 22 Mizer and 1.37 (0.26) and 1.45 (0.18) mg for the Respirgard II. For the 150 mg dose the System 22 Mizer delivered 7.16 (1.02) mg and the Respirgard II 4.34 (0.57) mg. Increasing the volume of fill from 3 to 6 ml increased pulmonary deposition with System 22 Mizer, and this was related to an increase in nebuliser output. Neither pulmonary deposition nor nebuliser output was increased by using a 6 ml solution in the Respirgard II. Increasing the volume of fill prolonged the time required for nebulisation with both nebulisers. The System 22 Mizer produced more nonpulmonary (gastric and oropharyngeal) deposition of drug, more frequent local adverse effects (cough, burning in the throat, and a metallic taste), and small reductions in lung function, particularly with the 150 mg pentamidine dose. Thus nebuliser type, volume of fill, and nebuliser dose affect the pulmonary deposition of pentamidine. A 300 mg dose of pentamidine via a Respirgard II is generally recommended as providing effective prophylaxis; our results suggest that similar pulmonary deposition can be produced with System 22 Mizer and 150 mg pentamidine. A clinical trial would be needed to show whether this regimen provides similar prophylactic benefit.
Topics: Acquired Immunodeficiency Syndrome; Drug Administration Schedule; Humans; Lung; Nebulizers and Vaporizers; Opportunistic Infections; Pentamidine; Pneumonia, Pneumocystis
PubMed: 2392791
DOI: 10.1136/thx.45.6.460 -
Acta Tropica May 2011Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and... (Review)
Review
Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for decades, there are no systematic reviews about their safety. The objective of this review was to identify and classify the main adverse effects associated with these drugs and to estimate the frequency of these effects, whenever possible. Intervention studies, case series and case reports containing information regarding clinical, laboratory or electrocardiographic adverse effects of drugs used for the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searched between August 13, 2008 and March 31, 2009. The 65 studies included in this review had treated a total of 4359 patients from 12 countries infected with eight different Leishmania species. Despite the small number of drugs used in these studies, a wide variability in the therapeutic regimens was observed. As a consequence, the adverse effects of pentavalent antimonials and pentamidine needed to be classified jointly according to system, irrespective of formulation, daily dose, duration of treatment, and route of administration. The frequencies of adverse effects were calculated based on the data of 32 articles involving 1866 patients. The most frequently reported clinical adverse effects of pentavalent antimonials and pentamidine were musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headache. Electrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic enzymes were additional adverse effects of pentavalent antimonials. Patients treated with liposomal amphotericin B had mild dyspnea and erythema. The adverse effects associated with miltefosine were vomiting, nausea, kinetosis, headache, diarrhea, and a mild to moderate increase in aminotransferases and creatinine. Although closer surveillance is needed for the treatment of cutaneous leishmaniasis, antileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatment are relatively uncommon.
Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leishmaniasis, Cutaneous; Pentamidine
PubMed: 21420925
DOI: 10.1016/j.actatropica.2011.02.007 -
PLoS Neglected Tropical Diseases Mar 2016Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL),... (Review)
Review
Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL), mucocutaneous leishmaniasis or extensive CL, requiring systemic treatment. Despite the substantial burden, evidence-based treatment guidelines are lacking. We conducted a systematic review of clinical studies reporting on treatment outcomes of CL due to L aethiopica in order to help identify potentially efficacious medications on CL that can be taken forward for clinical trials. We identified a total of 24 records reporting on 506 treatment episodes of CL presumably due to L aethiopica. The most commonly used drugs were antimonials (n = 201), pentamidine (n = 150) and cryotherapy (n = 103). There were 20 case reports/series, with an overall poor study quality. We only identified two small and/or poor quality randomized controlled trials conducted a long time ago. There were two prospective non-randomized studies reporting on cryotherapy, antimonials and pentamidine. With cryotherapy, cure rates were 60-80%, and 69-85% with antimonials. Pentamidine appeared effective against complicated CL, also in cases non-responsive to antimonials. However, all studies suffered from methodological limitations. Data on miltefosine, paromomycin and liposomal amphotericin B are extremely scarce. Only a few studies are available on DCL. The only potentially effective treatment options for DCL seem to be antimonials with paromomycin in combination or pentamidine, but none have been properly evaluated. In conclusion, the evidence-base for treatment of complicated CL due to L aethiopica is extremely limited. While antimonials remain the most available CL treatment in Ethiopia, their efficacy and safety in CL should be better defined. Most importantly, alternative first line treatments (such as miltefosine or paromomycin) should be explored. High quality trials on CL due to L aethiopica are urgently needed, exploring group sequential methods to evaluate several options in parallel.
Topics: Adolescent; Adult; Aged; Antiprotozoal Agents; Child; Child, Preschool; Cryotherapy; Ethiopia; Female; Humans; Leishmania; Leishmaniasis, Cutaneous; Male; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 26938448
DOI: 10.1371/journal.pntd.0004495 -
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 -
Biomolecules Apr 2021S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may...
S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used H-N HSQC experiments and molecular modeling to study the molecular interactions between S100P and p53 in the presence and absence of pentamidine. Our experimental analysis indicates that the S100P-53 complex formation is successfully disrupted by pentamidine, since S100P shares the same binding site for p53 and pentamidine. In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction.
Topics: Binding Sites; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Humans; Models, Molecular; Neoplasm Proteins; Pentamidine; Protein Binding; Protein Domains; Protein Interaction Mapping; S100 Proteins; Tumor Suppressor Protein p53
PubMed: 33923162
DOI: 10.3390/biom11050634 -
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 -
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 -
Microbiology Spectrum Jun 2023The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and their biofilm-relevant infections pose a threat to public health. The drug combination...
The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and their biofilm-relevant infections pose a threat to public health. The drug combination strategy provides a new treatment option for CRE infections. This study explored the synergistic antibacterial, antibiofilm activities as well as the efficacy against CRE of pentamidine combined with linezolid. This study further revealed the possible mechanisms underlying the synergy of the combination. The checkerboard and time-kill assays showed that pentamidine combined with linezolid had significant synergistic antibacterial effects against CRE strains (9/10). Toxicity assays on mammal cells (mouse RAW264.7 and red blood cells) and on Galleria mellonella confirmed that the concentrations of pentamidine and/or linezolid that were used were relatively safe. Antibiofilm activity detection via crystal violet staining, viable bacteria counts, and scanning electron microscopy demonstrated that the combination enhanced the inhibition of biofilm formation and the elimination of established biofilms. The G. mellonella infection model and mouse thigh infection model demonstrated the potential efficacy of the combination. In particular, a series of mechanistic experiments elucidated the possible mechanisms for the synergy in which pentamidine disrupts the outer membranes, dissipates the membrane potentials, and devitalizes the efflux pumps of CRE, thereby facilitating the intracellular accumulation of linezolid and reactive oxygen species (ROS), which ultimately kills the bacteria. Taken together, when combined with pentamidine, which acts as an outer membrane permeabilizer and as an efflux pump inhibitor, originally ineffective linezolid becomes active in CRE and exhibits excellent synergistic antibacterial and antibiofilm effects as well as a potential therapeutic effect on CRE-relevant infections. The multidrug resistance and biofilm formation of Gram-negative bacteria (GNB) may lead to incurable "superbug" infections. Drug combinations, with the potential to augment the original treatment ranges of drugs, are alternative treatment strategies against GNB. In this study, the pentamidine-linezolid combination showed notable antibacterial and antibiofilm activity both and against the problem carbapenem-resistant Enterobacteriaceae (CRE). Pentamidine is often used as an antiprotozoal and antifungal agent, and linezolid is a defensive Gram-positive bacteria (GPB) antimicrobial. Their combination expands the treatment range to GNB. Hence, the pentamidine-linezolid pair may be an effective treatment for complex infections that are mixed by GPB, GNB, and even fungi. In terms of mechanism, pentamidine inhibited the outer membranes, membrane potentials, and efflux pumps of CRE. This might be a universal mechanism by which pentamidine, as an adjuvant, potentiates other drugs, similar to linezolid, thereby having synergistic antibacterial effects on CRE.
Topics: Mice; Animals; Linezolid; Pentamidine; Carbapenem-Resistant Enterobacteriaceae; Anti-Bacterial Agents; Drug Combinations; Microbial Sensitivity Tests; Mammals
PubMed: 37125928
DOI: 10.1128/spectrum.03138-22