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The American Journal of Tropical... Nov 2021The management of visceral leishmaniasis (VL) in HIV-infected patients is complex because of high mortality rates, toxic drug-related side effects, and a high risk of...
The management of visceral leishmaniasis (VL) in HIV-infected patients is complex because of high mortality rates, toxic drug-related side effects, and a high risk of treatment failure and relapse. We report a case of active chronic VL in an HIV-1-infected woman presenting multiple secondary VL episodes over 7 years leading to massive splenomegaly and blood transfusion-dependent anemia despite several treatment courses and secondary prophylaxis. The patient was finally successfully treated with rescue treatment based on intravenous pentamidine. Twenty months after discontinuation of pentamidine the patient presented complete clinical and parasitological response. In patients with active chronic VL, treatment with intravenous pentamidine can be effective and should be considered as rescue treatment.
Topics: AIDS-Related Opportunistic Infections; Administration, Intravenous; Antiprotozoal Agents; Coinfection; Female; HIV Infections; Humans; Leishmania donovani; Leishmaniasis, Visceral; Middle Aged; Pentamidine; Recurrence; Secondary Prevention; Treatment Outcome
PubMed: 34781255
DOI: 10.4269/ajtmh.21-0600 -
ACS Infectious Diseases Dec 2021Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and...
Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as , , and , including polymyxin- and carbapenem-resistant strains.
Topics: Acinetobacter baumannii; Amidines; Anti-Bacterial Agents; Gram-Negative Bacteria; Klebsiella pneumoniae
PubMed: 34766746
DOI: 10.1021/acsinfecdis.1c00466 -
Frontiers in Cellular and Infection... 2021The involvement of the enteric nervous system, which is a source of S100B, in () infection (CDI) is poorly understood although intestinal motility dysfunctions are...
The involvement of the enteric nervous system, which is a source of S100B, in () infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from -infected mice. To investigate the role of S100B signaling in expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated mediated expression activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.
Topics: Animals; Bacterial Proteins; Bacterial Toxins; Clostridioides; Clostridioides difficile; Clostridium Infections; Diarrhea; Humans; Mice; Rats; S100 Calcium Binding Protein beta Subunit; Suppressor of Cytokine Signaling Proteins
PubMed: 34568098
DOI: 10.3389/fcimb.2021.739874 -
Eye (London, England) Oct 2022Acanthamoeba keratitis (AK) is an important cause of ocular morbidity in both contact lens wearers and non wearers. Medical management comprises prolonged empiric...
BACKGROUND
Acanthamoeba keratitis (AK) is an important cause of ocular morbidity in both contact lens wearers and non wearers. Medical management comprises prolonged empiric treatment with multiple drugs, leading to adverse effects and suboptimal cure. The present study evaluated the efficiency and safety of common antimicrobial agents used in treatment of AK.
METHODS
Six Acanthamoeba isolates (four AK, two water samples) were axenized and subjected to in vitro susceptibility testing against chlorhexidine, pentamidine isethionate, polymyxin B, miltefosine, and fluconazole to check for trophocidal and cysticidal activity. The safety profile was analysed by observing the cytotoxicity of the highest cidal concentration toward human corneal epithelial cell (HCEC) line.
RESULTS
Chlorhexidine had the lowest cidal concentration against both cysts and trophozoites (range 4.16-25 μg/ml) followed by pentamidine isethionate (range 25-166.7 μg/ml). Both agents were nontoxic to HCEC. Polymyxin B (range 25-200 μg/ml) and fluconazole (range 64-512 μg/ml) had relatively higher minimum inhibitory concentrations (MIC); fluconazole was nontoxic even at 1024 μg/ml, but cytotoxicity was observed at 400 μg/ml with polymyxin B. Miltefosine was not effective against cysts at tested concentrations. A. castellanii were more susceptible to all agents (except pentamidine isethionate) than A. lenticulata. Clinical isolates were less susceptible to polymyxin B and fluconazole than environmental isolates, reverse was true for miltefosine.
CONCLUSION
Chlorhexidine and pentamidine isethionate were the most effective and safe agents against both trophozoites and cysts forms of our Acanthamoeba isolates. Fluconazole had higher MIC but was nontoxic. Polymyxin B was effective at high MIC but therapeutic dose was found toxic. Miltefosine, at tested concentrations, could not inhibit cysts of Acanthamoeba. Clinical isolates had higher MICs for polymyxin B and fluconazole.
Topics: Acanthamoeba; Acanthamoeba Keratitis; Anti-Infective Agents; Chlorhexidine; Epithelium, Corneal; Fluconazole; Humans; Pentamidine; Polymyxin B; Water
PubMed: 34548636
DOI: 10.1038/s41433-021-01768-8 -
Rheumatology (Oxford, England) May 2022The use of biologic and targeted synthetic (b/ts) DMARDs in the treatment of RA is increasing. Therefore, prevention of b/tsDMARDs-induced infection is important. Here...
OBJECTIVES
The use of biologic and targeted synthetic (b/ts) DMARDs in the treatment of RA is increasing. Therefore, prevention of b/tsDMARDs-induced infection is important. Here we describe a prophylaxis protocol for preventing pneumocystis pneumonia (PCP) in RA patients treated with b/tsDMARDs.
METHODS
The study subjects were 3787 RA patients from the FIRST registry. They were divided into cohort 1 (n = 807, requiring prophylaxis against PCP based on physicians' assessment at the point of new treatment with or switch to b/tsDMARDs) and cohort 2 (n = 2980, receiving strategic PCP prophylaxis). The incidence and risk factors for PCP were investigated.
RESULTS
Twenty-six PCP cases were observed throughout the study. After the introduction of strategic PCP prophylaxis, PCP incidence diminished from 0.51/100 person-years (PYs) to 0.21/100 PYs (risk ratio = 0.42). Sulfamethoxazole and trimethoprim in combination (SMX-TMP) showed greater efficacy in the prevention of PCP than pentamidine inhalation (P <0.0001). The prophylaxis rate increased chronologically despite the falls in the average SMX-TMP dose and in the incidence of PCP. Subanalysis of the data for 929 patients from both groups who did not receive prophylaxis showed that old age, high BMI, coexisting lung diseases, low lymphocyte count, and low serum IgG levels increased the risk of PCP development. Development of PCP could be predicted (using an equation based on these variables) in patients not treated with glucocorticoids [area under the curve (AUC) = 0.910)], but less accurately in those on glucocorticoids (AUC = 0.746).
CONCLUSIONS
Our study clarified the risk factors for PCP in RA patients on b/tsDMARDs treatment and highlighted and defined the criteria for effective prophylaxis against PCP.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Glucocorticoids; Humans; Pneumonia, Pneumocystis; Registries; Retrospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 34382090
DOI: 10.1093/rheumatology/keab647 -
ChemMedChem Nov 2021A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II)...
Direct, Late-Stage Mono-N-arylation of Pentamidine: Method Development, Mechanistic Insight, and Expedient Access to Novel Antiparastitics against Diamidine-Resistant Parasites.
A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis.
Topics: Amidines; Antiparasitic Agents; Dose-Response Relationship, Drug; Drug Development; Drug Resistance; Leishmania mexicana; Molecular Structure; Parasitic Sensitivity Tests; Pentamidine; Structure-Activity Relationship
PubMed: 34357687
DOI: 10.1002/cmdc.202100509 -
Drug Design, Development and Therapy 2021Pentamidine is an anti-protozoal cationic aromatic diamidine drug and has been reported to exhibit anticancer properties. We aimed to identify the effect of pentamidine...
PURPOSE
Pentamidine is an anti-protozoal cationic aromatic diamidine drug and has been reported to exhibit anticancer properties. We aimed to identify the effect of pentamidine on proliferation and migration of human ovarian cancer (OC) cell lines and the related mechanisms.
METHODS
HO8910 and Caov3 ovarian cancer cells were treated with pentamidine. MTS and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. The protein levels of PTEN, phosphorylated Akt, Akt, N-cadherin, E-cadherin and snail were detected by Western blotting. Immunoprecipitation and Western blotting were used to detect ubiquitination levels of PTEN.
RESULTS
Our findings revealed that pentamidine inhibited both proliferation and migration of OC cells. Further investigation found that pentamidine increased the protein expression of PTEN and reduced phosphorylation levels of AKT in OC cells. Pentamidine treatment modulated PTEN stability through the ubiquitin/proteasome pathway. In addition, pentamidine inhibited the expression of N-cadherin and snail, and increased E-cadherin expression in a dose-dependent manner.
CONCLUSION
Pentamidine is involved in the maintenance of PTEN protein stability and suppresses proliferation and migration of OC cells.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; Ovarian Neoplasms; PTEN Phosphohydrolase; Pentamidine; Proto-Oncogene Proteins c-akt
PubMed: 34234416
DOI: 10.2147/DDDT.S311187 -
Journal of Travel Medicine Aug 2021Examination of viability of trypomastigotes before and after single-dose pentamidine treatment demonstrated that single-dose pentamidine substantially affected motility...
Examination of viability of trypomastigotes before and after single-dose pentamidine treatment demonstrated that single-dose pentamidine substantially affected motility of trypomastigotes, a proxy of drug efficacy. This suggests that single-dose pentamidine may be of added value to bridge time until suramin will be available for treatment of human East Africa trypanosomiasis.
Topics: Animals; Humans; Pentamidine; Trypanocidal Agents; Trypanosoma; Trypanosomiasis, African
PubMed: 34008033
DOI: 10.1093/jtm/taab080 -
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 -
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