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International Journal of Biological... May 2024Drug binding and interactions with plasma proteins play a crucial role in determining the efficacy of drug delivery, thus significantly impacting the overall...
Drug binding and interactions with plasma proteins play a crucial role in determining the efficacy of drug delivery, thus significantly impacting the overall pharmacological effect. AGP, the second most abundant plasma protein in blood circulation, has the unique capability to bind drugs and transport various compounds. In our present study, for the first time, we investigated whether AGP, a major component of the acute phase lipocalin in human plasma, can bind with pentamidine derivatives known for their high activity against the fungal pathogen Pneumocystis carinii. This investigation was conducted using integrated spectroscopic techniques and computer-based approaches. According to the results, it was concluded that compounds having heteroatoms (-NCH) in the aliphatic linker and the addition of a Br atom and a methoxy substituent at the C-2 and C-6 positions on the benzene ring, exhibit strong interactions with the AGP binding site. These compounds are identified as potential candidates for recognition by this protein. MD studies indicated that the tested analogues complexed with AGPs reach an equilibrium state after 60 ns, suggesting the stability of the complexes. This observation was further corroborated by experimental results. Therefore, exploring the interaction mechanism of pentamidine derivatives with plasma proteins holds promise for the development of bis-benzamidine-designed pharmaceutically important drugs.
Topics: Humans; Pentamidine; Protein Binding; Orosomucoid; Binding Sites; Molecular Dynamics Simulation; Molecular Docking Simulation
PubMed: 38582487
DOI: 10.1016/j.ijbiomac.2024.131405 -
Transplantation Proceedings May 2024Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that, in immunocompromised patients, can progress to respiratory failure and death. Since...
Pneumocystis jirovecii Pneumonia in a Liver Transplant Recipient With an Adverse Reaction to Trimethoprim/Sulfamethoxazole Treated With a Sulfonamide Desensitization Protocol: Case Report.
BACKGROUND
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that, in immunocompromised patients, can progress to respiratory failure and death. Since trimethoprim/sulfamethoxazole (TMP/SMX) chemoprophylaxis has become a standard management, the prognosis has improved. However, there are patients with a history of TMP/SMX intolerance who cannot receive chemoprophylaxis.
BACKGROUND
We report on a 53-year-old male liver recipient treated with a standard triple immunosuppressive regimen in whom TMP/SMX was waived because of a history of allergy manifested as a generalized rash with edema more than 30 years ago. At transplantation, the immunologic risk was assessed as low, and liver graft function was normal. In the third month after engraftment, he developed dyspnea at rest required constant passive oxygen therapy. Ceftriaxone, azithromycin, and clindamycin were implemented. Mycophenolate acid was stopped, and tacrolimus was reduced. High-resolution computed tomography revealed interstitial pneumonia. Pneumocystis jirovecii pneumoniae was diagnosed from bronchoalveolar lavage. Instead of TMP/SMX, pentamidine and caspofungin were also used for PJP, with no improvement. After 3 weeks, the patient deteriorated. Because of his life-threatening condition, TMP/SMX was introduced in the sulfonamide desensitization protocol, including hydrocortisone and clemastinum. Within 4 days, the patient stabilized with no signs of TMP/SMX intolerance. Pneumonia subsided within a month, and TMP/SMX was prescribed lifelong.
CONCLUSIONS
Prophylaxis for PJP with TMP/SMX still remains an important issue in transplant recipients. Adverse reaction to TMP/SMX in the past is not always a contraindication to reintroducing prophylaxis. The decision of prophylaxis avoidance should be analyzed carefully; in uncertain cases, a sulfonamide desensitization protocol should be considered.
Topics: Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination; Liver Transplantation; Pneumocystis carinii; Sulfonamides; Desensitization, Immunologic; Immunocompromised Host; Immunosuppressive Agents
PubMed: 38760300
DOI: 10.1016/j.transproceed.2024.03.022 -
PloS One 2024Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality.
OBJECTIVE
Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality.
METHODS
Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome.
RESULTS
Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not.
CONCLUSION
A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.
Topics: Humans; Adrenal Cortex Hormones; Lactate Dehydrogenases; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Steroids; Male; Female
PubMed: 38330061
DOI: 10.1371/journal.pone.0292507 -
Frontiers in Aging Neuroscience 2024The efficacy of current treatments is still insufficient for Alzheimer's disease (AD), the most common cause of Dementia. Out of the two pathological hallmarks of AD...
The efficacy of current treatments is still insufficient for Alzheimer's disease (AD), the most common cause of Dementia. Out of the two pathological hallmarks of AD amyloid-β plaques and neurofibrillary tangles, comprising of tau protein, tau pathology strongly correlates with the symptoms of AD. Previously, screening for inhibitors of tau aggregation that target recombinant tau aggregates have been attempted. Since a recent cryo-EM analysis revealed distinct differences in the folding patterns of heparin-induced recombinant tau filaments and AD tau filaments, this study focused on AD seed-dependent tau aggregation in drug repositioning for AD. We screened 763 compounds from an FDA-approved drug library using an AD seed-induced tau aggregation in SH-SY5Y cell-based assay. In the first screening, 180 compounds were selected, 72 of which were excluded based on the results of lactate dehydrogenase assay. In the third screening with evaluations of soluble and insoluble tau, 38 compounds were selected. In the fourth screening with 3 different AD seeds, 4 compounds, lansoprazole, calcipotriene, desogestrel, and pentamidine isethionate, were selected. After AD seed-induced real-time quaking-induced conversion, lansoprazole was selected as the most suitable drug for repositioning. The intranasal administration of lansoprazole for 4 months to AD seed-injected mice improved locomotor activity and reduced both the amount of insoluble tau and the extent of phosphorylated tau-positive areas. Alanine replacement of the predicted binding site to an AD filament indicated the involvement of Q351, H362, and K369 in lansoprazole and C-shaped tau filaments. These results suggest the potential of lansoprazole as a candidate for drug repositioning to an inhibitor of tau aggregate formation in AD.
PubMed: 38633982
DOI: 10.3389/fnagi.2024.1368291 -
Pathogens (Basel, Switzerland) Jun 2023Infection with and may lead to diffuse cutaneous leishmaniasis. The cure is exceptional, especially for the strange case of this lady. Case report: The patient...
Infection with and may lead to diffuse cutaneous leishmaniasis. The cure is exceptional, especially for the strange case of this lady. Case report: The patient acquired the disease in childhood and remained with lesions for over 30 years, albeit several treatments. She worsened after a pregnancy, developing disseminated lesions. Miltefosine with amphotericin B and pentamidine resulted in remission. Lesions reappeared after one year, accompanied by intra-nasal infiltration of the disease. The nasal spraying of a single ampoule of pentavalent antimoniate resulted in the sustained disappearance of the nasal symptoms and all the cutaneous lesions. After over eight years, she remains disease-free, albeit under renal replacement therapy. The high nasal mucosal antimonial concentration may explain the long-lasting cure via new MHC class I epitope-specific CD8+ cell clones against present in the nasal mucosa.
PubMed: 37513737
DOI: 10.3390/pathogens12070890 -
Journal of Voice : Official Journal of... Apr 2024Leishmaniasis represents an emerging public health issue in Mediterranean countries. The incidence of this condition has progressively risen in Northern Italy due to the...
Leishmaniasis represents an emerging public health issue in Mediterranean countries. The incidence of this condition has progressively risen in Northern Italy due to the growing number of immunocompromised people and probably due to climate changes. We hereby describe a case of relapsing laryngeal leishmaniasis in a female immunocompetent patient, presenting as aspecific chronic laryngitis. She was affected by severe asthma treated by inhaled steroid therapy, likely responsible for the parasite's diffusion through a locus minori resistentiae. The aspecific clinical presentation led to a delayed diagnosis and the lack of guidelines for the treatment caused multiple relapses. Biopsies of laryngeal lesions in the follow-up were performed by operative flexible videolaryngoscopy, thus avoiding general anesthesia and reducing associated healthcare costs. The aim of this report is to underline the diagnostic and therapeutic challenges that patients with this condition face and to present what is, to the best of our knowledge, the first application of prophylactic aerosolized pentamidine for relapsing laryngeal leishmaniasis.
PubMed: 38658203
DOI: 10.1016/j.jvoice.2024.04.006 -
PLoS Neglected Tropical Diseases May 2024In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is...
In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L. amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L. amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.
Topics: Amphotericin B; Animals; Brazil; Middle Aged; Antiprotozoal Agents; Humans; Male; Mice; Drug Resistance; Leishmania; Leishmania mexicana; Leishmaniasis, Cutaneous; HIV Infections; Parasitic Sensitivity Tests; Mice, Inbred BALB C; Leishmaniasis, Diffuse Cutaneous
PubMed: 38768213
DOI: 10.1371/journal.pntd.0012175 -
Antibiotics (Basel, Switzerland) Feb 2024The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections...
The aims of this study were (i) to determine if the combination of mitomycin C with pentamidine or existing antibiotics resulted in enhanced efficacy versus infections with MDR in vivo; and (ii) to determine if the doses of mitomycin C and pentamidine in combination can be reduced to levels that are non-toxic in humans but still retain antibacterial activity. Resistant clinical isolates of , a mutant strain over-expressing the MexAB-OprM resistance nodulation division (RND) efflux pump and a strain with three RND pumps deleted, were used. MIC assays indicated that all strains were sensitive to mitomycin C, but deletion of three RND pumps resulted in hypersensitivity and over-expression of MexAB-OprM caused some resistance. These results imply that mitomycin C is a substrate of the RND efflux pumps. Mitomycin C monotherapy successfully treated infected larvae, albeit at doses too high for human administration. Checkerboard and time-kill assays showed that the combination of mitomycin C with pentamidine, or the antibiotic gentamicin, resulted in synergistic inhibition of most strains in vitro. In vivo, administration of a combination therapy of mitomycin C with pentamidine, or gentamicin, to larvae infected with resulted in enhanced efficacy compared with monotherapies for the majority of MDR clinical isolates. Notably, the therapeutic benefit conferred by the combination therapy occurred with doses of mitomycin C close to those used in human medicine. Thus, repurposing mitomycin C in combination therapies to target MDR infections merits further investigation.
PubMed: 38391563
DOI: 10.3390/antibiotics13020177 -
Microbiology Spectrum Jun 2024Bacteria are involved in numerous interactions during infection and among host-associated microbial populations. serovar Typhimurium is a foodborne pathogen of great...
Bacteria are involved in numerous interactions during infection and among host-associated microbial populations. serovar Typhimurium is a foodborne pathogen of great importance as well as a model organism to study interactions within a microbial community. In this study, we found that . Typhimurium becomes tolerant to azithromycin when co-cultured with lactobacilli strains. Similarly, acidified media, from cell-free supernatant of lactobacilli cultures for instance, also induced the tolerance of . Typhimurium to azithromycin. The addition of membrane disruptors restored the normal sensitivity to azithromycin in acidified media, but not when lactobacilli were present. These results suggested that the acidification of the media led to modification in envelope homeostasis, but that a different mechanism promoted the tolerance to azithromycin in the presence of lactobacilli strains. To further understand how lactobacilli strains modify the sensitivity of . Typhimurium to azithromycin, a high-throughput assay was performed using the single-gene deletion collection of the . Typhimurium (1) in co-culture with and (2) in sterile acidic conditions (pH 5.5 media only). As expected, both screens identified genes involved in envelope homeostasis and membrane permeability. Our results also suggest that changes in the metabolism of . Typhimurium induce the tolerance observed in the presence of . Our results thus highlight two different mechanisms by which lactobacilli induce the tolerance of . Typhimurium to azithromycin.IMPORTANCEThis study provides valuable insights into the intricate interactions between bacteria during infections and within host-associated microbial communities. Specifically, it sheds light on the significant role of lactobacilli in inducing antibiotic tolerance in serovar Typhimurium, a critical foodborne pathogen and model organism for microbial community studies. The findings not only uncover the mechanisms underlying this antibiotic tolerance but also reveal two distinct pathways through which strains of lactobacilli might influence 's response to antibiotics. Understanding these mechanisms has the potential to enhance our knowledge of bacterial infections and may have implications for the development of strategies to combat antibiotic resistance in pathogens, such as . Furthermore, our results underscore the necessity to explore beyond the direct antimicrobial effects of antibiotics, emphasizing the broader microbial community context.
PubMed: 38916329
DOI: 10.1128/spectrum.03497-23