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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 -
Proceedings of the National Academy of... Apr 2024Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully...
Dysregulation of polyamine metabolism has been implicated in cancer initiation and progression; however, the mechanism of polyamine dysregulation in cancer is not fully understood. In this study, we investigated the role of MUC1, a mucin protein overexpressed in pancreatic cancer, in regulating polyamine metabolism. Utilizing pancreatic cancer patient data, we noted a positive correlation between MUC1 expression and the expression of key polyamine metabolism pathway genes. Functional studies revealed that knockdown of spermidine/spermine N1-acetyltransferase 1 (), a key enzyme involved in polyamine catabolism, attenuated the oncogenic functions of MUC1, including cell survival and proliferation. We further identified a regulatory axis whereby MUC1 stabilized hypoxia-inducible factor (HIF-1α), leading to increased SAT1 expression, which in turn induced carbon flux into the tricarboxylic acid cycle. MUC1-mediated stabilization of HIF-1α enhanced the promoter occupancy of the latter on promoter and corresponding transcriptional activation of , which could be abrogated by pharmacological inhibition of HIF-1α or CRISPR/Cas9-mediated knockout of . knockdown caused a significant reduction in the levels of SAT1-generated metabolites, N1-acetylspermidine and N8-acetylspermidine. Given the known role of MUC1 in therapy resistance, we also investigated whether inhibiting SAT1 would enhance the efficacy of FOLFIRINOX chemotherapy. By utilizing organoid and orthotopic pancreatic cancer mouse models, we observed that targeting SAT1 with pentamidine improved the efficacy of FOLFIRINOX, suggesting that the combination may represent a promising therapeutic strategy against pancreatic cancer. This study provides insights into the interplay between MUC1 and polyamine metabolism, offering potential avenues for the development of treatments against pancreatic cancer.
Topics: Mice; Animals; Humans; Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Polyamines; Signal Transduction; Acetyltransferases; Mucin-1
PubMed: 38547055
DOI: 10.1073/pnas.2315509121 -
Journal of Orthopaedic Translation Mar 2024Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in...
BACKGROUND
Prevention of adhesion formation following flexor tendon repair is essential for restoration of normal finger function. Although many medications have been studied in the experimental setting to prevent adhesions, clinical application is limited due to the complexity of application and delivery in clinical translation.
METHODS
In this study, optimal dosages of gelatin and pentamidine were validated by gelatin concentration test. Following cell viability, cell migration, live and dead cell, and cell adhesion assay of the Turkey tenocytes, a model of Turkey tendon repair was established to evaluate the effectiveness of the Pentamidine-Gelatin sheet.
RESULTS
Pentamidine carried with gelatin, a Food and drug administration (FDA) approved material for drug delivery, showed good dynamic release, biocompatibility, and degradation. The optimal dose of pentamidine (25ug) was determined in the in vivo study using tenocyte viability, migration, and cell adhesion assays. Further biochemical analyses demonstrated that this positive effect may be due to pentamidine downregulating the Wnt signaling pathway without affecting collagen expression.
CONCLUSIONS
We tested a FDA-approved antibiotic, pentamidine, for reducing adhesion formation after flexor tendon repair in both in vitro and in vivo using a novel turkey animal model. Compared with the non-pentamidine treatment group, pentamidine treated turkeys had significantly reduced adhesions and improved digit function after six weeks of tendon healing.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
This study for the first time showed that a common clinical drug, pentamidine, has a potential for clinical application to reduce tendon adhesions and improve tendon gliding function without interfering with tendon healing.
PubMed: 38511123
DOI: 10.1016/j.jot.2023.10.007 -
Frontiers in Drug Delivery May 2023Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the...
Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter ( AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y and system-B. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y-system inhibitor, but not a B-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y-system protein, CAT1, and the B-system protein, ATB, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y, and OCT to cross the BBB. This research highlights the potential of system-y to deliver drugs, including eflornithine, across the BBB to treat brain diseases.
PubMed: 38482132
DOI: 10.3389/fddev.2023.1113493 -
Indian Journal of Ophthalmology Apr 2024This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical... (Review)
Review
This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical features, diagnosis, medical and surgical therapy, as well as outcomes of Acanthamoeba keratitis (AK). AK is a significant cause of ocular morbidity, and early diagnosis with timely institution of appropriate therapy is the key to obtaining good outcomes. The varied presentations result in frequent misdiagnosis, and co-infections can increase the morbidity of the disease. The first line of therapy continues to be biguanides and diamidines, with surgery as a last resort.
Topics: Humans; Acanthamoeba Keratitis; Pentamidine; Biguanides
PubMed: 38454853
DOI: 10.4103/IJO.IJO_2627_23 -
Pharmaceutics Feb 2024Chagas disease and leishmaniasis are both neglected tropical diseases that affect millions of people around the world. Leishmaniasis is currently the second most... (Review)
Review
Chagas disease and leishmaniasis are both neglected tropical diseases that affect millions of people around the world. Leishmaniasis is currently the second most widespread vector-borne parasitic disease after malaria. The World Health Organization records approximately 0.7-1 million newly diagnosed leishmaniasis cases each year, resulting in approximately 20,000-30,000 deaths. Also, 25 million people worldwide are at risk of Chagas disease and an estimated 6 million people are infected with . Pentavalent antimonials, amphotericin B, miltefosine, paromomycin, and pentamidine are currently used to treat leishmaniasis. Also, nifurtimox and benznidazole are two drugs currently used to treat Chagas disease. These drugs are associated with toxicity problems such as nephrotoxicity and cardiotoxicity, in addition to resistance problems. As a result, the discovery of novel therapeutic agents has emerged as a top priority and a promising alternative. Overall, there is a need for new and effective treatments for Chagas disease and leishmaniasis, as the current drugs have significant limitations. Peptide-based drugs are attractive due to their high selectiveness, effectiveness, low toxicity, and ease of production. This paper reviews the potential use of peptides in the treatment of Chagas disease and leishmaniasis. Several studies have demonstrated that peptides are effective against Chagas disease and leishmaniasis, suggesting their use in drug therapy for these diseases. Overall, peptides have the potential to be effective therapeutic agents against Chagas disease and leishmaniasis, but more research is needed to fully investigate their potential.
PubMed: 38399281
DOI: 10.3390/pharmaceutics16020227 -
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 -
Scientific Reports Feb 2024Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits,...
Psychedelic substances induce profound alterations in consciousness. Careful preparation is therefore essential to limit adverse reactions, enhance therapeutic benefits, and maintain user safety. This paper describes the development of a self-directed, digital intervention for psychedelic preparation. Drawing on elements from the UK Medical Research Council (MRC) framework for developing complex interventions, the design was informed by a four-factor model of psychedelic preparedness, using a person-centred approach. Our mixed-methods investigation consisted of two studies. The first involved interviews with 19 participants who had previously attended a 'high-dose' psilocybin retreat, systematically exploring their preparation behaviours and perspectives on the proposed intervention. The second study engaged 28 attendees of an ongoing psilocybin retreat in co-design workshops, refining the intervention protocol using insights from the initial interviews. The outcome is a co-produced 21-day digital course (Digital Intervention for Psychedelic Preparation (DIPP)), that is organised into four modules: Knowledge-Expectation, Psychophysical-Readiness, Safety-Planning, and Intention-Preparation. Fundamental components of the course include daily meditation practice, supplementary exercises tied to the weekly modules, and mood tracking. DIPP provides a comprehensive and scalable solution to enhance psychedelic preparedness, aligning with the broader shift towards digital mental health interventions.
Topics: Humans; Hallucinogens; Psilocybin; Mental Health; Consciousness; Pentamidine
PubMed: 38374177
DOI: 10.1038/s41598-024-54642-4 -
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 -
The World Allergy Organization Journal Jan 2024Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the... (Review)
Review
Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or "sulfur allergy") will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.
PubMed: 38235260
DOI: 10.1016/j.waojou.2023.100856