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Avicenna Journal of Medicine Jan 2023pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has... (Review)
Review
pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has been a decline in pneumonia incidence in HIV since the introduction of antiretroviral medications. However, its incidence is increasing in non-HIV immunocompromised patients including those with solid organ transplantation, hematopoietic stem cell transplantation, solid organ tumors, autoimmune deficiencies, and primary immunodeficiency disorders. We aim to review and summarize the etiology, epidemiology, clinical presentation, diagnosis, and management of pneumonia in HIV, and non-HIV patients. HIV patients usually have mild-to-severe symptoms, while non-HIV patients present with a rapidly progressing disease. Induced sputum or bronchoalveolar lavage fluid can be used to make a definitive diagnosis of pneumonia. Trimethoprim-sulfamethoxazole is considered to be the first-line drug for treatment and has proven to be highly effective for pneumonia prophylaxis in both HIV and non-HIV patients. Pentamidine, atovaquone, clindamycin, and primaquine are used as second-line agents. While several diagnostic tests, treatments, and prophylactic regimes are available at our disposal, there is need for more research to prevent and manage this disease more effectively.
PubMed: 36969352
DOI: 10.1055/s-0043-1764375 -
Iranian Journal of Parasitology 2021are a causative agent of keratitis (AK) in immunocompetent individuals. Since access to propamidine isethionate (Brolene®) as a first-line treatment has been limited...
BACKGROUND
are a causative agent of keratitis (AK) in immunocompetent individuals. Since access to propamidine isethionate (Brolene®) as a first-line treatment has been limited in recent years, in the current study, we examined the effects of pentamidine isethionate against trophozoite and cyst forms of .
METHODS
This experimental study was conducted in the Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran, during 2019-2020. Pentamidine isethionate at concentrations of 50, 100, 200, 400, 600, 800, and 1000 μM were tested against trophozoites and cyst stages of T4 genotype, at 24- and 48-hour incubation period, and the viability was determined by trypan blue staining. In addition, the cytotoxic effect of the drug was examined in cells using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay.
RESULTS
The 50% inhibitory concentration (IC50) of pentamidine isethionate on trophozoite after 24 and 48h were 97.4 μM and 60.99 μM. These results on cyst after 24 and 48h were 470 μM and 175.5 μM, respectively. In MTT assay, the drug showed an inhibitory effect on cell growth with IC50 values of 115.4 μM and 87.42 μM after 24h and 48h, respectively.
CONCLUSION
Pentamidine isethionate exhibited an inhibitory effect on trophozoite and cyst. Given that the trophozoicidal activity of the drug is in the safe dose, it could be suggested as an alternative in patients with AK; however, further investigation is needed in an animal model to confirm the data.
PubMed: 35082884
DOI: 10.18502/ijpa.v16i4.7868 -
Drug Delivery and Translational Research Aug 2022Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood.... (Review)
Review
Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided. Created with BioRender.com.
Topics: Administration, Cutaneous; Drug Carriers; Drug Delivery Systems; Nanomedicine; Nanoparticles; Pentamidine; Pharmaceutical Preparations
PubMed: 35217992
DOI: 10.1007/s13346-022-01127-4 -
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 -
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 -
Antibiotics (Basel, Switzerland) Mar 2023The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to... (Review)
Review
The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.
PubMed: 36978495
DOI: 10.3390/antibiotics12030628 -
Pathogens (Basel, Switzerland) Sep 2022Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of... (Review)
Review
Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.
PubMed: 36297157
DOI: 10.3390/pathogens11101100 -
Frontiers in Veterinary Science 2022African trypanosomiasis is associated with , and pathogens in African animal trypanosomiasis (AAT) while and are responsible for chronic and acute human African... (Review)
Review
African trypanosomiasis is associated with , and pathogens in African animal trypanosomiasis (AAT) while and are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against and infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4-5 pairs apart in adenine-thymine-rich portions of DNA. It also suppresses type II topoisomerase in the mitochondria of parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against group and act the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.
PubMed: 35356785
DOI: 10.3389/fvets.2022.828111