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Brain Communications 2022Studies have correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes occurring in multiple sclerosis. The...
Studies have correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes occurring in multiple sclerosis. The relevance of S100B in multiple sclerosis pathology brought an emerging curiosity highlighting its use as a potential therapeutic target to reduce damage during the multiple sclerosis course, namely during inflammatory relapses. We examined the relevance of S100B and further investigated the potential of S100B-neutralizing small-molecule pentamidine in chronic experimental autoimmune encephalomyelitis. S100B depletion had beneficial pathological outcomes and based on promising results of a variety of S100B blockade strategies in an demyelinating model, we choose pentamidine to assay its role in the experimental autoimmune encephalomyelitis. We report that pentamidine prevents more aggressive clinical symptoms and improves recovery of chronic experimental autoimmune encephalomyelitis. Blockade of S100B by pentamidine protects against oligodendrogenesis impairment and neuroinflammation by reducing astrocyte reactivity and microglia pro-inflammatory phenotype. Pentamidine also increased regulatory T cell density in the spinal cord suggesting an additional immunomodulatory action. These results showed the relevance of S100B as a main driver of neuroinflammation in experimental autoimmune encephalomyelitis and identified an uncharacterized mode of action of pentamidine, strengthening the possibility to use this drug as an anti-inflammatory and remyelinating therapy for progressive multiple sclerosis.
PubMed: 35620168
DOI: 10.1093/braincomms/fcac076 -
Current Cardiology Reviews 2022Hypertension is a leading cause of cardiovascular disease and chronic kidney disease, resulting in premature death and disability. The Renin-Angiotensin-Aldosterone... (Review)
Review
INTRODUCTION
Hypertension is a leading cause of cardiovascular disease and chronic kidney disease, resulting in premature death and disability. The Renin-Angiotensin-Aldosterone System (RAAS) blockers, including Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), are used as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease. The use of RAS blockers is associated with the risks, such as hyperkalemia, angioedema, etc. The drugs potentiating them interact pharmacodynamically, resulting in adverse consequences. This review article focuses on the clinically important drug interactions of RAAS blockers.
MATERIALS AND METHODS
The electronic databases, such as Medline/PubMed Central/PubMed, Google Scholar, ScienceDirect, Cochrane Library, Directory of Open Access Journals (DOAJ), Embase, and reference lists were searched to identify relevant articles.
RESULTS
The risk of hyperkalemia may be enhanced potentially in patients receiving a RAS blocker and potassium-sparing diuretics, potassium supplements, trimethoprim, adrenergic betablockers, antifungal agents, calcineurin inhibitors, pentamidine, heparins or an NSAID, concomitantly. The patients taking ACE inhibitors and mTOR inhibitors, DPP4 inhibitors, alteplase, or sacubitril/valsartan concurrently may be at increased risk of developing angioedema.
CONCLUSION
Clinicians, pharmacists, and other healthcare practitioners should be accountable for medication safety. To avoid adverse implications, prescribers and pharmacists must be aware of the drugs that interact with RAAS blockers.
Topics: Humans; Renin-Angiotensin System; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Hyperkalemia; Hypertension; Drug Interactions; Renal Insufficiency, Chronic; Potassium; Angioedema
PubMed: 35546745
DOI: 10.2174/1573403X18666220511152330 -
International Journal of Infectious... Jul 2022Pneumocystis jirovecii is a common opportunistic fungal pathogen that commonly affects immunocompromised individuals and can cause P. jirovecii pneumonia. Extrapulmonary...
Pneumocystis jirovecii is a common opportunistic fungal pathogen that commonly affects immunocompromised individuals and can cause P. jirovecii pneumonia. Extrapulmonary P. jirovecii infections are extremely rare. Herein, we present a case of an HIV-positive, antiretroviral therapy-naïve patient who had extrapulmonary pneumocystosis (EPC). He presented with complaints of decreased appetite, abdominal fullness, and weight loss. Computed tomography (CT) revealed multiple low-attenuation masses in the spleen, liver, and both adrenal glands but no pulmonary involvement. A core-needle biopsy of a splenic lesion confirmed the diagnosis of EPC. The patient was initiated on intravenous trimethoprim-sulfamethoxazole (TMP-SMX) and CT-guided percutaneous catheter drainage of the splenic lesion was performed. Intravenous TMP-SMX therapy was completed in 3 weeks and intravenous pentamidine (250 mg daily) therapy was commenced. Pentamidine was completed after 3 weeks, and antiretroviral treatment (ART) was initiated with dolutegravir 50 mg and Descovy HT (emtricitabine [200 mg] and tenofovir alafenamide fumarate [25 mg]). After starting ART, the patient's clinical condition improved, and the abscesses gradually reduced. TMP-SMX is commonly used to treat EPC; however, there is no standard method of treatment. ART may become the key to EPC treatment in individuals with HIV infection.
Topics: HIV Infections; HIV Seropositivity; Humans; Male; Pentamidine; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 35398297
DOI: 10.1016/j.ijid.2022.03.058 -
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 -
Journal of Parasitic Diseases :... Mar 2022Leishmaniasis, one of the most prevalent yet neglected parasitic causes of death, yearns for therapeutic control and treatment. Severely toxic and inefficient modern-day...
Leishmaniasis, one of the most prevalent yet neglected parasitic causes of death, yearns for therapeutic control and treatment. Severely toxic and inefficient modern-day pentavalent antimonials, caters the search for naturally derived drugs, as efficient alternatives for disease treatment. The anti-promastigote activity of ten different plants selected for their ethnomedicinal properties revealed significant leishmanicidal capacity; the most potent being methanolic extract with an IC value of 21.4 µg/ml. a plant endemic to North-Eastern India that is of the Clusiaceae family, is replete with such medicinal qualities as antimicrobial, antiviral, antiparasitic, and antiproliferative activities. Computational biology with its tools such as molecular docking has opened new horizons aimed at a better understanding of biological systems, complexes, and their interactions, and subsequently drug discovery via in silico techniques. Therefore, an study was designed to evaluate the binding capability of six phytochemicals- cowanin, cowanol, cowaxanthone, norcowanin, rubraxanthone, and a basic xanthone, found in against Pentamidine, a synthetic anti-leishmanial drug. The active sites of three characteristic enzymes belonging to the parasite: O-acetylserine sulfhydrylase (OASS), Trypanothione reductase (TryR), and N-Myristoyltransferase (NMT) were chosen as target proteins. Results revealed lower binding energies and higher affinities, of nearly all the phytochemicals with respect to Pentamidine, indicating their leishmanicidal potential. Norcowanin showed the lowest average binding of - 9.8 kcal/mol against all the three enzymes under study.
PubMed: 35299910
DOI: 10.1007/s12639-021-01441-7 -
Frontiers in Pharmacology 2022Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body...
Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which may bring a cytokine storm in the body and cause severe sepsis. Existing molecules specialized in sepsis therapy are either in clinical trials or show mediocre effects. In this study, pentamidine, an approved drug used in the treatment of trypanosomiasis, was identified as a TLR4 antagonist. Saturation transferred difference (STD)-NMR spectra indicated that pentamidine directly interacted with TLR4's co-receptor myeloid differentiation protein 2 (MD2) . Cellular thermal shift assay (CETSA) showed that pentamidine binding decreased MD2 stability, which was supported by simulations that pentamidine binding rendered most regions of MD2 more flexible. Pentamidine was found to inhibit the formation of the TLR4/MD2/MyD88 complex and the activation of the TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream of the pro-inflammatory factors NO, TNF-α, and IL-1β. The bioisosteric replacement of the methylene group at the center 13' site of pentamidine by the ether oxygen group significantly decreased its interactions with MD2 and abolished its TLR4 antagonist activity. Furthermore, pentamidine enhanced the survival rate of septic mice and exerted an anti-inflammatory effect on organs. All these data provide strong evidence that pentamidine may be an effective drug in alleviating inflammation and sepsis.
PubMed: 35281916
DOI: 10.3389/fphar.2022.835081 -
Biochimica Et Biophysica Acta.... Jul 2022Exogenous polyunsaturated fatty acids (PUFAs) are readily incorporated into the synthesis pathways of A. baumannii membrane phospholipids, where they contribute to...
Exogenous polyunsaturated fatty acids (PUFAs) are readily incorporated into the synthesis pathways of A. baumannii membrane phospholipids, where they contribute to reduced bacterial fitness and increased antimicrobial susceptibility. Here we examine the impact of PUFA membrane modification on membrane organisation and biophysical properties using coarse grained MARTINI simulations of chemically representative membrane models developed from mass-spectrometry datasets of an untreated, arachidonic acid (AA) treated and docosahexaenoic acid (DHA) treated A. baumannii membranes. Enzymatic integration of AA or DHA into phospholipids of the A. baumannii membrane resulted in modulation of membrane biophysical properties. Membrane thickness decreased slightly following PUFA treatment, concomitant with changes in the lateral area per lipid of each lipid headgroup class. PUFA treatment resulted in a decrease in membrane ordering and an increase in lipid lateral diffusion. Changes in lateral membrane organisation were observed in the PUFA treated membranes, with a concurrent increase in ordered cardiolipin domains and disordered PUFA-containing domains. Notably, separation between ordered and disordered domains was enhanced and was more pronounced for DHA relative to AA, providing a possible mechanism for greater antimicrobial action of DHA relative to AA observed experimentally. Furthermore, the membrane active antimicrobial, pentamidine, preferentially adsorbs to cardiolipin domains of the A. baumannii model membranes. This interaction, and membrane penetration of pentamidine, was enhanced following PUFA treatment. Cumulatively, this work explores the wide-ranging effects of PUFA incorporation on the A. baumannii membrane and provides a molecular basis for bacterial inner membrane disruption by PUFAs.
Topics: Acinetobacter baumannii; Arachidonic Acid; Cardiolipins; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Pentamidine; Phospholipids
PubMed: 35276227
DOI: 10.1016/j.bbamem.2022.183908 -
International Journal of Molecular... Mar 2022The animal trypanosomiases are infections in a wide range of (domesticated) animals with any species of African trypanosome, such as , , , and . Symptoms differ between...
Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities of and Subgenus Trypanosomes to Diamidines and Melaminophenyl Arsenicals.
The animal trypanosomiases are infections in a wide range of (domesticated) animals with any species of African trypanosome, such as , , , and . Symptoms differ between host and infective species and stage of infection and are treated with a small set of decades-old trypanocides. A complication is that not all trypanosome species are equally sensitive to all drugs and the reasons are at best partially understood. Here, we investigate whether drug transporters, mostly identified in , determine the different drug sensitivities. We report that homologues of the aminopurine transporter TbAT1 and the aquaporin TbAQP2 are absent in , while their introduction greatly sensitises this species to diamidine (pentamidine, diminazene) and melaminophenyl (melarsomine) drugs. Accumulation of these drugs in the transgenic lines was much more rapid. is also inherently less sensitive to suramin than , despite accumulating it faster. Expression of a proposed suramin transporter, located in lysosomes, in , did not alter its suramin sensitivity. We conclude that for several of the most important classes of trypanocides the presence of specific transporters, rather than drug targets, is the determining factor of drug efficacy.
Topics: Animals; Arsenicals; Membrane Transport Proteins; Pentamidine; Suramin; Trypanocidal Agents; Trypanosoma; Trypanosoma congolense
PubMed: 35269985
DOI: 10.3390/ijms23052844 -
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 -
Microorganisms Feb 2022The sterol biosynthesis pathway of spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of...
The sterol biosynthesis pathway of spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of sterol-related genes is scarce. The present study investigated compensatory mechanisms of the sterol biosynthesis pathway using an inhibitor of HMG-CoA reductase (simvastatin) and by developing drug-resistant parasites to evaluate the impact on sterol remodeling, cross-resistance, and gene expression. Simvastatin-resistant parasites (SimR) underwent reprogramming of sterol metabolism manifested as an increase in cholestane- and stigmastane-based sterols and a decrease in ergostane-based sterols. The levels of the transcripts of sterol 24-C-methyltransferase (SMT), sterol C14-α-demethylase (C14DM), and protease subtilisin (SUB) were increased in SimR. SimR was cross-resistance to ketoconazole (a C14DM inhibitor) and remained sensitive to terbinafine (an inhibitor of squalene monooxygenase). Sensitivity of the SimR mutant to other antileishmanial drugs unrelated to the sterol biosynthesis pathway, such as trivalent antimony and pentamidine, was similar to that of the wild-type strain; however, SimR was cross-resistant to miltefosine, general serine protease inhibitor --tosyl-l-phenylalanine chloromethyl ketone (TPCK), subtilisin-specific inhibitor 4-[(diethylamino)methyl]--[2-(2-methoxyphenyl)ethyl]--(3R)-3-pyrrolidinyl-benzamide dihydrochloride (PF-429242), and tunicamycin. The findings on the regulation of the sterol pathway can support the development of drugs and protease inhibitors targeting this route in parasites.
PubMed: 35208853
DOI: 10.3390/microorganisms10020398