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American Family Physician Mar 2004Cutaneous leishmaniasis is a parasitic disease occurring throughout the Americas from Texas to Argentina, and in the Old World, particularly the Middle East and North... (Review)
Review
Cutaneous leishmaniasis is a parasitic disease occurring throughout the Americas from Texas to Argentina, and in the Old World, particularly the Middle East and North Africa. It is spread by the female sandfly. The condition is diagnosed every year in travelers, immigrants, and military personnel. Physicians in the United States must be alert to the diagnosis of leishmaniasis in travelers returning from endemic areas. Physicians working for short periods in endemic areas often must make the diagnosis and should be aware of local disease patterns. When faced with a possible leishmanial skin lesion, a skin scraping with microscopic analysis is the best test. Punch biopsies with tissue-impression smears also can be diagnostic. Needle aspiration of tissue fluid from the margin of a lesion can yield fluid for culture to isolate the organism and identify the species. Immunologic tests are being developed, including a highly sensitive polymerase chain reaction test. The treatment mainstay is pentavalent antimony (e.g., sodium stibogluconate). Not all patients require treatment; many lesions heal spontaneously. Antimonials have a high incidence of reversible adverse effects. Other medications used for treatment include amphotericin B, pentamidine isethionate, paromomycin, and antifungals. This disease must be considered in at-risk patients, and family physicians should know the basics of diagnosis and where to go for more help.
Topics: Animals; Antiprotozoal Agents; Diagnosis, Differential; Humans; Leishmania; Leishmaniasis, Cutaneous; Protozoan Vaccines
PubMed: 15053410
DOI: No ID Found -
PLoS Neglected Tropical Diseases Oct 2018American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The... (Randomized Controlled Trial)
Randomized Controlled Trial
An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region.
BACKGROUND
American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.
OBJECTIVES
The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.
MATERIALS AND METHODS
This study was conducted as a controlled, randomized, open-label clinical trial for a total number of 159 patients with CL. Individuals aged 16-64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.
RESULTS
From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.
CONCLUSION
The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02919605.
Topics: Adolescent; Adult; Antiprotozoal Agents; Brazil; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Injections, Intramuscular; Leishmaniasis, Cutaneous; Male; Middle Aged; Pentamidine; Treatment Outcome; Young Adult
PubMed: 30379814
DOI: 10.1371/journal.pntd.0006850 -
Biochimie Jul 2008Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and... (Review)
Review
Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24-48h after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death.
Topics: Animals; Antiparasitic Agents; DNA, Protozoan; Drug Delivery Systems; Eukaryota; Heterocyclic Compounds; Humans; Models, Molecular; Nucleic Acid Conformation; Pentamidine
PubMed: 18343228
DOI: 10.1016/j.biochi.2008.02.017 -
Pharmaceutics Mar 2018The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach...
The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach the brain through intranasal delivery. Mucoadhesive properties and stability testing in various environments were evaluated to examine the potential of these formulations to be effective drug delivery vehicles for intranasal delivery to the brain. Samples were prepared using thin film hydration method. Changes in size and ζ-potential of coated and uncoated niosomes with and without loading of pentamidine in various conditions were assessed by dynamic light scattering (DLS), while size and morphology were also studied by atomic force microscopy (AFM). Bilayer properties and mucoadhesive behavior were investigated by fluorescence studies and DLS analyses, respectively. Changes in vesicle size and ζ-potential values were shown after addition of chitosan glutamate to niosomes, and when in contact with mucin solution. In particular, interactions with mucin were observed in both drug free and pentamidine loaded niosomes regardless of the presence of the coating. The characteristics of the proposed systems, such as pentamidine entrapment and mucin interaction, show promising results to deliver pentamidine or other possible drugs to the brain via nasal administration.
PubMed: 29565809
DOI: 10.3390/pharmaceutics10020038 -
Trends in Parasitology Mar 2013Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African... (Review)
Review
Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites.
Topics: Animals; Aquaglyceroporins; Drug Resistance; Humans; Melarsoprol; Pentamidine; Phylogeny; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 23375541
DOI: 10.1016/j.pt.2012.12.005 -
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 -
Antibiotics (Basel, Switzerland) Jul 2023The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against larvae infected with an MDR strain of and...
Combination Therapy with Ciprofloxacin and Pentamidine against Multidrug-Resistant : Assessment of In Vitro and In Vivo Efficacy and the Role of Resistance-Nodulation-Division (RND) Efflux Pumps.
The aim of this work was to (i) evaluate the efficacy of a combination treatment of pentamidine with ciprofloxacin against larvae infected with an MDR strain of and (ii) determine if pentamidine acts as an efflux-pump inhibitor. Resistant clinical isolates, mutant strains overexpressing one of three RND efflux pumps (MexAB-OprM, MexCD-OprJ, and MexEF-OprN), and a strain with the same three pumps deleted were used. MIC assays confirmed that the clinical isolates and the mutants overexpressing efflux pumps were resistant to ciprofloxacin and pentamidine. The deletion of the three efflux pumps induced sensitivity to both compounds. Exposure to pentamidine and ciprofloxacin in combination resulted in the synergistic inhibition of all resistant strains in vitro, but no synergy was observed versus the efflux-pump deletion strain. The treatment of infected larvae with the combination of pentamidine and ciprofloxacin resulted in enhanced efficacy compared with the monotherapies and significantly reduced the number of proliferating bacteria. Our measurement of efflux activity from cells revealed that pentamidine had a specific inhibitory effect on the MexCD-OprJ and MexEF-OprN efflux pumps. However, the efflux activity and membrane permeability assays revealed that pentamidine also disrupted the membrane of all cells. In conclusion, pentamidine does possess some efflux-pump inhibitory activity, in addition to a more general disruptive effect on membrane integrity that accounts for its ability to potentiate ciprofloxacin activity. Notably, the enhanced efficacy of combination therapy with pentamidine and ciprofloxacin versus MDR strains in vivo merits further investigation into its potential to treat infections via this pathogen in patients.
PubMed: 37627656
DOI: 10.3390/antibiotics12081236 -
Antimicrobial Agents and Chemotherapy Oct 1977Pentamidine isethionate is a trypanocidal drug used for the treatment of Pneumocystis carinii pneumonitis. Hematological complications have occasionally been reported...
Pentamidine isethionate is a trypanocidal drug used for the treatment of Pneumocystis carinii pneumonitis. Hematological complications have occasionally been reported and include anemia, leukopenia, and thrombocytopenia. We report here several qualitative abnormalities of in vitro platelet function and coagulation that have not been described previously. Platelets were exposed in vitro to concentrations of pentamidine isethionate ranging from 0.5 to 100 mug/ml of platelet-rich plasma. Clot retraction, platelet adhesiveness to glass beads, and platelet aggregation (adenosine 5'-diphosphate [ADP], thrombin, epinephrine, collagen, and ristocetin) were inhibited in a dose-dependent fashion. The addition of pentamidine isethionate after aggregation had been initiated with ADP reversed both primary and, to a lesser degree, secondary aggregation. Platelet factor 3 availability and serotonin uptake and release (using collagen as the releasing agent) were not inhibited. Serotonin release with 10(-4) M ADP was slightly inhibited. Pentamidine isethionate prolonged the thrombin time of plasma at concentrations of 5 mug/ml and greater. The prothrombin time was prolonged at concentrations greater than 10 mug/ml of plasma. The inhibition of aggregation was reversed by washing and resuspension in plasma or by the addition of calcium or magnesium ions.
Topics: Amidines; Blood Coagulation; Blood Platelets; Drug Synergism; Humans; In Vitro Techniques; Pentamidine; Platelet Aggregation; Platelet Factor 3; Serotonin; Time Factors
PubMed: 921238
DOI: 10.1128/AAC.12.4.451 -
Hepatology (Baltimore, Md.) Sep 2017Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the...
UNLABELLED
Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells.
CONCLUSION
VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922-935).
Topics: Animals; Biopsy, Needle; Blotting, Western; Cytokines; Disease Models, Animal; Galactosamine; Immunohistochemistry; In Situ Nick-End Labeling; Lipopolysaccharides; Liver Failure, Acute; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Pentamidine; Random Allocation; Real-Time Polymerase Chain Reaction; Survival Rate
PubMed: 28470665
DOI: 10.1002/hep.29244 -
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