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PLoS Neglected Tropical Diseases Jun 2024In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.
BACKGROUND
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
TRIAL REGISTRATION
CTRI/2017/04/008421.
Topics: Humans; Amphotericin B; Phosphorylcholine; Bangladesh; Male; Antiprotozoal Agents; Adult; Adolescent; Female; Middle Aged; Young Adult; Child; India; Leishmaniasis, Visceral; Treatment Outcome; Leishmaniasis, Cutaneous; Drug Therapy, Combination
PubMed: 38900786
DOI: 10.1371/journal.pntd.0012242 -
ACS Omega Jun 2024Polymer materials are integral to diverse scientific fields, including chemical engineering and biochemical research, as well as analytical and physical chemistry. This...
Characterization of Modified PVDF Membranes Using Fourier Transform Infrared and Raman Microscopy and Infrared Nanoimaging: Challenges and Advantages of Individual Methods.
Polymer materials are integral to diverse scientific fields, including chemical engineering and biochemical research, as well as analytical and physical chemistry. This study focuses on the characterization of modified poly(vinylidene fluoride) (PVDF) membranes from both physical and chemical perspectives. Unfortunately, current surface characterization methods face various challenges when simultaneously measuring diverse material properties such as morphology and chemical composition. Addressing this issue, we introduce infrared scattering scanning near-field optical microscopy (IR-sSNOM), a modern technique with the ability to overcome limitations and provide simultaneous topographical, mechanical, and chemical information. We demonstrate the capabilities of IR-sSNOM for investigation of four samples of PVDF membranes modified with 2-(methacryloyloxyethyl)trimethylammonium iodide and/or methacryloyloxyethyl phosphorylcholine in various ratios. These membranes, desirable for their specific properties, represent a challenging material for analysis due to their thermal instability and mechanical vulnerability. Employing Fourier transform infrared (FTIR) microscopy, IR-sSNOM, and Raman microscopy, we successfully overcame these challenges by carefully selecting the experimental parameters and performing detailed characterization of the polymer samples. Valuable insights into morphological and chemical homogeneity, the abundance of modifying side chains, and the distribution of different crystal phases of PVDF were obtained. Most notably, the presence of modifying side chains was confirmed by FTIR microscopy, the Raman spectral mapping revealed the distribution of crystalline phases of the studied polymer, and the IR-sSNOM showed the abundance of chemically diverse aggregates on the surface of the membranes, thanks to the unique nanometer-scale resolution and chemical sensitivity of this technique. This comprehensive approach represents a powerful toolset for characterization of polymeric materials at the nano- and microscale. We believe that this methodology can be applied to similar samples, provided that their thermal stability is considered, opening avenues for detailed exploration of physical and chemical properties in various scientific applications.
PubMed: 38882160
DOI: 10.1021/acsomega.4c01197 -
PloS One 2024Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound...
Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 μM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 μM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 μM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.
Topics: Leishmania infantum; Humans; Antiprotozoal Agents; THP-1 Cells; Indoles; Hydrophobic and Hydrophilic Interactions; Phosphorylcholine; Macrophages; Inhibitory Concentration 50
PubMed: 38870204
DOI: 10.1371/journal.pone.0301901 -
RSC Advances Jun 2024Enzymes are biological catalysts with good biocompatibility and high efficiency and have been widely used in many fields, such as wastewater treatment, biosensors, and...
Enzymes are biological catalysts with good biocompatibility and high efficiency and have been widely used in many fields, such as wastewater treatment, biosensors, and the medical industry. However, their inherently low stability under conditions of practical use limits further applications. Zwitterionic polymers possessing a pair of oppositely charged groups in their repeating units can increase protein stability because of their good biocompatibility and high water content. In this study, zwitterionic copolymer nanogels comprising poly(2-methacryloyloxyethyl phosphorylcholine (MPC)--methacrylic acid--hydroxy succinimide ester (MNHS)) (PMS) were synthesized reversible addition-fragmentation chain-transfer polymerization (RAFT). β-Galactosidase (β-gal) was post-modified within zwitterionic polymer nanogels with a covalently-bound spacer and the activity was compared with that of directly immobilized β-gal and free β-gal. Compared with direct immobilization, covalent immobilization with a spacer could reduce the structural change of β-gal, as confirmed by the circular dichroism spectra. Although the activity of β-gal decreased after immobilization, the hybrids of the β-gal immobilized nanogels, termed hybrid nanogel-enzymes, demonstrated superior stability compared to the free enzymes. The hybrid nanogel-enzymes maintained their function against inactivation by organic solvents and proteinases owing to their high water content, anti-biofouling properties, and limited mass transfer. They can also withstand protein aggregation at high temperatures and maintain their activity. Compared to direct immobilization, immobilization with a spacer resulted in a dramatic increase in the enzyme activity and a slight decrease in the stability. These results indicate that polymer nanogels containing phosphorylcholine units are promising materials for enzyme immobilization, expanding the scope of enzyme applications.
PubMed: 38863819
DOI: 10.1039/d4ra02436b -
The Journal of Veterinary Medical... Jun 2024Immunoglobulin A (IgA) is notable for its broad specificity toward multiple bacteria. Phosphorylcholine (PC) plays a role in the infection of pathogenic bacteria...
Immunoglobulin A (IgA) is notable for its broad specificity toward multiple bacteria. Phosphorylcholine (PC) plays a role in the infection of pathogenic bacteria carrying PC and in the induction of IgA responses in the host immune system. The commercially available mouse monoclonal IgA, TEPC15-IgA, is a distinctive antibody with specificity for PC, warranting further exploration of its response to PC-bearing enteric bacteria. In this study, using 17 different enteric bacteria, including 3 aerobic and 14 anerobic bacteria that could be cultured in vitro, we confirmed that TEPC15-IgA recognizes 4 bacterial species: Lactobacillus taiwanensis, Limosilactobacillus frumenti, Streptococcus infantis, and Escherichia coli, although reactivity varied. Interestingly, TEPC15-IgA did not react with four of six Lactobacillus species used. Moreover, distinct target molecules associated with PC in L. taiwanensis and L. frumenti were evident, differing in molecular weight. These findings suggest that the natural generation of PC-specific IgA could prevent PC-mediated infections and potentially facilitate the formation of a microflora rich in indigenous bacteria with PC, particularly in the gastrointestinal tract.
PubMed: 38839348
DOI: 10.1292/jvms.23-0441 -
Nature Communications May 2024The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the...
The membrane-fusion-based internalization without lysosomal entrapment is advantageous for intracellular delivery over endocytosis. However, protein corona formed on the membrane-fusogenic liposome surface converts its membrane-fusion performance to lysosome-dependent endocytosis, causing poorer delivery efficiency in biological conditions. Herein, we develop an antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo. Leveraging specific lipid composition at an optimized ratio, such antifouling membrane-fusogenic liposome facilitates fusion capacity even in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups for protein-adsorption resistance. Consequently, the antifouling membrane-fusogenic liposome demonstrates robust membrane-fusion-mediated delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional membrane-fusogenic liposomes effective at 4% and 6% concentrations. When injected into mice, antifouling membrane-fusogenic liposomes can keep their membrane-fusion-transportation behaviors, thereby achieving efficient luciferase transfection and enhancing gene-editing-mediated viral inhibition. This study provides a promising tool for effective intracellular delivery under complex physiological environments, enlightening future nanomedicine design.
Topics: Liposomes; Animals; Mice; Humans; Membrane Fusion; Endocytosis; Transfection; Gene Editing; Protein Corona; Biofouling; Female; Lipids
PubMed: 38769317
DOI: 10.1038/s41467-024-46533-z -
Clinical Oral Investigations May 2024White spot lesions are the most common iatrogenic effect observed during orthodontic treatment. This study aimed to compare the surface characteristics and antibacterial... (Comparative Study)
Comparative Study
Evaluation of the surface characteristics and antibacterial properties of Titanium dioxide nanotube and methacryloyloxyethylphosphorylcholine (MPC) coated orthodontic brackets-a comparative invitro study.
OBJECTIVES
White spot lesions are the most common iatrogenic effect observed during orthodontic treatment. This study aimed to compare the surface characteristics and antibacterial action of uncoated and coated orthodontic brackets.
MATERIALS AND METHODS
Sixty commercially available stainless steel brackets were coated with TiO nanotubes and methacryloyloxyethylphosphorylcholine. The sample was divided into Group 1: uncoated orthodontic brackets, Group 2: Stainless steel brackets with TiO nanotubes coating, Group 3: Stainless steel brackets with methacryloyloxyethylphosphorylcholine coating, and Group 4: Stainless steel brackets with TiO nanotubes combined with methacryloyloxyethylphosphorylcholine coating. Surface characterization was assessed using atomic force microscopy and scanning electron microscopy. Streptococcus mutans was selected to test the antibacterial ability of the orthodontic brackets, total bacterial adhesion and bacterial viability were assessed. The brackets were subjected to scanning electron microscopy to detect the presence of biofilm.
RESULTS
The surface roughness was the greatest in Group 1 and least in Group 2 followed by Group 4 and Group 3 coated brackets. The optical density values were highest in Group 1 and lowest in Group 4. Comparison of colony counts revealed high counts in Group 1 and low counts in Group 4. A positive correlation between surface roughness and colony counts was obtained, however, was not statistically significant.
CONCLUSIONS
The coated orthodontic brackets exhibited less surface roughness than the uncoated orthodontic brackets. Group 4 coated orthodontic brackets showed the best antibacterial properties.
CLINICAL RELEVANCE
Coated orthodontic brackets prevent adhesion of streptococcus mutans and reduces plaque accumulation around the brackets thereby preventing formation of white spot lesions during orthodontic treatment.
Topics: Titanium; Orthodontic Brackets; Phosphorylcholine; Surface Properties; Streptococcus mutans; Anti-Bacterial Agents; Microscopy, Electron, Scanning; Nanotubes; Bacterial Adhesion; Microscopy, Atomic Force; Materials Testing; Stainless Steel; Methacrylates; Biofilms; Coated Materials, Biocompatible
PubMed: 38761310
DOI: 10.1007/s00784-024-05655-w -
Microbiology Spectrum Jun 2024Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment...
UNLABELLED
Post-kala-azar dermal leishmaniasis (PKDL) patients are a key source of parasites, hindering the goal of eliminating visceral leishmaniasis (VL). Monitoring treatment response and parasite susceptibility is essential due to increasing drug resistance. We assessed the drug susceptibility of PKDL isolates ( = 18) from pre-miltefosine (MIL) era (1997-2004) with isolates ( = 16) from the post-miltefosine era (2010-2019) and post-miltefosine treatment relapse isolates ( = 5) towards miltefosine and amphotericin B (AmB) at promastigote stage and towards sodium antimony gluconate (SAG) at amastigote stage. PKDL isolates were examined for mutation in gene-encoding AQP1 transporter, C26882T mutation on chromosome 24, and miltefosine-transporter (MT). PKDL isolates from the post-miltefosine era were significantly more susceptible to SAG than SAG-resistant isolates from the pre-miltefosine era ( = 0.0002). There was no significant difference in the susceptibility of parasites to miltefosine between pre- and post-miltefosine era isolates. The susceptibility of PKDL isolates towards AmB remained unchanged between the pre- and post-miltefosine era. However, the post-miltefosine era isolates had a higher IC value towards AmB compared with PKDL relapse isolates. We did not find any association between AQP1 gene sequence variation and susceptibility to SAG, or between miltefosine susceptibility and single nucleotide polymorphisms (SNPs in the MT gene. This study demonstrates that recent isolates of have resumed susceptibility to antimonials . The study also offers significant insights into the intrinsic drug susceptibility of parasites over the past two decades, covering the period before the introduction of miltefosine and after its extensive use.
IMPORTANCE
Post-kala-azar dermal leishmaniasis (PKDL) patients, a key source of parasites, hinder eliminating visceral-leishmaniasis. Assessment of the susceptibility of PKDL isolates to antimony, miltefosine (MIL), and amphotericin-B indicated that recent isolates remain susceptible to antimony, enabling its use with other drugs for treating PKDL.
Topics: Humans; Leishmania donovani; Phosphorylcholine; Leishmaniasis, Visceral; Antiprotozoal Agents; Antimony; Leishmaniasis, Cutaneous; Drug Resistance; Amphotericin B; Parasitic Sensitivity Tests; Antimony Sodium Gluconate; Mutation
PubMed: 38712926
DOI: 10.1128/spectrum.04026-23 -
Bioactive Materials Jul 2024Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality....
Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality. Antifouling coating strategies currently represent an efficient approach for addressing such complications. However, existing antifouling coatings have limitations in terms of both duration and effectiveness. Herein, we propose a durable zwitterionic polymer armor for catheters. This armor is realized by pre-coating with a robust phenol-polyamine film inspired by insect sclerotization, followed by grafting of poly-2-methacryloyloxyethyl phosphorylcholine (pMPC) via radical polymerization. The resulting pMPC coating armor exhibits super-hydrophilicity, thereby forming a highly hydrated shell that effectively prevents bacterial adhesion and inhibits the adsorption and activation of fibrinogen and platelets . In practical applications, the armored catheters significantly reduced inflammation and prevented biofilm formation in a rat subcutaneous infection model, as well as inhibited thrombus formation in a rabbit jugular vein model. Overall, our robust zwitterionic polymer coating presents a promising solution for reducing infections and thrombosis associated with vascular catheters.
PubMed: 38698921
DOI: 10.1016/j.bioactmat.2024.04.002 -
Biomolecules Mar 2024Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic... (Review)
Review
Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully understood, miltefosine exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca homeostasis of the parasites while sparing the human hosts. In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites. Both of these crucial organelles are involved in Ca regulation. Furthermore, miltefosine has the ability to activate a specific parasite Ca channel that responds to sphingosine, which is different to its L-type VGCC human ortholog. Here, we aimed to provide an overview of recent advancements of the anti-parasitic mechanisms of miltefosine. We also explored its multiple molecular targets and investigated how its pleiotropic effects translate into a rational therapeutic approach for patients afflicted by Leishmaniasis and American Trypanosomiasis. Notably, miltefosine's therapeutic effect extends beyond its impact on the parasite to also positively affect the host's immune system. These findings enhance our understanding on its multi-targeted mechanism of action. Overall, this review sheds light on the intricate molecular actions of miltefosine, highlighting its potential as a promising therapeutic option against these debilitating parasitic diseases.
Topics: Humans; Phosphorylcholine; Chagas Disease; Calcium; Leishmaniasis; Homeostasis; Animals; Antiprotozoal Agents; Mitochondria; Leishmania; Trypanosoma cruzi
PubMed: 38672424
DOI: 10.3390/biom14040406