scholarly journals Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis

2013 ◽  
Vol 57 (9) ◽  
pp. 4229-4236 ◽  
Author(s):  
Flaviana R. Fernandes ◽  
Weverson A. Ferreira ◽  
Mariana A. Campos ◽  
Guilherme S. Ramos ◽  
Kelly C. Kato ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Oral Treatment ◽  
Carbon Chain ◽  
Oral Route ◽  
Control Group ◽  
Pharmacokinetic Studies ◽  
Content Type ◽  
Transmission Electron ◽  
Parasitic Load ◽  
Chain Lengths

ABSTRACTThe need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected withLeishmania infantumafter a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.

scholarly journals Biochemical Characterization of CYP505D6, a Self-Sufficient Cytochrome P450 from the White-Rot FungusPhanerochaete chrysosporium

2018 ◽  
Vol 84 (22) ◽  
Author(s):  
Kiyota Sakai ◽  
Fumiko Matsuzaki ◽  
Lisa Wise ◽  
Yu Sakai ◽  
Sadanari Jindou ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cytochrome P450 ◽  
Phanerochaete Chrysosporium ◽  
Carbon Chain ◽  
Fatty Alcohols ◽  
White Rot ◽  
Wild Type ◽  
Content Type ◽  
Attractive Candidate ◽  
Chain Lengths

ABSTRACTThe activity of a self-sufficient cytochrome P450 enzyme, CYP505D6, from the lignin-degrading basidiomycetePhanerochaete chrysosporiumwas characterized. Recombinant CYP505D6 was produced inEscherichia coliand purified. In the presence of NADPH, CYP505D6 used a series of saturated fatty alcohols with C9–18carbon chain lengths as the substrates. Hydroxylation occurred at the ω-1 to ω-6 positions of such substrates with C9–15carbon chain lengths, except for 1-dodecanol, which was hydroxylated at the ω-1 to ω-7 positions. Fatty acids were also substrates of CYP505D6. Based on the sequence alignment, the corresponding amino acid of Tyr51, which is located at the entrance to the active-site pocket in CYP102A1, was Val51 in CYP505D6. To understand the diverse hydroxylation mechanism, wild-type CYP505D6 and its V51Y variant and wild-type CYP102A1 and its Y51V variant were generated, and the products of their reaction with dodecanoic acid were analyzed. Compared with wild-type CYP505D6, its V51Y variant generated few products hydroxylated at the ω-4 to ω-6 positions. The products generated by wild-type CYP102A1 were hydroxylated at the ω-1 to ω-4 positions, whereas its Y51V variant generated ω-1 to ω-7 hydroxydodecanoic acids. These observations indicated that Val51 plays an important role in determining the regiospecificity of fatty acid hydroxylation, at least that at the ω-4 to ω-6 positions. Aromatic compounds, such as naphthalene and 1-naphthol, were also hydroxylated by CYP505D6. These findings highlight a unique broad substrate spectrum of CYP505D6, rendering it an attractive candidate enzyme for the biotechnological industry.IMPORTANCEPhanerochaete chrysosporiumis a white-rot fungus whose metabolism of lignin, aromatic pollutants, and lipids has been most extensively studied. This fungus harbors 154 cytochrome P450-encoding genes in the genome. As evidenced in this study,P. chrysosporiumCYP505D6, a fused protein of P450 and its reductase, hydroxylates fatty alcohols (C9–15) and fatty acids (C9–15) at the ω-1 to ω-7 or ω-1 to ω-6 positions, respectively. Naphthalene and 1-naphthol were also hydroxylated, indicating that the substrate specificity of CYP505D6 is broader than those of the known fused proteins CYP102A1 and CYP505A1. The substrate versatility of CYP505D6 makes this enzyme an attractive candidate for biotechnological applications.

scholarly journals Clearance of Escherichia coli O157:H7 Infection in Calves by Rectal Administration of Bovine Lactoferrin

2014 ◽  
Vol 81 (5) ◽  
pp. 1644-1651 ◽  
Author(s):  
E. Kieckens ◽  
J. Rybarczyk ◽  
L. De Zutter ◽  
L. Duchateau ◽  
D. Vanrompay ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Clinical Symptoms ◽  
Oral Treatment ◽  
Experimental Treatment ◽  
Rectal Administration ◽  
Fecal Excretion ◽  
Severe Illness ◽  
Control Group ◽  
Bovine Lactoferrin ◽  
Content Type

ABSTRACTEnterohemorrhagicEscherichia coli(EHEC) strains, of whichE. coliO157:H7 is the best-studied serotype, are an important group of foodborne pathogens causing severe illness in humans worldwide. The main reservoirs for EHEC are ruminants, mostly cattle, which harbor the bacteria in their intestinal tracts without showing clinical symptoms. In this study, we used bovine lactoferrin, a natural occurring bactericidal and immunomodulating protein, as an antibacterial agent against EHEC infection in cattle. Nine 3-month-old Holstein-Friesian calves were experimentally infected with EHEC (strain NCTC12900). Three animals received a daily rectal spray treatment with bovine lactoferrin, three animals received an oral treatment, and three animals served as a control group. Blood samples were collected weekly and fecal samples twice weekly to monitor antibody responses and fecal excretion, respectively. Animals in the rectal group ceased shedding within 26 days of the experimental treatment and remained negative. This beneficial effect of bovine lactoferrin was not observed in the oral group, where animals were still shedding at the time of euthanasia (day 61). All groups developed serum responses, but no clear differences could be observed between the groups. However, the results indicate that the use of bovine lactoferrin as a rectal treatment can be a useful strategy to preclude further transmission of EHEC infections from cattle to humans.

Surface modification model of long afterglow phosphors by saturated fatty acid based Al-Zr coupling agent

2016 ◽  
Vol 45 (5) ◽  
pp. 330-334 ◽  
Author(s):  
Peng Yin ◽  
Can Xue ◽  
Bin Guo
Keyword(s):  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Coupling Agent ◽  
Water Resistance ◽  
Carbon Chain ◽  
Coupling Agents ◽  
Carbon Chain Length ◽  
Content Type ◽  
Long Afterglow ◽  
Chain Lengths

Purpose The purpose of this paper is to study the influence of different carbon chain lengths in coupling agents on the water resistance and compatibility of modified long afterglow phosphors and attempt to obtain their modification model and mechanism. Design/methodology/approach Three saturated-fatty-acid (caprylic, lauric, stearic acid)-based Al-Zr CAs (coupling agent) was synthesised and applied to modify the long afterglow phosphors SrMgAl4O8:Eu2+,Dy3+. Findings Results show that the coated amount on phosphors decreased from 13.41 to 6.53 per cent with the increased carbon chain length of fatty acid, and the better water resistant and suitability with organic resin can be obtained by lauric-based Al-Zr CA. Originality/value Considering that the decomposition process of modified phosphor was related with the decomposition performance of corresponding coupling agents and original phosphor, a method was first proposed to calculate the coated amount on phosphors by thermogravimetric analyser parameters.

scholarly journals Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

2011 ◽  
Vol 56 (1) ◽  
pp. 432-445 ◽  
Author(s):  
Partha Palit ◽  
Abhijit Hazra ◽  
Arindam Maity ◽  
R. S. K. Vijayan ◽  
Prabu Manoharan ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Oral Delivery ◽  
Leishmania Donovani ◽  
Reactive Oxygen Species Generation ◽  
Oral Route ◽  
Apoptotic Pathway ◽  
Content Type ◽  
Lead Compounds

ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects onL. donovanipromastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effectivein vitroand demonstrated strong efficaciesin vivothrough the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistantLeishmania donovanistrains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption ofLeishmaniapromastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

scholarly journals TheREnantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis

2013 ◽  
Vol 57 (10) ◽  
pp. 4699-4706 ◽  
Author(s):  
Stephen Patterson ◽  
Susan Wyllie ◽  
Laste Stojanovski ◽  
Meghan R. Perry ◽  
Frederick R. C. Simeons ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Visceral Leishmaniasis ◽  
Phase Ii ◽  
Leishmania Donovani ◽  
Oral Treatment ◽  
Parasite Burden ◽  
Content Type ◽  
Phase Ii Clinical Trials

ABSTRACTThe novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity againstMycobacterium tuberculosisin vitroandin vivoand is currently in phase II clinical trials for tuberculosis (TB). In contrast toM. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity againstLeishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although thein vitroandin vivopharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight−1, twice daily for 5 days. InM. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent inLeishmaniaspp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studiesin vitroindicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.

scholarly journals Influence of Capping Groups on the Synthesis of γ-Fe2O3 Nanocrystals

2004 ◽  
Vol 19 (4) ◽  
pp. 1208-1215 ◽  
Author(s):  
Ming Yin ◽  
Amanda Willis ◽  
Franz Redl ◽  
Nicholas J. Turro ◽  
Stephen P. O’Brien
Keyword(s):  
Self Assembly ◽  
Carbon Chain ◽  
Iron Pentacarbonyl ◽  
Decomposition Temperature ◽  
Molar Ratio ◽  
Molar Ratios ◽  
Nonpolar Solvents ◽  
Transmission Electron ◽  
Iron Precursor ◽  
Chain Lengths

Monodisperse and uniform γ-Fe2O3 (maghemite) nanocrystals of variable size were prepared by thermal decomposition of iron pentacarbonyl [Fe(CO)5] in the presence of surfactants, following controlled oxidation with trimethylamine N-oxide as a mild oxidant. The influence of carboxylic acids with variable alkyl carbon chain lengths on the synthesis of γ-Fe2O3 nanocrystals was investigated. The effect of the molar ratios of surfactant to iron precursor was also studied. The nanocrystals were characterized by x-ray diffraction (XRD) and transmission electron microscopy (TEM). XRD showed the particles were highly crystalline at the nanometer scale. The results showed that the size and shape of the nanocrystal is strongly influenced by the decomposition temperature of iron pentacarbonyl and closely related to the length of carbon chain of the capping groups and the molar ratio of surfactant to iron precursor. Following controlled evaporation from nonpolar solvents, self-assembly into two-dimensional arrays could be observed by TEM. It was also found that the distance between the nanocrystals in self-assembled structures matched the length of the capping molecules very well.

scholarly journals Efficacy of Meglumine Antimoniate in a Low Polymerization State Orally Administered in a Murine Model of Visceral Leishmaniasis

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Kelly C. Kato ◽  
Eliane de Morais-Teixeira ◽  
Arshad Islam ◽  
M. Fatima Leite ◽  
Cynthia Demicheli ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Visceral Leishmaniasis ◽  
Cell Monolayer ◽  
Peritoneal Macrophages ◽  
Hepatic Uptake ◽  
Oral Route ◽  
Cellulose Membrane ◽  
Content Type ◽  
Meglumine Antimoniate ◽  
Antileishmanial Drug

ABSTRACT Progress toward the improvement of meglumine antimoniate (MA), commercially known as Glucantime, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control of its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl5) or potassium hexahydroxyantimonate [MA-KSb(OH)6] and prepared under a low polymerization state. These compounds were compared to Glucantime regarding chemical composition, permeation properties across a cellulose membrane and Caco-2 cell monolayer, and uptake by peritoneal macrophages. MA-SbCl5 and MA-KSb(OH)6 were characterized as less polymerized and more permeative 2:2 Sb-meglumine complexes than Glucantime, which consisted of a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activities and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as a model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg of body weight/12 h for 30 days significantly reduced spleen and liver parasite burdens, in contrast to those for Glucantime at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl5 given orally was as efficacious as Glucantime by the parenteral route (80 mg Sb/kg/24 h intraperitoneally). These data taken together suggest that treatment with a less-polymerized form of MA by the oral route may be effective for the treatment of VL.

scholarly journals Characterization of Pseudomonas aeruginosa Growth onO-Acylcarnitines and Identification of a Short-Chain Acylcarnitine Hydrolase

2013 ◽  
Vol 79 (11) ◽  
pp. 3355-3363 ◽  
Author(s):  
Jamie A. Meadows ◽  
Matthew J. Wargo
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nitrogen Sources ◽  
Carbon Chain ◽  
Short Chain ◽  
Content Type ◽  
Nutrient Sources ◽  
Genomic Location ◽  
Amine Compounds ◽  
Chain Lengths ◽  
Hydrolysis Of

ABSTRACTTo survive in various environments, from host tissue to soil, opportunistic bacterial pathogens must be metabolically flexible and able to use a variety of nutrient sources. We are interested inPseudomonas aeruginosa's catabolism of quaternary amine compounds that are prevalent in association with eukaryotes. Carnitine and acylcarnitines are abundant in animal tissues, particularly skeletal muscle, and are used to shuttle fatty acids in and out of the mitochondria, where they undergo β-oxidation. We previously identified the genes required for carnitine catabolism as the first four genes in the carnitine operon (caiX-cdhCAB;PA5388toPA5385). However, the last gene in the operon,PA5384, was not required for carnitine catabolism. We were interested in determining the function of PA5384. Bioinformatic analyses along with the genomic location ofPA5384led us to hypothesize a role for PA5384 in acylcarnitine catabolism. Here, we have characterized PA5384 as anl-enantiomer-specific short-chain acylcarnitine hydrolase that is required for growth and hydrolysis of acetyl- and butyrylcarnitine to carnitine and the respective short-chain fatty acid. The liberated carnitine and its downstream catabolic product, glycine betaine, are subsequently available to function as osmoprotectants in hyperosmotic environments and induce transcription of the virulence factor phospholipase C,plcH. Furthermore, we confirmed that acylcarnitines with 2- to 16-carbon chain lengths, except for octanoylcarnitine (8 carbons), can be utilized byP. aeruginosaas sole carbon and nitrogen sources. These findings expand our knowledge of short-chain acylcarnitine catabolism and also point to remaining questions related to acylcarnitine transport and hydrolysis of medium- and long-chain acylcarnitines.

scholarly journals Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Stephen A. Wring ◽  
Ryan Randolph ◽  
SeongHee Park ◽  
George Abruzzo ◽  
Qing Chen ◽  
...  
Keyword(s):  
Oral Delivery ◽  
Oral Treatment ◽  
Kidney Tissue ◽  
Fungal Diseases ◽  
Pharmacokinetic Studies ◽  
Murine Models ◽  
Content Type ◽  
Disseminated Candidiasis ◽  
Invasive Fungal Diseases ◽  
Glucan Synthesis

ABSTRACT SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing <15% and <25% of hepatic blood flow, respectively. The terminal elimination-phase half-life was 5.5 to 8.7 h in rodents, and it was ∼9.3 h in dogs. The volume of distribution at steady-state was high (4.7 to 5.3 liters/kg), a finding suggestive of extensive tissue distribution. Exposure of SCY-078 in kidney tissue, a target organ for invasive fungal disease such as candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) and C max. SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices C max/MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC0–24, was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases.

scholarly journals The Effect of Surfactant-Modified Montmorillonite on the Cross-Linking Efficiency of Polysiloxanes

Materials ◽  
2021 ◽  
Vol 14 (10) ◽  
pp. 2623
Author(s):  
Monika Wójcik-Bania ◽  
Jakub Matusik
Keyword(s):  
Total Pore Volume ◽  
Cross Linking ◽  
X Ray Diffraction ◽  
X Ray ◽  
Transmission Electron ◽  
The Cross ◽  
Chain Lengths ◽  
First Time ◽  
Substituent Influence ◽  
Benzyl Substituent

Polymer–clay mineral composites are an important class of materials with various applications in the industry. Despite interesting properties of polysiloxanes, such matrices were rarely used in combination with clay minerals. Thus, for the first time, a systematic study was designed to investigate the cross-linking efficiency of polysiloxane networks in the presence of 2 wt % of organo-montmorillonite. Montmorillonite (Mt) was intercalated with six quaternary ammonium salts of the cation structure [(CH3)2R’NR]+, where R = C12, C14, C16, and R’ = methyl or benzyl substituent. The intercalation efficiency was examined by X-ray diffraction, CHN elemental analysis, and Fourier transform infrared (FTIR) spectroscopy. Textural studies have shown that the application of freezing in liquid nitrogen and freeze-drying after the intercalation increases the specific surface area and the total pore volume of organo-Mt. The polymer matrix was a poly(methylhydrosiloxane) cross-linked with two linear vinylsiloxanes of different siloxane chain lengths between end functional groups. X-ray diffraction and transmission electron microscopy studies have shown that the increase in d-spacing of organo-Mt and the benzyl substituent influence the degree of nanofillers’ exfoliation in the nanocomposites. The increase in the degree of organo-Mt exfoliation reduces the efficiency of hydrosilylation reaction monitored by FTIR. This was due to physical hindrance induced by exfoliated Mt particles.

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