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Molecules (Basel, Switzerland) Jul 2019This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical...
This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.
Topics: Calorimetry, Differential Scanning; Chemical Phenomena; Crystallization; Drug Stability; Kinetics; Pharmaceutical Preparations; Preservation, Biological; Solubility; Spectrum Analysis, Raman; Time Factors
PubMed: 31357587
DOI: 10.3390/molecules24152731 -
The Journal of Pharmacology and... Mar 2015Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric...
Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one-electron reduction of redox-active chemicals, including quinones and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone, and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide- and sulfonylurea-based sulfa drugs were found to be potent noncompetitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC50s = 31-180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole, and chlorpropamide. Higher concentrations of the sulfa drugs (IC50s = 0.37-19.4 μM) were required to inhibit redox cycling, presumably because of distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 μM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are "off-targets" of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity.
Topics: Alcohol Oxidoreductases; Animals; Humans; Mice; Oxidation-Reduction; PC12 Cells; Protein Structure, Secondary; Pterins; Rats; Sulfasalazine; Sulfathiazole; Sulfathiazoles
PubMed: 25550200
DOI: 10.1124/jpet.114.221572 -
Journal of Veterinary Diagnostic... Jan 2023spp., particularly , have received much attention as poultry pathogens in recent years. We report here the presence and antimicrobial resistance profile of 69 isolates...
spp., particularly , have received much attention as poultry pathogens in recent years. We report here the presence and antimicrobial resistance profile of 69 isolates obtained from 2,204 diagnostic submissions of broiler and layer chickens in 2019-2021. -positive chickens had lesions primarily in the respiratory tract, reproductive tract, and related serosal surfaces. spp. were initially identified based on their typical cultural characteristics on blood agar. The isolates were confirmed by a genus-specific PCR spanning 16S-23S rRNA and MALDI-TOF mass spectrometry. Phylogenetic analysis based on 16S rRNA gene sequence revealed distinct clades. Of the 69 isolates, 68 clustered with the reference strains of and 1 with genomospecies 1 and 2. Antimicrobial susceptibility testing of 58 of the 69 isolates by a MIC method showed variable responses to antimicrobials. The isolates were all susceptible to enrofloxacin, ceftiofur, florfenicol, and gentamicin. There was a high level of susceptibility to trimethoprim-sulfamethoxazole (98.0%), streptomycin (98.0%), amoxicillin (84.0%), sulfadimethoxine (71.0%), and neomycin (71.0%). All of the isolates were resistant to tylosin. There was resistance to penicillin (98.0%), erythromycin (95.0%), clindamycin (94.0%), novobiocin (90.0%), tetracycline (88.0%), oxytetracycline (76.0%), and sulfathiazole (53.0%). A high rate of intermediate susceptibility was observed for spectinomycin (67.0%) and sulfathiazole (40.0%). Our findings indicate a potential role of as an important poultry pathogen and cause of subsequent disease, alone or in combination with other pathogens. Continuous monitoring and an antimicrobial susceptibility assay are recommended for effective treatment and disease control.
Topics: Animals; Chickens; RNA, Ribosomal, 16S; Phylogeny; Pasteurellaceae; Anti-Bacterial Agents; Poultry Diseases; Microbial Sensitivity Tests
PubMed: 36401513
DOI: 10.1177/10406387221133782 -
Computational and Structural... 2021The current life-threatening and tenacious pandemic eruption of coronavirus disease in 2019 (COVID-19) has posed a significant global hazard concerning high mortality...
The current life-threatening and tenacious pandemic eruption of coronavirus disease in 2019 (COVID-19) has posed a significant global hazard concerning high mortality rate, economic meltdown, and everyday life distress. The rapid spread of COVID-19 demands countermeasures to combat this deadly virus. Currently, there are no drugs approved by the FDA to treat COVID-19. Therefore, discovering small molecule therapeutics for treating COVID-19 infection is essential. So far, only a few small molecule inhibitors are reported for coronaviruses. There is a need to expand the small chemical space of coronaviruses inhibitors by adding potent and selective scaffolds with anti-COVID activity. In this context, the huge antiviral chemical space already available can be analysed using cheminformatic and machine learning to unearth new scaffolds. We created three specific datasets called "antiviral dataset" (N = 38,428) "drug-like antiviral dataset" (N = 20,963) and "anticorona dataset" (N = 433) for this purpose. We analyzed the 433 molecules of "anticorona dataset" for their scaffold diversity, physicochemical distributions, principal component analysis, activity cliffs, R-group decomposition, and scaffold mapping. The scaffold diversity of the "anticorona dataset" in terms of Murcko scaffold analysis demonstrates a thorough representation of diverse chemical scaffolds. However, physicochemical descriptor analysis and principal component analysis demonstrated negligible drug-like features for the "anticorona dataset" molecules. The "antiviral dataset" and "drug-like antiviral dataset" showed low scaffold diversity as measured by the Gini coefficient. The hierarchical clustering of the "antiviral dataset" against the "anticorona dataset" demonstrated little molecular similarity. We generated a library of frequent fragments and polypharmacological ligands targeting various essential viral proteins such as main protease, helicase, papain-like protease, and replicase polyprotein 1ab. Further structural and chemical features of the "anticorona dataset" were compared with SARS-CoV-2 repurposed drugs, FDA-approved drugs, natural products, and drugs currently in clinical trials. Using machine learning tool DCA (DMax Chemistry Assistant), we converted the "anticorona dataset" into an elegant hypothesis with significant functional biological relevance. Machine learning analysis uncovered that FDA approved drugs, Tizanidine HCl, Cefazolin, Raltegravir, Azilsartan, Acalabrutinib, Luliconazole, Sitagliptin, Meloxicam (Mobic), Succinyl sulfathiazole, Fluconazole, and Pranlukast could be repurposed as effective drugs for COVID-19. Fragment-based scaffold analysis and R-group decomposition uncovered pyrrolidine and the indole molecular scaffolds as the potent fragments for designing and synthesizing the novel drug-like molecules for targeting SARS-CoV-2. This comprehensive and systematic assessment of small-molecule viral therapeutics' entire chemical space realised critical insights to potentially privileged scaffolds that could aid in enrichment and rapid discovery of efficacious antiviral drugs for COVID-19.
PubMed: 33391634
DOI: 10.1016/j.csbj.2020.12.028 -
Revista Argentina de Microbiologia 2019A novel microbiological system in microtiter plates consisting of five bioassays is presented for the detection and classification of antibiotic residues in milk. The...
A novel microbiological system in microtiter plates consisting of five bioassays is presented for the detection and classification of antibiotic residues in milk. The bioassays were optimized for the detection of beta-lactams (Bioassay B: Geobacillus stearothermophilus), macrolides (Bioassay M: Bacillus megaterium with fusidic acid), tetracyclines (Bioassay T: B. megaterium with chloramphenicol), quinolones (Bioassay Q: Bacillus licheniformis) and sulfamides (Bioassay QS: B. licheniformis with trimethoprim) at levels near the maximum residue limits (MRL). The response of each bioassay was interpreted visually (positive or negative) after 4-5.5h of incubation. The system detects and classifies beta-lactams (5μg/l of amoxicillin, 4μg/l of ampicillin, 36μg/l of cloxacillin, 22μg/l of amoxicillin, 3μg/l of penicillin, 114μg/l of cephalexin, 89μg/l of cefoperazone and 116μg/l of ceftiofur), tetracyclines (98μg/l of chlortetracycline, 92μg/l of oxytetracycline and 88μg/l of tetracycline), macrolides (33μg/l of erythromycin, 44μg/l of tilmicosin and 50μg/l of tylosin), sulfonamides (76μg/l of sulfadiazine, 85μg/l of sulfadimethoxine, 77μg/l of sulfamethoxazole and 87μg/l of sulfathiazole) and quinolones (94μg/l of ciprofloxacin, 98μg/l of enrofloxacin and 79μg/l marbofloxacin). In addition, the specificity values were high for B, T, Q (99.4%), M (98.8%) and QS (98.1%) bioassays. The control of antibiotics through this system can contribute to improving the quality and safety of dairy products.
Topics: Animals; Anti-Bacterial Agents; Biological Assay; Drug Residues; Microbiological Techniques; Milk
PubMed: 31056365
DOI: 10.1016/j.ram.2019.01.002 -
International Journal of Molecular... Dec 2022Sulfonamides used in veterinary medicine can be degraded via the Fenton processes. In the premise, the process should also remove the antimicrobial activity of...
Sulfonamides used in veterinary medicine can be degraded via the Fenton processes. In the premise, the process should also remove the antimicrobial activity of wastewater containing antibiotics. The kinetics of sulfathiazole degradation and identification of the degradation products were investigated in the experiments. In addition, their toxicity against , the MARA assay, and unselected microorganisms from a wastewater treatment plant and the river was evaluated. It was found that in the Fenton process, the sulfathiazole degradation was described by the following kinetic equation: r = k C C C C, where r is the initial reaction rate, k is the reaction rate constant, C is the concentration of sulfathiazole, Fe(II) ions, hydrogen peroxide and total organic carbon, respectively. The reaction efficiency and the useful pH range (up to pH 5) could be increased by UVa irradiation of the reaction mixture. Eighteen organic degradation products of sulfathiazole were detected and identified, and a possible degradation mechanism was proposed. An increase in the HO dose, to obtain a high degree of mineralization of sulfonamide, resulted in an increase in the ecotoxicity of the post-reaction mixture.
Topics: Iron; Hydrogen Peroxide; Anti-Bacterial Agents; Kinetics; Sulfathiazole; Ferrous Compounds; Oxidation-Reduction; Water Pollutants, Chemical
PubMed: 36555316
DOI: 10.3390/ijms232415676 -
Environmental Pollution (Barking, Essex... Jan 2021Aquatic pollution from emerging organic contaminants (EOCs) is of key environmental importance in India and globally, particularly due to concerns of antimicrobial...
Aquatic pollution from emerging organic contaminants (EOCs) is of key environmental importance in India and globally, particularly due to concerns of antimicrobial resistance, ecotoxicity and drinking water supply vulnerability. Here, using a broad screening approach, we characterize the composition and distribution of EOCs in groundwater in the Gangetic Plain around Patna (Bihar), as an exemplar of a rapidly developing urban area in northern India. A total of 73 EOCs were detected in 51 samples, typically at ng.L to low μg.L concentrations, relating to medical and veterinary, agrochemical, industrial and lifestyle usage. Concentrations were often dominated by the lifestyle chemical and artificial sweetener sucralose. Seventeen identified EOCs are flagged as priority compounds by the European Commission, World Health Organisation and/or World Organisation for Animal Health: namely, herbicides diuron and atrazine; insecticides imidacloprid, thiamethoxam, clothianidin and acetamiprid; the surfactant perfluorooctane sulfonate (and related perfluorobutane sulfonate, perfluorohexane sulfonate, perfluorooctanoic acid and perfluoropentane sulfonate); and medical/veterinary compounds sulfamethoxazole, sulfanilamide, dapson, sulfathiazole, sulfamethazine and diclofenac. The spatial distribution of EOCs varies widely, with concentrations declining with depth, consistent with a strong dominant vertical flow control. Groundwater EOC concentrations in Patna were found to peak within ∼10 km distance from the River Ganges, indicating mainly urban inputs with some local pollution hotspots. A heterogeneous relationship between EOCs and population density likely reflects confounding factors including varying input types and controls (e.g. spatial, temporal), wastewater treatment infrastructure and groundwater abstraction. Strong seasonal agreement in EOC concentrations was observed. Co-existence of limited transformation products with associated parent compounds indicate active microbial degradation processes. This study characterizes key controls on the distribution of groundwater EOCs across the urban to rural transition near Patna, as a rapidly developing Indian city, and contributes to the wider understanding of the vulnerability of shallow groundwater to surface-derived contamination in similar environments.
Topics: Animals; Cities; Environmental Monitoring; Groundwater; India; Life Style; Water Pollutants, Chemical
PubMed: 33038633
DOI: 10.1016/j.envpol.2020.115765 -
Chemistry Central Journal 2015Structural systematics is the comparison of sets of chemically related crystal structures with the aim to establish and describe relevant similarities and relationships....
BACKGROUND
Structural systematics is the comparison of sets of chemically related crystal structures with the aim to establish and describe relevant similarities and relationships. An important topic in this context is the comparison of hydrogen-bonded structures (HBSs) and their representation by suitable descriptors.
RESULTS
Three different description methods for HBSs are proposed, a graphical representation, a symbolic representation and connectivity tables. The most comprehensive description is provided by a modified graph of the underlying net topology of an HBS which contains information on the multiplicity of links, the directionality and chemical connectivity of hydrogen bonds and on symmetry relations. By contrast, the alternative symbolic representation is restricted to essential properties of an HBS, i.e. its dimensionality, topology type and selected connectivity characteristics of nodes. A comparison of their connectivity tables readily identifies differences and similarities between crystal structures with respect to the intermolecular interaction modes adopted by their functional groups. The application of these methods to the known polymorphs of sulfathiazole and sulfapyridine is demonstrated and it is shown that they enable the rationalisation of previously reported and intricate relationships.
CONCLUSIONS
The proposed methods facilitate the comprehensive description of the most important relevant aspects of an HBS, including its chemical connectivity, net topology and symmetry characteristics, and they represent a new way to recognise similarities and relationships in organic crystal structures. Graphical AbstractGraphical Representation of mixing of structures StzIV and StzV to give structure StzIII.
PubMed: 25649693
DOI: 10.1186/s13065-014-0076-x -
Irish Veterinary Journal 2018is an opportunistic pathogen of intensively reared poultry causing oophoritis, salpingitis, peritonitis and enteritis. infection often remains undiagnosed. Recently...
BACKGROUND
is an opportunistic pathogen of intensively reared poultry causing oophoritis, salpingitis, peritonitis and enteritis. infection often remains undiagnosed. Recently multi-drug resistant isolates have been described.
METHODS
A newly developed PCR restriction fragment length polymorphism assay targeting the 16S rRNA gene was used to identify and differentiate isolates from chicken, turkey and partridge samples originating from 18 different geographical locations in Thuringia, Germany. Antimicrobial susceptibility to 19 compounds of different classes was assessed.
RESULTS
Nineteen isolates were investigated. In 9 birds (47.4%) species were isolated exclusively while in 10 birds (52.6%) other bacterial or viral agents could be detected in addition. In one chicken a mixed infection of and genomospecies was identified. All isolates were susceptible to apramycin, florfenicol and neomycin and resistant to clindamycin, sulfathiazole and penicillin. Resistance to sulfamethoxim, spectinomycin, tylosin and oxytetracycline was observed in 93.3%, 93.3%, 86.7% and 80.0% of the field strains, respectively.
CONCLUSIONS
The PCR-RFLP assay allows specific detection and differentiation of spp. from poultry. Antimicrobial resistance of spp. is highly significant in Thuringian field isolates.
PubMed: 29441195
DOI: 10.1186/s13620-018-0116-2 -
Molecules (Basel, Switzerland) May 2017Secondary sulfonamides (-) incorporating acetoxybenzamide, triacetoxybenzamide, hydroxybenzamide, and trihydroxybenzamide and possessing thiazole, pyrimidine, pyridine,...
Secondary sulfonamides (-) incorporating acetoxybenzamide, triacetoxybenzamide, hydroxybenzamide, and trihydroxybenzamide and possessing thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups were synthesized. Lactoperoxidase (LPO, E.C.1.11.1.7), as a natural antibacterial agent, is a peroxidase enzyme secreted from salivary, mammary, and other mucosal glands. In the present study, the in vitro inhibitory effects of some secondary sulfonamide derivatives (-) were examined against LPO. The obtained results reveal that secondary sulfonamide derivatives (-) are effective LPO inhibitors. The K values of secondary sulfonamide derivatives (-) were found in the range of 1.096 × 10 to 1203.83 µM against LPO. However, the most effective inhibition was found for -(sulfathiazole)-3,4,5-triacetoxybenzamide (), with K values of 1.096 × 10 ± 0.471 × 10 µM as non-competitive inhibition.
Topics: Anti-Bacterial Agents; Enzyme Inhibitors; Isoxazoles; Lactoperoxidase; Pyridines; Pyrimidines; Sulfonamides; Thiadiazoles
PubMed: 28538675
DOI: 10.3390/molecules22060793