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American Journal of Veterinary Research Nov 2023To elucidate the cardiovascular effects of escalating doses of phenylephrine and norepinephrine in dogs receiving acepromazine and isoflurane.
OBJECTIVE
To elucidate the cardiovascular effects of escalating doses of phenylephrine and norepinephrine in dogs receiving acepromazine and isoflurane.
ANIMALS
8 beagles aged 1 to 2 years (7.4 to 11.2 kg).
METHODS
All dogs received acepromazine 0.01 mg/kg, propofol 4 to 5 mg/kg, and isoflurane and were mechanically ventilated. Mean arterial pressure (MAP) from a femoral artery catheter and continuous electrocardiogram were recorded. Cardiac output (CO) was measured with transpulmonary thermodilution. Systemic vascular resistance (SVR), global end-diastolic volume (GEDV), and global ejection fraction (GEF) were subsequently calculated. Phenylephrine and norepinephrine were infused in random order at 0.07, 0.3, 0.7, and 1.0 μg/kg/min. All variables were measured after 15 minutes of each infusion rate. The effects of dose, agent, and their interaction on the change of each variable were evaluated with mixed-effect models. A P < .05 was used for significance.
RESULTS
Atrial premature complexes occurred in 3 dogs during norepinephrine infusion at doses of 0.3, 0.7, and 1 μg/kg/min; no dysrhythmias were seen with phenylephrine administration. MAP increased during dose escalation (P < .0001) within each agent and did not differ between agents (P = .6). The decrease in HR was greater for phenylephrine (P < .0001). Phenylephrine decreased CO and GEF and increased GEDV and SVR (all P < .03). Norepinephrine decreased the SVR and increased CO, GEDV, and GEF (all P < .03).
CLINICAL RELEVANCE
Our results confirm that phenylephrine increases arterial pressures mainly through vasoconstriction in acepromazine-premedicated dogs while norepinephrine, historically considered a vasopressor, does so primarily through an increase in inotropism.
Topics: Animals; Dogs; Acepromazine; Isoflurane; Norepinephrine; Phenylephrine; Blood Pressure
PubMed: 37657733
DOI: 10.2460/ajvr.23.06.0147 -
Microbiology Spectrum Aug 2023Infections by pathogenic Acinetobacter species represent a significant burden on the health care system, despite their relative rarity, due to the difficulty of treating...
Infections by pathogenic Acinetobacter species represent a significant burden on the health care system, despite their relative rarity, due to the difficulty of treating infections through oral antibiotics. Multidrug resistance is commonly observed in clinical Acinetobacter infections and multiple molecular mechanisms have been identified for this resistance, including multidrug efflux pumps, carbapenemase enzymes, and the formation of bacterial biofilm in persistent infections. Phenothiazine compounds have been identified as a potential inhibitor of type IV pilus production in multiple Gram-negative bacterial species. Here, we report the ability of two phenothiazines to inhibit type IV pilus-dependent surface (twitching) motility and biofilm formation in multiple Acinetobacter species. Biofilm formation was inhibited in both static and continuous flow models at micromolar concentrations without significant cytotoxicity, suggesting that type IV pilus biogenesis was the primary molecular target for these compounds. These results suggest that phenothiazines may be useful lead compounds for the development of biofilm dispersal agents against Gram-negative bacterial infections. Acinetobacter infections are a growing burden on health care systems worldwide due to increasing antimicrobial resistance through multiple mechanisms. Biofilm formation is an established mechanism of antimicrobial resistance, and its inhibition has the potential to potentiate the use of existing drugs against pathogenic Acinetobacter. Additionally, as discussed in the manuscript, anti-biofilm activity by phenothiazines has the potential to help to explain their known activity against other bacteria, including Staphylococcus aureus and Mycobacterium tuberculosis.
Topics: Humans; Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Biofilms; Phenothiazines; Bacteria; Drug Resistance, Multiple, Bacterial
PubMed: 37341603
DOI: 10.1128/spectrum.01023-23 -
Analytical and Bioanalytical Chemistry Jul 2023For industrial processes, a fast, precise, and reliable method of determining the physiological state of yeast cells, especially viability, is essential. However, an...
For industrial processes, a fast, precise, and reliable method of determining the physiological state of yeast cells, especially viability, is essential. However, an increasing number of processes use magnetic nanoparticles (MNPs) for yeast cell manipulation, but their impact on yeast cell viability and the assay itself is unclear. This study tested the viability of Saccharomyces pastorianus ssp. carlsbergensis and Pichia pastoris by comparing traditional colourimetric, high-throughput, and growth assays with membrane fluidity. Results showed that methylene blue staining is only reliable for S. pastorianus cells with good viability, being erroneous in low viability (R = 0.945; [Formula: see text] = 5.78%). In comparison, the fluorescence microscopy-based assay of S. pastorianus demonstrated a coefficient of determination of R = 0.991 at [Formula: see text] ([Formula: see text] = 2.50%) and flow cytometric viability determination using carboxyfluorescein diacetate (CFDA), enabling high-throughput analysis of representative cell numbers; R = 0.972 ([Formula: see text]; [Formula: see text] = 3.89%). Membrane fluidity resulted in a non-linear relationship with the viability of the yeast cells ([Formula: see text]). We also determined similar results using P. pastoris yeast. In addition, we demonstrated that MNPs affected methylene blue staining by overestimating viability. The random forest model has been shown to be a precise method for classifying nanoparticles and yeast cells and viability differentiation in flow cytometry by using CFDA. Moreover, CFDA and membrane fluidity revealed precise results for both yeasts, also in the presence of nanoparticles, enabling fast and reliable determination of viability in many experiments using MNPs for yeast cell manipulation or separation.
Topics: Saccharomyces cerevisiae; Cell Survival; Methylene Blue; Pharmaceutical Preparations
PubMed: 37083758
DOI: 10.1007/s00216-023-04676-w -
Acta Parasitologica Mar 2024Leishmaniasis is a neglected disease with high prevalence and incidence in tropical and subtropical areas. Existing drugs are limited due to cost, toxicity, declining...
INTRODUCTION
Leishmaniasis is a neglected disease with high prevalence and incidence in tropical and subtropical areas. Existing drugs are limited due to cost, toxicity, declining efficacy and unavailability in endemic places. Drug repurposing has established as an efficient way for the discovery of drugs for a variety of diseases.
PURPOSE
The objective of the present work was testing the antileishmanial activity of thioridazine, an antipsychotic agent with demonstrated effect against other intracellular pathogens.
METHODS
The cytotoxicity for mouse peritoneal macrophages as well as the activity against Leishmania amazonensis, Leishmania mexicana and Leishmania major promastigotes and intracellular amastigotes, as well as in a mouse model of cutaneous leishmaniasis, were assessed.
RESULTS
Thioridazine inhibited the in vitro proliferation of promastigotes (50% inhibitory concentration-IC-values in the range of 0.73 µM to 3.8 µM against L. amazonensis, L. mexicana and L. major) and intracellular amastigotes (IC values of 1.27 µM to 4.4 µM for the same species). In contrast, in mouse peritoneal macrophages, the 50% cytotoxic concentration was 24.0 ± 1.89 µM. Thioridazine inhibited the growth of cutaneous lesions and reduced the number of parasites in the infected tissue of mice. The dose of thioridazine that inhibited lesion development by 50% compared to controls was 23.3 ± 3.1 mg/kg and in terms of parasite load, it was 11.1 ± 0.97 mg/kg.
CONCLUSIONS
Thioridazine was effective against the promastigote and intracellular amastigote stages of three Leishmania species and in a mouse model of cutaneous leishmaniasis, supporting the potential repurposing of this drug as an antileishmanial agent.
Topics: Animals; Thioridazine; Mice; Antiprotozoal Agents; Macrophages, Peritoneal; Leishmaniasis, Cutaneous; Leishmania; Mice, Inbred BALB C; Female; Inhibitory Concentration 50; Disease Models, Animal; Leishmania mexicana; Drug Repositioning; Leishmania major
PubMed: 38070122
DOI: 10.1007/s11686-023-00746-2 -
Photodiagnosis and Photodynamic Therapy Apr 2024The aim was to systematically review clinical studies that investigated the efficacy of antimicrobial photodynamic therapy (aPDT) in reducing oral yeasts growth (OYG) in... (Review)
Review
OBJECTIVE
The aim was to systematically review clinical studies that investigated the efficacy of antimicrobial photodynamic therapy (aPDT) in reducing oral yeasts growth (OYG) in individuals wearing implant overdentures (IO).
METHODS
The focused question was "Is aPDT effective in reducing OYG in patients wearing IO?" Literature search was performed in accordance with PRISMA guidelines. Indexed databases were searched without time and language restrictions up to and including January 2024. Clinical studies were included; and letters to the Editor, case-reports/case-series, perspectives/commentaries, in-vitro/ex-vivo studies, studies on animal models and expert opinions were excluded. The risk of bias was also assessed.
RESULTS
Two clinical studies were included and processed for data extraction. The study population comprised of 100 (mean age: 58.5 years) and 53 (mean age: 58.5 years) individuals. The numbers of males and females included in these studies ranged between 33 and 35 males and 18-67 females, respectively. In both studies, follow-up evaluations were performed after 60 days. In both studies, aPDT was performed using a 660 nm diode laser at a power of 100 mW and using methylene-blue as photosensitizer. Results from both studies showed that aPDT is effective in significantly reducing oral yeasts CFU/ml and improvement of OHRQoL of individuals using IO.
CONCLUSION
The aPDT is useful in reducing OYG on IO; however, further well-designed and power-adjusted studies are needed in this area of research.
Topics: Photochemotherapy; Humans; Photosensitizing Agents; Denture, Overlay; Methylene Blue; Lasers, Semiconductor; Yeasts; Clinical Trials as Topic
PubMed: 38548040
DOI: 10.1016/j.pdpdt.2024.104050 -
PeerJ 2024To study the efficacy of PAD Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model.
OBJECTIVE
To study the efficacy of PAD Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model.
METHODS
The diabetic rat DS model was developed by randomly selecting 2-month-old male Sprague-Dawley rats and dividing them into four groups. The palate and denture surfaces of rats in the PAD groups were incubated with 1 mg/mL toluidine blue O for 1 min each, followed by a 1-min exposure to 750-mW light-emitting diode light. The PAD-1 group received one radiation treatment, and the PAD-2 group received three radiation treatments over 5 days with a 1-day interval. The nystatin (NYS) group received treatment for 5 days with a suspension of NYS of 100,000 IU. The infection group did not receive any treatment. In each group, assessments included an inflammation score of the palate, tests for fungal load, histological evaluation, and immunohistochemical detection of interleukin-17 (IL-17) and tumor necrosis factor (TNF-α) conducted 1 and 7 days following the conclusion of treatment.
RESULTS
One day after treatment, the fungal load on the palate and dentures, as well as the mean optical density values of IL-17 and TNF-α, were found to be greater in the infection group than in the other three treatment groups ( < 0.05). On the 7th day after treatment, these values were significantly higher in the infection group than in the PAD-2 and NYS groups ( < 0.05). Importantly, there were no differences between the infection and PAD-1 groups nor between the PAD-2 and NYS groups ( 0.05).
CONCLUSIONS
PAD effectively reduced the fungal load and the expressions of IL-17 and TNF-α in the palate and denture of diabetic DS rats. The efficacy of multiple-light treatments was superior to that of single-light treatments and similar to that of NYS.
Topics: Animals; Male; Rats, Sprague-Dawley; Rats; Stomatitis, Denture; Disinfection; Diabetes Mellitus, Experimental; Tolonium Chloride; Tumor Necrosis Factor-alpha; Interleukin-17; Disease Models, Animal
PubMed: 38708351
DOI: 10.7717/peerj.17268 -
The Pan African Medical Journal 2023due to the widespread prescription of antipsychotic medications, their usage is cumulative. Evidence on the trends of medication use in Ethiopia and other parts of the...
INTRODUCTION
due to the widespread prescription of antipsychotic medications, their usage is cumulative. Evidence on the trends of medication use in Ethiopia and other parts of the world is lacking. The scant information on prescription trends and medication usage suggests that drug use is generally not sensible in both industrialized and emerging nations. So, the aim of this study was to assess the psychotropic medications prescribing pattern in Gebretsadik Shawo General Hospital, South West Ethiopia.
METHODS
from June 1 to July 31, 2019, a cross-sectional study on prescriptions for psychiatric drugs was conducted at Gebretsadik Shawo General Hospital. Using systematic random sampling, prescription records were obtained from the pharmacy dispensing book. Version 21 of the statistical program for social science was used to code and analyze the data.
RESULTS
the study included 355 prescription records containing psychotropic drugs in total. The bulk of those taking the psychotropic medication were aged 20 to 49. The most often administered classes of drugs remained antipsychotic, followed by tricyclic antidepressants, antiepileptics, anxiolytics/sedatives, anticholinergic and selective serotonin reuptake inhibitors. The most often ordered antipsychotic medication, which included 102 (23.18%) medications, was chlorpromazine. Tricyclic antidepressants, which included 56 medicines (12.73%) and 24 medications (5.45%), included amitriptyline and imipramine.
CONCLUSION
the results of this investigation showed that psychiatrists preferred traditional psychotropic medications, such as Antipsychotic tricyclic, antidepressants (TCAs) and phenothiazines, in high amounts possibly because these medications were readily available in this hospital and their prices suited patients' needs. Health care workers' interdisciplinary relationships and coherence would improve for the benefit of patients and services of higher quality.
Topics: Humans; Antipsychotic Agents; Antidepressive Agents, Tricyclic; Hospitals, General; Cross-Sectional Studies; Ethiopia; Drug Prescriptions; Psychotropic Drugs
PubMed: 37900209
DOI: 10.11604/pamj.2023.45.165.30374 -
Viruses Dec 2023Coronaviruses (CoVs) belong to the group of enveloped positive-sense single-strand RNA viruses and are causative agents of respiratory, gastro-intestinal, and central...
Coronaviruses (CoVs) belong to the group of enveloped positive-sense single-strand RNA viruses and are causative agents of respiratory, gastro-intestinal, and central nervous systems diseases in many host species, i.e., birds, mammals, and humans. Beta-CoVs revealed a great potential to cross the barrier between species by causing three epidemics/pandemics among humans in the 21st century. Considering the urgent need for powerful antiviral agents for decontamination, prevention, and treatment of BCoV infections, we turned our attention to the possibility of photodynamic inactivation with photosensitizers in combination with light irradiation. In the present study, we evaluated, for the first time, the antiviral activity of toluidine blue O (TBO) against Beta-coronavirus 1 (BCoV) in comparison to methylene blue (MB). First, we determined the in vitro cytotoxicity of MB and TBO on the Madin-Darby bovine kidney (MDBK) cell line with ISO10993-5/Annex C. Thereafter, BCoV was propagated in MDBK cells, and the virus titer was measured with digital droplet PCR, TCID assay and plaque assay. The antiviral activity of non-toxic concentrations of TBO was estimated using the direct inactivation approach. All effects were calculated in MAPLE 15 mathematical software by developing programs for non-linear modeling and response surface analysis. The median inhibitory concentration () of TBO after 72 h of incubation in MDBK cells was 0.85 µM. The antiviral activity of TBO after the direct inactivation of BCoV ( = 1) was significantly stronger than that of MB. The median effective concentration (EC) of TBO was 0.005 µM. The cytopathic effect decreased in a concentration-dependent manner, from 0.0025 to 0.01 µM, and disappeared fully at concentrations between 0.02 and 0.3 µM of TBO. The number of virus particles also decreased, depending on the concentration applied, as proven by ddPCR analysis. In conclusion, TBO exhibits significant potential for direct inactivation of BCoV in vitro, with a very high selectivity index, and should be subjected to further investigation, aiming at its application in veterinary and/or human medical practice.
Topics: Humans; Cattle; Animals; Coronavirus, Bovine; Photosensitizing Agents; Tolonium Chloride; Coronavirus; Coronavirus Infections; Methylene Blue; Pandemics; Antiviral Agents; Mammals
PubMed: 38257748
DOI: 10.3390/v16010048 -
European Journal of Pharmaceutical... Dec 2023Aldehyde oxidase (AOX) is a cytosolic drug-metabolizing enzyme which has attracted increasing attention in drug development due to its high hepatic expression, broad...
Aldehyde oxidase (AOX) is a cytosolic drug-metabolizing enzyme which has attracted increasing attention in drug development due to its high hepatic expression, broad substrate profile and species differences. In contrast, there is limited information on the presence and activity of AOX in extrahepatic tissues including ocular tissues. Because several ocular drugs are potential substrates for AOX, we performed a comprehensive analysis of the AOX1 expression and activity profile in seven ocular tissues from humans, rabbits, and pigs. AOX activities were determined using optimized assays for the established human AOX1 probe substrates 4-dimethylamino-cinnamaldehyde (DMAC) and phthalazine. Inhibition studies were undertaken in conjunctival and retinal homogenates using well-established human AOX1 inhibitors menadione and chlorpromazine. AOX1 protein contents were quantitated with targeted proteomics and confirmed by immunoblotting. Overall, DMAC oxidation rates varied over 10-fold between species (human ˃˃ rabbit ˃ pig) and showed 2- to 6-fold differences between tissues from the same species. Menadione seemed a more potent inhibitor of DMAC oxidation across species than chlorpromazine. Human AOX1 protein levels were highest in the conjunctiva, followed by most posterior tissues, whereas anterior tissues showed low levels. The rabbit AOX1 expression was high in the conjunctiva, retinal pigment epithelial (RPE), and choroid while lower in the anterior tissues. Quantification of pig AOX1 was not successful but immunoblotting confirmed the presence of AOX1 in all species. DMAC oxidation rates and AOX1 contents correlated quite well in humans and rabbits. This study provides, for the first time, insights into the ocular expression and activity of AOX1 among multiple species.
Topics: Humans; Rabbits; Animals; Swine; Aldehyde Oxidase; Vitamin K 3; Chlorpromazine; Oxidation-Reduction; Liver
PubMed: 37827455
DOI: 10.1016/j.ejps.2023.106603 -
Molecules (Basel, Switzerland) Nov 2023Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-,...
Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC and the selectivity index SI. The most active derivative, , showed an IC activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential.
Topics: Antineoplastic Agents; Magnetic Resonance Spectroscopy; Drug Screening Assays, Antitumor; Cell Proliferation; Molecular Structure; Structure-Activity Relationship
PubMed: 38005384
DOI: 10.3390/molecules28227662