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1.
Exp Parasitol ; 218: 108008, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32979343

RESUMO

Acanthamoeba sp. is a free living amoeba that causes severe, painful and fatal infections, viz. Acanthamoeba keratitis and granulomatous amoebic encephalitis among humans. Antimicrobial chemotherapy used against Acanthamoeba is toxic to human cells and show side effects as well. Infections due to Acanthamoeba also pose challenges towards currently used antimicrobial treatment including resistance and transformation of trophozoites to resistant cyst forms that can lead to recurrence of infection. Therapeutic agents targeting central nervous system infections caused by Acanthamoeba should be able to cross blood-brain barrier. Nanoparticles based drug delivery put forth an effective therapeutic method to overcome the limitations of currently used antimicrobial chemotherapy. In recent years, various researchers investigated the effectiveness of nanoparticles conjugated drug and/or naturally occurring plant compounds against both trophozoites and cyst form of Acanthamoeba. In the current review, a reasonable effort has been made to provide a comprehensive overview of various nanoparticles tested for their efficacy against Acanthamoeba. This review summarizes the noteworthy details of research performed to elucidate the effect of nanoparticles conjugated drugs against Acanthamoeba.


Assuntos
Acanthamoeba/efeitos dos fármacos , Amebicidas/administração & dosagem , Nanopartículas/administração & dosagem , Acanthamoeba/crescimento & desenvolvimento , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Amebíase/tratamento farmacológico , Amebíase/mortalidade , Amebíase/parasitologia , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/mortalidade , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Clorexidina/administração & dosagem , Clorexidina/farmacologia , Clorexidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Imunocompetência , Hospedeiro Imunocomprometido , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/mortalidade , Encefalite Infecciosa/parasitologia , Nanopartículas/classificação , Nanopartículas/uso terapêutico , Trofozoítos/efeitos dos fármacos
3.
Am J Surg ; 220(4): 1076-1082, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32139102

RESUMO

AIM: To compare the efficacy of Negative Pressure Wound Therapy (NPWT) with and without irrigation with 0.1% polyhexanide-betaine. METHODS: We randomized 150 subjects in a 16-week RCT to compare healing in patients with diabetic foot infections. NPWT delivered at 125 mm Hg continuous pressure. NPWT-I were administered at 30 cc per hour. RESULTS: There were no differences clinical treatment or outcomes: wound area after surgery (18.5 ± 19.0 vs. 13.4 ± 11.1 cm2, p = 0.50), duration of antibiotics (39.7 ± 21.0 vs. 38.0 ± 24.6 days, p = 0.40), number of surgeries (2.3 ± 0.67 vs. 2.2 ± 0.59, p = 0.85), duration of NPWT (148.1 ± 170.4 vs. 114.5 ± 135.1 h, p = 0.06), healed wounds (58.7% vs. 60.0%, p = 0.86), time to healing (56.3 ± 31.7 vs. 50.7 ± 27.8, p = 0.53), length of stay (13.8 ± 6.4 vs. 14.5 ± 11.2 days, p = 0.42), re-infection (20.0% vs. 22.7%, p = 0.69, and re-hospitalization (17.3% vs. 18.7, p = 0.83). CONCLUSIONS: The addition of irrigation to NPWT did not change clinical outcomes in patients with diabetic foot infections. CLINICAL TRIAL NUMBER: NCT02463487, ClinicalTrials.gov.


Assuntos
Biguanidas/administração & dosagem , Pé Diabético/terapia , Tratamento de Ferimentos com Pressão Negativa/métodos , Irrigação Terapêutica/métodos , Cicatrização , Administração Tópica , Adulto , Desinfetantes/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
4.
Cornea ; 39(2): 245-249, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31724982

RESUMO

PURPOSE: The aim of this study was to reduce the cytotoxicity and improve the amoebicidal effect of polyhexamethylene biguanide (PHMB) at low concentrations by combining it with histone deacetylase (HDAC) inhibitors. METHODS: To reduce the cytotoxic effect on human corneal epithelial (HCE) cells, the concentration of PHMB was reduced to 0.0002%. To enhance the amoebicidal effect of PHMB, HDAC inhibitors such as suberoylanilide hydroxamic acid, MS275, or MC1568 were combined with it. Acanthamoeba and HCE cells were treated with 3 combinations to evaluate the amoebicidal and cytotoxic effects. Microscopy and fluorescence-activated cell sorting analysis were performed to investigate the apoptotic cell death of Acanthamoeba by these combinatorial treatments. RESULTS: The low concentration of PHMB (0.0002%) alone demonstrated no cytopathic effects (CPEs) on HCE cells. Three combinatorial treatments using 0.0002% PHMB with 10 µM suberoylanilide hydroxamic acid, 10 µM MS275, or 10 µM MC1568 showed higher amoebicidal effects on A. castellanii trophozoites than PHMB alone. Fluorescence-activated cell sorting analysis confirmed that HDAC inhibitors increased the apoptotic cell death of Acanthamoeba. Mild CPEs were observed from HCE cells cotreated with PHMB and the HDAC inhibitors after 24 hours of exposure. CONCLUSIONS: Combinatorial treatments showed high amoebicidal effects on Acanthamoeba and low CPEs on HCE cells, which suggests their potential application for Acanthamoeba keratitis treatment.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Biguanidas/farmacologia , Desinfetantes/farmacologia , Epitélio Anterior/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Acanthamoeba castellanii/metabolismo , Anexina A5/metabolismo , Benzamidas/farmacologia , Biguanidas/administração & dosagem , Células Cultivadas , Desinfetantes/administração & dosagem , Sinergismo Farmacológico , Epitélio Anterior/metabolismo , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Humanos , Ácidos Hidroxâmicos/farmacologia , Microscopia de Fluorescência , Piridinas/farmacologia , Pirróis/farmacologia , Vorinostat/farmacologia
5.
Ann Surg ; 272(1): 55-64, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31599810

RESUMO

OBJECTIVE: To evaluate whether intraoperative subcutaneous wound irrigation with 0.04% polyhexanide can reduce surgical site infection (SSI) in elective laparotomies compared to saline. BACKGROUND: SSI is a common complication after gastrointestinal surgery. To date, there is a lack of evidence whether subcutaneous wound irrigation is beneficial in terms of reduction of SSI. METHODS: The RECIPE trial was an investigator initiated single-center, single-blind prospective, randomized controlled trial with 2 parallel treatment groups, comparing wound irrigation with 0.9% saline to antiseptic 0.04% polyhexanide solution in elective laparotomies. Primary endpoint was the rate of SSI within 30 days postoperatively according to Centers for Disease Control and Prevention criteria. RESULTS: Between February 02, 2015, and May 23, 2018, 456 patients were randomly assigned to saline (n = 228) or polyhexanide (n = 228). Final cohort for analysis comprised 393 patients (202 in the saline and 191 in the polyhexanide group). Overall rate of SSI was 28.2%, n = 111. Simple analysis with cross tabulation revealed that significantly fewer SSIs occurred in the polyhexanide group: n = 70 (34.7%) versus n = 41 (21.5%); P = 0.004. In a multiple logistic regression model the factor wound irrigation with polyhexanide [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.27-0.72; P = 0.001) was associated with risk reduction of SSI. Preoperative anemia (OR 2.08; 95% CI 1.27-3.40; P = 0.004) and more than 5 prior abdominal operations compared to none (OR 8.51; 95% CI 2.57-28.21; P < 0.001) were associated with SSI. CONCLUSIONS: Intraoperative subcutaneous wound irrigation with antiseptic 0.04% polyhexanide solution is effective in reducing SSI after elective laparotomies.


Assuntos
Biguanidas/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório , Desinfetantes/administração & dosagem , Laparotomia , Infecção da Ferida Cirúrgica/prevenção & controle , Irrigação Terapêutica/métodos , Feminino , Humanos , Cuidados Intraoperatórios , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória , Satisfação do Paciente , Estudos Prospectivos , Método Simples-Cego , Cloreto de Sódio/administração & dosagem
6.
Ther Apher Dial ; 24(1): 81-84, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31066988

RESUMO

Topical antibiotic and antiseptic agents have been documented to reduce exit-site infection (ESI) and peritonitis in PD. The aim of this randomized controlled study was to evaluate the efficacy of polyhexanide in the prevention of ESI and peritonitis. Patients were excluded if they had active infection, > 18 years of age, ESI and peritonitis within the previous 4 weeks, received PD for less than 3-months and history of allergy to either drug. All patients were followed up until catheter removal, death, switch to dialysis, transplantation or the end of the study. ESI, tunnel infection, peritonitis, catheter removal and microorganism cause of catheter-related infection were recorded prospectively during clinic follow-up. A total of 88 patients (41 povidone-iodine group; 47 polyhexanide group) were enrolled with a total follow-up duration of 480 and 555 patient-months for povidone-iodine and alternating group, respectively. There were no significant differences in the age, sex, BMI, time of PD, rate of DM, and S. aureus carriage state. A total of 8 ESI and 25 peritonitis episodes were detected during the study. ESI and peritonitis rates tended to be lower in polyhexanide group compared with the povidone-iodine group (0.06 episodes/patient-year vs. 0.12 episodes/patient-year; 0.26 episodes/patient-year vs. 0.32 episodes/patient-year, respectively), but were not significant statistically. Moreover, catheter removal was similar in both groups (0.04 / patient-year vs. 0.05 / patient-year). Polyhexanide is efficient and safe for the prevention of ESI and peritonitis and it may be used as an alternative procedure for the care of healthy exit sites.


Assuntos
Biguanidas/administração & dosagem , Infecções Relacionadas a Cateter/prevenção & controle , Peritonite/prevenção & controle , Povidona-Iodo/administração & dosagem , Adulto , Anti-Infecciosos Locais/administração & dosagem , Remoção de Dispositivo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/efeitos adversos , Diálise Peritoneal/métodos , Peritonite/etiologia , Estudos Prospectivos
7.
Yakugaku Zasshi ; 139(12): 1569-1581, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787647

RESUMO

To investigate medication adherence to oral antihyperglycemic agents and its associated factors in Japanese type 2 diabetic patients, a questionnaire survey was conducted in 983 adult patients receiving once-daily (QD) or twice-daily (BID) dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitor) or BID biguanides (BG) as monotherapy at 502 pharmacies in Japan. The percentage of patients with good adherence (the proportion of days in which patients took all pills as prescribed in the past 7 days ≥80%) was high (≥90%) in any dosing regimen with no significant difference among the groups. The following factors were identified as associating with good adherence: the longer duration of type 2 diabetes (≥1 year) (p=0.002), "Feeling your disease gets worse if you don't take medications" (p=0.031), "Not forgetting to bring along your medicine when you leave home" (p=0.007), "Feeling anxiety on taking medications for long period of time" (p=0.042), "Neither feeling nor not feeling anxiety on taking medications for a long period of time" (p=0.004), "Never run out of your medicine because you get a refill on time" (p=0.035), and the lower MMAS-4 score (p<0.001). Subgroup analyses revealed that adherence of younger patients (<65 years) with BG (BID) was lower than those with DPP-4 inhibitor (QD) (p=0.021). Additionally, around 60% of patients currently prescribed with QD preferred QD regimen, and ≥80% patients prescribed with BID equally preferred once-weekly or QD regimen, suggesting a large discrepancy exists between their preference and the actual regimen in patients on BID.


Assuntos
Biguanidas/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hipoglicemiantes/administração & dosagem , Adesão à Medicação , Administração Oral , Adulto , Idoso , Ansiedade , Feminino , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto Jovem
8.
Khirurgiia (Mosk) ; (7): 63-70, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31355817

RESUMO

AIM: Structural and functional analysis of cells from purulent-necrotic wounds in patients with diabetic foot syndrome undergoing ultrasonic treatment with 0.2% Lavasept solution. MATERIAL AND METHODS: It is presented morphological/ultrastructural analysis of wound specimens in 90 (DFS) patients aged 27-80 years with diabetic foot syndrome and purulent-necrotic complications who were hospitalized in the department of wounds and wound infections of the Vishnevsky Institute of Surgery in 2013-2016. Main group consisted of 75 patients, control group - 15 patients. Mean age was 58.4±8.2 years. All patients had diabetes mellitus type II for previous 13±4.5 years. Severity of foot tissue damage was assessed according to Wagner classification (F. Wagner, 1981). 46 (51.1%) patients had Wagner III-IV, 44 (48.9%) patients - Wagner II. Complex treatment included radical surgical management of purulent lesion, surgical revascularization for critical limb ischemia and foot reconstruction at the final stage. Additional measures were complete unloading of the foot, correction of carbohydrate metabolism and concomitant diseases. Topical treatment between surgical stages included dressing with 1.0% betadine solution (once a day). Ultrasonic cavitation was additionally applied in the main group. Electron microscopic examination of specimens was used before treatment, after 3-5 and 7-10 days in order to assess effectiveness of ultrasound cavitation for purulent-necrotic complications of DFS. RESULTS: Ultrasound cavitation with 0.2% Lavasept solution effectively cleans wounds from microbial and cellular detritus, destroys cellular membranes of biofilm-forming microorganisms, prevents their redo development and reinfection of the wound. Effective management of the wounds accelerates reparative processes that allows to perform foot reconstruction early.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Biguanidas/administração & dosagem , Pé Diabético/cirurgia , Necrose/cirurgia , Procedimentos Cirúrgicos Ultrassônicos , Administração Tópica , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Pé Diabético/tratamento farmacológico , Pé Diabético/patologia , Humanos , Pessoa de Meia-Idade , Necrose/tratamento farmacológico , Necrose/patologia , Soluções/administração & dosagem
9.
FASEB J ; 33(10): 10731-10741, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31251077

RESUMO

Prenatal nicotinic exposure (PNE) reportedly sensitizes bronchopulmonary C-fibers (PCFs) and prolongs PCF-mediated apnea in rat pups, contributing to the pathogenesis of sudden infant death syndrome. Serotonin, or 5-hydroxytryptamine (5-HT), induces apnea via acting on 5-HT receptor 3 (5-HT3R) in PCFs, and among the 5-HT3R subunits, 5-HT3B is responsible for shortening the decay time of 5-HT3R-mediated currents. We examined whether PNE would promote pulmonary 5-HT secretion and prolong the apnea mediated by 5-HT3Rs in PCFs via affecting the 5-HT3B subunit. To this end, the following variables were compared between the control and PNE rat pups: 1) the 5-HT content in bronchoalveolar lavage fluid, 2) the apneic response to the right atrial bolus injection of phenylbiguanide (a 5-HT3R agonist) before and after PCF inactivation, 3) 5-HT3R currents and the stimulus threshold of the action currents of vagal pulmonary C-neurons, and 4) the immunoreactivity (IR) and mRNA expression of 5-HT3A and 5-HT3B in these neurons. Our results showed that PNE up-regulated the pulmonary 5-HT concentration and strengthened the PCF 5-HT3R-mediated apnea. PNE significantly facilitated neural excitability by shortening the decay time of 5-HT3R currents, lowering the stimulus threshold, and increasing 5-HT3B IR. In summary, PNE prolongs the apnea mediated by 5-HT3Rs in PCFs, likely by increasing 5-HT3B subunits to enhance the excitability of 5-HT3 channels.-Zhao, L., Gao, X., Zhuang, J., Wallen, M., Leng, S., Xu, F. Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT3 receptors.


Assuntos
Apneia/etiologia , Apneia/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/inervação , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores 5-HT3 de Serotonina/fisiologia , Animais , Animais Recém-Nascidos , Apneia/genética , Biguanidas/administração & dosagem , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Pulmão/fisiopatologia , Masculino , Nicotina/administração & dosagem , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores 5-HT3 de Serotonina/genética , Serotonina/metabolismo , Agonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Morte Súbita do Lactente/etiologia
10.
Respir Physiol Neurobiol ; 266: 66-72, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063822

RESUMO

Respiratory reflexes arising from stimulating juxtapulmonary capillary (J) receptors by increasing doses of phenyl diguanide (PDG) were examined in 18 spontaneously breathing cats. In 60% an immediate and four-fold increase in breathing frequency (fR) was produced by doses as small as 5.1 ± µg/kg (range: 3.5-7.5) thus establishing that a significant increase in fR is produced by J receptors by stimulating them with minimal or threshold doses of PDG. In response to similar minimal doses of PDG J receptor afferent activity increased accompanied by acceleration of breathing rate. The response to supra threshold doses was either an apnoea followed by rapid shallow breathing (rsb) or to an apnoea preceded by rsb or only to rsb. Respiratory excursions counted from high-speed run records of intrapleural pressure revealed that the apnoeic response obtained in some cases was a phase of high-frequency breathing and not its suspension. These findings using a chemical stimulus demonstrate that J receptors, with some variability, have a very low threshold for stimulation resulting in notable respiratory acceleration. Thus their afferent output could increase significantly at low intensities of their physiological stimuli such as rise in cardiac output and incipient pulmonary congestion that are generated with mild exercise, to give rise to augmented breathing which is consequently seen.


Assuntos
Biguanidas/farmacologia , Capilares , Pulmão/fisiologia , Alvéolos Pulmonares/fisiologia , Reflexo/fisiologia , Taxa Respiratória/fisiologia , Células Receptoras Sensoriais/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Biguanidas/administração & dosagem , Gatos , Pulmão/efeitos dos fármacos , Pulmão/inervação , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/inervação , Reflexo/efeitos dos fármacos , Taxa Respiratória/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem
11.
J Diabetes Res ; 2019: 1365162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944827

RESUMO

Rationale: It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. Purpose: To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. Methods: The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients' evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. Results: Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI loss ≥ 5%, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. Conclusion: The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are useable for estimating the expected efficacy of aGLP-1.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Adulto , Idoso , Aterosclerose , Biguanidas/administração & dosagem , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Feminino , Grelina/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/administração & dosagem , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Período Pós-Prandial , Fatores de Risco , Compostos de Sulfonilureia/administração & dosagem , Resultado do Tratamento , Triglicerídeos/metabolismo , Perda de Peso
12.
Microsc Res Tech ; 82(6): 923-930, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30786090

RESUMO

To compare the smear layer removal ability and mineral content of root canal dentine after initial irrigation with NaOCl and final irrigation with MTAD, QMix, and 17% EDTA. Forty extracted human maxillary incisors before root canal preparation and irrigation with NaOCl were randomly divided into four groups (n = 10) according to the type of final irrigants used: MTAD, QMix, 17% EDTA, and control (sterile distilled water). Scanning electron microscopy (SEM) was used to assess the presence of smear layer. SEM energy-dispersive X-ray spectroscopy was used to quantify dentin mineral composition in MTAD, QMix, 17% EDTA group, and in no-treatment samples (no-treatment group; n = 10). Among the various chelating agents, there were no significant differences in the smear layer removal in the middle and coronal thirds (p > .05). In the apical third, QMix removed significantly more smear layer than 17% EDTA (p < .05), but similarly to MTAD (p > .05). Final irrigation with MTAD resulted in a significant increase in the carbon (C) value compared to EDTA (p < .001). There was no significant difference in the mineral composition between the MTAD and the QMix group, although the values of the mineral elements were significantly altered in the MTAD group. QMix had smear layer removal capability similar to MTAD but better than EDTA in the apical third. MTAD yielded the most pronounced effect on mineral component of root dentin; however, differences were significant only for C level compared to 17% EDTA.


Assuntos
Biguanidas/administração & dosagem , Ácido Cítrico/administração & dosagem , Cavidade Pulpar/efeitos dos fármacos , Dentina/química , Doxiciclina/administração & dosagem , Ácido Edético/administração & dosagem , Minerais/análise , Polímeros/administração & dosagem , Polissorbatos/administração & dosagem , Camada de Esfregaço , Humanos , Microscopia Eletrônica de Varredura , Hipoclorito de Sódio/administração & dosagem , Espectrometria por Raios X , Resultado do Tratamento
13.
Alcohol Clin Exp Res ; 43(4): 747-757, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735249

RESUMO

BACKGROUND: Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice. METHODS: Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 µg/mouse), endogenous agmatine enhancers (l-arginine [80 µg/mouse], arcaine [50 µg/mouse], aminoguanidine [25 µg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11. RESULTS: Agmatine (20 to 40 µg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80 µg/mouse) or arcaine (50 µg/mouse) and aminoguanidine (25 µg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I1 receptor agonist, moxonidine, and I2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I1 receptor antagonist, efaroxan, and I2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization. CONCLUSIONS: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.


Assuntos
Agmatina/farmacologia , Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Etanol/antagonistas & inibidores , Agmatina/antagonistas & inibidores , Animais , Arginina/administração & dosagem , Arginina/farmacologia , Benzofuranos/farmacologia , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Etanol/farmacologia , Guanidinas/administração & dosagem , Guanidinas/farmacologia , Idazoxano/farmacologia , Imidazóis/farmacologia , Receptores de Imidazolinas/agonistas , Receptores de Imidazolinas/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Camundongos , Microinjeções , Atividade Motora/efeitos dos fármacos
15.
Acta Biomater ; 80: 48-57, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30267886

RESUMO

There are increasing demands for long-term and controlled corneal drug delivery to treat various ocular diseases. Although biodegradable ocular inserts or contact lenses have been developed, the invasiveness and inefficiency of the approaches still need to be improved. Microneedle (MN) technology can deliver therapeutic molecules to the eye in a minimally invasive manner. However, the current ocular MN technology is limited to either short-term corneal drug delivery or retinal drug delivery by suprachoroidal injection. For long-term and minimally invasive corneal drug delivery, we have developed a detachable biodegradable MN that can be delivered to the inside of the cornea for sustained drug release. The detachable and biodegradable MN is a hybrid MN consisting of a drug-loaded biodegradable tip and a supporting base. The hybrid MN can be applied to the cornea by impact insertion, and it leaves only the drug-loaded biodegradable tip within the corneal tissue so that it can release the drug for a certain period. By concentration-controlled molding, the dimension of drug-loaded MN tips was precisely controlled and their detachability was optimized. The detachable tip and a supporting base were assembled to form a hybrid MN by pressure-assisted transfer molding. We carefully optimized the dimension of the drug-tip, injection dwell time, and insertion depth to achieve effective intracorneal injection of the drug-tip. The detachable hybrid MN was applied to an Acanthamoeba keratitis model wherein a biodegradable drug-tip was successfully delivered to the inside of the mouse cornea in vivo. Follow-up of the MN-treated cases for 7 days confirmed the therapeutic efficacy of the detachable biodegradable MN tips. STATEMENT OF SIGNIFICANCE: For the treatment of infectious diseases in the cornea, such as keratitis, eye drops need to be applied topically every hour for a couple of days. This is extremely uncomfortable, and poor compliance to such tightly scheduled drug administration can result in permanent scar formation in the cornea. In this work, we demonstrate a simple and rapid injection of biodegradable microneedle tips in the corneal tissue wherein the tips can deliver antibacterial drugs for 4 days to treat keratitis. Unlike other patch-style microneedle technologies, this approach allows for insertion depth-controlled and highly localized injection of detachable individual microneedle tips to the diseased tissue for sustained drug delivery. This overcomes the limitations of patch-style microneedles such as short-term drug delivery and unnecessary blockage of tissue.


Assuntos
Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Microinjeções/métodos , Agulhas , Ceratite por Acanthamoeba/tratamento farmacológico , Animais , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Córnea/parasitologia , Córnea/patologia , Dimetilpolisiloxanos/química , Feminino , Camundongos Endogâmicos C57BL , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Pressão
16.
Surg Infect (Larchmt) ; 19(7): 723-728, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30260766

RESUMO

BACKGROUND: Peritoneal lavage is often used for peritonitis, however, the volume and type of lavage fluid varies. Saline or Ringer's solution are used most often and lavage is performed until the fluid is clear. However, at present there is no irrigation fluid for peritoneal lavage with residual antiseptic activity. Because the combination of aqueous polyhexamethylenbiguanid-hydrochlorid (PHMB) and egg phosphatidylcholine containing oil/water emulsions (Lipofundin® MCT 20%, B. Braun AG, Melsungen, Germany) protect mammalian cells without neutralizing the antiseptic effect of PHMB, it seemed promising to investigate such human cell protecting, yet antibacterial combination for peritoneal lavage in a murine sepsis model. METHODS: After induction of colon ascendens stent peritonitis (CASP) in mice, the foci were eradicated by re-laparotomy, followed by twofold lavage with 2 × 3 mL of the tested emulsion. The following lavage fluids were investigated blindly: 10% Lipofundin/0.05% PHMB, 100% Lipofundin, 0.05% PHMB, and 0.9% saline. After 24 hours the animals were euthanized and organs, blood, and lavage fluid were examined for cytokine levels (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-6, IL-10), liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [gamma-GT], glutamate dehydrogenase [GLDH]), creatinine, and bacterial density. RESULTS: Only the combination of Lipofundin/PHMB (n = 23) increased the survival rate. Compared with saline alone, PHMB alone decreased the survival rate. Twenty-four hours after induction of peritonitis, the lowest number of colony forming units (CFU) was observed after lavage with PHMB/Lipofundin in all examined organs, blood, and lavage fluid (p < 0.01). Alanine aminotransferase, AST, and creatinine levels were increased after lavage with PHMB compared with the other lavage fluids (p < 0.05). CONCLUSIONS: Peritoneal lavage using 0.05% aqueous PHMB alone resulted in no survival benefit in a CASP murine model. The increase of liver enzymes and creatinine seem to be a toxic side effect of PHMB. However, an emulsion of 0.05% PHMB/10% Lipofundin decreased cytotoxicity while maintaining antiseptic efficiency. The advantage for survival was explained by decrease of bacterial load in organs, blood, and lavage fluid. The results provide a new option for the treatment of peritonitis using peritoneal lavage with the combination of PHMB/Lipofundin.


Assuntos
Biguanidas/uso terapêutico , Desinfetantes/uso terapêutico , Lavagem Peritoneal/métodos , Peritonite/terapia , Sepse/prevenção & controle , Animais , Carga Bacteriana/efeitos dos fármacos , Biguanidas/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Desinfetantes/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Peritonite/complicações , Sepse/terapia
17.
J Wound Care ; 27(8): 512-518, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30086255

RESUMO

OBJECTIVE: To evaluate if cleansing, using a solution containing the antimicrobial polyhexanide and the surfactant betaine (polyhexanide propylbetaine [PP], Prontosan Solution, B. Braun), can aid effective wound bed preparation (WBP). METHOD: A solution containing the PP was used in two different treatment regimens. Group A was treated with a single application at different time durations (2, 5, 10 and 15 minutes) to evaluate efficacy in the removal of residues from the wound bed. Group B was treated with PP for 10 minutes, followed by application of an inert dressing, at daily dressing changes for 14 days, to evaluate efficacy of debridement. RESULTS: A total number of 70 patients took part in the study. In Group A (n=40), after the two and five minute application, no change was observed. At 10 minutes, an improvement was seen in 4/10 cases and at 15 minutes the improvement was in 5/10 patients. In Group B (n=30), over the 14 days, an improvement in the condition of the tissue, i.e. the wound bed was cleaned and debrided in 73% of cases, was observed. Patients experienced a reduction in pain and no adverse effect or complication was reported. Periwound skin was improved in 29/30 cases, with only one case where the tissue deteriorated, as determined by the presence of maceration. CONCLUSION: PP is effective in helping debridement during wound cleansing. Efficacy depends on time of application. However, randomisation and further study is required to confirm these results.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Biguanidas/administração & dosagem , Desbridamento , Úlcera Cutânea/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bandagens , Betaína/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tensoativos/administração & dosagem , Fatores de Tempo , Cicatrização
18.
Diabetes Obes Metab ; 20(12): 2830-2839, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29974673

RESUMO

AIM: To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. MATERIALS AND METHODS: This retrospective, observational study extracted data from a large-scale hospital database (April 2008 to September 2016). Patients with T2DM aged ≥40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or α-glucosidase inhibitors [α-GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan-Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: ≥90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). RESULTS: We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, α-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for α-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1-G4+), followed by BGs at stages G1/G2. CONCLUSIONS: The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/patologia , Hipoglicemiantes/administração & dosagem , Insuficiência Renal/patologia , Índice de Gravidade de Doença , Administração Oral , Adulto , Idoso , Biguanidas/administração & dosagem , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/etiologia , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Tiazolidinedionas/administração & dosagem , Resultado do Tratamento
19.
BMC Urol ; 18(1): 49, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793457

RESUMO

BACKGROUND: Long-term use of indwelling urethral catheters is associated with high risk of urinary tract infection (UTI) and blockage, which may in turn cause significant morbidity and reduce the life of the catheter. A 0.02% polyhexanide irrigation solution has been developed for routine mechanical rinsing together with bacterial decolonization of suprapubic and indwelling urethral catheters. METHODS: Using a practice-like in vitro assay and standard silicon catheters, artificially contaminated with clinically relevant bacteria, experiments were carried out to evaluate the bacterial decolonization potential of polyhexanide vs. 1) no intervention (standard approach) and 2) irrigation with a saline (NaCl 0.9%) solution. Swabbing and irrigation was used to extract the bacteria. RESULTS: Irrigation with polyhexanide reduced the microbial population vs. the control catheters by a factor of 1.64 log10 (swab extraction) and by a factor of 2.56 log10 (membrane filtration). The difference in mean microbial counts between the two groups (0.90) was statistically significant in favor of polyhexanide when the liquid extraction method was used (p = 0.034). The difference between the two groups using the swab extraction method did not reach statistical significance. CONCLUSIONS: The saline and polyhexanide solutions are able to reduce bacterial load of catheters, which shows a combined mechanical and antimicrobial effect. Further research is required to evaluate the long-term tolerability and efficacy of polyhexanide in clinical practice.


Assuntos
Carga Bacteriana/efeitos dos fármacos , Carga Bacteriana/fisiologia , Biguanidas/administração & dosagem , Cateteres de Demora/microbiologia , Desinfetantes/administração & dosagem , Infecções Relacionadas a Cateter/prevenção & controle , Contagem de Colônia Microbiana/métodos , Composição de Medicamentos , Humanos , Soluções Farmacêuticas/administração & dosagem , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/isolamento & purificação , Cateterismo Urinário/efeitos adversos , Cateterismo Urinário/métodos , Infecções Urinárias/etiologia , Infecções Urinárias/prevenção & controle
20.
Hum Mol Genet ; 27(12): 2101-2112, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29659804

RESUMO

Niemann-Pick type C (NPC) disease is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients. We sought to identify novel compounds that decrease lysosomal cholesterol storage in NPC1I1061T/I1061T patient fibroblasts using a high-content screen with the cholesterol dye, filipin and the lysosomal marker, LAMP1. A total of 3532 compounds were screened, including 2013 FDA-approved drugs, 327 kinase inhibitors and 760 serum metabolites. Twenty-three hits were identified that decreased both filipin and LAMP1 signals. The majority of hits (16/21) were histone deacetylase (HDAC) inhibitors, a previously described class of modifiers of NPC cholesterol storage. Of the remaining hits, the antimicrobial compound, alexidine dihydrochloride had the most potent lysosomal cholesterol-reducing activity. Subsequent analyses showed that alexidine specifically increased levels of NPC1 transcript and mature protein in both control and NPC patient cells. Although unsuitable for systemic therapy, alexidine represents a unique tool compound for further NPC studies and as a potent inducer of NPC1. Together, these findings confirm the utility of high-content image-based compound screens of NPC1 patient cells and support extending the approach into larger compound collections.


Assuntos
Proteínas de Transporte/genética , Colesterol/genética , Inibidores de Histona Desacetilases/administração & dosagem , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Biguanidas/administração & dosagem , Colesterol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Fibroblastos/efeitos dos fármacos , Filipina/metabolismo , Inibidores de Histona Desacetilases/isolamento & purificação , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteína 1 de Membrana Associada ao Lisossomo/genética , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Metaboloma/efeitos dos fármacos , Mutação de Sentido Incorreto , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia
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