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INTRODUCTION: Intermediate-risk (IR) Non-Muscle Invasive Bladder Cancer (NMIBC) is associated with a high rate of tumor recurrence. To improve patient outcomes, it is recommended to use adjuvant intravesical therapy, by mitomycin C (MMC) or Bacillus Calmette Guerin (BCG). Gemcitabine (GMC) is a known molecule used in urothelial cancer. We aimed to study the efficacy and safety profile of a gemcitabine solution, compared to mitomycin C, in the treatment of IR NMIBC. MATERIAL: In this retrospective study, patients with IR NMIBC treated between 2016 and 2020 were selected from two participating centers using either gemcitabine (center A) as the intravesical chemotherapy regimen or mitomycin C (center B). The primary endpoint was recurrence rate and secondary end points were treatment interruption and its causes. RESULTS: In our cohort of 102 IR NMIBC patients, 49 patients received GMC and 53 MMC with a median follow-up of 30 months. Overall recurrence rate was 42.1% with 22.4% in the GMC group and 60.3% in the MMC group (P<0.01). This difference was also found in the multifactorial analysis. Course interruption was observed in 14.7% of all patients, primarily attributed to adverse events (46.6%), without difference between groups. CONCLUSION: Adjuvant intravesical gemcitabine in patients with IR NMIBC seems to be an interesting option associated with a lower tumor recurrence rate and a favorable tolerance profile when compared to MMC. Larger scale prospective randomized trials are needed to validate our findings. LEVEL OF EVIDENCE: III.
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During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.2 µm) and filled into 10 mL type I glass, manually sealed with bromobutyl rubber stoppers. A novel HPLC-MS stability indicating method for pancuronium quantification and its degradation product was developed and validated. This fast, sensitive and straightforward method was used to study the stability of the formulation using a semi-predictive method, enabling a very fast attribution of a temporary shelf-life, which was confirmed by a classic prospective stability study. The production line and the analytical tools set-up were performed in six weeks and the semi-predictive stability study was conducted in 90 days, allowing us to predict a shelf life, which was successfully confirmed by prospective study. In conclusion, using innovative methods, we were able to rapidly overcome the shortage of a critical drug.
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COVID-19 , Pancurônio , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Estudos Prospectivos , Pandemias , Estabilidade de Medicamentos , Composição de MedicamentosRESUMO
Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being "GMP-like") targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally "phage therapy 2.0" has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial-academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.
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Infecções Bacterianas/terapia , Doenças Ósseas Infecciosas/terapia , Artropatias/terapia , Terapia por Fagos , Infecções Relacionadas à Prótese/terapia , Proteínas Virais/uso terapêutico , Antibacterianos/uso terapêutico , Artrite Infecciosa/terapia , Bacteriófagos/enzimologia , Bacteriófagos/fisiologia , Ensaios de Uso Compassivo , Humanos , Osteomielite/terapia , Terapia por Fagos/normas , Proteínas Virais/metabolismoRESUMO
PURPOSE: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. METHODS: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. RESULTS: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. CONCLUSIONS AND RELEVANCE: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.
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Estradiol/análogos & derivados , Fístula/prevenção & controle , Hipospadia/cirurgia , Complicações Pós-Operatórias/tratamento farmacológico , Procedimentos Cirúrgicos Urológicos Masculinos/efeitos adversos , Administração Tópica , Método Duplo-Cego , Estradiol/administração & dosagem , Fístula/etiologia , Humanos , Lactente , Masculino , Cuidados Pré-Operatórios , Estudos Prospectivos , Procedimentos de Cirurgia Plástica/efeitos adversos , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/prevenção & controle , Resultado do Tratamento , Doenças Uretrais/etiologia , Doenças Uretrais/prevenção & controleRESUMO
Standard parenteral nutrition solutions are mixtures comprising interacting components that may degrade themselves over time. The objective of this study was to investigate the physicochemical and microbiological stability of a hospital preparation for parenteral nutrition in neonatology. The analyses were performed throughout the storage of the preparations at 2-8⯰C (up to 4 months). The extent of stability was based on the determination of amino acids dosage, visual and physicochemical properties (glucose and electrolytes concentrations, pH and osmolality measurements, particle counting) and microbiological analysis (sterility test). A thermal degradation of ascorbic acid was conducted to evaluate the antioxidant properties of the parenteral mixture. Physicochemical and microbiological controls were found to comply with the specifications. Amino acids showed a good stability throughout the 4months storage except for cysteine, which was progressively degraded to cystine, conferring a yellow coloration to parenteral solutions. Parenteral nutrition standards solutions remain stable for 4 months at 2-8⯰C, ensuring safe administration in preterm infants.
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Poor bioavailability and low residence time limit the efficiency of conventional biguanide-based eye drops against Acanthamoeba keratitis. The aim of this work was to formulate an original anti-amoebic thermoreversible ocular gel combining biguanide and metalloproteases inhibitor - chelating agent. Chlorhexidine digluconate (CHX)-ethylenediaminetetraacetic acid disodium salt (Na2EDTA) were compounded in poloxamer 407 saline solution. 0.02% CHX - 0.1% Na2EDTA loaded thermosensitive ocular gel exhibited appropriate pH (5.73⯱â¯0.06), iso-osmolality (314⯱â¯5â¯mOsm/kg), viscosity (ranged between 15 and 25â¯mPa.s) and thermal gelation (26.5⯰C and 33⯰C) properties. Bioadhesion of gel was successfully tested onto isolated bovine eyes as well as the assessment of CHX penetration into the cornea. Intracorneal CHX concentration was found greater than trophozoite minimum amoebicidal concentration and minimal cysticidal concentration after 15-min and 2-h ocular exposure, respectively, while any CHX permeation through the cornea was detected (<51â¯ng/cm2/h). Improvement of CHX ocular bioavailability was attributed to probable solubilization of tear film lipid layer by poloxamer. In vitro efficiency of CHX-Na2EDTA ocular gel was confirmed from the drastic reduction of trophozoite and cyst survival (to 25% and 2%, respectively), confirming the potential of the multicomponent pharmaceutical material strategy for the treatment of Acanthamoeba keratitis.
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Ceratite por Acanthamoeba/tratamento farmacológico , Amebicidas/administração & dosagem , Clorexidina/análogos & derivados , Ácido Edético/administração & dosagem , Administração Oftálmica , Amebicidas/farmacocinética , Amebicidas/farmacologia , Animais , Disponibilidade Biológica , Bovinos , Quelantes/administração & dosagem , Quelantes/farmacocinética , Quelantes/farmacologia , Química Farmacêutica/métodos , Clorexidina/administração & dosagem , Clorexidina/farmacocinética , Clorexidina/farmacologia , Córnea/metabolismo , Combinação de Medicamentos , Ácido Edético/farmacocinética , Ácido Edético/farmacologia , Géis , Concentração Osmolar , Temperatura , Trofozoítos/efeitos dos fármacos , ViscosidadeRESUMO
Characterization of cell death currently requires the use of indirect markers, which has largely limited the ability to monitor cell death processes inside the cell. Here, we introduce a new method for the characterization of cell death mechanisms using cadmium telluride quantum dots (CdTe-QDs). Using visible CdTe-QDs with mesenchymal cells (e.g. synoviocytes), live-stream imaging allowed for visualization of cadmium-induced cell death, combining characteristics of apoptosis and autophagy. Initially, similar anti-proliferative effect was observed between 10 µg/ml Cd2+ and CdTe-QDs at 24 h (cell index/cell density ratio decreased from 0.6 to -16.6, p < 0.05) using techniques that do not require the capacity of CdTe-QDs. Apoptosis was confirmed by the quantification of morphological parameters (reduced surface area, increased cell thickness) and positive labeling with annexin V. Autophagy was confirmed by monodansylcadaverine staining, identifying similar autophagic vacuoles with both Cd2+ and CdTe-QD. However, QD imaging allowed for visualization of cadmium elements inside cell structures and their kinetic changes leading to cell death. Cell death characteristics were similar in inflammatory and non-inflammatory environment but were induced up to 4 h earlier in the former. Therefore, live-stream imaging of a visible cytotoxic agent has useful applications not currently possible with indirect methods, including chronological monitoring of cell death.
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Apoptose/efeitos dos fármacos , Imagem Molecular/métodos , Pontos Quânticos/metabolismo , Cádmio/efeitos adversos , Cádmio/farmacologia , Compostos de Cádmio/química , Morte Celular/efeitos dos fármacos , Humanos , Cultura Primária de Células , Sinoviócitos/efeitos dos fármacos , Telúrio/químicaRESUMO
Chemotherapy products in hospitals include a reconstitution step of manufactured drugs providing an adapted dosage to each patient. The administration of highly iatrogenic drugs raises the question of patients' safety and treatment efficiency. In order to reduce administration errors due to faulty preparations, we introduced a new qualitative and quantitative routine control based on Fourier Transform Infrared (FTIR) and UV-Visible spectrophotometry. This automated method enabled fast and specific control for 14 anticancer drugs. A 1.2 mL sample was used to assay and identify each preparation in less than 90 sec. Over a two-year period, 9370 controlled infusion bags showed a 1.49% nonconformity rate, under 15% tolerance from the theoretical concentration and 96% minimum identification matching factor. This study evaluated the reliability of the control process, as well as its accordance to chemotherapy deliverance requirements. Thus, corrective measures were defined to improve the control process.
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Antineoplásicos/análise , Composição de Medicamentos/métodos , Erros de Medicação/prevenção & controle , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Humanos , Controle de Qualidade , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/métodos , Fatores de TempoRESUMO
INTRODUCTION: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis, for which bevacizumab is reported to be a new therapeutic option. In the present study, bevacizumab transport in porcine nasal mucosa was investigated to determine antibody bioavailability. MATERIAL AND METHODS: Transmucosal absorption of bevacizumab was examined by using nasal mucosa specimens mounted onto static vertical diffusion cells then treated with bevacizumab solution (25 mg mL(-1), 500 µg) for 2.5h. Bevacizumab concentrations were measured by enzyme-linked immunosorbent assays. Mucosal integrity was examined by histological examination of treated mucosa. RESULTS: Transmucosal transport of bevacizumab followed a Fickian diffusion process (permeability coefficient: [0.63 ± 22]× 10(-6) cm s(-1); and steady-state flux: 56.4 ± 19.6 µg cm(-2)h(-1)). Total recovery of bevacizumab throughout the 2.5h experiment was 83% of the initial dose distributed (i) at the mucosal surface (263 ± 73 µg; â¼53%) and (ii) into (95 ± 14 µg; â¼19%) and through (56 ± 26 µg; â¼11%) the mucosa. There was no evidence of any noticeable histological effects, confirming the harmlessness of nasal bevacizumab delivery. CONCLUSION: In the present study, absorption of bevacizumab into nasal mucosa was demonstrated, providing new fundamentals that are mandatory for further clinical trials in HHT patients.
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Inibidores da Angiogênese/farmacocinética , Anticorpos Monoclonais Humanizados/farmacocinética , Mucosa Nasal/metabolismo , Administração Intranasal , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/toxicidade , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/toxicidade , Bevacizumab , Disponibilidade Biológica , Transporte Biológico , Difusão , Ensaio de Imunoadsorção Enzimática , Mucosa Nasal/efeitos dos fármacos , Permeabilidade , Suínos , Telangiectasia Hemorrágica Hereditária/tratamento farmacológicoRESUMO
The interest of centralization of preparations of chemotherapy drugs is in addition to its economic aspect, to secure drugs circuit. The aims of this study are to determine needs in employees and equipments of 11 theoretical levels of production from 1,000 to 50,000 preparations per year and to determine the cost of chemotherapy's preparation for each theoretical unit. The operating cost was divided in four areas of expenditure: employees (66-78%), investment (5-15%), maintenance (3-15%) and consumables (4-16%). If we consider the 11 units, the theoretical cost varies between 27.4 for a unit with 50,000 preparations per year and 114.1 for a unit with 1,000 preparations per year. This study shows the importance of setting up an optimal unit of preparations according to its activity and highlights the high cost's variation in relation to the activity of the unit.
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Antineoplásicos/síntese química , Serviços Centralizados no Hospital/economia , Serviço de Farmácia Hospitalar/economia , Antineoplásicos/economia , Benchmarking , Serviços Centralizados no Hospital/organização & administração , Custos e Análise de Custo/métodos , Composição de Medicamentos/economia , Composição de Medicamentos/instrumentação , França , Humanos , Serviço Hospitalar de Engenharia e Manutenção/economia , Admissão e Escalonamento de Pessoal/economia , Admissão e Escalonamento de Pessoal/organização & administração , Serviço de Farmácia Hospitalar/organização & administração , Salários e Benefícios/economia , Recursos HumanosRESUMO
Often presented as metabolism byproducts, reactive oxygen species are linked to detrimental effects such as chronic wound, mutagenesis, cancer and skin ageing. However, recent in vitro and in vivo observations suggest that ROS, and mainly hydrogen peroxide, interfere with cell signaling acting like second messenger and inducing adaptive responses. This is particularly observed in skin wound healing where cells are exposed to H2O2 following injury. In this study, we developed and characterized an innovative formulation producing H2O2 at low concentrations, in order to mimic physiological inflammation phase. Then, this pro-oxidative formulation (CAM-GOx) was assayed in vitro on keratinocytes cell culture, compared to the blank formulation (CAM) and the anti-oxidative formulation (CAM-CAT) to assess whether oxidative stress was implied or not in cellular responses.
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Estresse Oxidativo/fisiologia , Cicatrização/fisiologia , Alginatos , Ensaios de Migração Celular , Células Cultivadas , Quitosana , Humanos , Peróxido de Hidrogênio/metabolismo , Queratinócitos/citologia , Microesferas , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Conventional formulations of chlorhexidine usually provide short-term efficiency, requiring repeated applications to maintain antibacterial activity. Therefore, appropriate release system of chlorhexidine controlling local drug delivery would reduce the number of applications and enhance patient compliance. The aim of this study was to develop a controlled release system based on medical polyurethane for the local delivery of chlorhexidine diacetate (CDA). CDA-loaded polyurethane films (CDA-Films) and CDA-loaded polyurethane sandwiches (CDA-Sandwiches) were obtained by casting and solvent evaporation. The physico-chemical aspects of CDA-loaded polyurethane systems were investigated, and the crystalline state of CDA in the polymeric system was highlighted. CDA-Films exhibited appropriate mechanical properties for further applications. Drug release was measured in two different media: (i) distilled water and (ii) physiological saline solution to mimic in vivo conditions. Drug release studies were performed up to 11days on CDA-Films and 29days for CDA-Sandwiches. Release of CDA depended on drug loading and the structure of the system. In particular, release of CDA from the sandwich system followed zero-order kinetic. The release rate was significantly lower in physiological solution. Antibacterial studies were carried out on CDA-Films against Staphylococcus aureus and Staphylococcus epidermidis showing 35days persisting antibacterial activity. In conclusion, the polyurethane-based system developed in this study is potentially useful as a local delivery system for CDA and could be used not only in surgery but also in dental and clinical applications.
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Anti-Infecciosos Locais/administração & dosagem , Clorexidina/administração & dosagem , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Poliuretanos , Administração Tópica , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/farmacocinética , Fenômenos Químicos , Clorexidina/química , Clorexidina/farmacocinética , Cristalização , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Técnicas In Vitro , Cinética , Fenômenos Mecânicos , Testes de Sensibilidade Microbiana , Polímeros/administração & dosagem , Polímeros/síntese química , Polímeros/farmacocinética , Poliuretanos/administração & dosagem , Poliuretanos/química , Poliuretanos/farmacocinética , Cloreto de Sódio/análise , Água/análiseRESUMO
Gangliosides, cell surface glycosphingolipids, are implicated in diverse biologic functions potentially important for tumor growth. Because expression of the GD3 ganglioside may have an impact on the melanoma malignancy, and therefore on the patient prognosis, we evaluated the feasibility of a retrospective immunohistochemical study of GD3 in paraffin embedded biopsies of primary melanomas. Immunoperoxidase staining of frozen and deparaffinized sections of melanoma lesions with two anti-GD3 antibodies was compared using Dako biotin-streptavidin detection kit. Residual ganglioside content was evaluated in the tissues submitted to routine histopathologic procedures using HPLC. A strong and reproducible staining was obtained with both antibodies on frozen sections of all 17 melanoma samples. However, only KM641 antibody could detect GD3 on deparaffinized sections. Biochemical quantification revealed that the Bouin fixative resulted in degradation of GD3. Additionally, most of GD3 was eluted from the tissue samples during dehydration and re-hydration steps. A subgroup of tumors particularly rich in GD3 could be detected on deparaffinized sections after standard formaldehyde fixation. Clinical evolution of such melanomas can now be compared to the group with low GD3 expression. However, any Bouin-fixed, paraffin-embedded biopsies should be excluded from such a retrospective study.
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Técnicas Citológicas/métodos , Gangliosídeos/análise , Melanoma/química , Neoplasias Cutâneas/química , Biópsia , Cromatografia Líquida de Alta Pressão , Estudos de Viabilidade , Secções Congeladas , Humanos , Técnicas Imunoenzimáticas , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
The success of the chemotherapeutic treatment of hydatid disease is based upon the drug ability to operate on the germinal layer and on the protoscolices of the hydatid cyst interior at adequate concentrations for sufficient periods. The goal of this study was to evaluate the ability of the drug diffusion through the cyst membrane from sheep hydatid cysts and the increase of drug concentration in the cyst environment. In the first part of this work, the permeation behaviour through the hydatid cyst membrane was studied with five model molecules, having different molecular descriptors (logP, molecular weight, polar surface area ...) onto static Franz glass diffusion cells. A good correlation has been observed between the permeation coefficient and the partition coefficient, log P (r=0.951). In the second part, albendazole-loaded nanoparticles (about 300 nm) prepared by the emulsion solvent evaporation method have shown a sufficient entrapment efficiency (36.4 +/- 6.4%) to raise the apparent solubility of albendazole. The diffusion of drug from the nanoparticles across the hydatid cyst membrane was also improved compare to albendazole suspension. These results have shown the interest of the albendazole-loaded nanoparticles for the treatment of hydatid cysts in the future.