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1.
J Aerosol Med Pulm Drug Deliv ; 27(3): 185-92, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23789705

RESUMO

BACKGROUND: Improved inhalation device/drug combinations are necessary to advance inhaled antibiotic therapy in cystic fibrosis (CF). Previously, for a novel drug/inhaler combination, equivalent lung deposition was demonstrated; here, we investigated its safety and pharmacokinetics. METHODS: In a randomized, open-labeled, multicenter, active controlled, parallel 28-day study, we compared a new tobramycin formulation (T100 PARI, 150 mg/1.5 mL) nebulized with a drug-specific PARI eFlow(®) nebulizer and TOBI(®) (300 mg/5 mL) nebulized with a PARI LC PLUS(®) nebulizer in 78 CF patients. RESULTS: Noninferiority of the primary endpoint peak plasma tobramycin concentrations and the secondary endpoint area under the concentration time curves in plasma were observed. Sputum concentrations exceeded expected minimum inhibitory concentrations of Pseudomonas aeruginosa and were the same across both treatment groups, as were tolerability and safety. The nebulization time (4.6 vs. 16.1 min) was much shorter for the new drug/device combination. CONCLUSION: Inhaled therapy with T100 PARI delivered by an investigational eFlow offers a patient treatment time benefit and comparable safety and pharmacokinetics.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Fibrose Cística/tratamento farmacológico , Pulmão/metabolismo , Tobramicina/administração & dosagem , Tobramicina/farmacocinética , Administração por Inalação , Adolescente , Adulto , Aerossóis , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Antibacterianos/química , Área Sob a Curva , Química Farmacêutica , Criança , Fibrose Cística/diagnóstico , Fibrose Cística/fisiopatologia , Monitoramento de Medicamentos , Desenho de Equipamento , Volume Expiratório Forçado , Alemanha , Humanos , Pulmão/fisiopatologia , Masculino , Nebulizadores e Vaporizadores , Escarro/metabolismo , Tobramicina/efeitos adversos , Tobramicina/sangue , Tobramicina/química , Resultado do Tratamento , Adulto Jovem
2.
Anticancer Res ; 30(4): 1353-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20530452

RESUMO

UNLABELLED: Antimicrobial central venous catheters are discussed as a device to reduce catheter-related infections. Previously we have reported a study with 223 adult surgical patients randomized to receive either a rifampicin-miconazole-loaded central venous catheter (CVC) (n=118) or a standard CVC (n=105). The antimicrobial CVC was shown to reduce catheter colonization (CC) and catheter-related local infection (CRI) significantly even at long-term catheterization. Here, we present further evaluation of the study focusing on possible benefits for high-risk patients. Subgroup analyses showed a pronounced reduction of CC and CRI in male, overweight and oncology patients. Important covariates were skin colonization for CC and oncological disease for CRI. Odds ratio (OR) for reducing CC was 0.076 (95% CI: 0.016-0.360) and CRI was reduced from 26% to 2.3% (p=0.001) in the cancer subgroup. Ex vivo long-term antimicrobial activity of modified catheters exceeded 4 weeks. CONCLUSION: Immunocompromized patients suffering from cancer, transplantation, and dialysis patients with a long-term vascular access may mostly benefit from rifampicin-miconazole-releasing catheters.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Antifúngicos/administração & dosagem , Cateterismo Venoso Central/métodos , Materiais Revestidos Biocompatíveis/administração & dosagem , Miconazol/administração & dosagem , Neoplasias/terapia , Rifampina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/prevenção & controle , Cateteres de Demora/microbiologia , Contaminação de Equipamentos/prevenção & controle , Feminino , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/crescimento & desenvolvimento , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/prevenção & controle , Neoplasias/microbiologia , Fatores de Risco , Adulto Jovem
3.
Prep Biochem Biotechnol ; 38(1): 87-93, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18080913

RESUMO

Increasing complications in incisional hernia surgery call for novel treatments. A gene expression analysis of injured tissues displays important parameters for tissue regeneration. Until today, no reliable method has been described for a quantitative gene expression analysis of hernia tissues. In this work, a protocol is described for the isolation of DNA-free total RNA of incisional hernias for the first time. Moreover, real-time RT PCR assays for collagen type I and III and TGF-beta1 are demonstrated for relative gene expression analyses. Both methods enable relative gene expression analyses of hernia tissues for the first time.


Assuntos
Colágeno Tipo III/análise , Colágeno Tipo I/análise , Hérnia Abdominal/patologia , RNA/isolamento & purificação , Fator de Crescimento Transformador beta1/análise , Animais , Sequência de Bases , Bioensaio/métodos , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Perfilação da Expressão Gênica , Hérnia Abdominal/genética , Hérnia Abdominal/cirurgia , RNA/genética , RNA/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fator de Crescimento Transformador beta1/genética
4.
Anticancer Res ; 27(1A): 223-33, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17352237

RESUMO

Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity [T/C (Test/Control) < 30%]: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts.


Assuntos
Erva-de-Passarinho/química , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Doxorrubicina/farmacologia , Humanos , Interleucina-6/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias/patologia , Preparações de Plantas/farmacologia , Proteínas de Plantas/farmacologia , Proteínas Inativadoras de Ribossomos Tipo 2 , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Toxinas Biológicas/farmacologia
5.
Anticancer Res ; 27(6B): 4195-200, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18225591

RESUMO

BACKGROUND: Extracts from Viscum album (VA-E) have been shown to induce apoptosis and immunoactivation. To exclude possible B-CLL propagating effects, the in vitro reactions of cultured peripheral blood B-CLL cells were analysed. PATIENTS AND METHODS: Intracellular expression of apoptosis-associated mitochondrial Apo2.7 and proliferation-associated Ki-67 molecules in B-CLL cells from patients treated with VA-E for 12 months were measured after incubation with various stimuli. RESULTS: Within the observation period, the susceptibility of the B-CLL cells towards the apoptosis-inducing potential of the VA-E significantly decreased. This effect could be due to the presence of physiologically-induced anti-mistletoe lectin antibodies which may block the effects of cytotoxic mistletoe lectins. No significant induction of Ki-67 was observed, but an increase of non-specific binding, even in untreated medium controls, did occur within the last months. CONCLUSION: In this in vitro setting of the observational study, no stimulation of leukemic cells from the patients treated with VA-E was profound.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Extratos Vegetais/farmacologia , Viscum album/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Feminino , Humanos , Antígeno Ki-67/biossíntese , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/biossíntese , Fito-Hemaglutininas/imunologia , Fito-Hemaglutininas/farmacologia , Mitógenos de Phytolacca americana/imunologia , Mitógenos de Phytolacca americana/farmacologia
6.
J Orthop Res ; 24(8): 1622-40, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16779814

RESUMO

The purpose of this study was to acquire information about the effect of an antibacterial and biodegradable poly-L-lactide (PLLA) coated titanium plate osteosynthesis on local infection resistance. For our in vitro and in vivo experiments, we used six-hole AO DC minifragment titanium plates. The implants were coated with biodegradable, semiamorphous PLLA (coating about 30 microm thick). This acted as a carrier substance to which either antibiotics or antiseptics were added. The antibiotic we applied was a combination of Rifampicin and fusidic acid; the antiseptic was a combination of Octenidin and Irgasan. This produced the following groups: Group I: six-hole AO DC minifragment titanium plate without PLLA; Group II: six-hole AO DC minifragment titanium plate with PLLA without antibiotics/antiseptics; Group III: six-hole AO DC minifragment titanium plate with PLLA + 3% Rifampicin and 7% fusidic acid; Group IV: six-hole AO DC minifragment titanium plate with PLLA + 2% Octenidin and 8% Irgasan. In vitro, we investigated the degradation and the release of the PLLA coating over a period of 6 weeks, the bactericidal efficacy of antibiotics/antiseptics after their release from the coating and the bacterial adhesion of Staphylococcus aureus to the implants. In vivo, we compared the infection rates in white New Zealand rabbits after titanium plate osteosynthesis of the tibia with or without antibacterial coating after local percutaneous bacterial inoculations at different concentrations (2 x 10(5)-2 x 10(8)): The plate, the contaminated soft tissues and the underlying bone were removed under sterile conditions after 28 days and quantitatively evaluated for bacterial growth. A stepwise experimental design with an "up-and-down" dosage technique was used to adjust the bacterial challenge in the area of the ID50 (50% infection dose). Statistical evaluation of the differences between the infection rates of both groups was performed using the two-sided Fisher exact test (p < 0.05). Over a period of 6 weeks, a continuous degradation of the PLLA coating of 13%, on average, was seen in vitro in 0.9% NaCl solution. The elution tests on titanium implants with antibiotic or antiseptic coatings produced average release values of 60% of the incorporated antibiotic or 62% of the incorporated antiseptic within the first 60 min. This was followed by a much slower, but nevertheless continuous, release of the incorporated antibiotic and antiseptic over days and weeks. At the end of the test period of 42 days, 20% of the incorporated antibiotic and 15% of the incorporated antiseptic had not yet been released from the coating. The antibacterial effect of the antibiotic/antiseptic is not lost by integrating it into the PLLA coating. The overall infection rate in the in vivo investigation was 50%. For Groups I and II the infection rate was both 83% (10 of 12 animals). In Groups III and IV with antibacterial coating, the infection rate was both 17% (2 of 12 animals). The ID50 in the antibacterial coated Groups III and IV was recorded as 1 x 10(8) CFU, whereas the ID50 values in the Groups I and II without antibacterial coating were a hundred times lower at 1 x 10(6) CFU, respectively. The difference between the groups with and without antibacterial coating was statistically significant (p = 0.033). Using an antibacterial biodegradable PLLA coating on titanium plates, a significant reduction of infection rate in an in vitro and in vivo investigation could be demonstrated. For the first time, to our knowledge, we were able to show, under standardized and reproducible conditions, that an antiseptic coating leads to the same reduction in infection rate as an antibiotic coating. Taking the problem of antibiotic-induced bacterial resistance into consideration, we thus regard the antiseptic coating, which shows the same level of effectiveness, as advantageous.


Assuntos
Antibacterianos/farmacocinética , Anti-Infecciosos Locais/farmacocinética , Materiais Revestidos Biocompatíveis , Fixação Interna de Fraturas , Infecções Relacionadas à Prótese/prevenção & controle , Implantes Absorvíveis , Animais , Técnicas In Vitro , Teste de Materiais , Técnicas Microbiológicas , Poliésteres/farmacocinética , Infecções Relacionadas à Prótese/tratamento farmacológico , Coelhos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus/efeitos dos fármacos , Titânio
7.
J Antimicrob Chemother ; 54(6): 1109-15, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15537696

RESUMO

OBJECTIVE: Central venous catheters (CVC) are a major cause of nosocomial bloodstream infections. Catheters modified with miconazole and rifampicin that constantly and slowly release antimicrobial substances are assumed to be beneficial in reducing rates of colonization and catheter-related infections. DESIGN AND SETTING: Prospective controlled non-blinded randomized clinical trial in two German university hospitals. PATIENTS: 223 adult inpatients with CVC between October 2000 and February 2002. Baseline characteristics, APACHE II score and therapeutic interventions were comparable. INTERVENTION: Randomization to receive either a miconazole and rifampicin modified catheter (n=118) or a standard triple-lumen CVC (n=105). MEASUREMENTS, DEFINITIONS: Microbiological evaluation was done after CVC removal. A catheter was considered colonized if growth of > or =15 cfu was found by semi-quantitative roll-plate technique from a proximal or distal catheter segment. A catheter-related infection (CRI) was defined as a colonized catheter with local signs of inflammation. A catheter-related bloodstream infection (CR-BSI) was defined as a colonized catheter with isolation of the same organism from the patient's blood with accompanying clinical signs of infection. RESULTS: A colonization of CVC was observed in six patients (5.1%) with a modified catheter and 38 patients (36.2%) with a standard catheter (P < 0.001). Five patients in the modified group (4.2%) and 18 in the standard group (17.1%) developed CRI (P=0.002). One assumed CR-BSI was detected in the standard group, with none in the modified group. No adverse effects related to the modified catheters and no antimicrobial resistance were observed. CONCLUSION: CVC supersaturated with miconazole and rifampicin were associated with a significantly lower risk for catheter colonization and catheter-related infections compared to standard catheters.


Assuntos
Anti-Infecciosos/uso terapêutico , Cateterismo Venoso Central/efeitos adversos , Cateteres de Demora/microbiologia , Miconazol/uso terapêutico , Rifampina/uso terapêutico , Sepse/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Cateterismo Venoso Central/instrumentação , Contaminação de Equipamentos/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/microbiologia , Micoses/prevenção & controle , Estudos Prospectivos , Sepse/microbiologia , Resultado do Tratamento
8.
J Biochem Biophys Methods ; 59(3): 217-27, 2004 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-15165753

RESUMO

Bacteria of implant infections are extremely resistant to antibiotics. One reason for this antibiotic resistance are transposons; the well-known transposon Tn10, for example, mediates tetracycline resistance to Escherichia coli. Two genes of Tn10, tetA and tetR, are essential for the mechanism of resistance. These genes encode a drug-specific efflux protein and a tetracycline repressor protein, respectively. Tn10 is also widely used in molecular biology. For example, tTA, a recombinant derivate of tetR, has been utilised for a highly efficient gene regulation system in mammalian cells. We have examined E. coli isolates from implant infections for tetracycline resistance and for the presence of tetR. A real-time PCR assay was developed for detection of tetR with SybrGreen using the Opticon PCR machine of MJ Research. This method offers a quick, sensitive, efficient, and reliable approach to the detection and quantification of genes. Clinical isolates of E. coli were examined successfully for tetracycline resistance and for the presence of tetR. The real-time PCR is effective using a variety of templates including isolated E. coli DNA, pure colonies, or liquid culture sources. Using quantified standard DNA, this assay can accurately detect as few as 15 copies. Moreover, this assay has the ability to quantify the number of tetR genes in the presence of contaminating mammalian DNA. In conclusion, the tetR real-time PCR offers new methods for detection and quantification of tetracycline-resistant bacteria and tTA in transfected cell-lines or transgenic animals.


Assuntos
Proteínas de Escherichia coli/genética , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Compostos Orgânicos , Reação em Cadeia da Polimerase/métodos , Resistência a Tetraciclina/genética , Transposases/genética , Benzotiazóis , Diaminas , Escherichia coli/classificação , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/análise , Perfilação da Expressão Gênica/métodos , Humanos , Sistemas On-Line , Infecções Relacionadas à Prótese/microbiologia , Quinolinas , Transposases/análise
9.
Arzneimittelforschung ; 52(7): 543-51, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12189778

RESUMO

UNLABELLED: The concentration-dependent toxic effects of exogenous noradrenaline (NA, CAS 51-41-2) on acute regional myocardial ischemia (MI) was investigated with and without alpha- and beta-adrenoceptor blockade. Electrically-driven rabbit Langendorff-hearts with depleted catecholamine stores were used (reserpin 7.0 mg/kg i.p. 16-24 h before preparation, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and quantitated from epicardial NADH-fluorescence photography. Starting after a reperfusion period of 20 min, hearts were treated with exogenous NA (10(-7), 10(-6) or 10(-5) mol/l). Adrenoceptors were blocked by propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l). Without adrenoceptor blockers, NA 10(-6) mol/l induced an increase in left ventricular pressure and a reduction in the relative coronary flow. Concomitantly, MI was enhanced. After adrenoceptor blockade, NA 10(-7) or 10(-6) mol/l had no influence on functional parameters. MI was not affected by NA 10(-7) mol/l, but MI was significantly enhanced by NA 10(-6) mol/l. MI enhancement by NA 10(-6) mol/l was completely prevented by superoxide dismutase (30 U/ml). Functional effects of NA 10(-5) mol/l were not completely inhibited by adrenoceptor blockers at the concentrations used, and arrythmias were observed. MI was also enhanced by NA 10(-5) mol/l. CONCLUSION: Deleterious effects on MI, that are independent on functional effects, are induced by NA in a micromolar concentration. These direct toxic effects are mediated by superoxide anion radicals. In lower concentrations (10(-7) mol/l), there is no evidence for direct toxic actions of NA independent of functional effects. MI enhancement by NA 10(-5), or 10(-6) mol/l without adrenoceptor blockers may have been caused in part by functional and arrythmogenic effects and/or through the generation of oxygen free radicals.


Assuntos
Agonistas alfa-Adrenérgicos/toxicidade , Coração/efeitos dos fármacos , Norepinefrina/toxicidade , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Estimulação Elétrica , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Microscopia de Fluorescência , Isquemia Miocárdica/induzido quimicamente , Isquemia Miocárdica/patologia , NAD/metabolismo , Perfusão , Pericárdio/efeitos dos fármacos , Pericárdio/metabolismo , Coelhos , Função Ventricular Esquerda/efeitos dos fármacos
10.
Int J Antimicrob Agents ; 19(6): 511-6, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12135842

RESUMO

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.


Assuntos
Anti-Infecciosos/administração & dosagem , Cateteres de Demora , Cálculos Urinários/tratamento farmacológico , Antibacterianos , Anti-Infecciosos/uso terapêutico , Bactérias/classificação , Bactérias/isolamento & purificação , Candida albicans/isolamento & purificação , Cateteres de Demora/microbiologia , Contagem de Colônia Microbiana , Humanos
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