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1.
J Oral Rehabil ; 43(11): 863-870, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27611605

RESUMO

More studies evaluating the outcome of dental implant restorations in diabetics are needed. To investigate the outcome of immediate function implant rehabilitations in diabetic patients. This retrospective cohort study included 70 diabetic patients (type 1 = six patients; type 2 = 64 patients; 33 females and 37 males, mean age=59 years), rehabilitated with 352 implants. Primary outcome measure was implant survival estimated at 5 years through the Kaplan-Meier product limit estimator using the patient as unit of analysis (first implant failure as reference); secondary outcome measures were marginal bone loss and biological complications. Risk indicators associated with bone loss >2·0 mm were tested in a multivariate logistic regression model. The level of significance considered was 5%. Seven patients were lost to follow-up (10%). Seven patients lost ten implants rendering a global implant cumulative survival rate for diabetic patients of 89·8% (type 1 = 80·0%; type 2 = 90·5%). The average (95% confidence interval) marginal bone loss at 1 and 5 years was 1·64 mm (0·00;3·32) and 2·55 mm (1·38;3·72) for type 1 diabetic patients, 0·79 mm (0·59;1·00) and 1·45 mm (1·09;1·82) for type 2 diabetic patients and 0·88 mm (0·65;1·10) and 1·56 mm (1·21;1·91) overall. Biological complications occurred in seven patients. Female gender (OR = 28·1) and smoking habits (OR = 10·3) were risk indicators for marginal bone loss >2·0 mm at 5 years when controlled for other variables of interest. Implant rehabilitations represent a valid treatment for diabetic patients, with a good risk/benefit ratio. Female gender and smoking habits were risk indicators for a higher marginal bone resorption at 5 years.


Assuntos
Perda do Osso Alveolar/prevenção & controle , Implantes Dentários , Prótese Dentária Fixada por Implante , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda do Osso Alveolar/fisiopatologia , Glicemia , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores de Risco
2.
J Oral Rehabil ; 42(8): 615-23, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25757870

RESUMO

More studies evaluating the outcome of short-length dental implants in immediate loading are needed. To evaluate the use of short-length tapered implants in immediate loading for complete edentulous maxillae rehabilitations using an All-on-4 design. This retrospective clinical study included a cohort of 43 patients with 172 implants (74 short-length implants) inserted in low bone quantity. The patients were followed between 4 months and 6 years (average = 3 years). Outcome measures were implant survival, marginal bone remodelling, biological and mechanical complications. Two patients with four short-length implants were lost to follow-up during the first year. Three short and three long implants failed in four patients, rendering an overall cumulative survival rate implant and patient level, respectively, of 95.7% and 95.1% for short implants, 100% for regular implants and 96.6% and 95.2% for long implants. The average marginal bone remodelling at 1 and 3 years was 0.97 and 1.25 mm for the short implants, 0.82 and 0.87 mm for regular implants and 0.87 and 0.98 mm for long implants. Three patients presented 4 short-length implants with peri-implant pockets (3 implants in 2 patients were pseudo-pockets). Mechanical complications were registered in 13 patients (7 provisional prostheses fractures and 6 abutment screw loosening). All complications were treated successfully. Within the limitations of this clinical study, the short-term outcome of fixed prosthetic complete edentulous maxillae rehabilitations supported by short-length implants inserted in low bone quantity areas is viable. Long-term clinical studies are necessary for evaluating the outcome of these implants.


Assuntos
Implantes Dentários , Planejamento de Prótese Dentária , Prótese Dentária Fixada por Implante , Carga Imediata em Implante Dentário , Arcada Edêntula/reabilitação , Adulto , Idoso , Idoso de 80 Anos ou mais , Falha de Restauração Dentária , Feminino , Humanos , Masculino , Maxila/fisiopatologia , Maxila/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
4.
Eur J Prosthodont Restor Dent ; 22(3): 125-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25831714

RESUMO

Peri-implant pathology is a multifactorial disease, incorporating biological and biomechanical components in its pathogenesis; however; few studies address the possible risk factors. This study investigated the effect of implant location and position characteristics on the occurrence of Peri-implant pathology. A total of 1350 patients with dental implants were included 270 patients with peri-implant pathology and 1080 healthy controls. Results demonstrated that in the absence of bacterial plaque and smoking, the variable proximity of the implant to other implants or teeth revealed a significant difference between groups with a protective effect, but not in the presence of bacterial plaque and smoking.


Assuntos
Implantação Dentária Endóssea/métodos , Implantes Dentários , Peri-Implantite/etiologia , Estomatite/etiologia , Adulto , Estudos de Casos e Controles , Placa Dentária/complicações , Prótese Dentária Fixada por Implante , Feminino , Seguimentos , Humanos , Arcada Parcialmente Edêntula/reabilitação , Arcada Parcialmente Edêntula/cirurgia , Masculino , Pessoa de Meia-Idade , Boca Edêntula/reabilitação , Boca Edêntula/cirurgia , Perda da Inserção Periodontal/etiologia , Índice Periodontal , Bolsa Periodontal/etiologia , Estudos Retrospectivos , Fatores de Risco , Fumar , Dente/patologia
5.
Clin Oral Implants Res ; 23(1): 49-54, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21504480

RESUMO

OBJECTIVES: The aim of the present multi-center study was to evaluate the treatment outcome of immediately restored one-piece single-tooth implants with a diameter of 3 mm after 1 year. MATERIAL AND METHODS: A total of 57 one-piece implants (NobelDirect 3.0) were inserted in 47 patients (26 females, 21 males) with a mean age of 31 years (range: 17-76 years) at five different centers. The implants replaced maxillary lateral incisors and mandibular incisors. The implants were placed either in conjunction with tooth extraction or in healed sites, and all implants were immediately restored with a provisional resin crown. If needed, the abutment part of the implant was prepared before crown cementation. The permanent crown was placed after 1.9-14.5 months. Radiographs were taken at implant insertion as well as after 6 and 12 months to evaluate the peri-implant marginal bone level and bone loss. Moreover, plaque, bleeding on probing and complications were assessed. RESULTS: A total of 44 patients (23 females, 21 males) with 54 implants were available for the 1-year follow-up. One implant was lost, thus the 1-year implant survival was 98%. A statistically significant mean marginal bone loss was observed between baseline and 6 months (1.1 mm, range: -0.7 to 4.4 mm; n=49) and between baseline and 12 months (1.6 mm, range: -0.8 to 4.6 mm; n=50). A total of 18% of the implants were characterized by a bone loss of more than 3 mm. No bleeding on probing was observed around 83% of the implants. Plaque was registered at 15% of the implants. The most common complications were related to the provisional crown, i.e. fracture (n=3) and loss of retention (n=3). CONCLUSIONS: A high 1-year implant survival was observed in the present study. However, the excessive peri-implant marginal bone loss around several implants indicates that this implant should be used with caution until further studies have been conducted.


Assuntos
Implantes Dentários para Um Único Dente , Incisivo/cirurgia , Adolescente , Adulto , Idoso , Perda do Osso Alveolar/etiologia , Colágeno , Planejamento de Prótese Dentária , Retenção em Prótese Dentária , Prótese Dentária Fixada por Implante , Restauração Dentária Temporária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minerais , Politetrafluoretileno , Estudos Prospectivos , Estatísticas não Paramétricas , Retalhos Cirúrgicos , Extração Dentária , Resultado do Tratamento
6.
Gut ; 59(11): 1476-84, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20947883

RESUMO

BACKGROUND AND AIMS: The intestinal microbiota plays a critical role in maintaining human health; however, the mechanisms governing the normal homeostatic number and composition of these microbes are largely unknown. Previously it was shown that intestinal alkaline phosphatase (IAP), a small intestinal brush border enzyme, functions as a gut mucosal defence factor limiting the translocation of gut bacteria to mesenteric lymph nodes. In this study the role of IAP in the preservation of the normal homeostasis of the gut microbiota was investigated. METHODS: Bacterial culture was performed in aerobic and anaerobic conditions to quantify the number of bacteria in the stools of wild-type (WT) and IAP knockout (IAP-KO) C57BL/6 mice. Terminal restriction fragment length polymorphism, phylogenetic analyses and quantitative real-time PCR of subphylum-specific bacterial 16S rRNA genes were used to determine the compositional profiles of microbiotas. Oral supplementation of calf IAP (cIAP) was used to determine its effects on the recovery of commensal gut microbiota after antibiotic treatment and also on the colonisation of pathogenic bacteria. RESULTS: IAP-KO mice had dramatically fewer and also different types of aerobic and anaerobic microbes in their stools compared with WT mice. Oral supplementation of IAP favoured the growth of commensal bacteria, enhanced restoration of gut microbiota lost due to antibiotic treatment and inhibited the growth of a pathogenic bacterium (Salmonella typhimurium). CONCLUSIONS: IAP is involved in the maintenance of normal gut microbial homeostasis and may have therapeutic potential against dysbiosis and pathogenic infections.


Assuntos
Fosfatase Alcalina/fisiologia , Intestino Delgado/enzimologia , Intestino Delgado/microbiologia , Metagenoma/fisiologia , Administração Oral , Fosfatase Alcalina/deficiência , Fosfatase Alcalina/farmacologia , Animais , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Fezes/microbiologia , Bactérias Aeróbias Gram-Negativas/isolamento & purificação , Bactérias Anaeróbias Gram-Negativas/isolamento & purificação , Homeostase/fisiologia , Metagenoma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Filogenia , Polimorfismo de Fragmento de Restrição , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/crescimento & desenvolvimento
7.
J Microbiol Methods ; 169: 105818, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31881287

RESUMO

Clostridium tyrobutyricum is the major agent that causes the blowing defect in cheese due to the germination of its dormant spores during the ripening stage. As a result, many of the affected cheeses show cavities and cracks, which cause the product loss in most cases. Nowadays, there is not a fast method capable of detecting milk contaminated with C. tyrobutyricum spores. The aim of this study has been to develop a fast and reliable method based on real time PCR (qPCR) to detect C. tyrobutyricum spores in raw milk. One of the main limitations has been to find a good procedure for the spore disruption to extract the DNA due to its high resistance. For this reason, different disruption methods have been tested, including chemical agents, bead beating, enzymatic and microwave treatment. Furthermore, an enzymatic treatment with subtilisin was applied for milk clarification and recovery of spores. The comparison of the assayed methods has been made using sterile milk spiked with C. tyrobutyricum spores, obtained in solid or liquid medium. The results showed that microwave treatment followed by a standard DNA purification step was found to be the best disruption method. The Ct values obtained for spores were higher than those found for vegetative cells by qPCR, for the same quantity of DNA. This difference could be due to the action of the Small Acid Soluble Proteins (SASP) in the DNA packaging of spores. Moreover, spores obtained in agar plate were found more resistant to disruption than those obtained in liquid medium. Subtilisin and microwave treatments were found to be successful for DNA extraction from C. tyrobutyricum spores in milk and subsequent identification by qPCR. However, the differences observed between the amplification of DNA from spores obtained in different media and from vegetative cells have to be taken into account to optimize a method for C. tyrobutyricum detection.


Assuntos
Queijo/microbiologia , Clostridium tyrobutyricum/genética , DNA Bacteriano/genética , Leite/microbiologia , Esporos Bacterianos/genética , Animais , Extratos Celulares/genética , Clostridium tyrobutyricum/isolamento & purificação , Microbiologia de Alimentos/métodos , Reação em Cadeia da Polimerase em Tempo Real , Esporos Bacterianos/metabolismo , Subtilisina/farmacologia
8.
Int J Oral Maxillofac Surg ; 47(8): 1079-1085, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29735198

RESUMO

The aim of this retrospective clinical study was to evaluate the short-term implant success rate and marginal bone loss in full-arch fixed prosthetic maxillary rehabilitations supported by implants in immediate function with the All-on-4 treatment concept placed with insertion torque of <30N·cm or ≥30N·cm. This study included 83 patients (69 female, 14 male) with 332 implants placed (120 inserted with <30N·cm and 212 inserted with ≥30N·cm) who were treated between January 2010 and March 2013. Outcome measures were implant success and marginal bone loss at 1year of follow-up. Ten patients (12.0%; 13 implants inserted with <30N·cm and 27 implants with ≥30N·cm) were lost to follow-up. The cumulative implant success rate was 97.5% at the patient level, and 98.3% for implants inserted with <30N·cm and 97.5% for implants inserted with ≥30N·cm. The mean±standard deviation marginal bone loss at 1year was 1.14±0.38mm for implants inserted with <30N·cm and 1.39±0.49mm for implants inserted with ≥30N·cm (significant difference; P<0.001, Wilcoxon signed rank test). These results indicate that implants with insertion torques of <30N·cm may render comparable success rates and marginal bone loss at 1year compared to implants inserted with insertion torques of ≥30N·cm.


Assuntos
Implantação Dentária Endóssea/métodos , Implantes Dentários , Prótese Dentária Fixada por Implante , Prótese Total Superior , Arcada Edêntula/reabilitação , Maxila/cirurgia , Perda do Osso Alveolar/epidemiologia , Falha de Restauração Dentária/estatística & dados numéricos , Planejamento de Dentadura , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Torque , Resultado do Tratamento
9.
Int J Oral Maxillofac Surg ; 46(12): 1592-1599, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28655434

RESUMO

The aim of this study was to evaluate the outcomes of immediate full-arch prostheses supported by zygomatic implants alone or in combination with standard fixtures after a minimum of 6 years of loading. From October 2008 to April 2010, 15 patients with severely atrophic maxillae were treated using four zygomatic implants or two zygomatic implants in conjunction with two conventional fixtures. All subjects received a fixed screw-retained prosthesis within 3hours of surgery, while the final restoration was delivered after 6 months. Follow-up examinations were scheduled to evaluate zygomatic implant survival, conventional dental implant success, prosthetic success, plaque and bleeding scores, marginal bone loss for conventional dental implants, and patient satisfaction. Forty-two zygomatic fixtures and 18 standard implants were placed. Patients were followed up for a minimum of 79 months (range 79-97 months, average 90.61 months). No implant was lost, leading to implant and prosthetic survival rates of 100%. Bone loss for conventional implants averaged 1.39±0.10mm after 6 years of function, leading to a 100% implant success rate. High levels of patient satisfaction were recorded. These medium-term results indicate that immediate full-arch rehabilitation supported by zygomatic implants could be considered a viable treatment modality for the severely atrophic maxilla.


Assuntos
Implantes Dentários , Prótese Dentária Fixada por Implante , Carga Imediata em Implante Dentário , Arcada Edêntula/reabilitação , Maxila/patologia , Maxila/cirurgia , Zigoma/cirurgia , Idoso , Atrofia , Feminino , Seguimentos , Humanos , Arcada Edêntula/diagnóstico por imagem , Masculino , Maxila/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos Prospectivos , Radiografia Panorâmica , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Zigoma/diagnóstico por imagem
10.
Clin Transl Oncol ; 17(2): 121-32, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25037851

RESUMO

PURPOSE: Sorafenib is a multikinase inhibitor that targets the MAPK pathway and is currently used for the treatment of hepatocellular and renal carcinoma. Recently, it has been shown that sorafenib is also cytotoxic to multiple myeloma (MM) cells. Here, we have further analyzed the mechanism of sorafenib-induced death in MM cells. METHODS: Cell death induced by sorafenib in MM cell lines and in plasma cells from MM patients was evaluated by analysis of gene expression by RT-MLPA and quantitative PCR, protein levels and functionality by Western blot and flow cytometry and gene silencing with siRNA. RESULTS: Cell death was characterized by phosphatidylserine exposure, ΔΨm loss, cytochrome c release and caspase activation, hallmarks of apoptosis. DL50 at 24 h ranged from 6 to 10 µM. Ex vivo treatment with 20 µM sorafenib induced apoptosis in around 80 % myeloma cells from six multiple myeloma patients. Sorafenib induced caspase-dependent degradation of Bcl-xL and Mcl-1 proteins, destabilizing the mitochondria and speeding up the development of apoptosis. Sorafenib treatment increased levels of Puma at mRNA and protein level and gene silencing with siRNA confirmed a relevant role for Puma in the induction of apoptosis. Co-treatment with the pan-caspase inhibitor Z-VAD-fmk prevented cell death to a variable degree depending on the cell line. In RPMI 8226 cells, Z-VAD-fmk prevented most of sorafenib-induced death. However, death in MM.1S was only prevented by co-incubation with both Z-VAD-fmk and the RIP1K inhibitor necrostatin-1, indicating that under conditions of inefficient caspase activation, sorafenib induces death by necroptosis. CONCLUSION: Our results demonstrate a key role for Puma in the triggering of sorafenib-induced apoptosis and that this drug can also induce death by necroptosis in multiple myeloma cells.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Mitocôndrias/patologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Western Blotting , Inibidores de Caspase/farmacologia , Caspases/química , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mieloma Múltiplo/metabolismo , Necrose , Niacinamida/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sorafenibe , Células Tumorais Cultivadas
11.
Clin Transl Oncol ; 17(8): 657-67, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25967100

RESUMO

PURPOSE: Human Apo2-Ligand/TRAIL secreted by natural killer cells and cytotoxic T lymphocytes plays an important role immunosurveillance controlling tumor growth and metastasis. Moreover, the fact that Apo2L/TRAIL is capable of inducing cell death in tumor cells but not in normal cells makes this death ligand a promising anti-tumor agent. Previous data from our group demonstrated that Apo2L/TRAIL was physiologically released as transmembrane protein inserted in lipid vesicles, called exosomes. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) resembling the natural exosomes, greatly improved Apo2L/TRAIL activity and were able to induce apoptosis in hematological malignancies. In this study, we have deepened in the underlying mechanism of action of LUV-TRAIL in hematologic cells. METHODS/PATIENTS: Cytotoxic ability of LUV-TRAIL was assessed on Jurkat cells either over-expressing the anti-apoptotic protein Mcl1 or down-regulating the pro-apoptotic protein Bim previously generated in our laboratory. We also tested LUV-TRAIL cytotoxic ability against primary human leukemic cells from T-cell ALL patient. RESULTS: Silencing Bim but not Mcl-1 over-expression partially protects Jurkat cells from apoptosis induced by sTRAIL. LUV-TRAIL induced caspase-8 and caspase-3 activation and killed Jurkat-Mcl1 and Jurkat-shBim more efficiently than sTRAIL independently of the mitochondrial pathway. On the other hand, LUV-TRAIL were clearly more cytotoxic against primary leukemic cells from a T-cell ALL patient than sTRAIL. CONCLUSION: Tethering Apo2L/TRAIL to the surface of lipid nanoparticles greatly increases its bioactivity and could be of potential use in anti-tumor therapeutics.


Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose , Imunoterapia , Leucemia/patologia , Leucemia/terapia , Lipossomos , Proteínas de Membrana/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Western Blotting , Proliferação de Células , Células Cultivadas , Regulação para Baixo , Humanos , Técnicas Imunoenzimáticas , Leucemia/imunologia , Leucemia/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
12.
J Med Chem ; 43(4): 690-705, 2000 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-10691695

RESUMO

A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.


Assuntos
Leucotrieno B4/antagonistas & inibidores , Quinolinas/síntese química , Resinas Acrílicas , Anafilaxia/tratamento farmacológico , Animais , Antialérgicos/síntese química , Antialérgicos/química , Antialérgicos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Líquido Ascítico/metabolismo , Granuloma/induzido quimicamente , Granuloma/tratamento farmacológico , Humanos , Técnicas In Vitro , Leucotrieno B4/biossíntese , Masculino , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Pleuropneumonia/tratamento farmacológico , Pneumonia/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
13.
J Med Chem ; 43(17): 3322-34, 2000 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-10966751

RESUMO

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4, 4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47.Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47.Na inhibited ionophore-stimulated LTB(4) formation with an IC(50) = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC(4) and PGE(2), 47.Na showed 9000-fold selectivity for inhibition of LTC(4) (IC(50) = 0.16 nM) over PGE(2) (IC(50) = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED(50) = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB(4), ED(50) = 2.5 mg/kg; LTE(4), ED(50) = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47.Na dosed orally blocked bronchoconstriction with an ED(50) = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47.Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB(4) and LTC(4) but not PGH(2) biosynthesis. However, 47.Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47.Na acts as a FLAP inhibitor.


Assuntos
Ácidos Carboxílicos/síntese química , Antagonistas de Leucotrienos/síntese química , Ácidos Pentanoicos/síntese química , Quinolinas/síntese química , Administração Oral , Anafilaxia/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Broncoconstrição/efeitos dos fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Eosinófilos/patologia , Cobaias , Humanos , Técnicas In Vitro , Antagonistas de Leucotrienos/química , Antagonistas de Leucotrienos/farmacocinética , Antagonistas de Leucotrienos/farmacologia , Leucotrieno B4/antagonistas & inibidores , Leucotrieno B4/biossíntese , Pulmão/patologia , Macaca fascicularis , Camundongos , Neutrófilos/metabolismo , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , Peritônio/metabolismo , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade
14.
Ann N Y Acad Sci ; 696: 205-15, 1993 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-8109828

RESUMO

The importance of leukotrienes as mediators of inflammation and bronchoconstriction was examined with two recently described 5-lipoxygenase inhibitors, zileuton and A-78773. Preclinical evaluation of these two molecules indicates that they are potent, selective, direct, reversible inhibitors of 5-lipoxygenase with activity in a variety of purified cells and in more complex biological systems such as whole blood, lung fragments, and tracheal tissues. In various animals models of inflammation and allergy, the molecules inhibited edema, inflammatory cell influx, and bronchospasm. These observations are consistent with the recent clinical success of zileuton in treating asthma and inflammatory bowel disease. In all preclinical systems tested thus far, A-78773 is more potent and longer acting than zileuton, indicating that the molecule could be even more effective in the clinic than zileuton and that both molecules are useful tools in defining the role of leukotrienes in preclinical and clinical settings.


Assuntos
Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase/farmacologia , Animais , Espasmo Brônquico/prevenção & controle , Cobaias , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Inflamação/prevenção & controle , Leucotrieno B4/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Ratos
15.
Artigo em Inglês | MEDLINE | ID: mdl-2470112

RESUMO

Recently identified Ascaris suum sensitive cynomolgus monkeys were further characterized to determine if a chronologic relationship existed between mediator release and onset of bronchoconstriction. In these anesthetized Ascaris-sensitive monkeys, aerosol antigen challenge of each animal produced rapid and severe bronchoconstriction, as determined by decreases in dynamic lung compliance (-80.2 +/- 4.1%) and airway conductance (-64.5 +/- 13.8%). Maximum changes were achieved within 5 min following exposure and remained substantially altered throughout the 30 min observation period. However, changes in pulmonary function related to duration of onset and maximum change seemed to have some correlation with each animals' sensitivity to the antigen. Comparison of pre- and post-challenge blood gas profiles, showed a progressive formation of respiratory acidosis through decreases in arterial blood pH, partial pressure of O2 (pO2), O2 saturation (sO2) and an increase in partial pressure of CO2 (pCO2). When arterial blood plasma was assayed by RIA for mediators of anaphylaxis, large increases in 5-hydroxyeicostetraenoi acid (5-HETE), leukotriene B4 (LTB4) and histamine were observed. No amount of prostaglandin F2-alpha (PGF2 alpha) or thromboxane A2 were detected. Two of the three monkeys also produced detectable amounts of leukotriene C4 (LTC4). Therefore, in Ascaris-sensitive monkeys, histamine is the predominate mediator released and is probably responsible for at least the early part (5-10 min) of the observed bronchoconstriction. However, mediators from the lipoxygenase pathway may also be playing a role in the antigen-induced bronchoconstriction, especially beyond the 10 min period following anaphylaxis.


Assuntos
Ascaris/imunologia , Asma/fisiopatologia , Dinoprosta/metabolismo , Liberação de Histamina , Ácidos Hidroxieicosatetraenoicos/metabolismo , Leucotrienos/metabolismo , Tromboxano B2/metabolismo , Animais , Antígenos de Helmintos/administração & dosagem , Dinoprosta/sangue , Histamina/sangue , Ácidos Hidroxieicosatetraenoicos/sangue , Leucotrienos/sangue , Macaca fascicularis , Masculino , Radioimunoensaio , Testes de Função Respiratória , Tromboxano B2/sangue , Fatores de Tempo
16.
Eur J Pharmacol ; 86(1): 27-34, 1982 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-6130955

RESUMO

The airway effects of adrenergic receptor stimulation/inhibition were investigated in sets of normal (N) and natively ascaris-sensitized (S) beagle dogs. In one group, the effect of beta-adrenergic stimulation/alpha-adrenergic inhibition in airway conductance (Gaw) and dynamic lung compliance (CDYN) were observed. For both N and S dogs, thymoxamine pretreatment served to enhance an isoproterenol inhibition of PGF2 alpha-induced Gaw decreases. No effect was observed in CDYN. In another set of animals, the effects of i.v. administration of norepinephrine (NE), epinephrine (EPI) and phenylephrine (PE), before and after pretreatment with propranolol/indomethacin were observed. For N dogs, all three alpha-adrenergic agents failed to produce bronchospasm; however, propranolol/indomethacin pretreatment significantly potentiated the effects of all three alpha-agents. No significant changes were observed in the CDYN response either prior to or after pretreatment with propranolol/indomethacin. In contrast, for S dogs, all three alpha-agonists produced moderate bronchoconstriction with or without propranolol/indomethacin pretreatment. In addition, the Gaw response to i.v. PE was statistically greater in S dogs than that observed in the N group. Finally, only i.v. PE produced significant decreases in the CDYN response in the S group of animals. These data suggest the presence of alpha-adrenergic influence in the canine airways and elaboration of this action appears to occur best in propranolol/indomethacin-pretreated animals.


Assuntos
Hipersensibilidade/fisiopatologia , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos/fisiologia , Sistema Respiratório/inervação , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Ascaris/imunologia , Dinoprosta , Cães , Feminino , Técnicas In Vitro , Indometacina/farmacologia , Isoproterenol/farmacologia , Masculino , Moxisilita/farmacologia , Contração Muscular/efeitos dos fármacos , Prostaglandinas F/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos
17.
Eur J Pharmacol ; 92(1-2): 69-75, 1983 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-6194999

RESUMO

The effects of calcium channel blockers, nifedipine and verapamil (i.v. and aerosol), were investigated in beagle dogs natively allergic to Ascaris suum antigen. Control exposures to an aerosol of Ascaris antigen provoked significant bronchopulmonary changes, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN). Pretreatment with either nifedipine or verapamil (200 micrograms/kg, i.v.) provided significant inhibition in the RL responses to Ascaris antigen (P less than 0.015) while neither agent significantly affected CDYN changes. When administered as an aerosol, verapamil (1.0%; 10 breaths) significantly inhibited both the RL and CDYN responses to Ascaris antigen (P less than 0.05), whereas a similar concentration of nifedipine was without effect. Resting basal levels of RL and CDYN were unaffected by either the i.v. route or by aerosols of either nifedipine or verapamil. These results suggest that calcium channel blockers may have beneficial effects against allergen-provoked bronchoconstriction; however, differences appear to exist in the choice of agent, route of administration and site of action.


Assuntos
Antígenos/efeitos adversos , Espasmo Brônquico/prevenção & controle , Nifedipino/uso terapêutico , Verapamil/uso terapêutico , Animais , Ascaris/imunologia , Cães , Feminino , Liberação de Histamina/efeitos dos fármacos , Masculino , Nifedipino/farmacologia , Verapamil/farmacologia
18.
Clin Implant Dent Relat Res ; 2(3): 138-46, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11359258

RESUMO

BACKGROUND: Immediate implant function is a psychological benefit for the patient and makes a substantial reduction in treatment cost possible. Currently, immediate function using Brånemark implants has become an accepted alternative for complete-arch fixed restorations in mandibles and for overdenture support for some other screw-shaped implants. Clinical documentation is lacking for other applications. PURPOSE: The purpose of this study was to investigate a concept for immediate function of Brånemark implants supporting fixed prosthesis in the esthetic regions of the jaws. MATERIALS AND METHODS: This retrospective clinical study included 49 consecutively treated patients with 94 implants supporting 54 fixed prostheses, all in esthetically critical regions: 23 of the prostheses were bridges, 14 in maxillae and 9 in mandibles; 31 of the prostheses were crowns, 22 in maxillae and 9 in mandibles. At surgery, the implant platform was positioned above the surrounding bone level and bicortical anchorage was the goal whenever possible. The minimum insertion torque for accepting the implant for immediate function was 32 Ncm. Provisional implant-supported prostheses without occlusal contacts were delivered at time of surgery, and final prostheses with normal occlusion were delivered 5 months later. RESULTS: Eighty-five of the implants (90%) have passed the 1-year and 40 (43%) the 2-year follow-ups, respectively. Two implants failed in one patient before the 6-month follow-up, and another two implants between the 6-month and the 1-year follow-up, in two other patients, giving a cumulative survival rate of 96%. The average bone resorption was 0.8 mm after the first year as evaluated from 35 patients with readable radiographs. The failed implants were replaced after 3 to 4 months with immediate function; these were successful in all cases (not included in this study). The number of complications was small and did not differ in character from those normally encountered at implant treatment using a conventional protocol. CONCLUSIONS: The cumulative survival rate of 96% at 1 and 2 years indicates that immediate function of Brånemark implants used in the esthetic zone in both jaws can be a viable concept. All failures occurred in fresh extraction sites, and extra care is recommended to avoid situations with ongoing inflammation in these situations.


Assuntos
Implantação Dentária Endóssea/métodos , Prótese Dentária Fixada por Implante , Prótese Parcial Imediata , Adolescente , Adulto , Idoso , Perda do Osso Alveolar/etiologia , Dente Pré-Molar , Dente Canino , Retenção em Prótese Dentária , Prótese Dentária Fixada por Implante/efeitos adversos , Falha de Restauração Dentária , Feminino , Seguimentos , Humanos , Incisivo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
Methods Find Exp Clin Pharmacol ; 8(8): 461-8, 1986 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2875234

RESUMO

SK&F 93944, a previously reported non-sedating histamine H1-receptor antagonist, was evaluated for its ability to block pharmacologic-and antigen-induced bronchoconstriction. In the isolated guinea pig trachea, SK&F 93944 (10(-9)-10(-7) M) produced a concentration-dependent inhibition of contractions produced by histamine (pKB = 9.5). Another histamine antagonist, mepyramine (10(-8)-10(-6) M), was less potent (pKB = 8.5). SK&F 93944 (10(-8), 10(-7) M) also significantly depressed the rapid initial phase of antigen-induced contraction of the guinea pig trachea from animals actively sensitized to ovalbumin, while having no effect on the later, more protracted phase of the contractile response. In anesthetized mongrel dogs, selective inhibition of histamine (20 micrograms/kg, i.v.)-induced bronchoconstriction was achieved by SK&F 93944 in doses as low as 30 micrograms/kg, i.v. Terfenadine, a purportedly selective histamine H1-receptor antagonist, blocked both histamine and acetylcholine-induced bronchoconstriction at doses similar to SK&F 93944. In mongrel dogs natively allergic to Ascaris suum antigen, pretreatment with aerosols of either SK&F 93944 or mepyramine (1%; 50 tidal breaths) significantly inhibited bronchospasm elicited by increasing aerosol concentrations of antigen. Thus, SK&F 93944 is a highly potent, selective histamine H1-receptor antagonist which is efficacious vs. pharmacologic and antigen-induced bronchoconstriction.


Assuntos
Brônquios/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Pirimidinonas/farmacologia , Animais , Antígenos/imunologia , Brônquios/fisiologia , Cães , Feminino , Cobaias , Histamina/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Ovalbumina/imunologia , Pirilamina/farmacologia , Traqueia/efeitos dos fármacos
20.
Rev Esp Cardiol ; 51(6): 488-93, 1998 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-9666702

RESUMO

Univentricular heart is an uncommon congenital heart disease. A select group of these patients (those with severe pulmonary stenosis or atresia) can reach adult age with different degrees of heart failure and severe chronic hypoxemia. Patients with adequate pulmonary tree development are likely to undergo heart transplantation when usual palliative techniques are contraindicated. Three cases of univentricular heart with pulmonary stenosis in which heart transplantation was the optimal choice are reported. Different techniques used to assess pulmonary tree development are analysed.


Assuntos
Transplante de Coração , Ventrículos do Coração/anormalidades , Estenose da Valva Pulmonar/cirurgia , Transposição dos Grandes Vasos/cirurgia , Adolescente , Adulto , Feminino , Humanos , Masculino , Estenose da Valva Pulmonar/congênito
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