RESUMO
von Willebrand disease (VWD) was first described nearly a century ago in 1924 by Erik Adolf von Willebrand. Diagnostic testing at the time was very limited and it was not until the mid to late 1900s that more tests became available to assist with the diagnosis and classification of VWD. Two of these tests are based on ristocetin, one being ristocetin-induced platelet aggregation (RIPA) and the other the von Willebrand factor (VWF) ristocetin cofactor assay (VWF:RCo). The VWF:RCo assay provides functional assessment of in vitro VWF binding to the platelet glycoprotein (Gp) complex, GPIb-IX-V. Despite some advancements and newer technologies utilizing the principles of the original VWF:RCo assay, the original assay is still referred to as the gold standard for measurement of VWF activity. This article will review the history of VWD diagnostic assays, including RIPA and VWF:RCo over the past 40 years, as well as the newer assays that measure platelet binding with or without ristocetin, and which have been developed with the aim to potentially replace platelet-based ristocetin-dependent assays.
Assuntos
Plaquetas/metabolismo , Ristocetina/uso terapêutico , Doenças de von Willebrand/tratamento farmacológico , Humanos , Agregação Plaquetária/efeitos dos fármacos , Ristocetina/administração & dosagem , Doenças de von Willebrand/diagnósticoRESUMO
Antimicrobial drug resistance is a serious public health problem and the development of new antibiotics has become an important priority. Ristocetin A is a class III glycopeptide antibiotic that is used in the diagnosis of von Willebrand disease and which has served as a lead compound for the development of new antimicrobial therapeutics. The 1.0 A resolution crystal structure of the complex between ristocetin A and a bacterial cell-wall peptide has been determined. As is observed for most other glycopeptide antibiotics, it is shown that ristocetin A forms a back-to-back dimer containing concave binding pockets that recognize the cell-wall peptide. A comparison of the structure of ristocetin A with those of class I glycopeptide antibiotics such as vancomycin and balhimycin identifies differences in the details of dimerization and ligand binding. The structure of the ligand-binding site reveals a likely explanation for ristocetin A's unique anticooperativity between dimerization and ligand binding.
Assuntos
Antibacterianos/química , Staphylococcus aureus Resistente à Meticilina , Ristocetina/química , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Biomimética/tendências , Parede Celular/química , Cristalização , Dimerização , Desenho de Fármacos , Humanos , Ligantes , Resistência a Meticilina , Ligação Proteica , Conformação Proteica , Ristocetina/metabolismo , Ristocetina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/análogos & derivados , Vancomicina/química , Vancomicina/metabolismo , Vancomicina/uso terapêutico , Raios XRESUMO
A prospective randomized double-blind study was performed to determine the effects of three colloids, Haemaccel, Gelofusine and albumin, and also saline on platelet activation, platelet aggregation (induced by adenosine diphosphate (ADP), epinephrine, collagen) platelet agglutination by ristocetin and other hemostatic variables in 55 patients undergoing primary unilateral total hip replacement. The fluids were administered according to normal clinical practice and assessments were made immediately before, at the end, and 2 h after the end of surgery. Surgery was accompanied by thrombin generation (increases in thrombin/antithrombin III complex, prothrombin F1 +2 fragment) platelet activation (betaTG) and compromised coagulation. Generally, the platelet activation appeared to result in platelet desensitization and brought about a persistent reduction in platelet aggregation to ADP and epinephrine, irrespective of the fluid used. Additionally, Haemaccel and Gelofusine inhibited ristocetin-induced platelet agglutination and albumin inhibited collagen-induced platelet aggregation. Gross inhibitory effects of Haemaccel that had been predicted from an earlier in vitro study did not occur. Particular fluids had selective additional effects on the hemostatic system. Albumin infusion served to maintain plasma albumin at normal concentrations postsurgery. The two gelatin preparations, Haemaccel and Gelofusine, maintained plasma viscosity. All three colloids led to a transient increase in activated partial thromboplastin time postsurgery and also a transient fall in the concentration of factor VIII, which were accompanied by a transient increase in bleeding time, but there was no measurable increase in blood loss. Inhibition of platelet aggregation by certain colloids may provide additional protection against the increased thrombotic risk in patients following major surgery.
Assuntos
Artroplastia de Quadril/métodos , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Agregação Plaquetária , Difosfato de Adenosina/metabolismo , Idoso , Albuminas/uso terapêutico , Antibacterianos/uso terapêutico , Antitrombina III/biossíntese , Tempo de Sangramento , Sangue/metabolismo , Coloides/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Epinefrina/biossíntese , Epinefrina/farmacologia , Feminino , Gelatina/química , Gelatina/uso terapêutico , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/biossíntese , Substitutos do Plasma/uso terapêutico , Ativação Plaquetária , Poligelina/uso terapêutico , Estudos Prospectivos , Precursores de Proteínas/biossíntese , Protrombina/biossíntese , Ristocetina/farmacologia , Ristocetina/uso terapêutico , Cloreto de Sódio/farmacologia , Succinatos/uso terapêutico , Trombina/biossíntese , Fatores de Tempo , beta-Tromboglobulina/biossínteseRESUMO
This review summarizes the current knowledge of the structure and function of von Willebrand factor and of the pathophysiologic features, diagnosis, classification, and treatment of von Willebrand's disease, the most common congenital bleeding disorder in humans. Specific regions of the von Willebrand factor subunit that are of functional importance have been identified. The structure of these functional domains of von Willebrand factor, as known to date, is described. A classification of von Willebrand's disease, based on the definition of structural and functional abnormalities of the molecule and initial characterization of genetic mutations, is discussed. With more precise characterization of molecular abnormalities, more selective therapeutic intervention for specific subtypes of von Willebrand's disease should eventuate.
Assuntos
Doenças de von Willebrand , Fator de von Willebrand , Sítios de Ligação , Transfusão de Sangue , Colágeno/metabolismo , Desamino Arginina Vasopressina/uso terapêutico , Fator VIII/metabolismo , Glicoproteínas/metabolismo , Heparina/metabolismo , Humanos , Agregação Plaquetária , Glicoproteínas da Membrana de Plaquetas/metabolismo , Ristocetina/uso terapêutico , Doenças de von Willebrand/classificação , Doenças de von Willebrand/terapia , Fator de von Willebrand/análise , Fator de von Willebrand/química , Fator de von Willebrand/fisiologiaRESUMO
Therapeutic efficacy of ristomycin in visceral actinomycosis, a severe disease difficult for diagnosis requiring long-term complex therapy was studied on 24 rabbits. The animals were divided into 4 groups. A model of thoracal actinomycosis was developed. 7 rabbits were treated with ristomycin. The other 7 rabbits were treated with ristomycin in combination with actinolysate, a specific immune preparation. 5 rabbits were treated with actinolysate alone and the other 5 rabbits received no treatment. alone and especially in combination with actinolysate was an efficient therapeutic agent for treatment of severe visceral actinomycosis. This allowed to recommend ristomycin for clinical trials in treatment of the disease.
Assuntos
Infecções por Actinomycetales/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Ristocetina/uso terapêutico , Infecções por Actinomycetales/mortalidade , Infecções por Actinomycetales/patologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Bacteriocinas/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Pulmão/patologia , Pneumopatias/mortalidade , Pneumopatias/patologia , Coelhos , Streptomyces , Fatores de TempoRESUMO
Experiments with a model of intraperitoneal or intragastric lincomycin-induced fatal colitis indicated that eremomycin, vancomycin and ristomycin administered orally in daily doses of 100, 100 and 200 mg/kg, respectively, for 5 days protected the animals from development of antibiotic-associated colitis (AAC), which was evident from prolongation of their life-span to 10-23 days against 3-9 days in the controls. Eremomycin administered intraperitoneally according to an analogous scheme protected the animals from development of AAC, prevented 45 per cent of the animals from death and prolonged the life-span of the other animals to 15-28 days against 3-9 days in the controls. Vancomycin administered intraperitoneally was somewhat more efficient. Still, unlike eremomycin it had a local irritating effect. The protective effect of ristomycin administered intraperitoneally was much lower than that of vancomycin and eremomycin.
Assuntos
Antibacterianos/uso terapêutico , Colite/tratamento farmacológico , Ristocetina/uso terapêutico , Vancomicina/uso terapêutico , Administração Oral , Animais , Antibacterianos/administração & dosagem , Colite/induzido quimicamente , Cricetinae , Modelos Animais de Doenças , Feminino , Glicopeptídeos , Injeções Intraperitoneais , Lincomicina , Mesocricetus , Ristocetina/administração & dosagem , Vancomicina/administração & dosagemRESUMO
The study of antibacterial and chemotherapeutic activity of eremomycin, a novel glycopeptide antibiotic showed that it inhibited the growth of gram positive and acid fast microbes. The antibacterial spectrum of the novel glycopeptide was close to that of ristomycin and vancomycin. However, the in vitro antibacterial activity of eremomycin was 2-10 times higher than that of ristomycin and vancomycin. It also inhibited the growth of oxacillin resistant microbes at concentrations 5.20 times lower than those of vancomycin and ristomycin. By the therapeutic efficacy in albino mice with staphylococcal or streptococcal sepsis eremomycin was 2-4 times as superior as vancomycin and ristomycin and by the chemotherapeutic indices it was more than 10 times as superior.
Assuntos
Antibacterianos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Glicopeptídeos/farmacologia , Glicopeptídeos/uso terapêutico , Camundongos , Ristocetina/farmacologia , Ristocetina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Vancomicina/farmacologia , Vancomicina/uso terapêuticoAssuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Antibacterianos/efeitos adversos , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Cloranfenicol/efeitos adversos , Cloranfenicol/uso terapêutico , Combinação de Medicamentos , Eritromicina/efeitos adversos , Eritromicina/uso terapêutico , Humanos , Resistência às Penicilinas , Penicilinas/efeitos adversos , Penicilinas/uso terapêutico , Rifampina/efeitos adversos , Rifampina/uso terapêutico , Ristocetina/efeitos adversos , Ristocetina/uso terapêutico , Tetraciclina/efeitos adversos , Tetraciclina/uso terapêutico , Vancomicina/efeitos adversos , Vancomicina/uso terapêuticoRESUMO
In vitro studies showed that ristomycin was the most active against actinomycetes causing actinomycosis as compared to benzylpenicillin, ampicillin, methicillin and lincomycin. The growth of the test microbes was inhibited by ristomycin in concentrations of 61--122 mg/ml. Since ristomycin was the most active against actinomycetes, its levels in the blood, parenchymatous organs, capsule and pus of actinomycomas of 5 rabbits infected wtih actino nycosis in the submaxillary area were determined. In the control healthy rabbit, the ristomycin levels were determined in the blood and organs. Ristomycin was administered intravenously in a single dose of 7000 mg/kg. Its concentrations in the animals were determined in 2.5 hours. The results of the experiments showed that ristomycin penetrated in therapeutic concentrations into the connective tissue capsule of actinomycoma. As for the other antibiotics tested earlier, they failed to penetrate this barrier. In 3 infected rabbits, ristomycin penetrated even the pus contained in actinomycoma. Ristomycin provides therapeutic concentrations in the disease focus and may produce a satisfactory therapeutic effect in treatment of actinomycosis.
Assuntos
Actinomicose/tratamento farmacológico , Permeabilidade da Membrana Celular/efeitos dos fármacos , Ristocetina/uso terapêutico , Absorção , Actinomyces/efeitos dos fármacos , Aerobiose , Animais , Testes de Sensibilidade Microbiana , Coelhos , Ristocetina/metabolismo , Fatores de Tempo , Distribuição TecidualRESUMO
A heat-treated factor VIII (F VIII) concentrate (Haemate P) has been administered to patients with various types of von Willebrand's disease (vWD). The 4 activities of F VIII/vWF as well as change in the multimeric structure of vWF were then studied. In 4 patients with type I vWF who were given a Ristocetin cofactor (Rcof) dose of 42-78 U/kg, there was a clear reduction of the bleeding time and an increase of F VIII: C, F VIII: Ag, Rcof and vWF: Ag for several hours. The recovery of Rcof. after 1 h was 50-75%. Although the multimeric composition of vWF in these patients was similar to that of normal plasma, the density of each multimer band was very low. After infusion, however, the density of all multimer bands increased for several hours, to decrease again after 24 h. In 4 patients with type II A vWD who received a dose of Rcof of 55-76 U/kg, the 4 activities of F VIII/vWF increased similarly as was the case in type I. All patients had only 3-4 smaller multimer bands. New larger and intermediate multimers appeared for several hours after infusion of the preparation. Two patients with type III vWD who received doses of Rcof of 52 and 65 U/kg showed also a similar increase in the 4 activities of F VIII/vWF after infusion. All the multimers lacking in these patients appeared for several hours after infusion.