Acompanhamento farmacoterapêutico a pacientes usuários de enfuvirtida / Pharmaceutical care of patients treated with enfuvirtide

Enfuvirtida é um inibidor de fusão que interfere nascélulas com a penetração do vírus HIV. Sua aplicaçãoé feita por via subcutânea, o que provoca efeitos nocivos no local da aplicação. Os pacientes em uso deenfuvirtida deixam de usá-la constantemente, sugerindo uma baixa adesão devido às diferentes reações quepodem ocorrer com a administração subcutânea do medicamento. O objetivo da pesquisa, portanto, foi avaliar a relação entre a adesão e o acompanhamento farmacoterapêutico a pacientes usuários de enfuvirtida. A pesquisa foi realizada com pacientes com AIDS emuso de enfuvirtida, no CRE Metropolitano. Dados do perfil clínico e sócio-econômico foram coletados por meio de entrevistas. As entrevistas foram agendadas, mensalmente, para verificar a adesão do paciente ao uso de enfuvirtida durante os meses de setembro de 2008 a junho de 2009. Algumas peculiaridades do uso da forma farmacêutica injetável e a posologia de duas vezes por dia são identificadas como fatores limitantes para o tratamento. A maioria dos pacientes reconhece a importância do tratamento. Porém, cerca de 40%relatam dificuldades na aplicação e são intolerantes às reações adversas causadas pela aplicação subcutânea. Cerca de 33% deles, devido à assistência que estão recebendo, ainda esperam a liberação de novos medicamentos para a troca de esquema sem interrompero uso de enfuvirtida.

Enfuvirtide is a fusion inhibitor that interferes with the penetration of HIV into cells. It is injected subcutaneously, causing adverse side effects at the application site. Patients using enfuvirtide often discontinue the treatment, suggesting low compliance due to the various reactions provoked by the subcutaneous administration of the drug. The objective of this research was thus to assess the connection between pharmacotherapeutic follow-up and adherence of patients to the enfuvirtide regimen. The survey was conducted on AIDS patients prescribed enfuvirtide at a Metropolitan CRE (Brazilian Specialty Public Health Center). Data on the clinical profile and socioeconomic conditions were collected by interview. The interviews were scheduled monthly, to monitor patient adherence to the enfuvirtide treatment over the period from September 2008 to June 2009. Some peculiarities of the use of the injectable pharmaceutical form and the twice-daily injections are identified as limiting factors for the treatment. Most patients recognized its importance, but about 40% reported difficulties in injecting the drug and were intolerant of the adverse reactions caused by subcutaneous administration. About 33% of them, due to the accompaniment they are receiving, are still awaiting the release of new medicines so as to change their treatment plan without interrupting the use of enfuvirtide.

Substituições de esquemas antirretrovirais no Estado do Paraná / Changes of antiretroviral regimen in Paraná

O controle da AIDS no Brasil apresenta resultados favoráveis devido à política seguida pelo Ministério da Saúde que dá ênfase conjunta, na prevenção e atenção à doença com o fornecimento gratuito dos medicamentos. O Ministério da Saúde através do Programa Nacional de DST/AIDS (PN-DST/AIDS) seleciona e compra os medicamentos antirretrovirais (ARVs) e os distribui aos estados. O PN-DST/AIDS distribui 17 medicamentos ARV, em 29 formas farmacêuticas a todos os estados do Brasil. No Paraná, o Centro de Medicamentos do Paraná (CEMEPAR) é o responsável pelo recebimento desses e pela distribuição às 36 Unidades Dispensadoras de Medicamentos (UDMs). Foi realizado um levantamento no estado do Paraná/CEMEPAR no período de janeiro a dezembro/2008 sobre as solicitações enviadas para cadastro de início de tratamento e/ou troca de esquema ARV onde foi observado que 70,56% referiu-se à troca de esquema e, também, que das 5.992 solicitações enviadas, 8,34% (500) apresentavam algum tipo de erro. A pesquisa demonstrou a importância da análise das solicitações, que é um serviço diferenciado realizado pelo estado do Paraná onde foi possível verificar a alta ocorrência de troca de esquemas e a necessidade de um acompanhamento farmacoterapêutico para melhorar a adesão ao tratamento.

The Aids control program in Brazil has been achieving favorable results, owing to the policy adopted by the Ministry of Health, which gives emphasizes both prevention and care for the disease, with the free distribution of medications. The Ministry of Health selects and buys all antiretroviral medications through the National Program DST/AIDS (PN-DST/AIDS) and distributes 17 ARV medications in 29 pharmaceutical forms to all states of Brazil. In Parana State, CEMEPAR (Medicine Center of Parana), is responsible for receiving these medications and redistributing them to the 36 Medicine Distribution Units (UDMs). All requests to change ARV regimen or to start ARV treatment are sent to CEMEPAR for analysis and authorization. An analysis was made of the requests sent to CEMEPAR from January to December 2008 by all of the UDMs where the patients received their medications and it was found that 70.56% were for changes of ARV regimen and that, in 8.34% of all requests, there was some kind of mistake. The survey demonstrated the importance of analyzing the requests, which is a specific service provided by the state of Parana, in which it was possible to observe the high frequency of changes of treatment schemes and a need for pharmacotherapeutic guidance, to improve patient adherence to the treatment.

Morphological and biochemical evidence of blood vessel damage and fibrinogenolysis triggered by brown spider venom.

The venom of the brown spider is remarkable because it causes dermonecrotic injury, hemorrhagic problems, hemolysis, platelet aggregation and renal failure. The mechanism by which the venom causes hemorrhagic disorders is poorly understood. Rabbits intradermally exposed to the venom showed a local hemorrhage starting 1 h after inoculation and reaching maximum activity between 2 and 3 days. Biopsies examined by light and transmission electron microscopy showed subendothelial blebs, vacuoles and endothelial cell membrane degeneration in blood vessels, plasma exudation into connective tissue, and fibrin and thrombus formation within blood vessels. Loxosceles intermedia venom incubated with fibrinogen partially degrades Aalpha and Bbeta chains of intact fibrinogen, and significantly cleaves all Aalpha, Bbeta and gamma chains when they were separated or when fibrinogen is denatured by boiling. Proteolytic kinetic studies showed that the Aalpha chain is more susceptible to venom hydrolysis than the Bbeta chain. The fibrinogenolysis is blocked by ethylenediamine tetraacetic acid and 1,10-phenanthroline, but not by other protease inhibitors. Human plasma incubated with the venom had coagulation parameters such as prothrombin time, activated partial thromboplastin time and thrombin time increased. Through molecular sieve chromatography, we isolated a venom toxin of 30 kDa with fibrinogenolytic activity. We propose that the local and systemic hemorrhagic disorders evoked in loxoscelism are consequences of direct venom fibrinogenolysis together with cytotoxicity to subendothelial structures and endothelial cells in blood vessels.

Extracellular matrix molecules as targets for brown spider venom toxins.

Loxoscelism, the term used to describe lesions and clinical manifestations induced by brown spider's venom (Loxosceles genus), has attracted much attention over the last years. Brown spider bites have been reported to cause a local and acute inflammatory reaction that may evolve to dermonecrosis (a hallmark of envenomation) and hemorrhage at the bite site, besides systemic manifestations such as thrombocytopenia, disseminated intravascular coagulation, hemolysis, and renal failure. The molecular mechanisms by which Loxosceles venoms induce injury are currently under investigation. In this review, we focused on the latest reports describing the biological and physiopathological aspects of loxoscelism, with reference mainly to the proteases recently described as metalloproteases and serine proteases, as well as on the proteolytic effects triggered by L. intermedia venom upon extracellular matrix constituents such as fibronectin, fibrinogen, entactin and heparan sulfate proteoglycan, besides the disruptive activity of the venom on Engelbreth-Holm-Swarm basement membranes. Degradation of these extracellular matrix molecules and the observed disruption of basement membranes could be related to deleterious activities of the venom such as loss of vessel and glomerular integrity and spreading of the venom toxins to underlying tissues.

Extracellular matrix molecules as targets for brown spider venom toxins

Loxoscelism, the term used to describe lesions and clinical manifestations induced by brown spider's venom (Loxosceles genus), has attracted much attention over the last years. Brown spider bites have been reported to cause a local and acute inflammatory reaction that may evolve to dermonecrosis (a hallmark of envenomation) and hemorrhage at the bite site, besides systemic manifestations such as thrombocytopenia, disseminated intravascular coagulation, hemolysis, and renal failure. The molecular mechanisms by which Loxosceles venoms induce injury are currently under investigation. In this review, we focused on the latest reports describing the biological and physiopathological aspects of loxoscelism, with reference mainly to the proteases recently described as metalloproteases and serine proteases, as well as on the proteolytic effects triggered by L. intermedia venom upon extracellular matrix constituents such as fibronectin, fibrinogen, entactin and heparan sulfate proteoglycan, besides the disruptive activity of the venom on Engelbreth-Holm-Swarm basement membranes. Degradation of these extracellular matrix molecules and the observed disruption of basement membranes could be related to deleterious activities of the venom such as loss of vessel and glomerular integrity and spreading of the venom toxins to underlying tissues

In vivo and in vitro cytotoxicity of brown spider venom for blood vessel endothelial cells.

The effect of brown spider (Loxosceles intermedia) venom on endothelial cells was investigated in vivo and in vitro. Morphological and ultrastructural observations by light microscopy and transmission electron microscopy showed that the venom acts in vivo upon vessel endothelial cells of rabbits that were intradermally injected, evoking vessel instability, cytoplasmic endothelial cell vacuolization, and blebs. Likewise, treatment of rabbit endothelial cells in culture with the venom led to loss of adhesion of the cells to the substrate. Endothelial cells in culture were metabolically radiolabeled with sodium [35S]-sulfate and the sulfated compounds (proteoglycans and sulfated proteins) from medium, cell surface, and extracellular matrix (ECM) were analyzed. Agarose gel electrophoresis and SDS-PAGE showed that the venom is active on the ECM and on cell surface proteoglycans, shedding these molecules into the culture medium. In addition, when purified heparan sulfate proteoglycan (HSPG) and purified laminin-entactin (LN/ET) complex were incubated with the venom we observed a partial degradation of the protein core of HSPG as well as the hydrolysis of entactin. The above results suggest that the L. intermedia venom has a deleterious effect on the endothelium of vessels both in vivo and in culture, removing important constituents such as HSPG and entactin that are involved in the adhesion of endothelial cells and of subendothelial ECM organization.

ELISA for the detection of venom antigens in experimental and clinical envenoming by Loxosceles intermedia spiders.

Enzyme linked immunosorbent assays (ELISA) were developed to detect antigens from Loxosceles intermedia spider venom. Hyperimmune horse anti-Loxosceles intermedia IgGs were prepared by immunoaffinity chromatography and used to set up a sandwich-type ELISA. The specificity of the assay was demonstrated by its capacity to correctly discriminate the circulating antigens in mice that were experimentally inoculated with L. intermedia venom from those inoculated with L. gaucho, L. laeta, and Phoneutria nigriventer spider venoms, Tityus serrulatus scorpion venom and Bothrops jararaca, Crotalus durissus terrificus, Lachesis muta muta and Micrurus frontalis snake venoms. Measurable absorbance signals were obtained with 0.8 ng of venom per assay. The ELISA also detected antigens in the sera of patients envenomed by L. intermedia. Therefore, after standardization for clinical use this ELISA may be a valuable tool for clinicians and epidemiologists.