The case of eculizumab: litigation and purchases by the Brazilian Ministry of Health / O caso do eculizumabe: judicialização e compras pelo Ministério da Saúde

ABSTRACT OBJECTIVES This study examined the purchases of eculizumab, a high-cost monoclonal antibody used in the treatment of rare diseases by Brazilian federal agencies, in terms of purchased quantities, expenditures, and prices. METHODS Eculizumab purchases made between March 2007 and December 2018 were analyzed, using secondary data extracted from the Federal Government Purchasing System (SIASG in Portuguese). The following aspects were assessed: number of purchases, purchased quantities, number of daily doses defined per 1,000 inhabitants per year, annual expenditures, and prices. The prices were adjusted by the National Broad Consumer Price Index for December 2018. Linear regression was used for trend analysis. RESULTS All acquisitions by federal agencies were made by the Brazilian Ministry of Health. The purchases began in 2009 with tender waiver to comply with legal demand. There was an increasing trend in the number of purchases and quantities acquired over time. Two hundred and eighty-three purchases were made, totaling 116,792 units purchased, 28.2% of them in 2018. The adjusted total expenses summed more than R$ 2.44 billion. After market approval by the Brazilian Health Regulatory Agency, the weighted average price fell approximately 35%, to values under the Medicines Market Chamber of Regulation established prices. CONCLUSION Eculizumab represented extremely significant expenditures for the Brazilian Ministry of Health during the period. All purchases were made to meet demands from lawsuits, outside the competitive environment. The market approval of eculizumab promoted an important price reduction. This study indicates the relevance of licensing and the need for permanent monitoring and auditing of drug purchases to meet legal demands.

RESUMO OBJETIVOS O estudo examinou as aquisições de eculizumabe, um anticorpo monoclonal de alto custo utilizado no tratamento de doenças raras, pelos órgãos federais brasileiros, em termos das quantidades compradas, gastos e preços. MÉTODOS Foram analisadas compras de eculizumabe realizadas entre março de 2007 e dezembro de 2018, por meio de dados secundários extraídos do sistema de compras do governo federal (Siasg). Foram examinados o número de compras, quantidades adquiridas, número de doses diárias definidas por 1.000 habitantes por ano, gastos anuais e preços praticados. Os preços foram corrigidos pelo índice nacional de preços ao consumidor amplo para dezembro de 2018. Regressão linear foi utilizada para análises de tendência. RESULTADOS Todas as aquisições por órgãos federais foram realizadas pelo Ministério da Saúde. As compras se iniciaram em 2009, sendo efetuadas por dispensa de licitação e para atendimento de demanda judicial. Houve tendência crescente no número de compras e quantidades adquiridas ao longo do tempo. Foram realizadas 283 compras, totalizando 116.792 unidades adquiridas, 28,2% compradas em 2018. Os gastos totais contratados corrigidos somaram mais de R$ 2,44 bilhões. Após a aprovação do registro pela Agência Nacional de Vigilância Sanitária, o preço médio ponderado caiu aproximadamente 35%, para valores abaixo dos preços estabelecidos pela Câmara de Regulação do Mercado de Medicamentos. CONCLUSÃO O eculizumabe representou gastos extremamente significativos para o Ministério da Saúde no período. Todas as compras foram feitas para atendimento de demandas judiciais, fora do ambiente competitivo. Seu registro promoveu queda importante nos preços praticados. O estudo aponta a relevância do registro sanitário e da necessidade de monitoramento e auditoria permanentes das compras de medicamentos para atendimento de demandas judiciais.

Treatment of hereditary angioedema due to C1 inhibitor deficiency in Argentina

The benefits of the worldwide approval of new drugs for the treatment of acute C1-INH-HAE attacks may still not reach all patients. Identifying the current barriers in the access to medication, as well as conducting a detailed assessment of the progress in this area, is essential to achieve universal treatment. Two hundred and twenty five patients registered in the Argentina Hereditary Angioedema Patient Association (AHAEPA) were randomly selected and invited to participate in a web based questionnaire on accessibility to icatibant and pdC1-INH, self-treatment, delay to treatment, and coverage. The data retrieved was compared to our previous reports in 2008 and 2013. We collected 156/225 answers. One hundred and eighteen (76%) patients have either pdC1-INH (n = 86), icatibant (n = 10) or both (n = 22), while 38 (24%) do not have access to treatment. In 2008, 26% had access while 82% had it in 2013. Thirty-two subjects (22%) self-inject themselves, similar to 29% in 2013, even though between studies, widespread self-injection training activities have taken place. However, considering injections by proxy, home treatment reached 56%. Only half of the patients decide to receive treatment early during the attack. Ninety-nine patients (63%) have full coverage, thirty (19%) have no coverage at all and the rest only obtain partial reimbursement. Twenty-nine families (31%) share a single treatment dose of the medication, better than 36% in 2013. Argentina's C1-INH-HAE patients had a sustained improvement in their access to medication. Efforts should continue to further improve accessibility and optimal management of HAE acute attacks to all patients in the country.

La aprobación mundial de los medicamentos para el ataque agudo del angioedema hereditario (HAE) no beneficia a todos los pacientes. Es necesario conocer las barreras de acceso a la medicación para el tratamiento universal. Doscientos veinticinco pacientes, registrados en la Asociación de Pacientes con Angioedema Hereditario (AHAEPA), fueron encuestados por internet acerca de su accesibilidad al icatibant y al concentrado del inhibidor de C1 (pdC1-INH), a la auto inyección de la medicación, al retraso del tratamiento y a la cobertura del medicamento. Comparamos esta información con la obtenida en nuestros estudios de 2008 y 2013. Recolectamos 156/225 respuestas. Ciento dieciocho (76%) pacientes tienen pdC1-INH (n = 86), icatibant (n = 10) o ambos (n = 22), mientras que 38 (24%) no tienen medicación. En 2008, 26% tenían acceso y en 2013, 82%. Treinta y dos (22%) se autoinyectan la medicación, similar al 29% en 2013. Sumando las aplicaciones por profesionales de la salud o familiares en la casa, el tratamiento fuera de las instituciones médicas alcanza el 56%. Solo la mitad decide tratarse tempranamente. Noventa y nueve (63%) tiene cobertura del 100%, 30 (19%) no tiene ningún tipo de cobertura, y el resto la tiene en forma parcial. Veintinueve familias (31%), solo tienen una dosis de tratamiento para todos, mejor que el 36% en 2013. Los pacientes con C1-INH-HAE han tenido una mejoría sustancial en el acceso a la medicación. Igualmente, los esfuerzos deben continuar para mejorar la accesibilidad y tratamiento óptimo de todos.

Anti-complementary phenolic acids from Lonicera japonica / 中国中药杂志

<p><b>OBJECTIVE</b>To study the anti-complementary phenolic acids from Lonicera japonica.</p><p><b>METHOD</b>The anti-complementary activity-directed isolation was carried out with the hemolysis test as guide. All isolation was evaluated for their in vitro anti-complementary activities. The structures were identified by various spectroscopic data including ESI-MS, 1H-NMR, 13C-NMR data.</p><p><b>RESULT</b>Fourteen compounds were isolated from the EtOAc fraction of L. japonica extracts, including 8 phenolic acids: 5-O-caffeoylquinic acid (1), chlorogenic (2), 4-O-caffeoylquinic acid (3), 3,5-di-O-caffeoylquinic acid (4), 4,5-di-O-caffeoylquinic acid (5), 3,4-di-O-caffeoylquinic acid (6), caffeic acid (7) and methyl caffeate acid (8); 3 iridoids: secologanoside (9), sweroside (10) and secoxyloganin (11); and 3 flavonoids: luteolin (12), quercetin (13) and kaempferol (14). Compounds 1-9 and 11-14 showed anti-complementary activity in different extents and 3,5-di-O-caffeoylquinic acid (4) exhibited the most significant activity against the classical pathway.</p><p><b>CONCLUSION</b>Compound 14 is obtained from this plant for the first time, phenolic acids are the main anti-complementary constituents of L. japonica and 3,5-di-O-caffeoylquinic acid(4) is a potential complement inhibitor with strong activity, which worthy to be studied further in the future.</p>

Angioedema hereditario: Tratamiento del ataque agudo en la Argentina / Hereditary angioedema: Treatment of acute attacks in Argentina

En el mundo, el angioedema hereditario (HAE) afecta a 1 de cada 50 000 personas. Produce episodios de angioedema cutáneo, abdominal y laríngeos que generan gran incapacidad. La mortalidad por la enfermedad oscila entre 15 y 50%. Aunque en Argentina un concentrado plasmático de C1 inhibidor (pdC1INH) ha estado aprobado y disponible por décadas para el tratamiento del ataque agudo, solo 15 (26%) de 58 pacientes había recibido pdC1INH alguna vez hasta el año 2008, y solo 2(3.4%) lo usaban regularmente. Luego de la aprobación de los nuevos medicamentos para HAE, incluido el icatibant en Argentina y de la publicación de las guías terapéuticas, 42 (82%) de 51 pacientes del grupo original tienen pdC1INH para tratar el próximo ataque. Sin embargo, 16 (18%) de estos pacientes continúan sin acceso a la medicación y otros 15 (35.7%) acceden a través de otro enfermo en forma espuria. Solo 12 (28.6%) de los pacientes con el medicamento puede auto tratarse en su domicilio. La mejora en el acceso a la medicación es importante pero debe extenderse a todos los afectados y facilitarse el auto-tratamiento.

In the world, hereditary angioedema (HAE) affects 1every 50 000 persons. It is characterized by highly disabling and recurrent episodes of cutaneous, abdominal and laryngeal episodes of angioedema. Asphyxia related mortality ranges from 15 to 50%. In Argentina a plasma derived C1 inhibitor concentrate (pdC1INH) has been available for the treatment of acute attacks for many decades, however, only15 (26%) out of 58 patients had received pdC1INH at least once until 2008, and only2 (3.4%) had used it regularly. After worldwide approval of the new drugs for the treatment of acute HAE attacks, adding icatibant to pdC1INH in Argentina, and after publication of the therapeutic guide for the country, 42 (82%) out of 51 patients from the original group has pdC1INH available to treat their next attack. However, 16 (18%) patients continue without access to medication and other 15 (35.7%) obtain their therapy spuriously through some other affected relative in their environment. Only 12 (28.6%) patients of the group self-treated at home. Access to treatment has greatly improved, but needs to be extended to all patients and self-treatment at home should be encouraged.

Chemical constituents of Rabdosia japonica var. glaucocalyx and their anti-complementary activity / 中国中药杂志

To study the chemical constituents of Rabdosia japonica var. glaucocalyx and their anti-complementary activity on the basis of preliminary studies. Target isolation guided by anti-complementary activity test, compounds in the chloroform and n-butanol fractions were isolated and purified by silica gel and Sephadex LH-20 column chromatographies, and preparative HPLC. The structures were identified by various spectroscopic data including ESI-MS, 1H-NMR and 13C-NMR data. The compounds were evaluated for anti-complementary activity in vitro. Eleven compounds were isolated from the chloroform and n-butanol soluble fractions and identified as stigmasterol (1), stigmas-9 (11) -en-3-ol (2), glaucocalyxin D (3), kamebakaurin (4), maslinic acid (5), corosolic acid (6), minheryins I (7), diosmetin (8), caffeic acid ethylene ester (9), caffeic acid (10) and vitexin (11). Isoquercetrin, rutin, quercetin, 3-methylquercetin, luteolin, 7-methylluteolin, and apigenin which were isolated from the preliminary studies together with compounds 9 and 10 showed inhibition of the complement system by the classical pathway. Compounds 2, 4, 6-9 and 11 were obtained from this plant for the first time. Caffeic acid (10) showed the strongest activity in vitro with a CH50 value of 0.041 g x L(-1).

Isolation of an anti-complementary polysaccharide from the root of Bupleurum chinense and identification of its targets in complement activation cascade / 中国天然药物

AIM@#To isolate and characterize the anti-complementary polysaccharide from the root of Bupleurum chinense.@*METHODS@#Bioactivity-guided fractionation and purification was used to obtain the anti-complementary polysaccharide from the hot-water extract of the root of Bupleurum chinense. The polysaccharide was characterized by various chemical and spectral analyses. The anti-complementary activities were evaluated by hemolytic assay in vitro. The action targets were identified in the system with individual complement-depleted sera.@*RESULTS@#A homogeneous polysaccharide BC-PS2 was isolated as an anti-complementary agent. It was identified as a branched polysaccharide with an average molecular weight about 2 000 KDa, composed of Glc, Ara, Gal, and Man in the ratio 3.5 : 2.4 : 2.0 : 1.0, respectively, along with a trace of Rha and Xyl, and only 1.11% of protein. The main linkages of the residues of BC-PS2 include terminal, 1, 6-linked, 1, 3-linked and 1, 3, 6-linked Glcp, terminal and 1, 5-linked Araf, terminal, 1, 4-linked, 1, 6-linked and 1, 4, 6-linked Galp, terminal, and, 1, 4-linked and 1, 4, 6-linked Manp. The bioassay experiments revealed that BC-PS2 inhibited complement activation on both the classical and alternative pathways, with CH50 and AP50 of (0.222 ± 0.013) and (0.356 ± 0.032) mg·mL(-1), respectively. Preliminary mechanism studies indicated that BC-PS2 interacted with C1q, C2, and C9 components.@*CONCLUSION@#The results demonstrated that BC-PS2 is an anti-complementary polysaccharide, and should be important constituent of the root of Bupleurum chinense for its application in the treatment of diseases associated with the excessive activation of complement system.

Anti-complementary constituents of Pogostemon cablin / 中国中药杂志

Guided by anti-complementary activity, silica gel, Sephadex LH-20 and reversed-phase column chromatographies were used for fractionation and isolation of the ethyl acetate and n-butanol soluble fractions of Pogostemon cablin. Eighteen compounds were obtained, including 15 flavonoids: 5-hydroxy-3,7,3',4'-tetramethoxyflavone (1), 5-hydroxy-7,3',4'-trimethoxyflavanone (2), 5,4'-dihydroxy-3,7,3'-trimethoxyflavone (3), 5-hydroxy-3,7,4'-trimethoxyflavone (4), 5,4'-dihydroxy-7,3'-dimethoxyflavone (5), luteolin (6), quercetin-7,3', 4'-trimethyl ether (7), ermanine (8), 3,5,7- trihydroxy-3', 4'-dimethoxyflavone (9), quercetin (10), apigenin (11), kaempferol (12), 5-hydroxy-7,3',4'-trimethoxyflavone (13), kaempferol-7-O-beta-D-glucopyranoside (14) and kaempferol-3-O-beta-D-glucopyranoside-7-O-alpha-L-rhamnoside (15); one triterpenoid: oleanic acid (16); and 2 phenolic acids: vanillic acid (17) and benzylalcohol (18). The isolation of 5, 7, 8, 12-15 and 18 from the Pogostemon genus is reported for the first time. All isolates were evaluated for their in vitro anti-complementary activities on the classical pathway and alternative pathway. And the targets of the most potent constituent in complement activation cascade were identified using complement-depleted sera. Compounds 3, 7, 10, 12 and 16 exhibited anti-complementary activities toward the classical pathway and alternative pathway (CH50 0.072-1.08 g x L(-1), AP50 0.39-0.49 g x L(-1)), while 5 and 6 showed inhibitory effect on the classical pathway only. Mechanism study indicated that 7 interacted with C1q, C2, C5 and C9 components.

Synergistic suppression of pre-perfusion of donor livers with recipient serum and cobra venom factor treatment on hyperacute rejection following liver xenotransplantation / Supressão sinérgica da rejeição hiperaguda no xenotransplante hepático com uso da pre-perfusão dos fígados doadores tratados com soro do receptor e com fator veneno de cobra

PURPOSE: To investigate synergistic suppression of donor liver pre-perfusion with recipient serum (RS) and cobra venom factor (CVF) treatment on hyperacute rejection (HAR) following liver xenotransplantation. METHODS: Guinea-pigs (GP, n=24) and Sprague-Dawley rats (SD, n=24) were recruited. Before transplantation, serum was collected from SD rats and used for preparation of inactivated complements. GP and SD rats were randomly assigned into four groups (n=6), respectively: RS group, CVF group, RS+CVF group and control group. Orthotopic liver xenotransplantation was performed with modified two-cuff technique. The survival time and liver function of recipients, morphological and pathological changes in rat livers were investigated. RESULTS: There was no piebald like change in the recipient livers in all experiment groups. The survival time of recipients in all experiment groups was longer than that in control group (p<0.05). Moreover, the survival time in the RS+CVF group was markedly longer than that in the RS group (p<0.01) and CVF group (p<0.05). The serum ALT level in all experiment groups were lower than that in the control group (p<0.05). Furthermore, the ALT level in the RS+CVF group was significantly lower than that in the CVF group (p<0.05) and RS group (p<0.01). The histological damages were significantly improved when compared with the control group, and the histological damages in the RS+CVF group were milder than those in the remaining groups (p<0.05) CONCLUSION: Pre-perfusion of donor liver with recipient serum and cobra venom factor treatment can exert synergistic suppressive effects on the hyperacute rejection following liver xenotransplantation.

OBJETIVO: Investigar a supressão sinérgica da pré-perfusão do doador de fígado com soro do receptor (SR) e tratamento com fator veneno de cobra (FVC) na rejeição hiperaguda (RHA) após o xenotransplante de fígado. MÉTODOS: Foram utilizados Cobaias (GP, n=24) e ratos Sprague-Dawley (SD, n=24). Antes do transplante foram coletadas amostras de soro dos ratos SD e usados para a preparação dos complementos inativados. Cobaias GP e ratos SD foram randomicamente distribuídos em quatro grupos (n=6), respectivamente: grupo RS, grupo FVC, grupo SR+FVC e grupo controle. Xenotransplante ortotópico do fígado foi realizado com a técnica de dois cuffs modificados. Foram investigados o de tempo de sobrevida, a função hepática dos receptores e alterações morfopatológicas em fígados de ratos. RESULTADOS: Não houve alteração na coloração do parênquima dos fígados nos receptores. O tempo de sobrevida dos receptores em todos os grupos experimentais foi mais longo do que o grupo controle (p<0,05). Além disso, o tempo de sobrevida do grupo SR+ FVC foi marcadamente maior do que o grupo SR (p<0,01) e o grupo FVC (p<0,05). O nível sérico ALT foi menor em todos os grupos experimentais do que o grupo controle (p<0,05). O nível de ALT no grupo SR+ FVC foi significantemente menor do que no grupo FVC (p<0,05) e o grupo SR (p<0,01). As alterações histológicas foram significantemente melhoradas quando comparado com o grupo controle, e os danos histológicos no grupo SR+ FVC foram mais moderados do que nos grupos restantes (p<0,05). CONCLUSÃO: Pré-perfusão do fígado doador com soro do receptor e fator veneno de cobra pode exercer efeito supressor sinérgico da rejeição hiperaguda após xenotransplante de fígado.

Angioedema hereditario: Guía de tratamiento / Hereditary angioedema: A therapeutic guide

El angioedema hereditario (HAE) es una enfermedad rara, autosómica dominante, caracterizada por episodios que comprometen la piel, el tracto gastrointestinal y la laringe. Tiene una mortalidad histórica por asfixia del 15 al 50%. Es producida por la deficiencia funcional del C1 inhibidor. La identificación de la bradiquinina como mediador principal ha estimulado el desarrollo de nuevos medicamentos para tratar la enfermedad. El tratamiento del HAE se establece en consensos internacionales. El desarrollo de guías para el tratamiento de la enfermedad permite ordenar el uso de procedimientos diagnósticos y drogas. Describimos aquí algunas características farmacológicas de los medicamentos utilizados en el tratamiento del HAE en la Argentina: el concentrado plasmático de C1 inhibidor, el antagonista de la bradiquinina, icatibant, el andrógeno atenuado danazol y los agentes anti-fibrinolíticos ácidos épsilon aminocaproico (EACA) y tranexámico. Asimismo, se describe su forma de uso y del control de los eventos adversos más frecuentes, así como las recomendaciones del último consenso internacional, aplicables para conformar una primera guía de tratamiento del HAE en la Argentina.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by episodes of edema involving the skin, gastrointestinal tract and larynx. HAE has a historical asphyxia mortality of 15% to 50%. It is the consequence of functional C1 inhibitor deficiency. The identification of bradykinin as the principal mediator of the disease has lead to the development of new drugs for its treatment. HAE management and treatment are agreed by international consensus decision. A therapeutic guide for the treatment of the disease is important to improve diagnosis and treatment. We here describe the pharmacology of drugs available for the treatment of HAE in Argentina: plasma derived C1 Inhibitor, the bradykinin antagonist: icatibant, the attenuated androgen danazol and the anti-fibrinolytic agents epsilonaminocaproic acid and tranexamic acid. Furthermore, we describe drug use and adverse effects control, as well as the last international consensus document recommendations applicable to Argentina to conform a first guide to HAE treatment in our country.

Effects of complement inhibiting component of Ephedra sinica on immunological inflammation following acute spinal cord injury in rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the effects of complement inhibiting component of Ephedra sinica on immunological inflammation following acute spinal cord injury (SCI) in rats.</p><p><b>METHODS</b>The complement inhibiting component of Ephedra sinica was isolated by multiple precipitation steps and thin layer chromatography, and then the activity was analyzed. Fifty healthy SD rats were selected and randomly divided into the control group and the experimental group, 25 in each group. Induction of SCI was performed following a modified Allen's weight-drop method. The complement inhibiting component from Ephedra sinica (15 mg/kg) dissolving in 5 mL normal saline was immediately administered by gastrogavage after SCI, once daily. Equal volume of normal saline was administered to rats in the control group by gastrogavage. Hematoxylin and eosin (H&E) staining and C3 immunohistochemical staining were performed in SCI tissue at 12 h, day 1, 3, 7, and 14 after SCI. C3 positive expressions and myeloperoxidase (MPO) activity were assessed. Intercellular adhesion molecule-1 (ICAM-1) mRNA expression level was evaluated by Real-time PCR technique.</p><p><b>RESULTS</b>C3 positive expression, MPO activity, and ICAM-1 mRNA level were significantly weaker in the Ephedra sinica group than in the control group at all time points (12 h, day 1, day 3, day 7, and day 14 after SCI) (P < 0.01, P < 0.05).</p><p><b>CONCLUSIONS</b>There existed complement system activation following acute SCI. The complement inhibiting component of Ephedra sinica significantly reduced immunological inflammation after SCI, and played an important role in secondary SCI.</p>

Preparation procedures of anti-complementary polysaccharides from Houttuynia cordata / 中国中药杂志

<p><b>OBJECTIVE</b>To establish and optimize the preparation procedures of the anti-complementary polysaccharides from Houttuynia cordata.</p><p><b>METHOD</b>Based on the yield and anti-complementary activity in vitro, the conditions of extraction and alcohol precipitating process were optimized by orthogonal tests. The optimal condition of deproteinization was determined according to the results of protein removed and polysaccharide maintained. The best decoloring method was also optimized by orthogonal experimental design.</p><p><b>RESULT</b>The optimized preparation procedures were given as follows: extract the coarse powder 3 times with 50 times volume of water at 90 degrees C for 2 hours every time, combine the extracts and concentrate appropriately, equivalent to 0.12 g of H. cordata per milliliter. Add 4 times volume of 90% ethanol to the extract, allow to stand for 24 hours to precipitate totally, filter and the precipitate was successfully washed with anhydrous alcohol, acetone and anhydrous ether. Resolve the residue with water, add trichloroacetic acid (TCA) to a concentration of 20% to remove protein. Decoloration was at a concentration of 3% with activated carbon at pH 3.0, 50 degrees C for 50 min. The above procedures above were tested 3 times, resulting in the average yield of polysaccharides at 4.03% (RSD 0.96%), the average concentrations of polysaccharides and protein at 80.97% (RSD 1.5%) and 2.02% (RSD 2.3%), and average CH50 at 0.079 g x L-(-1) (RSD 3.6%).</p><p><b>CONCLUSION</b>The established and optimized procedures are repeatable and reliable to prepare the anti-complementary polysaccharides with high quality and activity from H. cordata.</p>

Anti-complement activity of polysaccharide B3-PS2 purified from Herba Scutellariae Barbatae / 药学学报

The polysaccharide B3-PS2 was extracted and purified from Herba Scutellariae Barbatae through chromatography of DEAE-cellulose and Sephacryl S-300 column. Average molecular weight of B3-PS2 was about 1,100 kD. It was composed of Glc, Gal and Ara in the ratio of 2.7:2.7:1.0, along with trace of Man, Rha, Fuc and Xyl. B3-PS2 inhibited complement activation on the classic pathways with CH50 value of (0.23 +/- 0.03) mg mL(-1). The targets of B3-PS2 upon the complement system were C1r, C1s, C3 and C4. These results suggested that anti-complementary activity of B3-PS2 was closed to its positive control heparin. It strongly suggested that the polysaccharide B3-PS2 from Herba Scutellariae Barbatae could be a potential candidate in treating those complement-associated diseases.

F(ab')2 antibody fragments against Trypanosoma cruzi calreticulin inhibit its interaction with the first component of human complement

Trypanosoma cruzi calreticulin (TcCRT), described in our laboratory, retains several important functional features from its vertebrate homologues. We have shown that recombinant TcCRT inhibits the human complement system when it binds to the collagenous portion of C1q. The generation of classical pathway convertases and membrane attack complexes is thus strongly inhibited. In most T. cruzi-infected individuals, TcCRT is immunogenic and mediates the generation of specific antibodies. By reverting the C1q / TcCRT interaction, a parasite immune evasion strategy, these antibodies contribute to the host / parasite equilibrium. In an in vitro correlate of this situation, we show that the C1q / TcCRT interaction is inhibited by F(ab')2 polyclonal anti-TcCRT IgG fragments. It is therefore feasible that in infected humans anti-TcCRT antibodies participate in reverting an important parasite strategy aimed at inhibiting the classical complement pathway. Thus, membrane-bound TcCRT interacts with the collagenous portion C1q, and this C1q is recognized by the CD91-bound host cell CRT, thus facilitating parasite internalization. Based on our in vitro results, it could be proposed that the in vivo interaction between TcCRT and vertebrate C1q could be inhibited by F(ab')2 fragments anti-rTcCRT or against its S functional domain, thus interfering with the internalization process.

Chemical investigation and anti-complement activity of chrysanthemum morifolium ramer

The 80% EtOH extract of aerial parts [leaves and stem] of Chrysanthemum morifolium showed a significant anti-complement activity [IC[50]= 5.65 micro g/ml]. Bioassay guided fractionation of the active extract has led to the isolation of a coumarin [scopoletin], orthocoumarinic acid 8-glucoside, melilotoside, 3,5- dicaffeoylquinic acid and the numbing principle [N-isobutyl-2-trans-4-trans-5-[alpha-thienyl]- decadienamide]. The structures of these compounds were elucidated by means of TLC, FAB-MS and 1D and 2 D NMR spectroscopy

Hereditary and acquired angioedema: experience with patients in Puerto Rico

Hereditary (HAE) and acquired (AAE) angioedema are vascular reactions involving the sub mucosal tissues, representing localized edema caused by dilatation and increased permeability of the capillaries. HAE and AAE are clinical disorders characterized by angioedema that require prompt differentiation from other causes of angioedema in order to receive the most pertinent and effective therapeutic interventions. The aim of this report is to describe the clinical characteristics of patients with both HAE and AAE identified and followed at the Immunology Clinic of the University Hospital at the Puerto Rico Medical Center, their response and side effects to danazol therapy and their comparison with other series of similar patients reported in the literature. Overall, the patients in this sample presented a similar clinical profile compared to other reported series in the literature.

Edema angioneurótico hereditario / Hereditary angioneurotic edema

Angiodema, or angioneurotic edema (AE), is a condition characterized by the extravasation of fluid and its entry into interstitial tissues that may occur on any level. It becomes a vital urgency when it compromises the air way. Its pathophysiology is complex, with two recognizable pathways. One is mediated by mast cells and the other is not. The hereditary angioneurotic edema(HAE) belongs to this last group. A patientwith diagnosed HAE with air way involvement, that consults again within a year because of a compartimental sindrome in the upper limb, is presented in this article. Aspects about epidemiology, pathophysiology, clinical manifestations and laboratory in HAE, as wel as current available acute and chronic treatment alternatives are discussed

El sistema del complemento sérico: parte 1, mecanismos de reacción y efectos biológicos / The serum complement system: part1, activation mechanisms and biological effects

A un siglo de su descubrimiento por Bordet, se trata de poner un poco de orden en los mecanismos de activación del complemento a través de su hasta ahora conocidas rutas de activación clásica o de C1 y la vía alterna o de la properdina. Se hace además referencia a otras vías de activación descritas más recientemente como la activación iniciada por la lectina de unión a la manosa (MBL). Se destaca también la actividad de los componentes inhibidores o controladores, que frenan la actividad del sistema, evitando la producción de daños por la formación y liberación de péptidos con potente acción biológica derivados del mismo, tal el caso de las anafilatoxinas. Se hace además referencia a la presencia de receptores para el complemento, ubicados en la membrana de diversas células del sistema inmunológico, responsables de muchas de las principales actividades del sistema, como la fagocitosis de microorganismos a través de la unión de receptores para C3b (principal opsonina) sobre la membrana de las células fagocitarias

Chemical and biological properties of endotoxin from leptospira interrogans serovars canicola and icterohaemorrhagiae

Endotoxin-like activity was extracted with phenol-chloroform-petroleum ether (PCP) from Leptospira interrogans serovars icterohaemorrhagiae and canicola. Chemical analysis of leptospiral cells obtained from the PCP extract i9ndicated the following distribution of lipopolysaccharide (LPS), protein and polysaccharide in mg/ml:3.0, 4.5 anmd 1.0 for icterohaemorrhagiae and 3.,3, 5.6 and for canicola. The preparations presented several biological activities: positive Limulus test (1.0 pg/ml) for icterohaemorraahagiae and canicola PCP extract and 0.5 pg/ml for E. coli 0111:B4 LPS, lethality for chicken embryos (LD 50 45, 25 and 1.0) for ecterohaemorrhagiae, canicola and E. coli 0111:B4 LPS, pyrogenicity in rabbits with an average increase in rectal temperature of 0.6 grade C, 0.9 grade C and 2.2 grade C for canicola, icterohaemorrhagiae and E. coli 0111: B4 LPS, reacted with complement inhibiting the lysis of sheep red blood cells 62%, 75% and 90% for 2.0 ug/ml of icterohaemorrhagiae, canicola PCP extract and E. coli 0111:B4 LPS. The PCP extract showed no cytotoxicity on chicken embryo fibroblasts and epithelial cells