Desarrollo de un producto anti-toxina shiga para la prevención del síndrome urémico hemolítico / Development of a product anti-Shiga toxin for prevention of the hemolytic uremic syndrome

El síndrome urémico hemolítico (SUH) típico es una enfermedad huérfana causada por cepas de Escherichia coli productoras de toxina Shiga (Stx) y caracterizada por daño renal agudo, anemia hemolítica microangiopática y plaquetopenia. Es endémico en Argentina, el país con mayor incidencia de SUH en el mundo. Debido al rol fundamental de la Stx en su patogenia, se puede considerar que, como otras toxemias conocidas, el SUH podría ser tratado con anticuerpos. Este trabajo describe el desarrollo de un nuevo tratamiento capaz de neutralizar el efecto tóxico de distintas variantes de la Stx. El tratamiento consiste en fragmentos F(ab')2 provenientes de un antisuero equino cuya eficacia y potencia contra Stx1 y Stx2 se comprobó en diferentes modelos preclínicos. El producto mostró ser seguro en animales, presentó la farmacocinética descripta para compuestos similares y se pudo establecer una posible ventana terapéutica para su adecuada administración. En conjunto, los resultados preclínicos obtenidos validan la realización de un estudio clínico de primer uso en humanos. En dicho estudio, que se realizará en el Hospital Italiano de Buenos Aires, se analizará la seguridad y la farmacocinética del producto en voluntarios adultos sanos. Estos resultados sentarán las bases para la realización del estudio clínico fase II en pacientes pediátricos con infección por cepas de E. coli productoras de Stx.

The typical hemolytic uremic syndrome (HUS) is an orphan disease caused by Shiga toxin(Stx) -producing Escherichia coli strains and characterized by acute kidney damage, microangiopathic hemolytic anemia and low platelet count. It is endemic in Argentina, the country with the highest incidence of HUS in the world. Stx is essential for its development and therefore, HUS is considered a toxemic non-bacteremic disorder, which could be treated with antibodies. Herein we describe the development of a new treatment capable of neutralizing the toxic effect of Stx and its variants. The treatment consists of F(ab')2 fragments from an equine antiserum whose efficacy and potency against Stx1 and Stx2 were proved in different preclinical models. The product was shown to be safe in animals. Furthermore, the anti-Stx F(ab')2 pharmacokinetic was shown to be similar to that of analogous compounds and a therapeutic window for its administration was determined. Altogether, these preclinical results warrant testing in humans. The phase I clinical trial will be performed at the Hospital Italiano in Buenos Aires to evaluate the safety and pharmacokinetics of the product in healthy adult volunteers. Based on the results of this study, a phase II clinical trial will be planned in pediatric patients diagnosed with infection by Stx-producing E. coli strains.

Gene mutations of platelet glycoproteins and response to tirofiban in acute coronary syndrome / Mutações gênicas das glicoproteínas plaquetárias e resposta ao tirofiban na síndrome coronariana aguda

CONTEXT AND OBJECTIVES: Glycoprotein inhibitors (abciximab, eptifibatide and tirofiban) are used in patients with unstable angina and non-ST-segment elevation myocardial infarction before percutaneous coronary intervention. Of these, tirofiban is the least effective. We hypothesized that the response to tirofiban might be associated with glycoprotein gene mutations. DESIGN AND SETTING: Prospective study at Emergency Unit, Heart Institute (InCor), University of São Paulo. METHOD: Intrahospital evolution and platelet aggregation in response to tirofiban were analyzed in relation to four glycoprotein mutations in 50 patients indicated for percutaneous coronary intervention: 17 (34%) with unstable angina and 33 (66%) with non-ST-segment elevation myocardial infarction. Platelet aggregation was analyzed using the Born method. Blood samples were obtained before and one hour after tirofiban infusion. Glycoproteins Ia (807C/T ), Ib (Thr/Met) , IIb (Ile/Ser ) and IIIa (PIA ) were the mutations selected. RESULTS: Hypertension, dyslipidemia, diabetes, smoking, previous coronary artery disease and stroke were similar between the groups. Mutant glycoprotein IIIa genotypes had lower platelet aggregation before tirofiban administration than that of the wild genotype (41.0% ± 22.1% versus 55.9% ± 20.8%; P = 0.035). Mutant glycoprotein IIIa genotypes correlated moderately with lower platelet inhibition (r = -0.31; P = 0.030). After tirofiban administration, platelet glycoprotein Ia, Ib, IIb and IIIa mutations did not influence the degree of inhibition of platelet aggregation or intrahospital mortality. CONCLUSIONS: Mutations of glycoproteins Ia, Ib, IIb and IIIa did not influence platelet aggregation in response to tirofiban in patients with unstable angina and non-ST-segment elevation myocardial infarction.

RESUMO CONTEXTO E OBJETIVOS: Inibidores da glicoproteína (abciximab, eptifibatide, tirofiban) são utilizados em pacientes com angina instável e infarto do miocárdio sem elevação do segmento ST (IAMSSST) antes da intervenção coronária percutânea. Dentre eles, o tirofiban é o menos eficaz. Nossa hipótese é que a resposta ao tirofiban possa estar associada a mutações no gene da glicoproteína. DESENHO E LOCAL: Estudo prospectivo na Unidade de Emergência do Instituto do Coração (InCor), Universidade de São Paulo (USP). MÉTODOS: Foram analisadas a evolução intra-hospitalar e agregabilidade plaquetária em resposta ao tirofiban de 4 mutações da glicoproteína em 50 pacientes com indicação para intervenção coronária percutânea, 17 (34%) com angina instável e 33 (66%) com IAMSSST. A agregação plaquetária foi analisada pelo método de Born. Amostras de sangue foram obtidas antes e uma hora após infusão do tirofiban. As glicoproteínas Ia (807C/T ), Ib (Thr/Met ), IIb (Ile/Ser ) e IIIa (PIA ) foram as mutações selecionadas. RESULTADOS: Hipertensão, dislipidemia, diabetes, tabagismo, doença coronariana e acidente vascular cerebral prévios foram semelhantes entre os grupos. Observou-se menor agregabilidade plaquetária dos genótipos mutantes da glicoproteína IIIa antes da administração de tirofiban do genótipo selvagem (41% ± 22% versus 56% ± 21%; P = 0,035). Genótipos mutantes da glicoproteína IIIa correlacionaram-se moderadamente com menor inibição plaquetária (r = -0,31; P = 0,030). Após a administração tirofiban, as mutações das glicoproteínas Ia, Ib, IIb, e IIIa não influenciaram o grau de inibição da agregação plaquetária e mortalidade intra-hospitalar. CONCLUSÕES: Mutações das glicoproteínas Ia, Ib, IIb e IIIa não influenciaram a agregação plaquetária em resposta ao tirofiban nos pacientes com angina instável e IAMSSST.

FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction?

Abstract Background Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration. Methods All data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearson’s coefficient (p < 0.05 was significant). Results During the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 1–10; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p < 0.01) and bite location (hand/arm vs. leg: p < 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217;p < 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS ≤ 3 (indicating mild envenomation). Conclusions Considerable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients’ symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available.

Efficacy of Combination Treatment with Intracoronary Abciximab and Aspiration Thrombectomy on Myocardial Perfusion in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Coronary Stenting

PURPOSE: We aimed to investigate whether combination therapy using intracoronary (IC) abciximab and aspiration thrombectomy (AT) enhances myocardial perfusion compared to each treatment alone in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: We enrolled 40 patients with STEMI, who presented within 6 h of symptom onset and had Thrombolysis in MI flow 0/1 or a large angiographic thrombus burden (grade 3/4). Patients were randomly divided into 3 groups: 10 patients who received a bolus of IC abciximab (0.25 mg/kg); 10 patients who received only AT; and 20 patients who received both treatments. The index of microcirculatory resistance (IMR) was measured with a pressure sensor/thermistor-tipped guidewire following successful PCI. Microvascular obstruction (MVO) was assessed using cardiac magnetic resonance imaging on day 5. RESULTS: IMR was lower in the combination group than in the IC abciximab group (23.5+/-7.4 U vs. 66.9+/-48.7 U, p=0.001) and tended to be lower than in the AT group, with barely missed significance (23.5+/-7.4 U vs. 37.2+/-26.1 U, p=0.07). MVO was observed less frequently in the combination group than in the IC abciximab group (18.8% vs. 88.9%, p=0.002) and tended to occur less frequently than in the AT group (18.8% vs. 66.7%, p=0.054). No difference of IMR and MVO was found between the IC abciximab and the AT group (66.9+/-48.7 U vs. 37.2+/-26.1 U, p=0.451 for IMR; 88.9% vs. 66.7%, p=0.525 for MVO, respectively). CONCLUSION: Combination treatment using IC abciximab and AT may synergistically improve myocardial perfusion in patients with STEMI undergoing primary PCI (Trial Registration: clinicaltrials. gov Identifier: NCT01404507).

Patients with Arthritis Undergoing Surgery: How Should We Manage Tumour Necrosis Factor Blocking Agents Perioperatively?: A Systematic Literature Review

We systematically reviewed the literature on the infectious risk in patients treated with tumour necrosis factor blocking agents (TNF-BA) undergoing surgery: we searched the Medline (PubMed) and the online archive from the Annual European Congress of Rheumatology and the Annual Scientific Meeting of the American College of Rheumatology. Of total 1259 reports, 14 were finally analysed. With one exception all were retrospective. Four of 6 studies compared patients on TNF-BA with those not receiving TNF-BA, and found an increased risk of infection with the use of TNF-BA. None of the other studies which compared continued with discontinued treatment at surgery found an increased risk of infection, when the medication was continued perioperatively. In conclusion, while in theory there is an increased risk of infections when TNF-BA are administered perioperatively, the available literature does not necessarily support this. It rather appears that patients receiving TNF-BA are a priori at a higher risk of postoperative infections. Scheduling surgery at the end of the drug interval and adding one "safety" week prior to surgery should be an acceptable plan in daily clinical practice.

Tratamiento con agentes anti-TNFα en la enfermedad de Crohn: ¿qué fármaco debemos utilizar y cuándo?: [revisión] / Treatment with anti-TNFα agents in Crohn's disease: what drug we have to use and when?: [revision]

Crohn's disease (CD) is often very difficult to treat. Almost ten years ago "biologic" agents were introduced in the armamentarium to control CD. Although there are many new drugs in the pipeline, only two antiTNF agents have been released to the market (infliximab and, recently, adalimumab) and probably in 2008 certolizumab will be approved. A review of available evidence suggests that the three antibodies are effective in the induction and maintenance of response, and (to a lesser extent) remission. Infliximab has been very useful in fistulizing disease, and preliminary data do suggest that adalimumab and certolizumab will be also. Cost and long-term safety limit the use of these agents in daily practice. To maximize benefits and minimize risks, good patient selection and strict adherence to Clinical Guidelines seem the key points. It has been suggested that these drugs should be used in early disease to avoid progression, but current data are very scarce to generalize this recommendation. In anycase, we think that the use of "biologics" will provoke a dramatic change in CD treatment in the next 10 years.

Crohn’s disesae (CD) is often very difficult to treat. Almost ten years ago "biologic" agents were introduced inthe armamentarium to control CD. Although there are many new drugs in the pipeline, only two antiTNF agents have been released to the market (infliximab and, recently, adalimumab) and probably in 2008 certolizumabwill be approved. A review of available evidence suggests that the three antibodies are effective in the induction and maintenance of response, and (to alesser extent) remission. Infliximab has been very useful in fistulizing disease, and preliminary data do suggest that adalimumab and certolizumab will be also. Cost and long-term safety limit the use of these agents in daily practice. To maximize benefits and minimize risks, good patient selection and strict adherence to Clinical Guidelines seem the key points. It has been suggestedthat these drugs should be used in early disease to avoid progression, but current data are very scarce to generalize this recommendation. In anycase, we think that the use of "biologics" will provoke a dramaticchange in CD treatment in the next 10 years.

Acute myocardial infarction secondary to myocardial bridge treated with drug-eluting stent.

We report a case of myocardial bridge in left anterior descending coronary artery associated with acute anterior wall myocardial infarction. The patient had many unusual features like coronary ectasia and atherosclerosis within the myocardial bridge segment. The patient was treated with drug-eluting stent under intravascular ultrasound guidance with good result over 6 months follow-up.

The Long-term Clinical Results of a Platelet Glycoprotein IIb/IIIa Receptor Blocker (Abciximab: ReoPro (R) ) Coated Stent in Patients with Coronary Artery Disease

BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro (R) ) -coated stent in a porcine model was reported. ReoPro (R) inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE) : cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro (R) -coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p=0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p=0.002). The restenosis and TVR rates of the ReoPro (R) -coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p=0.062; and 9.2% (7/76) vs. 14.7% (11/75) ; p=0.327]. CONCLUSION: A ReoPro (R) -coated stent is safe, and may be effective in the prevention of coronary restenosis.

The current practice of percutaneous transluminal coronary angioplasty (PTCA) and stent deployment and their long-term results in unstable and stable angina.

Percutaneous transluminal coronary angioplasty with stent implantation is a universally accepted therapeutic option for patients with coronary artery disease. Since introduction in 1977, angioplasty techniques have been greatly improved; the availability of better hardware, greater operator experience, better patient selection and the judicious use of adjunctive therapy like heparin, clopidogrel, platelet receptor antagonists like abciximab and the use of atherectomy/rotablator in given situations has greatly improved procedural outcome today. Angioplasty alleviates symptoms in patients with stable angina and also in unstable angina especially in high risk patients like those with pulmonary oedema, cardiogenic shock or patients refractory to conventional modes of therapy, though cost may be a prohibiting factor. The outcome of angioplasty in diabetic patients is universally poor and bypass surgery is always a better option. Women with coronary artery disease tend to have complex lesions with a sub-optimal outcome and a higher incidence of restenosis. Use of abciximab is always beneficial in both men and women.

Long-Term Clinical Benefits of a Platelet Glycoprotein IIb/IIIa Receptor Blocker, Abciximab (ReoPro (R) ), in High-Risk Diabetic Patients undergoing Percutaneous Coronary Intervention

BACKGROUND: High-risk percutaneous coronary interventions (PCIs) are associated with a high complication rate, a low procedural success rate and a high restenosis rate, especially in diabetics. We sought to determine whether abciximab (ReoPro (R) ) therapy affects long-term clinical outcomes of Korean patients with diabetes undergoing high-risk PCI. METHODS: One hundred and nineteen patients with 152 lesion sites were administered ReoPro (R) among 2, 231 patients who underwent PCI at Chonnam National University Hospital from March 1999 to Feb 2001. These 119 patients were divided into two groups, 30 were allocated to a diabetic group (Group I, 57.7 +/- 8.2 years, 22 male), and 89 to a non-diabetic group (Group II, 59.6 +/- 10.8 years, 68 male). Early and long-term clinical outcomes after PCI were analyzed. RESULTS: In terms of clinical diagnosis, the number of acute myocardial infarctions in Group I was 25 (83.3%) and 76 in Group II (85.4%). As for risk factors, target artery lesions, and ACC/AHA types, no differences were found between the two groups. The number of patients with total occlusion was 21 (55.3%) and 62 (53.9%), and the number with a thrombus-containing lesion was 28 (93.3%) and 88 (98.9%) in Groups I and II, respectively. The procedure was successful in 27 (90.0%) in Group I, and in 80 (89.9%) in Group II, and no differences were evident between the two groups in terms of bleeding complications. No major adverse cardiac events (MACE), including myocardial infarction, repeat revascularization or cardiac death, were observed in Group I, but 8 cases of MACE occurred in Group II during hospitalization. Clinical follow-up was performed in 116 patients (97.5%) over 18.5 +/- 6.7 (5-28) months. The number of overall MACEs was 10 (3.3%) in Group I and 14 (15.7%) in Group II (p=0.038). CONCLUSION: ReoPro (R) used in high-risk PCI in diabetics was effective in terms of early clinical outcomes, but its long-term clinical benefits were not proven.

A Case of Successful Primary Coronary Intervention for the Total Occlusion of Left Main Stem with the Aid of Abciximab

A 61-yr-old male patient presented with severe chest pain with cardiogenic shock due to an extensive anterolateral myocardial infarction. Two-dimensional echocardiogram showed severe left ventricular systolic dysfunction (ejection fraction=17%). Emergent coronary angiogram obtained immediately after placing temporary pacing electrode revealed total thrombotic occlusion in the left main stem. We performed direct coronary intervention using kissing balloon technique with the aid of Abciximab (ReoPro(R)) infusion. Residual stenosis with thrombus remained even after high pressure balloon dilatations, therefore we placed two stents, one in the ostia of left anterior descending (LAD) and the other in left circumflex artery (LCX). Coronary angiogram after kissing stents showed improved LAD and LCX flows without residual stenosis. Chest pain resolved and blood pressure normalized after coronary intervention. The whole procedure time was 15 min. Follow-up coronary angiogram taken one week later showed patent previous stented arteries, and echocardiography demonstrated 40% of left ventricular ejection fraction. The clinical course for one-year follow-up was uneventful.

Prospective observational study of primary angioplasty of the infarct-related artery for acute myocardial infarction.

Primary angioplasty has been shown to reduce rates of in-hospital mortality, recurrent ischaemia and infarction. However, the role of primary stenting and abciximab is presently undergoing evaluation. This study attempted to examine the feasibility, safety and outcomes of primary angioplasty in the treatment of acute myocardial infarction. Data in 100 patients who underwent primary angioplasty for evolving acute myocardial infarction was prospectively analysed to assess the safety and efficacy of various modalities. Twenty patients were in Killip class III and above. Multivessel (2 or more vessels) disease was noted in more than 52 cases. Procedural success was 99 percent; 86 patients received primary stenting, majority of them had Kalam-Raju stent implantation. Adjunct treatment included abciximab infusion in 22 and intra-aortic balloon pump support in 12. Overall mortality rate was six percent with a mortality of 2.2 percent in non-cardiogenic shock patients. Recurrent ischaemic events were noted in five, three of them had successful reperfusion with repeat angioplasty. None of the patients had emergency coronary artery bypass surgery. It is concluded that primary angioplasty is safe and effective with high procedural success. Recurrent ischaemic events are low, possibly due to routine use of stenting and selective use of abciximab.

In-vitro inhibition of antiplatelet autoantibodies by intravenous immunoglobulins and Rh immunoglobulins.

Autoimmune thrombocytopenia (AITP) is caused by autoantibodies to platelet glycoprotein antigens. Intravenous immunoglobulin (i.v.IgG) and Rh immunoglobulin infusions have found great significance in the treatment of AITP patients not responding to corticosteroids and other modes of therapy. In our study, it was observed that immunoglobulins (i.v.IgG & Rh), and their Fab fragments inhibited the binding of antiplatelet autoantibodies to normal platelets, from 15.8 to 90.7% and 25.6 to 90.08% respectively; whereas, their Fc portion did not show any inhibition. The presence of specific anti-idiotypic antibodies to antiplatelet autoantibodies was established by using monoclonal antibodies to Glycoprotein IIb/IIa and Glycoprotein Ib/IX, as the specific idiotype source. The i.v.IgG and Rh immunoglobulin products reacted with the monoclonal antibodies, only through their Fab and not through the Fc portions, thereby confirming its specific anti-idiotype activity.