Effectiveness and safety of biological and target synthetic drugs treatment for psoriatic arthritis: a systematic review with network meta-analysis.

BACKGROUND: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA. METHODS: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence. RESULTS: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety. CONCLUSIONS: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available. PROTOCOL REGISTRATION: PROSPERO: CRD42022315577.

A Novel Apilic Antivenom to Treat Massive, Africanized Honeybee Attacks: A Preclinical Study from the Lethality to Some Biochemical and Pharmacological Activities Neutralization.

Massive, Africanized honeybee attacks have increased in Brazil over the years. Humans and animals present local and systemic effects after envenomation, and there is no specific treatment for this potentially lethal event. This study evaluated the ability of a new Apilic antivenom, which is composed of F(ab')2 fraction of specific immunoglobulins in heterologous and hyperimmune equine serum, to neutralize A. mellifera venom and melittin, in vitro and in vivo, in mice. Animal experiments were performed in according with local ethics committee license (UFRJ protocol no. DFBCICB072-04/16). Venom dose-dependent lethality was diminished with 0.25-0.5 µL of intravenous Apilic antivenom/µg honeybee venom. In vivo injection of 0.1-1 µg/g bee venom induced myotoxicity, hemoconcentration, paw edema, and increase of vascular permeability which were antagonized by Apilic antivenom. Cytotoxicity, assessed in renal LLC-PK1 cells and challenged with 10 µg/mL honeybee venom or melittin, was neutralized by preincubation with Apilic antivenom, as well the hemolytic activity. Apilic antivenom inhibited phospholipase and hyaluronidase enzymatic activities. In flow cytometry experiments, Apilic antivenom neutralized reduction of cell viability due to necrosis by honeybee venom or melittin. These results showed that this antivenom is effective inhibitor of honeybee venom actions. Thus, this next generation of Apilic antivenom emerges as a new promising immunobiological product for the treatment of massive, Africanized honeybee attacks.

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

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.

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.

Gene mutations of platelet glycoproteins and response to tirofiban in acute coronary syndrome.

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.

A Preclinical Consortium Approach for Assessing the Efficacy of Combined Anti-CD3 Plus IL-1 Blockade in Reversing New-Onset Autoimmune Diabetes in NOD Mice.

There is an ongoing need to develop strategic combinations of therapeutic agents to prevent type 1 diabetes (T1D) or to preserve islet ß-cell mass in new-onset disease. Although clinical trials using candidate therapeutics are commonly based on preclinical studies, concern is growing regarding the reproducibility as well as the potential clinical translation of reported results using animal models of human disorders. In response, the National Institutes of Health Immune Tolerance Network and JDRF established a multicenter consortium of academic institutions designed to assess the efficacy and intergroup reproducibility of clinically applicable immunotherapies for reversing new-onset disease in the NOD mouse model of T1D. Predicated on prior studies, this consortium conducted coordinated, prospective studies, using joint standard operating procedures, fixed criteria for study entry, and common reagents, to optimize combined anti-CD3 treatment plus interleukin-1 (IL-1) blockade to reverse new-onset disease in NOD mice. We did not find that IL-1 blockade with anti-IL-1ß monoclonal antibody or IL-1trap provided additional benefit for reversing new-onset disease compared with anti-CD3 treatment alone. These results demonstrate the value of larger, multicenter preclinical studies for vetting and prioritizing therapeutics for future clinical use.

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.

New treatment paradigms in psoriatic arthritis: an update on new therapeutics approved by the U.S. Food and Drug Administration.

PURPOSE OF REVIEW: The purpose of this study is to give an overview of the new treatments approved by the U.S. Food and Drug Administration (FDA) for use in psoriatic arthritis (PsA). RECENT FINDINGS: FDA has approved three new drugs for PsA: Certolizumab-pegol: a PEGylated Fc-free tumour necrosis factor inhibitor (TNFi); ustekinumab: an anti interleukin (IL)-12 and IL-23 mAb; and apremilast and oral phosphodiesterase 4 inhibitor. On well designed and extensive developing programmes, all three drugs proved to be effective for the treatment of most PsA manifestations, including peripheral arthritis, skin involvement, enthesitis, dactylitis, quality of life and radiographic progression in patients failing traditional disease modifying drugs (DMARDs) and TNFi. Safety profile of all three drugs seems to be reassuring until now, although long-term data are still not available. Although Certolizumab-pegol is likely to be placed among the other TNFi, ustekinumab and apremilast, due to lower efficacy on arthritis, are being more frequently used as second-line therapy after TNFi failure, especially among rheumatologists. SUMMARY: There are new therapeutic options approved for the treatment of PsA. For the first time, well proved effective therapies with a different mechanism of action than the inhibition of TNF alpha are available for the treatment of this progressive disease.

Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis.

Biological agents directed against tumor necrosis factor (TNF) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs. To evaluate the efficacy and safety of the anti-TNF agents infliximab, etanercept, adalimumab, golimumab, and certolizumab for the treatment of ankylosing spondylitis, we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE, MEDLINE, Cochrane Controlled Trials Register and LILACS databases (September/2012), manual literature search, and the gray literature. Study selections and data collection were performed by two independent reviewers, with disagreements solved by a third reviewer. The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws. The meta-analysis was performed using the Review Manager(®) 5.1 software by applying the random effects model. Eighteen studies were included in this review. No study of certolizumab was included. Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % CI 1.91; 2.56) and 24 weeks (RR 2.68; 95 % CI 2.06; 3.48) compared with controls, which was also true for several other efficacy outcomes. Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks. Adalimumab, infliximab, etanercept, and golimumab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis. Safety outcomes deserve further study, especially with respect to long-term follow-ups.

Comparative study of the efficacy and safety of two polyvalent, caprylic acid fractionated [IgG and F(ab')2] antivenoms, in Bothrops asper bites in Colombia.

The efficacy and safety of two polyvalent horse-derived antivenoms in Bothrops asper envenomings were tested in a randomized, double-blind, clinical trial performed in Colombia. Both antivenoms were manufactured from the same pool of hyperimmune plasma. Antivenom A was made of F(ab')2 fragments, generated by pepsin digestion and caprylic acid precipitation, whereas antivenom B consisted of whole IgG molecules produced by caprylic acid precipitation followed by ion-exchange chromatography. Besides the different nature of the active substance, antivenom B had higher protein concentration, slightly higher turbidity and aggregate content. No significant differences were observed in the efficacy of antivenoms. Both halted local and systemic bleeding (P = 0.40) within 6-12 h of treatment in 100% of the cases, and restored blood coagulation (P = 0.87) within 6-24 h in 84.7% of patients, and within 48 h in all of them, in agreement with restoration of plasma fibrinogen concentration. Venom concentrations in serum dropped significantly (P < 0.001), to very low levels, 1 h after antivenom infusion. Nevertheless, eight patients (11.1%), four for each antivenom, presented recurrence of venom antigenaemia at different times, from 6 to 96 h, with clinical significance (recurrent coagulopathy) only in one group B patient (2.9%). Serum creatine kinase (CK) activity was increased, as a consequence of local myonecrosis. There was no significant difference (P = 0.51) in the incidence of early adverse reactions to antivenom administration (28.9% for patients of group A and 20.6% for patients of group B), most of the reactions being mild, mainly cutaneous. The most frequent complications were cellulitis (16.7%), abscess formation (5.6%), acute renal failure (8.3%), and compartmental syndrome (5.6%). In conclusion, IgG and F(ab')2 antivenoms, prepared by caprylic acid fractionation, presented similar efficacy and safety profiles for the treatment of B. asper envenomings in Colombia.

Efficacy of IgG and F(ab')2 antivenoms to neutralize snake venom-induced local tissue damage as assessed by the proteomic analysis of wound exudate.

Proteomic analysis of wound exudates represents a valuable tool to investigate tissue pathology and to assess the therapeutic success of various interventions. In this study, the ability of horse-derived IgG and F(ab')(2) antivenoms to neutralize local pathological effects induced by the venom of the snake Bothrops asper in mouse muscle was investigated by the proteomic analysis of exudates collected in the vicinity of affected tissue. In experiments involving the incubation of venom and antivenom prior to injection in mice, hemorrhagic activity was completely abolished and local muscle-damaging activity was significantly reduced by the antivenoms. In these conditions, the relative amounts of several intracellular and extracellular matrix proteins were reduced by the action of antivenoms, whereas the relative amounts of various plasma proteins were not modified. Because not all intracellular proteins were reduced, it is likely that there is a residual cytotoxicity not neutralized by antivenoms. In experiments designed to more closely reproduce the actual circumstances of envenoming, that is, when antivenom is administered after envenomation, the number of proteins whose amounts in exudates were reduced by antivenoms decreased, underscoring the difficulty in neutralizing local pathology due to the very rapid onset of venom-induced pathology. In these experiments, IgG antivenom was more efficient than F(ab')(2) antivenom when administered after envenomation, probably as a consequence of differences in their pharmacokinetic profiles.

Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile.

Nimotuzumab is an EGFR-targeting antibody that has demonstrated encouraging clinical results in the absence of severe side-effects observed with other approved anti-EGFR antibodies. We investigated whether different clinical behavior of nimotuzumab is related to its bivalent/monovalent binding profile. Binding properties of nimotuzumab and cetuximab, the most development of anti-EGFR antibodies, were studied in vitro using chip surfaces and cells with varying EGFR expression levels. Experimental observations demonstrated that in contrast to cetuximab, the intrinsic properties of nimotuzumab required bivalent binding for stable attachment to the cellular surface, leading to nimotuzumab selectively binding to cells that express moderate to high EGFR expression levels. At these conditions, both antibodies bound bivalently, and accumulated to similar degrees. When EGFR density is low, nimotuzumab monovalent interaction was transient, whereas cetuximab continued to interact strongly with the receptors. We compared the in vitro anti-tumor efficacy of nimotuzumab and cetuximab. Cetuximab decreased the cell viability and induced apoptosis for all the tested cell lines, effects which did not depend on EGFR expression level. In contrast, nimotuzumab also provoked significant anti-cellular effects, but its anti-tumor capacity decreased together with EGFR expression level. Cetuximab Fab fragment was able to impact tumor cell survival, whereas nimotuzumab fragment totally lost this effect. Tumor-xenograft experiments using cells with a high EGFR expression revealed similar tumor growth inhibiting effects for both antibodies. This study suggests an explanation for nimotuzumab clinical profile, whereby anti-tumor activity is obtained in absence of severe toxicities due to its properties of bivalent binding to EGFR.

Effect of IIb-IIIa glycoprotein inhibitors in a partial limb amputation model submitted to warm ischemia in rats.

Viability and functional results of a segment replantation depend on the prevention of deleterious effects of ischemia. Prolonged ischemia leads to alterations in the microcirculation: thrombosis, edema, production of oxygen free radicals, and platelet aggregation. The effect of IIb-IIIa glycoprotein inhibitors was tested in a partial limb amputation model submitted to warm ischemia. The male Wistar rats were divided into four groups: G1 with 0 hours of ischemia and saline ( N = 20), G2 with 6 hours of ischemia and saline ( N = 24), G3 with 6 hours of ischemia and abciximab ( N = 23), and G4 with 6 hours of ischemia and tirofiban ( N = 29). The limbs were observed for 7 days and classified as viable or nonviable. Viability and mortality rates were obtained and analyzed by Q-square and Fisher exact tests ( P < 0.05). The viability rates were 100% (G1), 30% (G2), 77.78% (G3), and 80.95% (G4). G2 was statistically different from G1, G3, and G4. G1, G3, and G4 were not statistically different. Transoperative and postoperative mortalities were not statistically different. The administration of abciximab and tirofiban improved limb salvage after ischemia and reperfusion and did not modify mortality rates significantly.

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

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.

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.

Infantile Kawasaki disease and peripheral gangrene.

We report a 1-month-old infant with Kawasaki disease and peripheral gangrene. We advocate using the newly published American Heart Association guidelines advising early laboratory and echocardiogram investigations in infants with fever but without other classic manifestations of Kawasaki disease. Initiation of early therapy may prevent this serious complication with its permanent sequelae.

Impaired myocardial perfusion score and inflammatory markers in patients undergoing primary angioplasty for acute myocardial infarction.

BACKGROUND: Microcirculatory dysfunction during acute myocardial infarction is mediated by various mechanisms including inflammation, thrombus, or plaque embolization. We hypothesize that patients with acute myocardial infarction and admission Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMP) < 2 had increased inflammatory status as measured by high sensitivity C-reactive protein (hs-CRP). METHODS: From January 2002 to December 2003, 166 patients (178 lesions) were referred for primary percutaneous coronary intervention. Patients were stratified based on pre-PCI TMP < 2 or TMP 2. Univariate and multivariate predictors of in-hospital and 30-day death were determined with logistic regression. RESULTS: Pre-PCI TMP < 2 was found in 66% vs 34% with TMP 2 (P < .001). Hs-CRP levels were high in both groups but not significantly different (37.9 +/- 6 vs 33.7 +/- 6 mg/L, P = .63). Patients with TMP < 2 had higher WBC (12.83 +/-4.55 x 10(-3) vs 10.83 +/- 3.00 x 10(-3), P = .04), lower ejection fraction (40 +/- 11% vs 46 +/- 12%, P < .001), and higher admission CK-MB levels (116 +/- 13 ng/mL vs 55 +/- 13 ng/mL, P = .006). Death occurred in 12% in the poorTMP group vs 1.8% in the good TMP group (P = .03). Advanced age, use of an intra-aortic balloon pump, and elevated admission WBC were independently associated with in-hospital and 30-day death. CONCLUSIONS: High hs-CRP levels were not associated with impaired myocardial perfusion score. Microcirculatory impairment may be related to an increased inflammatory process, independent from high hs-CRP levels.

ST-segment resolution 60 minutes after combination treatment of abciximab with reteplase or reteplase alone for acute myocardial infarction (30-day mortality results from the resolution of ST-segment after reperfusion therapy substudy).

The combination of abciximab with thrombolytic therapy when treating acute ST-elevation myocardial infarction has been hypothesized to enhance microvascular perfusion. Resolution of ST-segment elevation after thrombolytic therapy is believed to be a marker of myocardial reperfusion and to predict mortality rate. Among 16,588 patients enrolled in the Fifth Global Use of Strategies to Open Occluded Arteries in Acute Myocardial Infarction trial, 1,764 consecutive patients from selected centers had their study electrocardiograms evaluated by a core laboratory for ST-segment deviation resolution 60 minutes after treatment. Patients were categorized into 4 groups: complete resolution (>70%), partial resolution (<70% to 30%), no resolution (<30%), and worsening ST-segment deviation. Patients treated with reteplase or a combination of reteplase plus abciximab had similar rates of complete resolution (32% vs 34%), partial resolution (29% vs 27%), no resolution (15% vs 16%), and worsening ST-segment elevation (23 vs 23%; p = 0.59). The 30-day mortality rates in these 4 groups were 2.1%, 5.2%, 5.5%, and 8.1% (p <0.001). Even after accounting for baseline variables, incomplete ST-segment resolution (<70%) was associated with an increased risk of death within 30 days (adjusted hazard ratio 2.41, 95% confidence interval 1.25 to 4.63, p <0.008). Thus, ST-segment resolution at 60 minutes was no different in patients treated with full-dose reteplase from those treated with a combination of abciximab and reteplase. Patients with >70% ST-segment resolution within 60 minutes had markedly decreased mortality rates, irrespective of treatment.