Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s).

Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbß3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000-100 000 platelets/µL), to severe (20 000 to <50 000/µL), to profound (<20 000/µL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to ~14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin-induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab-associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind αIIbß3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune-mediated, with antibodies recognizing the αIIbß3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second-generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI-associated thrombocytopenia.

Safe administration of Crotalidae equine immune F(ab')2 antivenom in a patient who suffered anaphylaxis from Crotalidae polyvalent immune Fab antivenom.

Allergic reactions to Crotalidae polyvalent immune Fab and Crotalidae immune F(ab')2 are uncommon but potentially life-threatening. It is unknown whether cross-reactivity reactions exist between these two antivenoms. We report a case of a patient who suffered anaphylaxis from Crotalidae polyvalent immune Fab but subsequently was safely administered Crotalidae immune F(ab')2 after a presumed Agkistrodon contortix (copperhead) envenomation. This single case supports the safety of Crotalidae immune F(ab')2 administration in patients with a history of anaphylaxis to Crotalidae polyvalent immune Fab treatment.

Crotalidae Polyvalent Immune Fab and Cost-Effective Management of Hospital Admissions for Snakebites.

BACKGROUND: Venomous snakebites are a common clinical scenario in the Southeastern United States. CroFab® (Crotalidae Polyvalent Immune Fab (Ovine), BTG, Wales, UK) antivenom is indicated in cases involving pit vipers and is known to be expensive. The treatment protocol for snakebites is based on clinically subjective measures triggering the application, or escalation of, antivenom administration. The purpose of this study is to characterize the use of CroFab at our institution and to evaluate the impact of its use regarding cost and overall outcomes. We suspect that it is often used but potentially less often needed. We hypothesized that CroFab use was associated with increased length of stay (LOS) without an observed difference in patient outcomes. MATERIALS AND METHODS: A retrospective chart review of snakebite patients at our level-1 trauma center from 2000 to 2016 was performed. Snakebite location, snake species, number of vials of CroFab administered, hospital LOS, intensive care unit (ICU) LOS, and complications were identified for each patient. Patients were divided into CroFab (C) and no CroFab (NC) groups. RESULTS: One hundred ninety patients with venomous snakebites were included. 53.7% of patients received CroFab. There was no difference in the complication rate of C versus NC groups, (P = .1118). CroFab use was associated with longer hospital LOS (P < .0001) and ICU LOS (P < .0001). DISCUSSION: CroFab use was associated with increased LOS in our patient population. There was no difference in observed outcomes between the C and NC groups. These findings imply that CroFab is potentially over-used in our patient population.

Use of Crotalidae equine immune F(ab')2 antivenom for treatment of an Agkistrodon envenomation.

INTRODUCTION: Anavip (F(ab')2AV) is a lyophilized F(ab')2 immunoglobulin fragment derived from horses immunized with venom from Bothrops asper and Crotalus durissus. It was approved by the FDA in 2015 for treatment of North American rattlesnake envenomation but not for Agkistrodon envenomation. Published data regarding the efficacy and safety of Anavip in treating Agkistrodon envenomations is limited. We present a case of a patient treated with Anavip after confirmed Agkistrodon laticinctus envenomation. CASE DETAILS: A 77 year-old man was bitten on his fifth finger by a captive A. laticinctus. He was taken to a local emergency department where he received a 10 vial initial dose of F(ab')2AV for pain and swelling and was transferred. At the receiving facility, his pain had improved and his swelling had not progressed. Over the next 30 h, his platelets declined to 132,000/mm3 and he received an additional 4 vials of F(ab')2AV. The remainder of his course was unremarkable with complete recovery by 3 months. DISCUSSION: This case provides an additional published datapoint on the use of this F(ab')2AV in the treatment of envenomation by Agkistrodon.

Moderate-to-severe Vipera berus envenoming requiring ViperaTAb antivenom therapy in the UK.

BACKGROUND: Bites by the European adder (Vipera berus) in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunoloski zavod antivenom supply around 2012, the UK changed its national choice of antivenom for Vipera berus to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice. METHODS: A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for V. berus envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom. RESULTS: One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten (n = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital (n = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5-66.5) h, longer for children than adults (52.5 vs 41.3 h). CONCLUSION: ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.

Prevalence of Acute Hypersensitivity Reactions in Pediatric Patients Receiving Crotalidae Polyvalent Immune Fab.

INTRODUCTION: Studies of acute hypersensitivity reactions in pediatric populations receiving Crotalidae Polyvalent Immune Fab (CPIF) are complicated by small size, wide age ranges, and diverse definitions of such reactions. METHODS: This is a retrospective chart review of patients aged 13 years or younger treated with CPIF for Crotalid envenomation from November 2006 to 2016. The primary outcome was the presence of an acute hypersensitivity reaction to CPIF and was defined as the development of any of the following symptoms within 3 hours of initiation of CPIF infusion: urticaria, wheezing or respiratory distress, angioedema, hypotension, nausea, and/or vomiting. Demographics, CPIF dose to control and total dose, bite location, level of care, and length of stay were also recorded. RESULTS: Thirty-four patients were ultimately treated with CPIF. Ages ranged from 10 months to 13 years. Twenty-one patients (60%) were male, 24 (70.6%) were admitted to the ICU, and the median length of stay was 2 days with a range of 1-11 days. Zero patients developed an acute hypersensitivity reaction to CPIF. CONCLUSION: Acute hypersensitivity reactions to CPIF did not occur in this cohort. Such reactions are rare with the use of CPIF in pediatric patients.

Snake bites by European vipers in Mainland France in 2017-2018: comparison of two antivenoms Viperfav® and Viperatab®.

Context: Today, immunotherapy with Fab or F(ab')2 fragments is considered as a gold standard treatment for patients bitten by vipers. We compared the efficiency of two antivenoms, Viperfav® and Viperatab®, in mainland France in 2017-2018 with data provided by the French poison control centre (PCC).Methods: Patients with a moderate (2a and 2b) or severe (3) envenomation after a European viper bite and treated with immunotherapy were included and the markers chosen were the risk of post-antivenom treatment worsening, duration of hospital stay and persistent functional discomfort on day 15. Statistical studies were based on multivariate data analysis.Results: Two hundred and ninety-seven cases were recorded. One hundred and eighty-two (61.3%) patients received Viperfav® and 115 (38.7%) received Viperatab®. Compared to Viperfav®, use of Viperatab® significantly increased the risk of post-antivenom treatment worsening (OR* 12.05; 95%CI [3.11; 46.70]; p < .001). No significant difference between these antivenoms was recorded with respect to the duration of hospital stay and persistent functional discomfort on day 15. Viperfav® and Viperatab® have a similar tolerance (p > .21). Otherwise, duration of hospitalisation was significantly increased by a delay of immunotherapy infusion of more than 12 h (OR 2.70; 95%CI [1.45-5.06]; p = .002) or a preventive administration of LMWH (OR 6.55; 95%CI [1.58-27.13]; p=.02).Discussion: While Viperfav® and Viperatab® have a similar tolerance, our data show that Viperatab® was associated with a higher risk of post-antivenom treatment worsening compared to Viperfav®. Furthermore, this study confirms that the antivenom should be used as soon as possible. Indeed, patients receiving the immunotherapy infusion from the grade 2b presented significantly more frequent exacerbated symptoms (OR 3.99; 95%CI [1.16-13.73]; p=.028) after the antivenom infusion compared to grade 2a group.Conclusions: Whereas no significant difference between these antivenoms was recorded with respect to the duration of hospital stay and persistent functional discomfort on day 15, use of Viperatab®, compared to Viperfav®, significantly increased the risk of post-antivenom treatment worsening (OR* 12.05; 95%CI [3.11; 46.70]; p < .001). Taken together, these data show that Viperfav® is the treatment of choice for the management of snake bites in France.

Certolizumab Pegol: A Review in Moderate to Severe Plaque Psoriasis.

Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α. Subcutaneous certolizumab pegol is indicated for the treatment of various immune-mediated inflammatory diseases (IMIDs), including moderate to severe plaque psoriasis. In pivotal phase III trials in adults with moderate to severe plaque psoriasis, significantly more patients receiving certolizumab pegol 200 mg or 400 mg once every 2 weeks than placebo recipients achieved a ≥ 75% reduction in PASI score (PASI75 responder) and a PGA score of clear/mostly clear with a ≥ 2 point improvement from baseline (PGA0/1 responder) at week 12 (CIMPACT) or 16 (CIMPASI-1 and -2). In CIMPACT, certolizumab pegol 400 mg once every 2 weeks was superior to etanercept (highest recommended dosage) at 12 weeks, with certolizumab pegol 200 mg once every 2 weeks demonstrating non-inferiority, but not superiority, to etanercept. The clinical benefits of certolizumab pegol were maintained during the maintenance phase (to week 48) and the open-label extension phase of these trials. Certolizumab pegol is unique among the biologics, with the absence of an Fc fragment conferring pharmacokinetic advantages; most notably, its minimal transfer across the placenta, and low relative infant dose during breastfeeding in conjunction with its low oral bioavailability. Certolizumab pegol was generally well tolerated and no new safety signals were identified in these phase III trials, which complements its established safety profile in other IMIDs. Certolizumab pegol is a useful option for the treatment of moderate to severe plaque psoriasis and provides an important treatment option for women of childbearing age, for whom there are limited options available.

Recovery from Copperhead Snake Envenomation: Role of Age, Sex, Bite Location, Severity, and Treatment.

INTRODUCTION: Few data exist to understand the recovery phase of pit viper envenomation. A recently published placebo-controlled clinical trial affords this opportunity. The purpose of this study is to examine the time course of recovery from copperhead snake (Agkistrodon contortrix) envenomation patients managed with and without the use of antivenom, stratified by age, sex, anatomic site of envenomation, initial severity of envenomation, and geographic region. METHODS: This is a post-hoc subgroup analysis of data from a multi-center double-blinded clinical trial of Fab antivenom (FabAV) vs. placebo. Outcomes were the Patient-Specific Functional Scale (PSFS) score at 3, 7, 10, and 14 days after envenomation. Least-squares mean PSFS score curves were calculated for each subgroup, and repeated measures ANOVA was used to estimate between-group comparisons. RESULTS: Seventy-two subjects were included, of whom 44 received FabAV. Males demonstrated better overall recovery than females (model predicted PSFS score 6.18 vs 4.99; difference 1.19; 95% CI 0.12 to 2.25; p = 0.029). No sex difference was found in response to FabAV. Overall recovery and effect of FabAV were similar in adult vs adolescent patients, patients with upper vs lower extremity envenomation, and patients with initially mild vs moderate envenomation signs. Analysis by geographic location was not successful due to ANOVA mode instability. CONCLUSIONS: Male victims of copperhead snake envenomation demonstrate slightly better recovery than females, but response to Fab antivenom overall is similar across all subgroups studied.

Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates.

Antibody-drug conjugates (ADCs) are promising therapies for haematological cancers. Historically, their therapeutic benefit is due to ADC targeting of lineage-restricted antigens. The C-X-C motif chemokine receptor 4 (CXCR4) is attractive for targeted therapy of haematological cancers, given its expression in multiple tumour types and role in cancer "homing" to bone marrow. However, CXCR4 is also expressed in haematopoietic cells and other normal tissues, raising safety challenges to the development of anti-CXCR4 ADCs for cancer treatment. Here, we designed the first anti-CXCR4 ADC with favourable therapeutic index, effective in xenografts of haematopoietic cancers resistant to standard of care and anti-CXCR4 antibodies. We screened multiple ADC configurations, by varying type of linker-payload, drug-to-antibody ratio (DAR), affinity and Fc format. The optimal ADC bears a non-cleavable linker, auristatin as payload at DAR = 4 and a low affinity antibody with effector-reduced Fc. Contrary to other drugs targeting CXCR4, anti-CXCR4 ADCs effectively eliminated cancer cells as monotherapy, while minimizing leucocytosis. The optimal ADC selectively eliminated CXCR4+ cancer cells in solid tumours, but showed limited toxicity to normal CXCR4+ tissues, sparing haematopoietic stem cells and progenitors. Our work provides proof-of-concept that through empirical ADC design, it is possible to target proteins with broad normal tissue expression.

Incidence of allergic reactions to Crotalidae polyvalent immune Fab.

CONTEXT: The administration of Crotalidae polyvalent immune Fab (FabAV) currently requires close observation, so patients can be monitored for hypersensitivity reactions. The objective of this study was to evaluate the occurrence of hypersensitivity reactions to FabAV. METHOD: This was a retrospective cohort study utilizing data from a statewide poison center database in the United States. Records of all patients envenomated by a rattlesnake and treated with FabAV between January 2002 and December 2014 were evaluated. Patients with acute hypersensitivity reactions were identified, and reactions were evaluated descriptively. RESULTS: A total of 1340 adult and pediatric patients received FabAV during the study period. Of these, 19 (1.4%) patients had a potential reaction to FabAV, with 10 requiring a reduction in infusion rate, but none requiring discontinuation of the antivenom. Reactions occurred during the loading dose (n = 10), maintenance doses (n = 4), or were delayed reactions (n = 6). Symptoms recorded included pruritus (n = 8), hives (n = 8), rash (n = 7), vomiting (n = 7), nausea (n = 6), dyspnea or wheezing (n = 4), diaphoresis (n = 3), throat irritation (n = 2), and mild hypotension (n = 2). One patient was given a concomitant administration of low dose epinephrine infusion until completion of the antivenom course. However, none of the reactions were considered to be life-threatening. CONCLUSION: FabAV appears to be associated with a low incidence of acute hypersensitivity reactions. Patients may not require placement in a location capable of detecting and rapidly responding to hemodynamic and/or airway issues for FabAV monitoring alone.

Adverse Events in the Efficacy of Crotalidae Polyvalent Immune Fab Antivenom vs Placebo in Recovery from Copperhead Snakebite Trial.

OBJECTIVE: To compare the incidence of hypersensitivity reactions following copperhead envenomation treated with Fab antivenom (FabAV) or placebo. METHODS: Patients with copperhead snakebites received treatment and follow-up in a prospective, randomized, double-blind, placebo-controlled trial of FabAV or placebo. The treatment allocation ratio was 2:1 (FabAV:placebo). All of the included patients received at least one dose of study treatment. We reviewed all treatment-emergent adverse events (AEs) using a previously published scale to classify likely hypersensitivity reactions as mild, moderate, or severe. RESULTS: We enrolled 74 patients at 13 sites. Forty-five patients received FabAV, and 29 patients received placebo. Five FabAV patients and 4 placebo patients had moderate envenomations; the rest were mild. Twenty-five FabAV patients and 8 placebo patients had at least 1 AE. Mild skin reactions occurred in 11 (24%) FabAV patients (pruritis, urticaria, rash, ecchymosis, erythema) and 1 (3%) placebo patient (pruritis). Moderate gastrointestinal AEs occurred in 7 (16%) FabAV patients (nausea, vomiting, constipation, diarrhea, oral paresthesia) and in 2 (7%) placebo patients (nausea). Respiratory AEs occurred in 3 (7%) FabAV patients (dyspnea, pulmonary embolism, nasal congestion, sneezing) and no placebo patients. Hypotension occurred in 1 patient in each group. CONCLUSIONS: In a randomized controlled trial of FabAV for copperhead bites, the incidence of hypersensitivity reactions was low. Most reactions were mild skin reactions.

Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials.

Importance: Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. Objective: To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Design, Setting, and Participants: Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm2 with diffuse or banded fundus autofluorescence patterns. Interventions: Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Main Outcomes and Measures: Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I-profile genetic biomarker. Results: A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm2 (95% CI, 0.00-0.31 mm2; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm2 (95% CI, -0.13 to 0.24 mm2; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm2 (95% CI, -0.07 to 0.24 mm2; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I-profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. Conclusions and Relevance: In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm2 per year. Trial Registration: ClinicalTrials.gov Identifier: NCT02247479 and NCT02247531.

Acute adverse events associated with the administration of Crotalidae polyvalent immune Fab antivenom within the North American Snakebite Registry.

Background: Crotalidae Polyvalent Immune Fab (Fab Antivenom) is the primary Viperid antivenom used in the United States since 2000. Adverse event data associated with its use are limited. The purpose of this study is to describe the prevalence of acute adverse events associated with the use of Fab antivenom. Methods: The American College of Medical Toxicology's Toxicology Investigators Consortium maintains a prospective case registry of poisoned and envenomated patients managed by medical toxicologists at the bedside. This registry includes the North American Snakebite sub-registry. We performed a review of 438 cases entered into the Snakebite sub-registry. Results: A total of 373 (85.2%) received at least one vial of Fab Antivenom. Forty percent were children. Adverse events occurred in 10 patients (2.7%) of whom six were adults. Rash was the most common adverse event. More severe adverse events (hypotension, bronchospasm, and/or angioedema) occurred in four (1.1%) patients. Prophylaxis was administered prior to Fab antivenom in 4.0%. Eight patients received various treatments for their adverse events. Neither the initial number of Fab antivenom vials, atopic history, nor prior envenomation correlated with the prevalence of adverse events. Discussion: This prevalence of adverse events was lower than in previous studies and in a meta-analysis of 11 studies. The types of adverse events and treatments used are consistent with those in previous reports. There were no prior reports of prophylaxis use with which to compare. Conclusion: The prevalence of Fab antivenom adverse events in the North American Snakebite Registry was 2.7%.

KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa.

BACKGROUND: Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. METHODS: This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. RESULTS: Of 182 subjects, 169 received at least one infusion of KB001-A (n=83) or placebo (n=86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p=0.995). A 3.2 increase in ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p=0.003). Mean changes from baseline in log10 sputum neutrophil elastase (NE) had a non-significant decrease (-0.27, 95% CI: -0.58,0.04, p=0.084) while IL-8 concentrations at week 16 were significantly lower (-0.27, 95% CI: -0.55,0.00, p=0.048) among KB001-A subjects (n=16) relative to placebo (n=13). CONCLUSIONS: KB001-A was safe and well-tolerated and associated with a modest FEV1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.

Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists.

Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.

Antithrombotic treatment during coronary angioplasty after failed thrombolysis: strategies and prognostic implications. Results of the RESPIRE registry.

BACKGROUND: Thrombolysis is still used when primary angioplasty is delayed for a long time, but 25%-30% of patients require rescue angioplasty (RA). There are no established recommendations for antithrombotic management in RA. This registry analyzes regimens for antithrombotic management. METHODS: A retrospective, multicenter, observational registry of consecutive patients treated with RA at 8 hospitals. All variables were collected and follow-up took place at 6 months. RESULTS: The study included 417 patients. Antithrombotic therapy in RA was: no additional drugs 22.3%, unfractionated heparin (UFH) 36.6%, abciximab 15.5%, abciximab plus UFH 10.5%, bivalirudin 5.7%, enoxaparin 4.3%, and others 4.7%. Outcomes at 6 months were: mortality 9.1%, infarction 3.3%, definite or probable stent thrombosis 4.3%, revascularization 1.9%, and stroke 0.5%. Mortality was related to cardiogenic shock, age > 75 years, and anterior location. The stent thrombosis rate was highest with bivalirudin (12.5% at 6 months). The incidence of bleeding at admission was high (14.8%), but most cases were not severe (82% BARC ≤2). Variables independently associated with bleeding were: femoral access (OR 3.30; 95% CI 1.3-8.3: p = 0.004) and post-RA abciximab infusion (OR 2.26; 95% CI 1.02-5: p = 0.04). CONCLUSIONS: Antithrombotic treatment regimens in RA vary greatly, predominant strategies consisting of no additional drugs or UFH 70 U/kg. No regimen proved predictive of mortality, but bivalirudin was related to more stent thrombosis. There was a high incidence of bleeding, associated with post-RA abciximab infusion and femoral access.

Abciximab-induced acute profound thrombocytopenia postpercutaneous coronary intervention.

Abciximab (c7E3 Fab) is one of the three potent intravenous glycoprotein IIb/IIIa receptor inhibitors (along with eptifibatide and tirofiban) that have shown significant positive outcomes when used in patients with intracoronary thrombus. However, major side effects have been reported with its use including hypotension, major bleeding and thrombocytopenia. This case is a 53-year-old man presenting with acute chest pain diagnosed with non-ST-elevation myocardial infarction, who underwent percutaneous coronary intervention with abciximab and heparin infusion and developed acute profound thrombocytopenia (platelet count <20,000/L) within 9 hours of infusion. This case demonstrates the importance of routinely monitoring the platelet count prior to and 2-4 hours following abciximab infusion and differentiating other causes of acute profound thrombocytopenia, particularly pseudothrombocytopenia and heparin-induced thrombocytopenia.

Abciximab-induced delayed profound thrombocytopaenia.

Abciximab, the first approved glycoprotein (GP IIb/IIIa) inhibitor, is being widely used during acute coronary syndromes and offers the promising approach to antithrombotic therapy. We present a case of a young woman who initially received abciximab infusion for undergoing percutaneous coronary intervention of left anterior descending artery and was eventually diagnosed with abciximab-induced delayed thrombocytopaenia. This case outlines the importance of close follow-up of these patients to prevent serious adverse events.