Search

Objective: New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients., Methods: RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients., Results: Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy., Conclusion: Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti-TNF treatment in patients with RA.

Objective: To assess the timing of onset of clinical benefit following the initial infusion of infliximab and to obtain additional safety experience of infliximab when given in an office setting to patients with rheumatoid arthritis (RA). In addition, the safety of reducing the infusion time from 2 hours to 1 hour was evaluated., Methods: Patients (n = 553) with active RA despite receiving methotrexate (MTX) were treated with infliximab 3 mg/kg given over 2 h at baseline (Week 0), and Weeks 2, 6, and 14 in this multicenter open-label trial. Patients continued to receive a stable dose of MTX (> or = 7.5 mg/wk). At selected sites, patients tolerating the first 4 infusions were eligible to receive 2 additional infusions at twice the usual infusion rate (given over 1 h). Patients returned for efficacy assessments at 48 h following the initial infusion and several times throughout study participation., Results: By 48 h following the first infusion, significant (p < 0.001) improvements were observed in duration of morning stiffness (34% mean improvement), physician's global disease assessment scores (30%), patient's global disease assessment scores (25%), and patient's pain assessment scores (30%). By Week 16, 52 to 63% mean improvements in these efficacy variables were observed (p < 0.001), the significant improvement was maintained through the end of study participation in the subset of patients who received the additional 1 h infliximab infusions. Through 16 weeks, 10% (54/553) of patients reported an adverse event associated with at least 1 of the 4 infusion procedures; the majority were mild and transient in nature. In the subset of 197 patients who received 2 additional infusions over 1 h, no increase in the frequency or severity of infusion-related adverse events was observed compared to the 2 h infusion., Conclusion: Infliximab administered to patients with RA in an outpatient setting resulted in significant clinical improvement within 48 h that was sustained with additional infusions. Approximately 10% of patients experienced an infusion reaction, highlighting the need for direct supervision over patient treatment. Patients who tolerated infliximab infusions given over 2 h also tolerated a 1 h infusion.

INFLIXIMAB: Is a chimeric antitumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn's disease and rheumatoid arthritis. A LONG TERM SAFETY: In several placebo controlled, randomized clinical trials and open trials, 771 patients have been given infliximab (a further 192 received placebo). Follow-up for safety has included the time of study (12 weeks after the last infusion), plus 3 additional years. GENERAL TOLERANCE: Acute infusion reactions (headache, fever, chills, urticaria, chest pain) were seen in 17% of patients receiving infliximab compared with 7% of those receiving placebo. While infections were reported more frequently overall in the patients given infliximab (26% over 27 weeks of follow-up versus 16% of placebo-treated patients over 20 weeks of follow-up), there was no increased risk of serious infections. There was no difference in the overall mortality rate between the groups. AT THE POINT OF VIEW IMMUNOLOGIC: While low titres of autoantibodies developed in less than 10% of patients, drug-induced lupus was seen in less than 1%, with these cases resolving upon discontinuation of the drug. Overall, infliximab showed an acceptable safety profile.

Infliximab is a chimeric anti-tumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn's disease and rheumatoid arthritis. In several placebo controlled, randomized clinical trials and open trials, 771 patients have been given infliximab (a further 192 received placebo). Follow-up for safety has included the time of study (12 weeks after the last infusion), plus three additional years. Acute infusion reactions (headache, fever, chills, urticaria, chest pain) were seen in 17% of patients receiving infliximab compared with 7% of those receiving placebo. While infections were reported more frequently overall in the patients given infliximab (26% over 27 weeks of follow-up versus 16% of placebo-treated patients over 20 weeks of follow-up), there was no increased risk of serious infections. There was no difference in the overall mortality rate between the groups. While low titres of autoantibodies developed in less than 10% of patients, drug-induced lupus was seen in less than 1%, with these cases resolving upon discontinuation of the drug. Overall, infliximab showed an acceptable safety profile.

Objective: To investigate the longterm consequences of tumor necrosis factor-alpha (TNF-alpha) blockade in patients with rheumatoid arthritis (RA), to compare changes after repeated infusion of cA2 monoclonal antibody with those occurring after the initial treatment, and to investigate significant correlations of cellular or serological changes to the duration of clinical benefit for each patient., Methods: A clinical trial testing TNF-alpha monoclonal antibody cA2 in treatment of RA showed this therapeutic agent is highly effective. A dosage of 1 mg/kg or 10 mg/kg cA2, given in a single infusion, was compared to placebo. After clinical relapse all patients were (re)treated with 3 or 10 mg/kg cA2. In parallel to this clinical study, we investigated cellular and molecular changes induced by in vivo blockade of TNF-alpha., Results: After an initial transient increase, T lymphocyte counts were not significantly different from starting values throughout the observation period. Monocyte counts as well as serum interleukin 6 (IL-6) and soluble intercellular adhesion molecule 1 (sICAM-1) concentrations remained decreased for several weeks after infusion. After a repeated infusion, increases in numbers of T cells and decreases in monocytes and IL-6 and sICAM-1 concentrations were evident again. Changes in cell counts, however, were smaller, especially in the group initially treated with the low dose (1 mg/kg), despite a higher retreatment dosage of 3 or 10 mg/kg cA2. Similarly, in this group decrease of IL-6 and sICAM-1 concentrations was less pronounced, was delayed to Day 7 after infusion, and lasted for a shorter period than seen after initial treatment., Conclusion: We conclude that in vivo TNF-alpha blockade leads to prolonged cellular and serological changes. This effect appears to be less pronounced after repeated infusion of cA2 compared to the initial treatment, mainly in the low dose group.

Unlabelled: The aim of the study is to investigate which of two treatment options of saline lavage induced ARDS in rabbits is better in terms of oxygenation and prevention of barotrauma: combined high peak pressure ventilation with surfactant administration and inhaled nitric oxide or veno-venous ECMO combined with low peak inspiratory pressure ventilation., Materials and Methods: After saline lavage (10 cc/kg repeated as long as foamy retrieval was observed) two combined therapeutic strategies were examined: ventilation with high inspiratory pressures (35 cm H2O) with additional exogenous surfactant administration (100 mg/kg) and inhaled nitric oxide (10 PPM) (n=5, group 1) and low inspiratory pressure (20 cm H2O) ventilation under veno-venous ECMO support (n=5, group 2). The FiO2 was maintained at 1.0 in both groups. The paO2/FiO2 ratio was calculated in 30 minute intervals for 4 hours. After that the animals were sacrificed and the lungs examined macro- and microscopically. Aeration was described in a semiquantitative method using the alveolar expansion index. Oxygenation in group 1 was significantly better than in group 2, it increased significantly after surfactant but not after additional nitric oxide administration. However, the lungs in group 1 showed severe signs of baro/ergotrauma (Hyaline membranes, air leaks, infiltration of polymorphonuclear (PMN) granulocytes and macrophages, break down of alveolar capillary membranes) after 4 hrs of combined therapy, whereas the lungs in group 2 appeared normal. Adding surfactant and NO to a high tidal volume ventilation improved oxygenation, but did not prevent baro/ergotrauma. Ventilation with low inspiratory pressures combined with ECMO caused little baro/ergotrauma but adequate oxygenation could not be achieved, probably due to anatomical features of the rabbit which do not allow appropriate blood flow within the ECMO-circuit.

Background & Aims: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit., Methods: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>/=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied., Results: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation., Conclusions: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments.

Background & Aims: Anti-tumor necrosis factor alpha monoclonal antibody treatment (infliximab) reduces clinical signs and symptoms in patients with Crohn's disease. The effects of infliximab on mucosal histopathologic abnormalities in Crohn's ileocolitis were studied., Methods: Thirteen patients with steroid-refractory Crohn's disease were treated with a single infusion of infliximab (5-20 mg/kg), and 5 were treated with placebo. Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy. Severity of inflammation was assessed by a histological score. Immunohistochemical stainings with antibodies against HLA-DR, CD68, tumor necrosis factor alpha, intercellular adhesion molecule 1, lymphocyte function-associated antigen, CD4, CD8, and interleukin 4 were performed., Results: Total histological activity score was reduced significantly in both ileitis and colitis after infliximab. This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells. Mucosal architecture returned to normal in 4 patients at 4 weeks. The number of lamina propria mononuclear cells decreased because of a global reduction of CD4(+) and CD8(+) T lymphocytes and CD68(+) monocytes. Aberrant colonic epithelial HLA-DR expression completely disappeared. The percentage of intercellular adhesion molecule 1 and lymphocyte function-associated antigen 1-expressing and interleukin 4- and tumor necrosis factor-positive lamina propria mononuclear cells sharply decreased., Conclusions: Infliximab dramatically decreases histological disease activity in Crohn's ileocolitis. Signs of active inflammation nearly disappear accompanied by a profound down-regulation of mucosal inflammatory mediators.

Objective: To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients., Methods: In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26., Results: Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients., Conclusion: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.

Neonatal asphyxia is a major topic of neonatal research. However, no clear-cut physiologic parameters exist which enable an early identification of neonatal infants who are either at risk to develop brain damage or posthypoxic heart failure. Parameters indicating dysfunction of the heart and kidneys as creatinine and creatinine kinase have been evaluated. In our study, 47 asphyxiated infants (umbilical artery pH < 7.18 and either a 1-min Apgar score < 4 or a 5-min Apgar score < 7) were compared to 27 nonasphyxiated controls regarding significant differences in creatinine, creatinine kinase, its MB fraction, and a newly introduced myocardial hypoxia indicator -- troponin T -- to establish the value of these parameters in the retrospective diagnosis of asphyxia. Further we evaluated two subsets of these 47 asphyxiated infants with either subsequent signs of encephalopathy (seizures) or heart failure. Creatinine, creatinine kinase and troponin T were significantly elevated in asphyxiated infants compared with controls; no differences were found in creatinine kinase and its MB fraction. In asphyxiated infants with heart failure, troponin T was significantly higher than in the other asphyxiated infants. However, none of the parameters studied was significantly different in patients with brain damage compared with asphyxiated infants without neurological sequelae. Troponin T has a high positive predictive value in the postnatal diagnosis of asphyxia. The diagnostic power of troponin T equals that of creatinine. However, troponin T is more sensitive in the identification of infants with asphyxia and cardiocirculatory failure than creatinine. Creatinine kinase and its MB fraction have no diagnostic value.

Background: Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease., Methods: We conducted a 12-week multicenter, double-blind, placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn's disease that was resistant to treatment. All had scores on the Crohn's Disease Activity Index between 220 and 400 (scores can range from 0 to about 600, with higher scores indicating more severe illness). Patients were randomly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight, 10 mg per kilogram, or 20 mg per kilogram. Clinical response, the primary end point, was defined as a reduction of 70 or more points in the score on the Crohn's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications., Results: At four weeks, 81 percent of the patients given 5 mg of cA2 per kilogram (22 of 27 patients), 50 percent of those given 10 mg of cA2 per kilogram (14 of 28), and 64 percent of those given 20 mg of cA2 per kilogram (18 of 28) had had a clinical response, as compared with 17 percent of patients in the placebo group (4 of 24) (p<0.001 for the comparison of the cA2 group as a whole with placebo). Thirty-three percent of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index), as compared with 4 percent of the patients given placebo (P=0.005). At 12 weeks, 41 percent of the cA2-treated patients (34 of 83) had had a clinical response, as compared with 12 percent of the patients in the placebo group (3 of 25) (P=0.008). The rates of adverse effects were similar in the groups., Conclusions: A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe, treatment-resistant Crohn's disease.

Background: Whether and when to transfuse in anemia of prematurity is highly controversial. Some authors suggest transfusions simply if the hemoglobin (Hb) level is below a defined normal range. Others propose the use of clinical or laboratory parameters in anemic patients to decide whether to transfuse or not., Hypothesis: A decreasing amount of circulating Hb should cause a compensatory increase in cardiac output (CO) and an increase in arterial serum lactate., Materials and Methods: In 56 anemic preterm infants (not in respiratory or hemodynamic failure) we analyzed CO after the first week of life using a Doppler sonographic method. At the same time serum lactate levels, Hb levels and oxygen saturation were registered. Nineteen of these patients were given transfusion when they demonstrated clinical signs of anemia by tachycardia > 180/min, tachypnea, retractions, apneas and centralization (group 2). The remaining 37 patients were not transfused (group 1). Serum lactate, CO, heart rate (HR), oxygen delivery, respiratory rate, capillary refill and Hb were analyzed in both groups and in group 2 before and 12-24 h after transfusion. Data between groups 1 and 2 and in group 2 before and after transfusion were compared., Results: In the 56 patients studied no linear correlation between Hb and CO or between Hb and serum lactate was found. Nor could any correlation be demonstrated between the other variables studied. Examining the subgroups separately, a negative linear correlation was demonstrated between serum lactate and oxygen delivery in group 2. No other significant correlations were detected. However, when the pre- and post-transfusion data were compared in group 2 (increase of Hb from 9.45 (SD 3.44) to 12.5 (SD 3.8) g/100 ml), the CO decreased from 281.3 (SD 162.6) to 224 (SD 95.7) ml/kg per min (p < 0.01) and serum lactate decreased significantly from 3.23 mmol/l (SD 2.07) before to 1.71 (SD 0.83) after transfusion. Oxygen delivery was 35.8 (+/- 0.19) ml/kg per min group 1, 27.8 (+/- 0.05) pre- and 43.4 (+/- 0.07) post-transfusion in group 2 (p < 0.01)., Conclusions: CO measurements and serum lactate levels add little information to the decision-making process for blood transfusions, as neither CO nor serum lactate levels correlate with HB levels in an otherwise asymptomatic population of preterm infants. In infants where the indication for blood transfusion is made based on traditionally accepted clinical criteria, serum lactate is an additional laboratory indicator of impaired oxygenation, as it correlates significantly with oxygen delivery. A significant lower oxygen delivery in patients in whom blood transfusion is indicated and an increase in oxygen induced by transfusion demonstrate the value of these criteria in identifying preterm infants who benefit from transfusion.

In paediatric resuscitation scenarios, emergency physicians have sufficient skills in endotracheal intubation. They are successful in about 80% of the cases as US studies indicate. However, vascular access is much more of a critical problem and emergency physicians succeed in only 50%. Therefore, intraosseous access has become an internationally widely used and accepted method for venous access. In Germany, however, only case reports concerning this technique have been published. Based on the authors' experience shared with Sussmane and Raszynski in the US, we used the technique of intraosseous access in 18 paediatric resuscitative situations. Eleven patients survived who would not have done so without quick intravenous access. As complications we recorded a minor fracture, one compartment syndrome, which did not require surgical intervention, and a postmortally discovered minor fat embolism, which was of no clinical significance. Courses teaching this method should be offered in Germany to spread knowledge of this life-saving technique.

The platelet glycoprotein (GP) IIb/IIIa receptor can bind fibrinogen, von Willebrand factor, and other adhesive ligands; this binding is the final common pathway mediating platelet aggregation. The purpose of this study was to evaluate the safety and platelet inhibitory characteristics of the Fab fragment of the murine monoclonal anti-GPII/IIIa 7E3 antibody (m7E3 Fab) when administered intravenously as a single bolus dose, as a single and repeat bolus dose, and as a single bolus dose followed by continuous infusions of varying duration. Various dosage regimens of m7E3 Fab were studied in 74 patients with stable angina. Dosage regimens included single doses of m7E3 Fab from 0.1 to 0.3 mg/kg, a single dose of 0.20-0.30 mg/kg, and a repeat dose of 0.05 mg/kg, or a loading dose followed by a continuous infusion of m7E3 Fab for up to 36 hours. To assess the effect of m7E3 Fab on platelet function, quantitative blockade of GPIIb/IIIa receptors, inhibition of ex vivo platelet aggregation, and template bleeding time were measured in all patients. Dose-dependent inhibition of platelet function was evident in response to escalating bolus doses of m7E3 Fab, with maximum inhibition observed at 0.25-0.30 mg/kg body weight; at the 0.30 mg/kg dose, mean (+/- SE) GPIIb/IIIa receptor blockade was 81 +/- 3%, ex vivo platelet aggregation in response to 20 microM ADP was 14 +/- 6% of baseline, and the median bleeding time was > 20 minutes. Although platelet function gradually recovered following a single bolus injection, platelet inhibition could be sustained by continuous, low-dose infusion of the antibody. Platelet inhibition occurred within minutes, but m7E3 Fab that did not bind to platelets cleared rapidly from circulation. Sixteen percent of the m7E3 Fab-injected subjects exhibited low titer, human anti-murine antibody responses. No significant bleeding or allergic reactions were observed in any patients. One of the 74 patients developed transient thrombocytopenia soon after receiving m7E3 Fab. These studies establish that m7E3 Fab can be administered safely at doses that cause profound inhibition of platelet function.

The use of exogenous surfactant and nitric oxide in neonates has reduced the number of infants requiring ECMO. The purpose of this study was to demonstrate whether these two therapeutic options might reduce the number of over 28 days old children with severe ARDS requiring ECMO, without reducing changes of survival and morbidity. Over a 30 month period all non-neonatal ARDS patients transferred to our institution for ECMO evaluation were treated based on a study-algorithm. If they did not fulfill "fast entry criteria" (paO2 < 40 for more than 3 hrs.) we first tried different ventilation, vasodilatation, and hemodynamic strategies for max. 4 hrs. (inv. I/E ratio, HFOV, epoprostenol, high doses norepinephrine. If the OI did not decrease by < 10, 30-280 mg natural surfactant or 1-20 ppm nitric oxide were treatment options depending on the degree of pulmonary hypertension measured by echocardiography and by mixed venous saturation measurements. It was possible to use NO and surfactant sequentially. The patients had different etiologies of ARDS as near drowning, pneumonia, immunosuppression, and sepsis. If their OI did not decrease by 10 in 8 hrs. ECMO was installed. Nineteen patients were evaluated, 6 improved with conventional therapy, their OI decreased without a relapse (mean OI at begin of the study: 38). Six patients improved with surfactant therapy alone (mean OI: 54), 4 patients improved after surfactant and sequential NO-treatment, 3 patients were initially treated with NO, 1 sequentially with surfactant. One patient did not show any benefit from NO or surfactant and was put on ECMO. Three patients died (withdrawal of life support because of severe brain damage caused by the underlying disease). We could not observe any respiratory related failure. No patient had to be discharged on oxygen. A sophisticated treatment algorithm integrating different modern ARDS treatment options can reduce the number of patients requiring ECMO. We speculate however that these options can only be used effectively in centers involved in ARDS treatment quite frequently and that these centers have to provide ECMO as one of their therapeutic tools.

Background: Patients with unstable angina despite intensive medical therapy, ie, refractory angina, are at high risk for developing thrombotic complications: myocardial infarction or coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA). Chimeric 7E3 (c7E3) Fab is an antibody fragment that blocks the platelet glycoprotein (GP) IIb/IIIa receptor and potently inhibits platelet aggregation., Methods and Results: To evaluate whether potent platelet inhibition could reduce these complications, 60 patients with dynamic ST-T changes and recurrent pain despite intensive medical therapy were randomized to c7E3 Fab or placebo. After initial angiography had demonstrated a culprit lesion suitable for PTCA, placebo or c7E3 Fab was administered as 0.25 mg/kg bolus injection followed by 10 micrograms/min for 18 to 24 hours until 1 hour after completion of second angiography and PTCA. During study drug infusion, ischemia occurred in 9 c7E3 Fab and 16 placebo patients (P = .06). During hospital stay, 12 major events occurred in 7 placebo patients (23%), including 1 death, 4 infarcts, and 7 urgent interventions. In the c7E3 Fab group, only 1 event (an infarct) occurred (3%, P = .03). Angiography showed improved TIMI flow in 4 placebo and 6 c7E3 Fab patients and worsening of flow in 3 placebo patients but in none of the c7E3 Fab patients. Quantitative analysis showed significant improvement of the lesion in the patients treated with c7E3 Fab, which was not observed in the placebo group, although the difference between the two treatment groups was not significant. Measurement of platelet function and bleeding time demonstrated > 90% blockade of GPIIb/IIIa receptors, > 90% reduction of ex vivo platelet aggregation to ADP, and a significantly prolonged bleeding time during c7E3 Fab infusion, without excess bleeding., Conclusions: Combined therapy with c7E3 Fab, heparin, and aspirin appears safe. These pilot study results support the concept that effective blockade of the platelet GPIIb/IIIa receptors can reduce myocardial infarction and facilitate PTCA in patients with refractory unstable angina.

The remarkable progress in immunologic techniques in the development of monoclonal antibodies offers the potential for powerful new tools for the detection of cardiovascular disorders, such as acute myocardial necrosis and acute deep venous thrombosis, in an accurate, safe, and noninvasive manner. Historically the use of monoclonal antibodies has been viewed as a tool dominated by the field of oncology. However, because of the relative ease of identifying and characterizing well-defined, unique antigens on necrotic cells, blood clots, and cellular components of the circulatory system, the chance for success in developing a clinically useful diagnostic product is significantly enhanced. In addition to being unique, these antigenic sites are also virtually universal in their expression by the targeted tissues or cells in the human population. Also, the epitope for these antibodies is less prone to "shedding" than many of the tumor markers present on the surface of malignant cells. This review describes the clinical experience with two immunoscintigraphic diagnostic agents specifically designed for the assessment of cardiovascular disorders resulting in the death of myocytes and the formation of acute blood clots indium-111 antimyosin-Fab-diethylenetriamine pentaacetic acid for the detection of myocardial necrosis and technetium-99m antifibrin Fab' (T2G1s) for the detection of acute venous thrombosis.

Background: The T2G1s monoclonal antifibrin antibody binds specifically to fibrin but not to fibrinogen., Methods and Results: In a canine model of acute arterial thrombosis, we determined the feasibility of imaging thrombi using a 99mTc-labeled Fab' fragment. In 14 dogs, 10 carotid and 13 femoral artery thrombi were produced using 2-hour temporary occlusion, crush injury, and local thrombin injection methods. A sham-operated carotid artery served as control. Antifibrin antibody was injected intravenously at the end of temporary occlusion. Serial planar radionuclide images were obtained immediately and at 1 and 2 hours. Following killing the dogs at 2 hours, we measured antibody uptake ex vivo in 5-mm-long segments of thrombus, the adjacent injured artery, and a control artery. Antibody was cleared from the blood with a mean +/- SD t1/2 of 121 +/- 23 minutes. The thrombi weighed 218 +/- 140 mg. Antibody uptake in the thrombi was patchy, and the thrombi were closely adherent to the injured arterial wall. In the segment with maximal ex vivo antibody uptake, the ratio of control artery to blood counts/g/sec was 0.65 +/- 0.46, the injured artery-to-blood ratio was 2.35 +/- 1.01 (p less than 0.0001 versus control), and the thrombus-to-blood ratio was 4.24 +/- 2.58 (p less than 0.0001 versus control). In three dogs, an isotype-matched ovarian tumor antibody labeled with 111In was injected with T2G1s but was not taken up in the thrombus or the adjacent arterial wall. Visual analysis of the in vivo carotid radionuclide images showed uptake by 2 hours in all 10 carotid thrombi. Quantitative image analysis, measured as the thrombus-to-opposite carotid artery ratio, showed increasing uptake over time with ratios of 1.1 +/- 0.3, 1.6 +/- 2.0, and 2.2 +/- 1.3 on the immediate, 1-hour, and 2-hour images, respectively. All quantitative ratios of 1.3 or greater were visually identified., Conclusions: 99mTc-labeled Fab' fragments of the T2G1s antibody are taken up specifically by acute arterial thrombi after intravenous injection. Uptake is progressive over a 2-hour period, and all thrombi are detected by radionuclide imaging at 2 hours. These results show that it is feasible to noninvasively detect arterial thrombi within 2 hours of formation.

Antifibrin scintigraphy is a new and innovative approach to the diagnosis of acute deep venous thrombosis (DVT). Many antifibrin monoclonal antibodies (Mo-Abs) have been described, but only two, 59D8 and T2G1s, have undergone broad preclinical or clinical investigation. Both of these MoAbs recognize an epitope on the amino terminal end of fibrin. The epitope for 59D8 and T2G1s is available for binding only on newly formed, acute thrombi. Preclinical studies have confirmed the specificity of these MoAbs for acute DVT, and have demonstrated their ability to image experimentally induced DVT. Preliminary clinical studies in patients with signs or symptoms of DVT have evaluated indium-111 59D8 Fab and technetium-99m T2G1s Fab'. Fragments of the intact MoAbs are employed to promote faster blood clearance and to reduce immunogenicity. The initial clinical studies indicate that antifibrin scintigraphy has a diagnostic accuracy approaching 90%. Antifibrin scintigraphy has the potential for overcoming many of the deficiencies of both invasive (contrast venography) and noninvasive (Doppler/ultrasound, impedance plethysmography) methods for detecting DVT. With a single procedure, it provides an accurate and rapid evaluation of both lower extremities, both above and below the knee. Because of its unique specificity for acute DVT, it should have excellent potential for use in patients with suspected acute, recurrent DVT, a condition difficult to diagnose by all currently employed tests for DVT.

The recent development of monoclonal antibodies against components of coagulated blood may provide new approaches to the diagnosis of venous thrombosis. Scanning with an indium-111-labeled Fab fragment of a murine monoclonal antifibrin antibody (59D8) and ascending contrast venography were performed in 33 patients. Images of the calves, popliteal fossae, thighs, and pelvis were obtained immediately, 4-6 hours, and 24 hours after injection of 2 mCi (74 MBq) of the antibody. All images were read in a blinded manner. Findings in both studies were positive in 28 patients and negative in three. In 19 patients not undergoing heparin therapy, 19 specific anatomic sites were positive on venograms and 29 were positive on antibody images (19 sites matched). In 14 patients undergoing heparin therapy, 34 sites were positive on venograms and 27 were positive on antibody images (22 sites matched). In most patients, positive results were noted within 1 hour of antibody injection. No adverse effects were noted with the antibody preparation. Preliminary data suggest that antifibrin antibody imaging is sensitive in detecting clots, is safe to use, and may have a role in diagnosing and managing venous thrombosis.

To explore the effect of physiologic hypertrophy superimposed on pathologic hypertrophy, hearts from female control rats (C), renal hypertensive rats (H), rats conditioned with a 10-12 wk swimming program (Sw), and hypertensive rats trained by the swimming program (H-Sw) were perfused in an isolated working rat-heart apparatus. Systolic blood pressure was approximately 100 mmHg in C and Sw and was 160 mmHg in H and H-Sw. The swimming program had no effect on blood pressure. Compared with C, heart weight was increased by 30% in Sw, 47% in H, and 77% in H-Sw. At high preload and afterload, cardiac output (milliliters per gram dry LV weight) was decreased in H, increased in Sw, and partially restored towards normal in H-Sw. Ejection fraction, percent fractional shortening, and mean velocity of circumferential fiber shortening were enhanced in Sw, depressed in H, and normalized in H-Sw when compared with C. Coronary flow and myocardial oxygen consumption in this series of hearts were depressed in H, with no restoration in H-Sw, but coronary effluent lactate/pyruvate ratios were only elevated in the hearts of H-Sw. Coronary vascular responses were examined in a second series of experiments which used microspheres. In this series, the depressed coronary flow observed in H was partially restored towards normal in H-Sw and the inner/outer myocardial flow ratio was normal when hearts were perfused at 140 cm aortic pressure but was somewhat depressed in both H and H-Sw when the hearts were perfused at 80 cm aortic pressure. These studies demonstrate that hypertrophic hearts from renal hypertensive rats have diminished coronary flow and depressed cardiac function when they are studied in the isolated working heart apparatus, yet there is no evidence of myocardial ischemia. Superimposition of a chronic swimming program results in increased hypertrophy but restoration of cardiac function partially or completely to normal. Thus, pathologic and physiologic hypertrophy are biologically distinct entities. Physiologic hypertrophy may partially ameliorate the defects associated with pathologic hypertrophy.

To evaluate the combined effects of cardiac overload imposed by hypertension and by chronic exercise, male and female rats were made hypertensive by unilateral renal artery stenoses and made to exercise in an 8-10-wk swimming program. Sedentary normotensive animals, sedentary hypertensive animals and normotensive animals exposed to the swimming program were also studied. Hypertension was associated with the development of cardiac hypertrophy, and this was exaggerated in hypertensive swimmers. Actomyosin, Ca2+-myosin, and actin-activated Mg2+-myosin ATPase activities were enhanced in normotensive swimmers, depressed in hypertensives and were normal or increased in hypertensive swimmers. Myosin isoenzyme analysis showed a predominant V1 pattern in normals; an increase in percent V1 isoenzyme is swimmers; a predominant V3 pattern in hypertensives; and a return to the predominant V1 pattern in hypertensive swimmers. These findings suggest that the hypertrophy imposed by hypertension and hypertrophy imposed by physical training using a chronic swimming program are distinctly different biological phenomena. Physical training by swimming prevents the changes in cardiac myosin induced by hypertension despite the exaggeration of hypertrophy.

Previous reports have documented a cardiomyopathy in rats resulting from streptozotocin-induced diabetes. In order to determine the reversibility of streptozotocin-induced cardiomyopathy to insulin therapy, hearts from rats made diabetic by streptozotocin for 6 weeks and then treated with insulin for 3 weeks were compared with untreated diabetic rats and control rats not injected with streptozotocin. When perfused in an isolated working heart apparatus with 5.5 mM glucose as substrate, hearts from untreated diabetic rats when compared to hearts from either streptozotocin-injected rats treated with insulin or control rats showed significant depressions in peak left ventricular pressure, maximal positive and negative dP/dt, oxygen extraction, lactate production and effluent lactate; pyruvate ratio. Ca2+-actomyosin ATPase was also depressed in untreated diabetics. As left atrial pressure was raised in untreated diabetic rats, a decline in cardiac output was observed, whereas in insulin-treated or control groups there was no such negative response. Indices of cardiac performance were significantly greater in insulin-treated rats when compared to control rats suggesting overcorrection with insulin therapy. To explore whether insulin treatment may have a beneficial effect on the myocardium control rats were made hyperinsulinemic for 6 to 7 weeks. Shorter isovolumic relaxation times and elevated values for Ca2+-actomyosin ATPase were observed in hearts from hyperinsulinemic animals when compared to hearts from control animals. These results demonstrate complete reversibility of streptozotocin-induced cardiomyopathy and confirm that this condition is due to insulin deficiency and not to a primary cardiotoxic effect of streptozotocin.

To explore the interactions of physiologic and pathologic hypertrophy, four groups of hearts were studied in an isolated working rat heart apparatus. Cardiac contractile proteins were also evaluated. The groups were hearts of female control sedentary rats; rats subjected to a 10-week swimming programme; rats with renal hypertension; and hypertensive rats subjected to a 10-week swimming programme. The swimming programme in normotensive female rats caused a 30% cardiac hypertrophy, in hypertensive animals 46% hypertrophy, and in combined hypertension and swimming 70% hypertrophy. Ca2+-myosin ATPase activity and actin-activated myosin ATPase were elevated in hearts of swimmers, depressed in hearts of hypertensive sedentary animals and similar to control values in hearts of hypertensive swimmers. Myosin V1 isoenzyme content was increased in hearts of swimmers, depressed in hearts of hypertensives, but normal in hearts of hypertensive swimmers. Reciprocal relationships were seen with the V3 isoenzyme. Stroke work, mean velocity of circumferential fibre shortening, and per cent fractional shortening at the midwall showed increased values for hearts of swimmers, depressed values for hearts of hypertensives, and normal values or values above the control for hearts of hypertensive swimmers. Myocardial flow measured with microspheres was increased in the left ventricle of swimmers, depressed in hearts of hypertensives and still depressed in hypertensive swimmers, but significantly higher than in the hypertensives alone. The correlation of actin-activated ATPase activity and of fractional shortening was linear among the four groups. These studies demonstrate that physiologic and pathologic hypertrophy in the rat have distinctly opposite effects on contractile proteins and contractile performance. When one type of hypertrophy is superimposed on the other the effects are additive.

The objective of this investigation was to compare intrinsic cardiac function in male and female rats. The first series of experiments (Series I) compared hearts from age-matched males and females at 18 weeks of age. Since body and heart weight were 65 and 51 per cent greater respectively in male rats in this study, a second series of experiments was performed (Series II) where heart mass was matched in males and females by studying males at 10 weeks of age and females at 18 weeks of age. Cardiac function was studied in an isolated working heart apparatus at similar heart rates and at controlled levels of end-diastolic pressure and aortic diastolic pressure (ADP). In Series I coronary flow and end-diastolic volume (both per g LV) were the same in male and female hearts, while stroke work (per g LV), ejection fraction and fractional shortening were significantly greater in male hearts but only as the ADP was increased. In Series II all of these measurements were significantly greater in male hearts at all loading conditions. The magnitude of the differences between male and female hearts was greater in Series II than in Series I which may have been due to a Frank-Starling effect in male hearts from Series II. The results indicate that intrinsic cardiac function is moderately greater in male rats compared to female rats. Studies employing similar size male and female hearts suggest that differences in heart mass may have accounted for the differential response to ADP in Series I.

To evaluate the effects of sex hormones on heart function and biochemistry, gonadectomy (GX) was performed in postpubertal male (M) and female (F) rats and compared with sham-operated controls (SH). The groups were MSH; MGX; MGX replaced with testosterone 3 mg/day s.c. (MGX + T), FSH, and FGX replaced with estrogen 2 mg/day (FGX + E), progesterone 0.4 mg/day (FGX + P), estrogen and progesterone (FGX + EP), or testosterone 2 mg/day (FGX + T). Body weight was decreased in MGX and was decreased further in MGX + T. Heart weight was decreased in both MGX and MGX + T. Body weights were increased in FGX and FTX + P and were increased further in FGX + T but were normal in FGX + E and FGX + EP. Heart weights were unchanged in F groups except in FGX + T, where it was increased. Cardiac performance in perfused hearts, as measured by stroke work, ejection fraction, fractional shortening and mean velocity of circumferential fiber shortening, was decreased in MGX but was slightly increased in MGX + T. Papillary muscle studies showed increases in time to peak tension and one-half relaxation in MGX, but these were decreased in MGX + T. Isotonic shortening studies showed decreased velocity of shortening in MGX and increased velocity in MGX + T. Heart function was significantly decreased in FGX and FGX + P compared with FSH but was similar to FSH in FGX + E and FGX + EP. FGX + T had greater stroke work and ejection fraction than FSH and FGX.(ABSTRACT TRUNCATED AT 250 WORDS)

Hearts of rats made hypertensive (BP greater than 150 mmHg) by left renal artery clipping and sham operated controls were studied in two series of experiments. In series I, cardiac function was studied in an isolated working heart apparatus at weeks 4, 9 to 10 and 16 to 17 post-surgery. In series II, coronary flow was studied during normoxic and anoxic retrograde perfusions at days 6 to 9 and at weeks 4 and 10 post-surgery. In series I, when compared with controls, hypertensives had lower body weights at weeks 4 and 9 to 10, and higher left ventricular weights at each period. Heart function was depressed for hypertensives when compared with controls as measured by lower stroke volume, peak left ventricular systolic pressure, stroke work, ejection fraction, positive dP/dt, peak aortic flow, and maximal flow acceleration. Relaxation rate as measured by negative dP/dt was also depressed. Hearts from hypertensives had significantly lower coronary flows and MVO2, and increased percent oxygen extraction and effluent lactate/pyruvate ratios. LVEDP was significantly elevated for hypertensives, when LVEDV (ml) was similar for hypertensives and controls. Myocardial actomyosin ATPase activity was depressed for hypertensives at weeks 9 to 10 and 16 to 17 post-surgery. In series II, when hearts were perfused retrogradely, coronary flow was lower for hypertensives than for controls during normoxia at days 6 to 9 and at week 4, and during anoxia at all time periods. The findings demonstrate that impaired coronary vascular reserve develops within days of the development of hypertension in rats, and this can be associated with impaired ventricular function.

A multicenter double-blind randomized study was designed to evaluate and compare the safety and diagnostic efficacy of gadopentetate dimeglumine (Gd-DTPA) (0.1 mmol/kg) against a saline placebo for use as an IV contrast agent for MR. The randomization code provided for a 2:1 ratio of Gd-DTPA and saline patients. Six investigators studied 88 patients with signs and symptoms of a cerebral lesion. Although safety data were complete in all 88 cases, only 83 had valid efficacy data (57 received Gd-DTPA, 26 placebo). Three patients were excluded from efficacy evaluation because of incomplete scans or scans with severe motion artifacts. Two patients were excluded for protocol variations (did not have a mass lesion). The protocol required that spin-echo MR images be acquired both before and after infusion at mode 1, 500/30/2 (TR/TE/excitations), and at a single-echo mode 2 sequence within a selected range, 1500-2000/56-90/2. Additional TEs could also be used at the discretion of each investigator. Efficacy was determined by comparing post- with preinjection images for relative degree of enhancement and improvement of diagnostic ability after injection, and by comparing these results with placebo results. Enhancement was reported in 43 (75%) of 57 Gd-DTPA patients and in none of the 26 placebo patients. Improvement of diagnostic ability was noted in 37 of 57 Gd-DTPA patients and in no placebo patients. Of 17 patients receiving Gd-DTPA for whom no diagnosis could be made before infusion, nine of 17 were diagnosed after infusion. By comparison, none of five patients not diagnosed before infusion of placebo could be diagnosed after infusion. Of 43 patients in whom lesion enhancement was observed after Gd-DTPA infusion, the diagnosis changed after infusion in 16 (37%) and the number of lesions detected after infusion increased in 10 (23%). Safety studies showed no clinically significant abnormal trends. Minor changes in blood pressure, pulse, and serum iron levels were noted in a higher percentage of Gd-DTPA patients. This study confirms that Gd-DTPA is an efficacious contrast agent for use with MR and that it exhibits excellent patient tolerance. Enhancement allows for a decisive diagnosis to be made in selected cases in which such capability had previously been lacking with unenhanced MR.

The purpose of this study was to determine whether a chronic swimming program could reverse the decreased cardiac function and altered myosin biochemistry found in hearts of rats with established renal hypertension. Ten wk after the onset of hypertension [midpoint (m)], hearts from normotensive controls (C) and hypertensives (H) were studied in an isolated working heart apparatus, and myosin biochemistry was analyzed. Half of the control and hypertensive animals were then subjected to a 10-wk swimming program (Sw) and their hearts were compared with those from age-matched sedentary rats. Body weight was no different at the midpoint of the study between Cm and Hm or at the end point (e) of the study among Ce, Swe, He, or H-Swe. Swimming had no effect on blood pressure in either normotensive or hypertensive rats. Dry heart weight was increased by 46% in Hm compared with Cm and by 36% in He, 21% in Swe, and 61% in H-Swe when compared with Ce. Hypertension was associated in both the mid- and end-point studies, with decreases in coronary flow, stroke work (both per gram left ventricle), ejection fraction, and midwall fractional shortening. In addition, actin-activated myosin adenosinetriphosphatase (ATPase) activity was decreased in Hm and He associated with an increase in the content of the V3 myosin isoenzyme. Although the coronary deficit was not corrected in H-Swe, stroke work, ejection fraction, and fractional midwall shortening were normalized compared with control hearts. Myosin ATPase activity and the myosin isoenzyme distribution were similarly restored in H-Swe.(ABSTRACT TRUNCATED AT 250 WORDS)

Both the diagnostic accuracy and sensitivity of the MRI diagnosis of central nervous system neoplasms appear to be improved by the administration of a paramagnetic contrast agent, Gd DTPA.

To more fully characterize the alterations in myocardial adrenergic and cholinergic receptors induced by the diabetic state, we investigated the binding characteristics of (--) [3H] dihydroalprenolol to beta adrenergic receptors (bAR), [3H] prazosin to alpha adrenergic receptors (aAR), and [3H] quinuclidinyl-benzilate to muscarinic cholinergic receptors (MCR) in myocardial membranes derived from rats 8 wk after treatment with streptozotocin. We also studied an equal number of animals from three control groups: free-eating nondiabetics, pair-weighted nondiabetics, and streptozotocin-treated animals treated daily with insulin. Diabetic hearts demonstrated 27% fewer bAR (P less than 0.01) and 31% fewer aAR (P less than 0.01) than free-eating controls, without changes in MCR, and without changes in antagonist affinity, agonist affinity, or agonist slope factor (pseudo-Hill coefficient) for any class of receptors. Food restriction had no effect on receptor characteristics, and treatment of diabetic rats with insulin prevented any downregulation of cardiac bAR or aAR. The parallel decrease in both bAR and aAR suggests that streptozotocin-induced hypothyroidism is not the primary causative factor of bAR downregulation in this model, since hypothyroidism produces upregulation of aAR. Furthermore, the lack of change in cardiac MCR suggests that the adrenergic receptor alterations are not the result of nonspecific abnormalities of protein synthesis in the diabetic heart. Further studies are required to establish the physiologic significance of these receptor alterations, but these data support the hypothesis that altered adrenergic receptor properties may underlie, at least in part, the chronotropic and inotropic abnormalities of cardiac performance that are associated with the diabetic state.

Physiological cardiac hypertrophy was produced in female rats by subjecting them to a swimming program for 8 wk. Conditioned rats (C) had body weights similar to sedentary control rats (S), but hearts from C weighed 33% more than hearts from S. Heart function was assessed in an isolated working-heart apparatus at similar heart rates and aortic diastolic pressures and over a range of 5-20 cmH2O left atrial filling pressure (LAP). At any given LAP, absolute values for cardiac output and coronary flow were greater (p less than 0.001) in C than S, but when these values were normalized for dry left ventricular (LV) weight, no differences were observed. Peak LV systolic pressure and ejection fraction were greater (p less than 0.01) in C than S at all LAP. Derived measures of contractility calculated at the midwall demonstrated greater (p less than 0.01) velocity and extent of circumferential fiber shortening in C compared with S. Therefore, chronic swimming in female rats leads to enhanced contractile performance of the left ventricle despite a marked degree of hypertrophy. These results contrast with our earlier observations in female rats trained by running where neither hypertrophy nor enhanced function were observed.