Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Activated recombinant coagulation factor VII (rFVIIa) effectively prevents and controls bleeding in patients with coagulopathy. Data show that rFVIIa may reduce blood loss and eliminate the need for transfusion in patients with normal haemostasis undergoing major surgery. We assessed the efficacy of rFVIIa in patients with normal haemostasis undergoing repair surgery of major traumatic fracture of the pelvis or the pelvis and acetabulum, who were expected to have a large volume of blood loss. METHODS: We performed a double-blind, randomized, placebo-controlled trial involving 48 patients undergoing major pelvic-acetabular surgery. Patients were randomized to receive an i.v. bolus injection of rFVIIa 90 microg kg(-1) or placebo as add-on therapy at the time of the first skin incision. All patients also received intraoperative salvaged red blood cells (RBC). RESULTS: There was no significant difference in the total volume of perioperative blood loss, the primary outcome variable, between the rFVIIa and placebo groups. In addition, there were no differences between the two groups in the total volume of blood components, including salvaged RBC transfused, number of patients requiring allogeneic blood components, total volume of fluids infused, total operating time, time taken after entry to the intensive care unit to reach normal body temperature and acid-base status, and time spent in hospital. No adverse events, in particular thromboembolic events, were reported in either group. CONCLUSIONS: In patients with normal haemostasis undergoing repair surgery of traumatic pelvic-acetabular fracture, the prophylactic use of rFVIIa does not decrease the volume of perioperative blood loss.

Different effects of nocturnal parafunction on the masticatory system: the Weak Link Theory.

It is proposed that damage to the masticatory system from intense parafunction can be assessed more accurately by the Weak Link Theory. The theory predicts that the more intense and the more prolonged the forces, the more the tendency of damage to either. 1. the periodontal tissue; 2. the teeth; or 3. the orofacial structures. To test the theory, 22 subjects were selected based on reports of nocturnal bruxism. Each was assessed for masticatory system breakdown on the Russell Periodontal Index, the Helkimo Dysfunction Index, and a Tooth Wear Index. A Bruxcore (Forgione, A. 1974 J Dent Res 53:127) was used to obtain an objective score of bruxism. Five of eleven subjects with mild bruxism scored high on only one index. Significantly more subjects (ten of eleven) with moderate to severe bruxism scored high on one index only.

Monoclonal antibodies in lymphoid neoplasia: principles for optimal combined therapy.

Rituximab and other monoclonal antibody therapies now in development have the potential to markedly impact the treatment of non-Hodgkin's lymphoma (NHL). These agents have significant single-agent activity, distinct mechanisms of action, and, in the case of rituximab and other unconjugated antibodies, favorable toxicity profiles that are nonoverlapping with the adverse effects associated with conventional chemotherapy. These properties may allow for the use of novel combination therapies with enhanced outcomes for patients. Systematic evaluation of rationally designed combinations through randomized, prospective trials is required to determine the clinical utility of these novel agents and combinations will live up to their potential.

Peptides related to the carboxyl terminus of human platelet factor IV with antibacterial activity.

A peptide (C13) corresponding to the last 13 amino acids of the carboxyl terminus of human platelet factor IV was found to be antibacterial. Amino acid substitutions predicted to disrupt either the amphipathic or alpha-helical nature of C13 rendered the peptide inactive. Antibacterial activity was demonstrated in normal human serum on bacteria which had been previously exposed to low levels of cefepime, a beta-lactam antibiotic. Peptide analogues were examined for more potent antibacterial activity in an antibacterial assay that employed normal human serum and low levels of cefepime. A peptide analogue (C18G) with 80-fold more antibacterial activity than C13 was identified. Studies in C8-deficient sera confirmed an essential role of human serum complement for optimal antibacterial activity. Additional studies showed low levels of cefepime, although not essential, enhanced the antibacterial activity of C18G. Animal protection experiments demonstrated that either peptide C18G or an analogue with all D amino acids (C18X) significantly increased the survival of neutropenic mice when coadministered with a low level of cefepime. This work has resulted in the identification of a new group of antibacterial peptides.

The safety, efficacy and compliance of terazosin therapy for benign prostatic hyperplasia.

The primary objective of the present interim analysis of an open label study initiated in December 1988 is to provide further insight into the long-term safety, efficacy and compliance of terazosin, a long-acting selective alpha 1-blocker, for the treatment of symptomatic benign prostatic hyperplasia (BPH). A total of 45 normotensive patients with symptomatic BPH was enrolled into this study. The dose of terazosin was titrated to 5 mg. during a 1-month period provided adverse reactions and orthostatic hypotension were not observed. The subjects were maintained on 5 mg. terazosin throughout the 24-month followup. The peak and mean urinary flow rates, obstructive and irritative Boyarsky symptom scores, and systolic and diastolic blood pressures were evaluated at 2, 6, 12, 18 and 24 months after initiation of therapy. Of the 45 subjects 21 (47%) exhibited a durable clinical response with no significant adverse events during the 24-month followup. The obstructive and irritative symptom scores decreased by 63% and 35%, respectively, after 2 months of terazosin therapy. These improvements in obstructive and irritative symptom scores were maintained throughout the 2-year followup. The peak and mean urinary flow rates improved by 42% and 48%, respectively, after 2 months of terazosin therapy. The changes in mean urinary flow rate increased, whereas the changes in peak urinary flow rate decreased during followup. Of the patients 6 (13%) were withdrawn from the study due to an adverse event. Our study demonstrates the safety, efficacy and compliance of terazosin therapy for BPH during a 2-year followup.

Human monoclonal antibody homodimers. Effect of valency on in vitro and in vivo antibacterial activity.

Human IgG1 mAb dimers specific for either group B streptococci or Escherichia coli K1 bacteria were formed using chemical cross-linkers. The effect of antibody valency on biologic efficacy was investigated by comparing the IgG dimers against the corresponding IgG monomers. Binding activity and relative avidity were assessed using Ag binding and competition ELISA, and functional activity was analyzed using opsonophagocytic assays. These in vitro assays revealed that the dimers were greater than or equal to 50-fold more active than the monomers. A neonatal rat infection model showed the in vivo protective efficacy of the dimers was greater than or equal to 20-fold greater than that of the monomers. Enhancing the activity of mAb by chemical cross-linking may be a useful strategy for salvaging low affinity IgG mAb that possess poor functional properties.

Comparison of functional activities between IgG1 and IgM class-switched human monoclonal antibodies reactive with group B streptococci or Escherichia coli K1.

The influence of valence and heavy chain on antibody activity was investigated using transfectoma-derived, class-switched IgG1 and IgM human monoclonal antibodies (MAbs) reactive with the bacterial pathogens Escherichia coli K1 and group B Streptococcus species. IgG-IgM pairs were compared in vitro for antigen binding and opsonic activities and in vivo for protective efficacy in neonatal rats. For the anti-E. coli pair, the IgM MAb was 1000-fold more potent in all assay formats. Importantly, the 50% protection dose (PD50) of the IgM MAb was 10-20 ng/rat, while 100 micrograms of the IgG MAb was only minimally protective. For the group B streptococcal MAbs, the IgM was 100- and 4500-fold more potent in binding and opsonization assays, respectively. However, while 20 micrograms of IgM protected neonatal rats, 100 micrograms of IgG MAb was partly protective. These experiments demonstrate the utility of recombinant DNA technology for creating a panel of antibodies that may aid in selecting potential immunotherapeutic candidates.

A dose titration study evaluating terazosin, a selective, once-a-day alpha 1-blocker for the treatment of symptomatic benign prostatic hyperplasia.

The efficacy and safety of terazosin, a selective long-acting alpha-1-adrenergic blocker, were evaluated in 45 normotensive patients with symptomatic benign prostatic hyperplasia ranging from 50 to 76 years old. All patients underwent a complete urodynamic evaluation and transrectal prostatic ultrasonography before enrollment into the study. The dose of terazosin was titrated to 5 mg. per day for a 1-month interval, provided adverse drug reactions were not observed. Of the patients 39 (87%) completed the dose titration study. The parameters used to assess the effectiveness of terazosin included peak and mean urinary flow rates, micturition symptom scores and the global assessment by the patient of symptomatic improvement. Over-all, the mean systolic and diastolic blood pressures changed by less than 1%. The peak and mean urinary flow rates increased by 42 and 48%, respectively. The obstructive and irritative symptom scores improved by 63 and 35%, respectively. Over-all, 30 of the 45 participants (67%) indicated that the voiding symptoms were markedly improved while on terazosin. Five patients did not complete the dose titration study due to development of adverse drug reactions, including erectile dysfunction (7%), tiredness (7%), light-headedness (4%), palpitations (4%), nasal congestion (2%) and asymptomatic hypotension (2%). There were 25 patients (55%) followed on terazosin for 4 to 10 months (mean 6.5 months). The improvements in urinary flow rates and symptom scores were maintained for this interval. Although this preliminary experience with terazosin is encouraging, the ultimate role of terazosin for the long-term treatment of benign prostatic hyperplasia needs further evaluation.

The safety and efficacy of terazosin for the treatment of benign prostatic hyperplasia.

The efficacy and safety of terazosin was evaluated in 28 normotensive patients with symptomatic benign prostatic hyperplasia (BPH) ranging in age between 52-72 years. The parameters utilized to assess the efficacy of terazosin included peak and mean urinary flow rate, micturition symptom score and the patients' global assessment of symptomatic improvement. The dose of terazosin was titrated to 5 mg/day over a one-month interval, provided significant adverse drug reactions were not observed. Twenty-two (79%) of the 28 patients completed the terazosin dose-titration study, 5 (18%) were withdrawn owing to adverse drug reactions and 1 (3%) was withdrawn owing to poor compliance. Overall, the mean systolic blood pressure, increased 3 mmHg (3%) and the diastolic blood pressure decreased 1 mmHg (1%). The peak and mean urinary flow rates increased 63% and 61%, respectively. The obstructive and irritative symptom scores decreased 62% and 33%, respectively. The improvements in urinary flow rates and symptom scores were clinically and statistically significant. Overall, 61% of the patients indicated that their voiding symptoms were markedly improved on terazosin and 64% of the participants have elected to voluntarily continue on terazosin indefinitely. In conclusion, terazosin represents a safe and effective treatment for symptomatic BPH.

Human monoclonal antibodies to group B streptococcus. Reactivity and in vivo protection against multiple serotypes.

Group B streptococcal (GBS) infections cause significant mortality and morbidity among infants. Passive antibody immunotherapy has been proposed as treatment for infected infants. To this end, two human mAb-secreting cell lines were produced by EBV immortalization of human B cells. The mAbs were specific for the group B polysaccharide and bound to strains of all five serotypes as demonstrated by ELISA and crossed immunoelectrophoresis. The mAbs reacted and opsonized 100% (132/132) of the clinical isolates tested which represented all four capsule types. Both prophylactic and therapeutic protection with these mAbs were demonstrated in neonatal rats given lethal infections of types Ia and III human clinical isolates. These data indicate that a single human mAb directed against the group B carbohydrate can protect against GBS infections caused by the different serotypes. This antibody may be useful in the passive immunotherapy of infants infected with GBS.

Human monoclonal antibody with protective activity for Escherichia coli K1 and Neisseria meningitidis group B infections.

We produced human monoclonal antibody that demonstrated specific reactivity to the K1 capsule of Escherichia coli and the group B polysaccharide of Neisseria meningitidis. The antibody was nonreactive with several strains of K1- E. coli and other gram-negative bacteria. All E. coli K1 clinical isolates tested were reactive with the antibody. When assayed for in vitro opsonophagocytic ability, the antibody caused bacterial removal only in the presence of human complement and neutrophils, an observation suggesting a non-bacteriolytic, neutrophil-dependent killing mechanism. Finally, and perhaps most importantly, the antibody was highly protective for infectious disease when used prophylactically in three animal models. The data suggest a potential use for human monoclonal antibodies in preventing and/or treating infections of the blood.

Identification of synaptic acetylcholine receptor sites in retina with peroxidase-labeled alpha-bungarotoxin.

An alpha-bungarotoxin-horseradish peroxidase conjugate, which binds specificity to nicotinic acetylcholine receptors, was synthesized. This conjugate was bound by 5-7% of the synapses in the inner plexiform layer of the chicken retina. Bipolar ribbon synapses as well as amacrine synapses bound the conjugate.