Human Antibody Fragments Specific for the Epidermal Growth Factor Receptor Selected from Large Non-immunised Phage Display Libraries

Antibodies to EGFR have been shown to display anti-tumour effects mediated in part by inhibition of cellular proliferation and angiogenesis, and by enhancement of apoptosis. Humanised antibodies are preferred for clinical use to reduce complications with HAMA and HAHA responses frequently seen with murine and chimaeric antibodies. We have used depletion and subtractive selection strategies on cells expressing the EGFR to sample two large antibody fragment phage display libraries for the presence of human antibodies which are specific for the EGFR. Four Fab fragments and six scFv fragments were identified, with affinities of up to 2.2 nM as determined by BIAcore analysis using global fitting of the binding curves to obtain the individual rate constants (k_a and k_d). This overall approach offers a generic screening method for the identification of growth factor specific antibodies and antibody fragments from large expression libraries and has potential for the rapid development of new therapeutic and diagnostic reagents.     

The COX-2 specific inhibitor,valdecoxib, is an effective,opioid-sparing analgesic in patients undergoing total knee arthroplasty

This multicenter, randomized, double-blind, placebo-controlled study evaluated the analgesic efficacy and opioid-sparing effects of valdecoxib, a potent COX-2 specific inhibitor, in patients undergoing knee replacement. Patients received morphine by patient-controlled analgesia (PCA), and valdecoxib 40 mg or 80 mg daily, or placebo, for up to two days. Efficacy was assessed by the cumulative amount of morphine administered over 48 hours, pain intensity and patient's evaluation of medication. Morphine consumption over 48 hours by patients receiving valdecoxib 40 mg or 80 mg daily plus morphine was 83.7% and 75.8% (P < 0.05) of the total amount consumed by patients receiving morphine alone. Patients receiving valdecoxib 40 mg and 80 mg daily experienced significantly lower maximum pain intensity on Day 2 (P < 0.05), and rated their study medication significantly higher than patients receiving morphine alone. Valdecoxib plus morphine was well tolerated. Thus, valdecoxib in combination with morphine provides multi-modal analgesia that reduces pain and opioid use and increases patient satisfaction following knee replacement surgery.     

Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients

BACKGROUND: Arthritis and hypertension are common comorbid conditions affecting elderly adults. Use of nonsteroidal anti-inflammatory drugs in patients treated with antihypertensive medication can lead to destabilization of blood pressure control and other cardiorenal events. The potential for similar interactions with cyclooxygenase-2-specific inhibitors has not been fully explored. The authors evaluated the cardiorenal safety of two new cyclooxygenase-2-specific inhibitors, celecoxib and rofecoxib.METHODS: This study was a 6-week, randomized, parallel-group, double-blind trial in patients with osteoarthritis who were > or =65 years of age and were taking antihypertensive agents. Patients received once-daily celecoxib 200 mg or rofecoxib 25 mg. The primary endpoints were the development of edema, changes in systolic blood pressure, and changes in diastolic blood pressure as measured at any time point in the study. Measurements occurred at baseline and after 1, 2, and 6 weeks of treatment. FINDINGS: Eight hundred ten patients received study medication (celecoxib, n = 411; rofecoxib, n = 399). Nearly twice as many rofecoxib- compared with celecoxib-treated patients experienced edema (9.5% vs. 4.9%, P = 0.014). Systolic blood pressure increased significantly in 17% of rofecoxib- compared with 11% of celecoxib-treated patients (P = 0.032) at any study time point. Diastolic blood pressure increased in 2.3% of rofecoxib- compared with 1.5% of celecoxib-treated patients (P = 0.44). At week 6, the change from baseline in mean systolic blood pressure was +2.6 mmHg for rofecoxib compared with -0.5 mmHg for celecoxib (P = 0.007). CONCLUSIONS: Patients taking antihypertensive therapy and receiving cyclooxygenase-2-specific inhibitors should be monitored for the development of cardiorenal events. Patients receiving celecoxib experienced less edema and less destabilization of blood pressure control compared with those receiving rofecoxib.