The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study.

STUDY OBJECTIVE: To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro. DESIGN: Phase 1 trial with dose escalation. SETTING: Two university-affiliated hospital clinics. SUBJECTS: Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex. INTERVENTIONS: The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored. MEASUREMENTS AND MAIN RESULTS: Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively. CONCLUSIONS: At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.

Salvage procedures for complications of total ankle arthroplasty.

Total ankle arthroplasty (TAA) has been a satisfactory procedure with a low failure rate only when applied to the rheumatoid patient. For the active, posttraumatic patient, ankle joint fusion is superior and avoids the attendant high failure rate. In general, salvage of failed TAA is best solved by ankle fusion. Only in one of five cases (a compliant patient with a clear-cut correctable technical error) was a good result achieved with a revision arthroplasty. To maintain limb length, the authors transplanted iliac crest autogenic bone to fill a large defect. When tightly packed with bone, the joint is slightly distracted and compression enhances fusion. For septic loosening, osteotomy of the malleoli and fusion without grafting is recommended. Persistent pain unassociated with loosening an infection may be treated by removal of impingement of bone overgrowth. Soft tissue release to improve motion is rarely successful. Marginal skin slough was a problem in 8.5% of 71 cases. To facilitate healing, debridement of nonfunctional exposed tendons may be advisable.