Zyn-Linker delivery of antirheumatic agents.

Despite our increasing ability to manage rheumatoid arthritis through systemic medication, refractory joints require local administration of more aggressive therapy in a substantial number of patients. These studies tested whether a new class of molecules designated Zyn-Linkers could deliver and retain therapeutics in a joint. Zyn-Linkers are synthetic lipid-like molecules designed to insert into cell membranes and enhance drug delivery to cells. After intra-articular injection into the knee of NZW rabbits, Zyn-Linkers bound rapidly and homogenously to synovial lining cells. Chelating Zyn-Linkers which contained Re-186 or Y-90 were synthesized to evaluate localization and retention after intra-articular injection. Initial studies using Re-186 Zyn-Linker gave excellent localization as evaluated by whole-body imaging: counts in the knee region represented > 90% of counts present in the whole body for at least 4-6 days postinjection. Similar results were obtained using a Y-90 Zyn-Linker and this agent was used for biodistribution studies due to its greater stability and ease of preparation. Efficacy and safety of Y-90 Zyn-Linker as a potential radiation synovectomy agent were estimated by extrapolation of biodistribution data to humans. A therapeutically effective dose of 8,000 cGy to synovium was calculated to require intra-articular injection of 3.4 mCi Y-90 Zyn-Linker, a value less than or equal to doses of particulate Y-90 agents used clinically in Europe. The predicted safety profile for Y-90 Zyn-Linker was excellent, with estimated doses to nontarget organs and tissues falling well within FDA-recommended safety levels for research-only radiopharmaceuticals. In addition to exhibiting desirable localization and retention properties, Zyn-Linkers may also be synthesized to release antirheumatic drugs such as methotrexate at controlled rates. This suggests substantial potential for these drug delivery molecules as chemical synovectomy agents which may be used concurrently with systemic chemotherapy to improve management of refractory joints.

Ear disease in three aboriginal communities in Western Australia.

Surveys of ear disease amongst Aboriginal people in two isolated bush communities (Wiluna and La Grange) and one urban community (Kwinana) in Western Australia were undertaken in 1988 or 1989. The age-adjusted prevalence odds ratio (relative risk) of perforations of the tympanic membrane for Wiluna compared with Kwinana was 5.0 (95% confidence interval [CI] 2.7-12.2) and 6.8 (95% CI 3.5-13.9) for La Grange compared with Kwinana. The relative risk of mild hearing loss, in comparison with Kwinana, was 2.5 (95% CI 1.5-4.3) for Wiluna and 3.2 (95% CI 2.0-5.0) for La Grange. There was no significant difference in the relative risk of moderate or severe hearing loss or impedance pattern B, usually interpreted as "glue ear", in any of the three communities. Overall, the urban Aboriginal community had less ear disease and hearing loss than either of the isolated bush communities, but even this community did not approach the much lower levels of prevalence in Australia as a whole.