Allosteric modulators of α4ß2 nicotinic acetylcholine receptors: a new direction for antidepressant drug discovery.

Allosteric modulation of ligand-gated ion channels has been intensively studied in the past three decades and is now an established strategy to control receptor function in numerous disease states. Allosteric sites on the GABA(A) receptor are targets for widely prescribed drugs that are used for a variety of pathophysiological states including insomnia and epilepsy. Modulators might be especially valuable to control receptors for which the design of selective orthosteric drugs has proven difficult due to safety issues (e.g., α4ß2 nicotinic acetylcholine receptors and might have several advantages over orthosteric ligands. Modulators influence the action of the endogenous agonist but generally have no effect of their own on the unoccupied receptor. Moreover, the higher subtype selectivity exerted by modulators and that the effects of modulators depend on the simultaneous presence of agonist help to overcome safety problems by preventing over-dosage compared with the administration of orthosteric drugs.

Implementation and outcomes of a transfusion-related acute lung injury surveillance programme and study of HLA/HNA alloimmunisation in blood donors.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality. Antibodies against human leucocyte antigens (HLA) and human neutrophil antigens (HNA) are often detected in the implicated donors. We investigated the incidence and aetiology of TRALI in Lombardy. Moreover, we determined the rate of HLA and HNA alloimmunisation and the HNA genotype in a cohort of local blood donors. MATERIALS AND METHODS: During a 2-year observational study in eight blood transfusion services, suspected TRALI cases were collected and characterised by means of HLA and HNA antibody screening of implicated donors, donor/recipient cross-matching and HLA/HNA molecular typing. In addition, 406 Italian donors were evaluated for alloimmunisation and in 102 of them HNA gene frequencies were determined. RESULTS: Eleven cases were referred to the central laboratory, of whom three were diagnosed as having TRALI, seven as having possible TRALI and one as having transfusion-associated circulatory overload. Seven TRALI cases were immune-mediated whereas in three we did not find either alloantibodies in implicated donors or a positive reaction in the cross-match. The most frequently implicated blood component was red blood cells (in 5 males and in 1 female), whereas four cases of TRALI were associated with transfusion of fresh-frozen plasma (in 3 females and in 1 male). The frequency of reported TRALI/possible TRALI cases was 1:82,000 for red blood cells and 1:22,500 for fresh-frozen plasma. No cases were observed for platelets. Overall, the frequency of HLA or HNA alloimmunisation in blood donors was 29% for females and 7% for males. The latter could be related, at least in part, to natural antibodies. HNA gene frequencies showed that HNA-1b is more frequent than HNA-1a in our sample of donors. DISCUSSION: The recently adopted national policy to prevent TRALI, i.e. using only plasma donated by males, would have had a positive impact in our setting.