Isolation and {\it in vitro}-immunosuppressive characterization of a novel cyclosporine metabolite

Cyclosporine (CsA) has shown great benefit to organ transplant recipients, as an immunosuppressive drug. To optimize CsA immunosuppressive therapy, pharmacodynamic evaluation of serial patient serum samples after CsA administration, using mixed lymphocyte culture (MLC) assays, revealed in vitro serum immunosuppressive activity of a CsA-like, ether-extractable component, associated with good clinical outcome in vivo. Since the in vitro immunosuppressive CsA metabolites, M-17 and M-1, are erythrocyte-bound, the immunosuppressive activity demonstrated in patient serum suggests that other immunosuppressive metabolites need exist. To test this hypothesis and obtain CsA metabolites for study, ether-extracted bile from tritiated and nonradioactive CsA-treated pigs was processed by novel high performance liquid and thin-layer chromatography (HPLC and HPTLC) techniques. Initial MLC screening of potential metabolites revealed a component, designated M-E, to have immunosuppressive activity. Pig bile-derived M-E was characterized as a CsA metabolite, by radioactive CsA tracer studies, by 56% crossreactivity in CsA radioimmunoassay, and by mass spectrometric (MS) analysis. MS revealed a CsA ring structure, hydroxylated at a site other than at amino acid one. M-E was different than M-1 and M-17, as demonstrated by different retention properties for each metabolite, using HPTLC and a novel rhodamine B/ $\alpha$-cyclodextrin stain, and using HPLC, performed by Sandoz, that revealed M-E to be different than previously characterized metabolites. The immunosuppressive activity of M-E was quantified by determination of mean metabolite potency ratio in human MLC assays, which was found to be 0.79 $\pm$ 0.23 (CsA, 1.0). Similar to parent drug, M-E revealed inter-individual differences in its immunosuppressive activity. M-E demonstrates inhibition of IL-2 production by concanavalin A stimulated C3H mouse spleen cells, similar to CsA, as determined with an IL-2 dependent mouse cytotoxic T-cell line. ^

THE DISCHARGED PSYCHIATRIC PATIENT: POST-HOSPITAL ADJUSTMENT AND FACTORS AFFECTING REHOSPITALIZATION

Discharged psychiatric patients were studied six months post-discharge to determine those demographic, social and clinical characteristics affecting positive or negative adjustment and the degree to which the use of mental health services and medication compliance mediated the effects. With the exception of those with primary or secondary diagnoses of OBS, substance abuse or mental retardation, sixty-three psychiatric subjects between the ages of eighteen and sixty-four were chosen from all admissions into the hospital and interviewed six months after discharge using a specially designed questionnaire.^ The subjects' adjustment to community living was found to be marginal. Although not engaged in destructive activities, over half were living with their family members who supported them financially and emotionally. Most were unemployed and had been so for a long time. Others worked sporadically and frequently changed residences. Most did have substantial social ties with extended family and with friends with whom they interacted regularly, but one-fourth were socially isolated. Almost three-quarters continued to obtain regular mental health services after discharge and followed medication instructions under the supervision of their physician. The use of mental health services after discharge and the use of medication did not appear to affect the subjects' community adaption or their rate of rehospitalization.^ Forty percent of those discharged were rehospitalized by the end of the follow-up period. Four levels of risk of rehospitalization emerged. The highest risk was associated with a history of five or more prior hospitalizations, living alone, and social isolation. One third or more of the subjects expressed a need for more counseling, leisure time activities, case-manager assistance, vocational guidance, supervised housing, and placement into a transitional residential treatment program.^ Recommendations were made to enhance the ability to predict recidivism, to develop interorganizational casework management programs linking the patient and family to the community mental health system and to create computerized tracking and monitoring programs that systematically report patient treatment regimen and progress cross-sectionally and longitudinally. ^