The contrasting careers of two structural types of CMHCs

Changes in funding, clientele, and services from 1971 to 1980 were examined cross sectionally and with cohorts for two types of CMHCs that differ in their structure for providing inpatient service. Inpatient provider CMHCs grew in revenues and shifted from reliance on federal funds to revenues from services and states. Inpatient-affiliated CMHCs fell in revenues (in constant dollars) and changed little in their proportional reliance on federal dollars. Inpatient provider CMHCs averaged more additions and episodes of care than inpatient-affiliated CMHCs. Inpatient-affiliated CMHCs grew more from 1971 to 1976, but from 1976 to 1980 inpatient provider CMHCs grew, while inpatient-affiliated CMHCs dropped or grew less. The relatively poor final showing of inpatient-affiliated CMHCs parallels findings with total revenues.The views expressed are those of the authors and do not necessarily represent the views of the National Institute of Mental Health. The authors are indebted to Ronald Manderscheid, Ph.D., and James Thompson, M.D., for suggestions.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999