Phase I trial of an implanted battery-powered, programmable drug delivery system for continuous doxorubicin administration.

A second generation, implantable drug administration device (DAD, Medtronic, Inc, Minneapolis) which contains a 20-mL drug reservoir, a lithium-thionyl-chloride battery, a peristaltic roller pump, a microprocessor circuit, and an acoustic transducer has entered clinical trials. After surgical placement, drug is entered into and removed from the DAD percutaneously through a Silastic "fill port" using a standard gauge needle and syringe. The pump is noninvasively programmed using a hand-held telemetry wand to administer the drug in a continuous infusion, bolus, or bolus-delay mode. Because of the apparent improved therapeutic index of continuous-infusion doxorubicin (CID), a phase I trial of the Medtronic DAD with CID was begun. Thirteen pumps in 13 patients have functioned for a median of 153 days (range, 11 to 395 days) with one pump still functioning. Four pumps ceased function at 170, 278, 331, and 370 days, respectively; there was a catheter-tip clot on one of the pumps that later malfunctioned. All other pumps functioned until the death of the respective patients. In 84 pump refills, without drug extravasation, the median drug delivery error (actual residual volume--calculated residual volume/calculated residual volume X 100%) was 14%. Doxorubicin was compatible with all components of the drug pathway and did not significantly decompose during two weeks in the drug reservoir. The starting dose of CID was 2.0 mg/m2/d and the maximum tolerated dose was 4.1 mg/m2/d (range, 3.5 to 5.5). A median cumulative doxorubicin dose of 244 mg/m2 per patient (range, 10 to 583 mg/m2) has been infused.(ABSTRACT TRUNCATED AT 250 WORDS)

A programmable and implantable pumping system for systemic chemotherapy: a performance analysis in 52 patients.

We have prospectively evaluated the performance of the implanted battery-powered Medtronic (Minneapolis) SynchroMed infusion system. Between July 1984 and July 1986, fifty-three SynchroMed pumps were implanted in 52 patients for phase I and II trials of low-dose continuous-infusion doxorubicin (N = 35) or vinblastine (N = 17). The median duration of pump function was 145 days (mean, 180; range, 20 to 787 +) and the systems infused drugs for 61% (range, 32% to 100%) of their patient implant time. During 10,045 patient days (27.5 years) of implantation, there have been no failures of the pump mechanism and pump accuracy was excellent (2.2% error rate in 256 analyzed refills). The median cost of the hospitalization for implantation was +17,140 in 14 analyzed cases. Complications requiring a second surgical procedure occurred with 13 systems (24%). Two of the complications were related to localized cutaneous hypersensitivity to vinblastine, four were directly related to system complications, and seven were secondary to implant procedure problems. Seven patients (13%) requested removal of the device after tumor progression occurred. Based on this experience, the company has made improvements in certain aspects of system design and has implemented a comprehensive user training program to minimize procedure-related problems. The Medtronic SynchroMed is an accurate and sophisticated system that allows infusion of low-dose doxorubicin and of vinblastine for prolonged periods. Extravasation of these vesicant agents must be carefully prevented. The financial cost of this implanted system may limit its use to patients with an expected survival of 5 months or longer.

Immunofluorescent localisation of cytokeratin antigens in mitotic HeLa cells using monoclonal antibodies.

The organisation of cytokeratin filaments in mitotic HeLa cells has been analysed by immunofluorescence microscopy using a monoclonal antibody which recognises proteins with apparent subunit molecular weights of 52 kDa and 57 kDa and which binds exclusively to cytokeratin-type filaments. Mitotic cells were prepared for microscopic analysis by hypotonic swelling, centrifugation onto glass slides, brief pre-extraction with 0.1% Triton X-100 and fixation in 80% ethanol. This procedure gave particularly good resolution of intermediate filaments and preservation of chromosome morphology. In prometaphase-metaphase cells the antigen was present in an anastomosing filament network which completely or partially enclosed the chromosomes, in filament fragments and in cytoplasmic aggregates. The epichromosomal filament network was absent from cells in anaphase or later stages of mitosis. In these cells non-filamentous antigen was often located in a narrow band defining the periphery of individual chromosomes and in variable numbers of cytoplasmic filaments or fragments. The results suggest that extensive disaggregation and reformation of cytokeratin filaments occurs during mitosis and that disaggregated cytokeratin proteins are frequently located adjacent to mitotic chromosomes.

Pharmacokinetics and pharmacodynamics of long-term continuous-infusion doxorubicin.

Steady-state plasma levels of doxorubicin and doxorubicinol were analyzed in 32 patients with advanced cancer, each of whom was given doxorubicin by long-term continuous infusion at progressively increasing infusion rates. Patients received doxorubicin for 2 to 50 weeks at rates of 0.2 to 6.1 mg/m2/day. Dose-limiting stomatitis and leukopenia were observed. The mean maximum steady-state doxorubicin concentration was 6.04 ng/ml at a mean maximum infusion rate of 3.92 mg/m2/day. Clearance mechanisms did not appear to be saturated at the durations or infusion rates used in this study. The maximum steady-state doxorubicin level and the ln (initial WBC) were significant correlates of the ln (nadir WBC) (p = 0.002 and 0.02, respectively). A model was constructed according to these two parameters that significantly describes ln (nadir WBC) (p = 0.001). Neither age, infusion rate, nor doxorubicinol level correlated with nadir WBC. Stomatitis did not correlate with any of these parameters. The demonstration of this pharmacodynamic relationship highlights the potential importance of pharmacologic data collection in ongoing attempts to predict the clinical effects of anticancer drugs.

The relationship between research and service development: an illustrative example of a pilot study introducing complementary therapies into primary care.

In this paper the commissioners of an evaluation and the researchers jointly review the relationship between research and service development at a local level in an evaluated health authority pilot project to introduce complementary therapies into primary care. The article discusses the importance of organisational arrangements between the research and the service development, focusing on the close working relationship between researchers and stakeholders in the research and corresponding service development. The relationship between the research and service development was not linear and the benefits were not based solely on outcomes of the treatment but also on the ways the evaluation gave insight into how the pilot service was delivered. Factors such as personal commitment to the project and close working relationships by all concerned are important. These elements are rarely emphasised but have to be taken into account if evidence-based health care is to achieve its potential.

Continuous venous infusion of doxorubicin in advanced sarcomas.

Seventeen patients with advanced sarcoma were treated with continuous venous infusion of doxorubicin for a mean of 118 days, achieving total doses up to 1097 mg/m2. Three partial responses and one minor response were obtained. Major toxic effects were stomatitis and hand-foot syndrome. There was a low incidence of leukopenia (18%) and clinical cardiotoxicity (11%). Continuous venous infusion is a safe means of administering doxorubicin, with a response rate similar to that observed with bolus doxorubicin in metastatic sarcoma.

Self-starting mode locking in a Cr:forsterite laser by use of non-epitaxially-grown semiconductor-doped silica films.

We demonstrate RF sputtered, non-epitaxially-grown semiconductor nanocrystallite-doped silica films for mode locking a Cr:forsterite laser. We controlled the size and the optical properties of the nanocrystallites by varying the ratio of InAs to SiO(2) during fabrication. Femtosecond pump-probe measurements were performed to characterize the nonlinear optical properties of these films, revealing their lower saturation fluences. Using the InAs-doped silica films as saturable absorbers permitted self-starting Kerr-lens mode locking (KLM), generating pulses of 25-fs duration with 91-nm spectral bandwidth at 1.3 microm . We also describe saturable-absorber mode-locked operation without KLM and investigate its dependence on intracavity dispersion.