Phase I clinical and pharmacological study of intraperitoneal cis-bis-neodecanoato( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar liposome vesicles.

PURPOSE: To perform a phase I study of intraperitoneal cis-bis-neodecanoato ( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar vesicles (L-NDDP) for peritoneal carcinomatosis or sarcomatosis. METHODS: Eligible patients had normal renal, hematologic, and liver functions. Laparoscopy was performed on the first two courses for evaluation, adhesiolysis, and chemotherapy administration. Afterwards, chemotherapy was administered through a peritoneal catheter. Up to six courses were allowed. Peritoneal imaging with technetium-labeled sulfur colloid was used to determine adequate distribution prior to each course. Volunteering patients underwent pharmacokinetics studies during the second course. RESULTS: Fifteen of 16 registered patients, seven women and eight men (median age 53 years (range 26-76) and median performance status of 1) were assessable. Diagnoses were: malignant mesothelioma (six patients), signet ring cell (three), colon adenocarcinoma, pseudomyxoma peritonei, gastrointestinal stromal tumor (two each), and ovarian carcinoma (one). Median number of courses was two (range, one to six) Dose-limiting toxicity symptoms were fatigue and abdominal pain. Hematologic toxicities were minimal. Peri-operative complications included one colonic perforation requiring primary closure, a peritoneal catheter malfunction, a port site hematoma, and an ascites leak requiring re-suture. Five patients survived at least 3 years. Pharmacokinetics studies indicated a rapid but low absorption of drug into the systemic circulation, with a prolonged retention of platinum in the plasma compartment. Peritoneal L-NDDP exposure was 17 to 49-times greater than in the plasma compartment. CONCLUSIONS: Peritoneal cavity exposure to L-NDDP is prolonged, and systemic absorption is limited, yielding a high peritoneal/plasmatic ratio. The recommended dose for phase II studies is 400 mg/m2 every 28 days.

Monitoring the retention of a protein antigen in complete Freund's adjuvant, alum, and pluronic F-127 gel formulations by X-ray fluorescence.

Adjuvants function by protecting antigens from rapid degradation or dispersal. The effectiveness of experimental adjuvants can be assessed by measuring antibody titers to the antigen of interest or, less frequently, by evaluating the retention and distribution of antigen at the application site. In this study, we used X-ray fluorescence (XRF) to monitor the release of an iodinated protein (I-bovine serum albumin) from several adjuvant formulations after its subcutaneous injection in rats. The interaction of the tagged antigen with an external Am-241 source leads to the emission of iodine X-rays from the application site; the number of these X-rays is proportional to the concentration of the protein remaining at the injection site. The disappearance of the iodine X-rays, and hence the antigen, from the injection site followed first-order kinetics for all adjuvant formulations tested; mean half-life values were as follows: in 50% Freund's adjuvant, 17.1 +/- 1.1 h; in 4-hour-old 25% Alum, 11.78 +/- 0.08 h; in 4-h-old 50% Alum, 13.2 +/- 2 h; in 3-day-old 50% Alum, 15.8 +/- 1.5 h; and in 240 mg/mL Pluronic F-127, 7.9 +/- 0.7 h. We conclude that XRF is an easy, reliable, noninvasive method to monitor the retention of antigens in these adjuvant solutions.

Neutron activation of NDDP, a liposomal platinum antitumor agent.

UNLABELLED: Cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [NDDP] is a liposome-entrapped platinum compound currently, in phase II clinical trials, that has been shown to undergo intraliposomal activation. The objective of this study was to determine the feasibility of activating NDDP and using the induced radioactivity to monitor NDDP distribution and penetration. METHODS: Neutron activation analysis (NAA) was done on NDDP using the nuclear reactor at Texas A & M University, College Station, Texas. After a 3-hour irradiation, the NDDP samples were analyzed using an HPGE (high purity germanium) detector to determine the activation of the radioisotopic platinum. This was followed by HPLC-UV analysis to determine the stability of NDDP after exposure to the reactor's core. RESULTS: Platinum radioisotopes were produced along with potassium-40 and sodium-24. Irradiation did not result in any significant degradation of NDDP. CONCLUSIONS: (1) Irradiating fully synthesized NDDP is feasible for diagnostic use if a purification step is taken after the irradiation, and (2) radiation exposure is lessened by irradiating NDDP after synthesis rather than starting with high-specific-activity isotopes.

Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent.

L-NDDP is a liposome-entrapped platinum compound currently in phase 2 clinical trials that has been shown to undergo intraliposomal activation. The degradation/activation kinetics of liposome entrapped cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [L-NDDP] at different conditions of pH, and temperature is presented. Liposomes were reconstituted in a solution of 0.9% sodium chloride (NaCl) in water (pH 5) at room temperature (formulation conditions currently used in the ongoing clinical trials). In the temperature experiments, L-NDDP 0.9% sodium chloride liposomes were incubated in a water-bath at 40, 60, and 80 degrees C. In the pH experiments, these solutions were compared to water, phosphate with and without chloride ion present, phosphate buffer without chloride ion at pH 3.1, 5.0, and 7.4, and glycine buffer with and without chloride ion. In 0.9% sodium chloride at room temperature, the chemical degradation/activation of liposome-bound NDDP was biphasic, with most of the degradation (approximately 45% conversion) occurring during the first hour after formation of the liposome suspension. NDDP degradation was pH dependent: when using pH 3 phosphate buffer as a reconstituting solution, liposome-bound NDDP degraded rapidly, whereas in pH 7.4 phosphate buffer it was stable for > 72 h. NDDP degradation was also temperature-dependent, the 50% point decreasing from 12 h at 25 degrees C to 9.5 h at 40 degrees C, 3.8 h at 60 degrees C, and 0.3 h at 80 degrees C when using 0.9% NaCl in water as a reconstituting solution. Using glycine buffer solution with and without NaCl at room temperature, no NDDP degradation over a 72 h period was observed at 25 degrees C; however, at 40 degrees C, only 68% NDDP remained intact at 72 h. Atomic absorption spectrophotometry (AAS) analysis of the eluting fractions after injection of L-NDDP samples reconstituted in chloride-containing and non chloride-containing solutions clearly indicated that the formation of DACH-Pt-Cl2 was only observed when chloride-containing solutions were used and was first detected at 3 h when using 0.9% NaCl in water as a reconstituting solution. These results indicate that pH and temperature, and not the presence of chloride ion, are the main factors leading to the activation of NDDP. Since 45% of NDDP is already degraded at 1 h in the same conditions, it is concluded that (1) the first active intermediates of L-NDDP formed within the liposomes are the DACH-Pt chloro-aquo and diaquo intermediates, and (2) the in vivo, antitumour activity of L-NDDP is most likely mediated by direct intracellular delivery of the active species.

Outcome and cost of family physicians' care--pilot study of three diagnosis-related groups in elderly inpatients.

BACKGROUND: Health care analysts have speculated whether a primary-care-based delivery system would improve outcomes and costs for the currently preponderantly specialist-directed United States system. This pilot study compares outcomes and costs of family physicians' care with those of other physicians' care for three diagnosis-related groups (DRGs) and shows the feasibility of a larger scale research program using the Pennsylvania MedisGroups data base. METHODS: A cross-sectional comparison of outcomes and costs of hospital care given by either family physicians or other physicians was conducted using patients aged 65 years and older who were hospitalized during 1990. The study population was 2420 inpatients: 847 with DRG 174 (gastrointestinal bleeding), 628 with DRG 243 (medical back pain), and 945 with DRG 296 (metabolic disorders). Patients were stratified into five admission severity groups for each DRG. Comparison variables were MedisGroups major morbidity classification, in-hospital mortality, mean length of stay, and total charges. RESULTS: The family physician group delivered inpatient care to the elderly with gastrointestinal bleeding at significantly less cost than other physicians without any compromise of effectiveness. There was a similar but less striking trend for medical back pain. Results were variable for metabolic disorders. CONCLUSIONS: The results of this pilot study apply only to the three DRGs in the region at the time investigated. Generalizations should be avoided before additional DRGs are studied throughout the rest of the state. This pilot study demonstrates the feasibility of such research.