Exchange of macromolecules between plasma and peritoneal cavity in ascites tumor-bearing, normal, and serotonin-injected mice.

Fluorescein-labeled dextrans (FITC-D) from 3 to 5000 kDa (Stokes' radii from 1 to 40 nm) were used to study influx from the plasma into the peritoneum and efflux from the peritoneal cavity into the plasma in normal and ascites tumor-bearing mice and in mice whose peritoneal vessels had been rendered hyperpermeable by serotonin. Two syngeneic transplantable murine ascites tumors were studied: mouse ovarian tumor and the TA3/St breast adenocarcinoma. To control for effects of peritoneal fluid volume, influx and efflux were also analyzed in mice that had received 5 ml of 5% bovine serum albumin i.p. as "artificial ascites." Following i.v. or i.p. injection, levels of FITC-D in the plasma and peritoneal fluid were quantitated by fluorimetry at successive time intervals from 5 to 360 min posttracer injection. Influx and efflux data were analyzed with a model consisting of three compartments (plasma, peritoneal cavity, and the extravascular space of all other organs) to yield kinetic parameters that characterized macromolecular transport. Depending on the size of the FITC-D tracer, from 3- to 50-fold more FITC-D accumulated in mouse ovarian tumor or TA3/St tumor ascites fluid, and 3- to 10-fold more FITC-D accumulated in the peritoneum of serotonin-treated than normal mice, all of it intact by gel exclusion chromatography. Influx of the FITC-D from plasma into the peritoneum, as characterized by the rate constant k1, was 2- to 40-fold greater in ascites tumor-bearing animals and 2- to 10-fold greater in serotonin-treated animals than in controls. Control animals with artificial ascites showed at most a 4-fold increase in the value of k1. As judged by fluorescence microscopy, the permeability of peritoneal-lining vessels in ascites tumor-bearing animals was greatly increased to FITC-D of 70 to 5000 kDa. Efflux of FITC-D, characterized by the rate constant k2, was reduced from 5- to 50-fold in ascites tumor-bearing animals but was unchanged or actually somewhat enhanced following serotonin treatment. Efflux in animals that had received artificial ascites was reduced 2.5- to 12.5-fold, correlating increased peritoneal fluid volume with decreased efflux. We conclude that tracer accumulation in malignant ascites fluid results from both increased influx as well as impaired efflux. Influx, and to a lesser extent efflux, were significantly affected by tracer size. However, within the range of FITC-D tested, we found no absolute size barrier to macromolecular transport from plasma to the peritoneal cavity, or vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)

Macrophage function in murine allogeneic bone marrow radiation chimeras in the early phase after transplantation.

We tested several of the functions of macrophages (M phi) in the early phase after allogeneic bone marrow transfer to get information about this important aspect of the nonspecific immune system in the T-cell-deficient recipient. On days 3-5 after transfer, the number of M phi was reduced in the spleen, liver, lungs, and peritoneal cavity (Pe). The phagocytosis of sheep red blood cells (SRBC) by these M phi was normal or even enhanced, as in the case of Pe-M phi. Already on days 8-12 after transfer, the number of M phi in spleen and liver exceeded that of controls, whereas the number was still reduced in lungs and Pe. We examined their ability to kill P815 tumor cells, to produce tumor necrosis factor-alpha (TNF alpha), to phagocytose SRBC, to produce reactive oxygen intermediates (ROI) in vitro and to kill Listeria monocytogenes in vivo. Most functions were normal and often even enhanced, depending on the organ origin, but the ability of Pe-M phi to produce ROI was reduced. Proliferative response to macrophage colony-stimulating factor (M-CSF) and killing of YAC-1 tumor cells revealed a high frequency of macrophage precursor cells in the spleen and liver and a high natural killer (NK) activity in the liver. Altogether, enhanced nonspecific immune function, especially preactivated M phi, may enable chimeras to survive attacks by opportunistic pathogens.

Superoxide production of peritoneal macrophages in experimental gram-negative sepsis; influence of in vitro and in vivo supplements of zinc.

Although zinc is essential for the optimum function of the immune system, there is some controversy regarding treatment with zinc during acute infections where low serum zinc levels are often recorded. The aim of the present study was to investigate the influence of in vitro and in vivo zinc supplementation on the potentially toxic metabolic activity of peritoneal macrophages during infection. Rats were made septic by implanting a gelatin capsule containing known amounts of E. coli, and Bacteroides fragilis into the abdomen. Peritoneal macrophages were harvested by peritoneal lavage 72 hours after the induction of sepsis. Superoxide release was measured after stimulation with phorbol myristate acetate (PMA) or serum treated zymosan (STZ). Macrophages from septic rats released significantly higher amounts of superoxide compared with macrophages from sham operated controls after stimulation with both PMA and STZ. Following in vitro supplementation, zinc inhibited the superoxide production of macrophages harvested from septic rats after stimulation with both PMA and STZ. In vivo supplementation with zinc resulted in increased superoxide production from septic macrophages when stimulated with STZ, whereas stimulation with PMA produced no significant changes. Thus, in vitro incubation inhibited the superoxide production of peritoneal macrophages in intraabdominal sepsis, whilst in vivo administration of zinc produced no such effect, and the effect seemed to vary depending on the stimuli used to initiate the respiratory burst.

Utilization of a murine model to optimize volume and dwell time of intraperitoneal cisplatin.

The pharmacokinetics of intraperitoneal (ip) cisplatin were investigated in a murine model. Groups of six animals were studied at initial cisplatin concentrations (Ci) of 50, 100, 200, and 400 micrograms/ml, and at injection volumes (V) of 0.5, 1, 2, and 4 ml. For each Ci and V, four dwell times (Dt) between 1.5 and 120 min were studied. At 180 min mice were killed and five tissues (heart, kidney, liver, bowel, and peritoneum) were obtained for platinum measurement. Platinum recovered from the peritoneal cavity at the end of the dwell time and platinum tissue levels were determined by a radioactive tracer assay using Pt 195m-labeled cisplatin. A total of 384 mice were studied. The permeability times the effective surface area product (pS) was found to be independent of Ci, V, and Dt. Platinum tissue levels were proportional to absorbed dose. As the ratio of platinum tissue level to absorbed dose is constant, it is not possible to change Ci, V, nor Dt to minimize toxicity from a given absorbed dose. This study suggests that the therapeutic index of an individual intraperitoneal cisplatin treatment will not be changed by modifying Ci, V, nor Dt.

Body fluid and endometrial concentrations of ketoconazole in mares after intravenous injection or repeated gavage.

After single oral administration of ketoconazole (30 mg/kg bodyweight [bwt]) in 50 ml of corn syrup to a healthy mare, the drug was not detected in serum. Ketoconazole in 0.2 N HC1 was administered intragastrically to six healthy adult horses in five consecutive doses of 30 mg/kg bwt at 12 h intervals. Ketoconazole concentrations were measured in serum, synovial fluid, peritoneal fluid, cerebrospinal fluid (CSF), urine and endometrium. Mean peak serum ketoconazole concentration was 3.76 micrograms/ml at 1.5 to 2 h after intragastric administration. Mean peak synovial concentration was 0.87 micrograms/ml 3 h after the fifth dose. Similarly, mean peritoneal concentration peaked 3 h after the fifth dose at 1.62 micrograms/ml. Mean endometrial concentrations peaked at 2.73 micrograms/ml 2 h after the fifth dose. Ketoconazole was detected in the CSF of only one of the six mares at a concentration of 0.28 micrograms/ml 3 h after the fifth dose. The highest measured concentration of ketoconazole in urine was 6.15 micrograms/ml 2 h after the fifth dose. A single intravenous injection of ketoconazole (10 mg/kg bwt) was given to one of the six mares; the overall elimination rate constant was estimated at 0.22/h and bioavailability after oral administration was 23 per cent.

Modulation of proline and glucosamine incorporation into tissue repair cells by peritoneal macrophages.

The purpose of this study was to determine the patterns of [14C]proline and [14C]glucosamine incorporation by tissue repair cells (TRC) as modulated by postsurgical macrophages. Rabbits underwent a midline laparotomy followed by resection (2.0 cm) and reanastomosis of their ileum. Another group of rabbits underwent peritoneal wall abrasion with sterile gauze until punctate bleeding developed. Postoperative (1-28 days) exudate cells (PEC) were recovered from the peritoneal cavity after reanastomosis, and (TRC) were obtained directly from the injured peritoneal surface after abrasion. Since the postsurgical exudate was composed mainly of macrophages, we examined the effect of postsurgical macrophage-spent media on the incorporation of [14C]proline, [14C]glucosamine, and [3H]thymidine by TRC. After 7 days of culture, Postsurgical Day 7 TRC were incubated with spent media from postsurgical PEC (greater than 90% macrophages). When TRC were cultured with macrophage-spent media, the number of TRC increased significantly compared to that of fresh medium-treated controls. The incorporation of [3H]thymidine by TRC was also enhanced by macrophage-spent media. The incorporation of [14C]proline and [14C]glucosamine by TRC was also enhanced when incubated with macrophage-spent medium. However, when data were expressed on a per cell basis, incorporation of [14C]proline and [14C]glucosamine by TRC cultured with macrophage-spent media was the same or less than that by cells incubated with fresh medium. These data suggest that the increase in incorporation of glucosamine and proline into connective tissue protein by postsurgical repair cells may be directly modulated by macrophages recruited in response to surgical injury and that this increase is due to the fibroproliferative effect of postsurgical macrophages.

Pharmacokinetics and body fluid and endometrial concentrations of trimethoprim-sulfamethoxazole in mares.

Six healthy adult mares were each given a single IV injection of trimethoprim (TMP)-sulfamethoxazole (SMZ) at a dosage of 2.5 mg of TMP/kg of body weight and 12.5 mg of SMZ/kg. Serum concentrations of each drug were measured serially over a 24-hour period. For TMP, the mean overall elimination rate constant (K) was 0.43/hr and the elimination half-life (t1/2) was 1.9 hours. The apparent volume of distribution (at steady state) was 1.62 L/kg and TMP clearance was 886 ml/hr/kg. For SMZ, K was 0.22/hr and t1/2 was 3.53 hours. The apparent volume of distribution at steady state was 0.33 L/kg and SMZ clearance was 78.2 ml/hr/kg. Each mare was then given 5 consecutive oral doses of TMP-SMZ at a rate of 2.5 mg of TMP/kg and 12.5 mg of SMZ/kg at 12-hour intervals. Trimethoprim and SMZ concentrations were measured in serum, synovial fluid, peritoneal fluid, CSF, urine, and endometrium. Although both mean TMP and SMZ serum concentrations were higher after the 5th dose than after the 1st dose, only the mean TMP concentration was significantly (P less than 0.05) different. After the 5th oral dose, concentrations of TMP and SMZ attained in body fluids (except CSF) and endometrial tissue were equal to or exceeded reported minimum inhibitory concentrations for Corynebacterium pseudotuberculosis, Staphylococcus sp, Streptococcus zooepidemicus, and several obligate anaerobes. Absorption of both drugs was variable after oral administration.

Isolated intraperitoneal accumulation of bile after surgical or diagnostic procedures.

In 1969-1986 intraperitoneal accumulation of bile occurred in 21 patients after elective cholecystectomy or choledochotomy (n = 16) or percutaneous fine-needle cholangiography or biopsy (n = 5). The cause was established in all but one of the surgical cases, viz. T-tube removal (8), injury to the common bile duct (3), unrecognized aberrant bile duct (3) and leakage from liver biopsy (1). The intraperitoneal accumulation of bile led to laparotomy in 19 cases, when the median amount of bile found was 500 ml (range 100-3,500 ml). Mortality was nil, and only few and relatively minor complications could be attributed to the accumulation of bile--pleural effusion (2 cases), wound rupture (1), lower-limb venous thrombosis (1) and strictured hepatojejunostomy (1). There were no infectious complications. It is concluded that intraperitoneal accumulation of bile alone after elective surgical or invasive diagnostic procedures does not usually lead to severe complications, and that it seems distinctly less noxious than the bile peritonitis associated with acute cholecystitis.

Androgen metabolism by human peritoneal macrophages.

Peritoneal macrophages (PM) were obtained by peritoneal dialysis from a regularly menstruating woman with renal failure. Macrophages (10(6) cells) were incubated at 37 degrees C for various periods of time (0-4 hr) in the presence of 14C-androstenedione or 3H-androstenedione and various concentrations (0.06-5.06 microM) of nonradiolabeled androstenedione (A). Testosterone (T) formed was purified by column chromatography, thin layer chromatography, acetylation, and recrystalization to constant 3H:14C ratios. The rate of formation of T from A was linear for nearly 2 hr. Conversion of A to T was linear at cell numbers in the incubation up to 1 x 10(6). The formation of T from A followed Michaelis-Menten kinetics at concentrations of A between 0.06 and 5.06 microM. The apparent Km of the enzyme for A was 0.75 microM and the Vmax for T formation from A in these cells was 33.9 pmol x hr-1 x 10(6) cells-1. PM were obtained also from normal patients (n = 6) and patients with endometriosis (n = 5). The rate of T synthesis from A in PM obtained from patients with endometriosis [527 +/- 263 pmol x hr-1 x 10(6) cells-1 (mean +/- SEM, n = 5)] was similar to that observed in PM obtained from normal patients [518 +/- 226 pmol x hr-1 x 10(6) cells-1 (mean +/- SEM, n = 6)]. We observed a near 30-fold variation in the rate of formation of T from A by PM obtained from different individuals (range 54 to 1580 pmol x hr-1 x 10(6) cells-1). Further study is needed to elucidate the physiologic significance of PM androgen metabolism and its relationship to reproductive function.

Pharmacokinetics of carboplatin after intraperitoneal administration.

The pharmacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i.p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had received carboplatin (200-500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24 +/- 11. The peritoneal clearance of carboplatin was 8 +/- 3 ml/min, which was 12 times less than the plasma clearance (93 +/- 32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34% +/- 14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet = Dose - amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

The intraperitoneal delivery of radiolabeled monoclonal antibodies: studies on the regional delivery advantage.

The i.p. delivery of murine monoclonal antibody was compared with i.v. delivery in normal mice and rats, in normal nude mice and in those with i.p. human ovarian carcinoma xenografts. In normal rats, all classes of antibodies and antibody fragments evaluated were cleared from the peritoneal cavity at comparable rates. The regional delivery (Rd1) advantage to the peritoneal cavity following i.p. delivery was thus most dependent on the rate of clearance of the antibody or fragment from the blood stream. Determining the exact i.p. delivery advantage was problematic due to the difficulty in reliably obtaining peritoneal fluid later than 9-10 h after i.p. injection in normal animals. During the first 9 h following i.p. injection, the Rd(0-9/0-9) was, for a murine IgG2ak Fab greater than F(ab')2 greater than IgG (at 13.6 greater than 10 greater than 7.9). Two murine IgMs evaluated differed in Rd(0-9) at 27.1 and 9.2 respectively. When blood levels were extrapolated to infinity, these Rd (0-9/affinity) values were considerably lower with the Fab having the highest Rd at 4.67. The i.p. Rd advantage was almost solely due to the i.p. antibody levels seen in the first 24 h after injection, as after that time, blood levels become comparable to those seen following i.v. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. injection. Normal tissues obtained at sacrifice 5-7 days after i.p. or i.v. injection in rats showed comparable levels of radioantibody activity, whether the injection was i.p. or i.v. (except for higher diaphragmatic levels following i.p. delivery). In nude mice with i.p. human-derived ovarian tumors, intact IgG clearance from the peritoneal cavity to the blood was considerably slower than in normal animals, and early i.p. tumor uptake of specific antibody was significantly higher than that following i.v. antibody delivery. With higher early tumor uptake and lower systemic exposure, early tumor/nontumor ratios were significantly greater than those for i.v. delivery, though not beyond 48 h after i.p. injection. This study demonstrates the pharmacokinetic rationale for i.p. monoclonal antibody delivery, especially for agents cleared rapidly from the blood, such as antibody fragments. In addition, definite i.p. delivery benefit for antibody specific to i.p. tumors in the i.p. ovarian cancer system was shown soon after injection. These data regarding i.p. antibody delivery should be useful in rationally planning diagnostic and therapeutic studies involving the i.p. delivery of unmodified and immunoconjugated monoclonal antibodies.

Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (iproplatinum, CHIP) in patients with normal and impaired renal function and following intraperitoneal administration.

CHIP is a quadrivalent platinum (Pt) complex, introduced clinically as a less toxic alternative to cis-platinum. The drug's major route of excretion is via the kidneys, and in this study the pharmacokinetics of unchanged CHIP, filterable Pt and total Pt have been determined following intravenous administration to patients with a range of renal function. Total Pt and filterable Pt in plasma decayed biexponentially and was fitted to a two-compartment model, whereas unchanged CHIP declined monoexponentially and was best fitted to a one-compartment model, according to Akaike's information criteria. There is a correlation between the unchanged CHIP clearance and 51Cr-EDTA clearance. The pharmacokinetics of CHIP was determined following intraperitoneal (i.p.) administration (dose, 150-300 mg m-2 4 h dwell time) and a regional advantage (peritoneal peak concentration/plasma peak concentration) of approximately 30 fold was seen. It is likely that the dose of CHIP will need to be reduced in patients with impaired renal function, and the use of i.p. CHIP in ovarian carcinoma warrants further study.

Pharmacokinetics of intraperitoneally administered dipyridamole in cancer patients.

The pharmacokinetics of i.p. administered dipyridamole was studied in six patients to explore the feasibility of using this drug as a modulator of antimetabolite activity in extravascular spaces. Infusions of dipyridamole (50 mg/m2 in 2 liters of normal saline) into the peritoneal cavity resulted in peak drug concentrations 5 to 20 times higher in that cavity than in the plasma. The peritoneal decay data for dipyridamole fitted very well to a single compartment open pharmacokinetic model with one exponential term, while the plasma data are adequately described by a single compartment model with two exponentials (a short absorption phase). The mean peritoneal half-life for total extractable dipyridamole was 3.3 +/- 1.9 (SD) h, and the mean peritoneal clearance was 0.4 +/- 0.3 liters/h/m2. The mean plasma half-life of total dipyridamole in our patients was 2.2 +/- 1.2 h, and the mean clearance value was 5.7 +/- 4.7 liters/h/m2. The area under the concentration versus time curve was calculated to be 626 +/- 312 microM-h for the peritoneal cavity and 45 +/- 20 microM-h for the plasma. Using membrane ultrafiltration, we have measured the concentration of free (non-protein bound) dipyridamole in each patient. While the peritoneal clearance values of free and total drug are comparable, the plasma clearance of free dipyridamole was 47 +/- 39 liters/h/m2. This increased plasma clearance resulted in a plasma area under the concentration versus time curve of 8.3 +/- 5.1 microM-h, which suggests minimal systemic exposure. Our data show that instillation of dipyridamole into the peritoneal cavity resulted in much higher local drug exposure than systemic exposure, confirming the feasibility of using this drug to augment antimetabolite activity within the peritoneal cavity. Since dipyridamole is highly protein bound in the plasma but less so in the peritoneal cavity, these data imply that peritoneal exposure to active (free) dipyridamole is far greater than systemic exposure in our patients.

Cyclophosphamide modulates arachidonic acid metabolism by peritoneal macrophages.

The treatment of mice with a single dose of cyclophosphamide (Cy) (200 mg/kg) enhanced the chemiluminescence (CL) response of peritoneal macrophages (PM) triggered with opsonized zymosan (OpZ). The enhanced CL response could not be attributed to the stimulation of the cyanide-insensitive respiratory burst, since neither superoxide anion release nor immune complex-triggered cytotoxicity, an oxygen-dependent lytic mechanism, were increased in Cy-PM. Then, products of the oxidative metabolism of arachidonic acid were measured. It was found that Cy-PM exhibited increased release of prostaglandin E2 and leukotriene C4 in response to OpZ when compared with resident PM. In contrast, similar levels of thromboxane B2 production were observed in both populations. The activation of macrophage arachidonic acid metabolism reported here may contribute to the immunomodulating action of Cy.

The effect of diphenylamine derivatives on arachidonic acid metabolism in rat peritoneal macrophages.

The effect of diphenylamine derivatives such as diclofenac sodium, mefenamic acid and lobenzarit disodium on arachidonic acid metabolism in rat peritoneal macrophages was examined. Lobenzarit disodium has no effect on prostaglandin E2 production as measured by radioimmunoassay although two other diphenylamine derivatives have a potent inhibitory activity. Three diphenylamine derivatives have no effect on Ca2+ ionophore-stimulated release of radioactivity from (3H)arachidonic acid-labeled macrophages. HPLC analysis revealed that lobenzarit disodium had no effect on the synthesis of lipoxygenase products as observed in diclofenac sodium and mefenamic acid. It is concluded that lobenzarit disodium, although its fundamental chemical structure resembles diclofenac sodium and mefenamic acid, has no inhibitory activity on arachidonic acid metabolism, suggesting that immunomodulatory activities of lobenzarit disodium are manifested without interfering with arachidonic acid metabolism.

Down-regulation of insulin receptors in Propionibacterium acnes-activated macrophages in the mouse.

Intraperitoneal administration of Propionibacterium acnes in CD-1 mice was associated with the reduction in number of insulin receptors in peritoneal macrophages (M phi), and with elevated levels of insulin in plasma and the peritoneal cavity. When insulin levels returned to normal, insulin receptors in P. acnes-M phi were still reduced. Insulin appears to contribute significantly to the down-regulation of the M phi-insulin receptors during the early stage of activation. Other biologically active substances released during M phi activation might assume greater influence on insulin resistance in activated M phi at a later stage. The induction of transient hyperinsulinemia in P. acnes-treated mice might be attributed to the effect of concurrently elevated interleukin-1 (IL-1) released in the early course of M phi activation.

Phase I/pharmacokinetic study of intraperitoneal cisplatin and etoposide.

We administered cisplatin and etoposide by peritoneal dialysis to 39 patients with i.p. malignancies in order to investigate the toxicity, pharmacokinetics, and clinical activity of this 2-drug combination. All patients received i.v. sodium thiosulfate concurrently with the i.p. chemotherapy. Myelosuppression, nausea, vomiting, and malaise were the primary toxicities encountered. The maximum tolerated dose of etoposide was 350 mg/m2, when administered with a fixed dose of cisplatin, 200 mg/m2. Although the total (free and protein-bound) etoposide exposure for the peritoneal cavity was only 1.5-fold greater than that for the plasma, the free (non-protein bound) etoposide peritoneal exposure was 65-fold greater than the plasma. Tumor regressions were noted in patients with ovarian and pancreatic carcinomas. This study is the first demonstration of the large pharmacokinetic advantage that exists for the i.p. administration of highly protein-bound drugs, and it also documents the clinical activity of i.p. cisplatin and etoposide.

Intraperitoneal penetration of ticarcillin/clavulanic acid (Timentin).

Thirty-eight patients undergoing elective abdominal surgery were given 3.0 g ticarcillin plus 0.2 g clavulanic acid as a single intravenous injection at varying times prior to the operation. Sterile assay discs were placed on the peritoneal surface in order to measure peritoneal fluid levels of each agent. Simultaneous serum levels were also measured. A total of 38 serum and peritoneal samples were analysed. There was rapid penetration of both agents into peritoneal fluid. The mean peritoneal fluid levels of ticarcillin were 70% (S.D. 13) of the serum level and 67% (S.D. 4) for clavulanic acid. The peritoneal levels of both agents declined in parallel to the serum levels (the half-lives being about 1 h) and the ratio of ticarcillin-clavulanic acid in serum and peritoneal fluid did not vary significantly with time.

Modulation of the peritoneal clearance of liposomal cytosine arabinoside by blank liposomes.

Liposomes containing cytosine arabinoside (ara-C) release drug slowly and can be used to maintain a locally high concentration of ara-C in the peritoneal cavity for intracavitary chemotherapy. However, a significant amount of active drug does reach the systemic circulation and contributes to systemic toxicity. We have devised a novel method of decreasing toxicity and increasing intraperitoneal half-life by pretreatment with "blank" liposomes containing no active drug. This technique has resulted in prolongation of intraperitoneal half-life of the liposomal ara-C from 21 h to 165 h, enabling maintenance of a therapeutic drug concentration even at 11 days after initial injection. One hundred percent cures (60-day survival) were achieved with a single-dose therapy begun 1 day after i.p. implantation of 10(6) L1210 leukemia cells.