PubMed Health⌕ Search

Biomedical subjects

H M Burt

Publications and source records attributed to H M Burt.

At least 19 recordsLinked to original sources
PubMed2006

The Gurnham equation in characterizing the compressibility of pharmaceutical materials.

Limitations of the Heckel equation in characterizing material compression behavior have been well reported. In this work, the Gurnham equation, which was first introduced in chemical engineering, is proposed as an alternate method of evaluating the compressibility of pharmaceutical powders. The Gurnham equation was adapted for tablet compression and the estimated slope parameter c was proposed to represent material compressibility. Data from the compression of four commonly used excipients (microcrystalline cellulose, corn starch, lactose monohydrate, and dibasic calcium phosphate dihydrate) and one drug (acetaminophen) were evaluated using the Gurnham equation. Using compression data at different peak pressures, linear relationships between porosity and lnPressure of the five materials were obtained. The determined parameter c expresses the compressibility of materials. The analysis of previous experimental data, including granulations, mixtures and co-processed materials also indicates that c might be a representative parameter for material compressibility.

Acetaminophen↗
PubMed2006

The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis.

OBJECTIVE: Curcumin and quercetin are antioxidant molecules with anti-proliferative, anti-inflammatory and immunosuppressive activities. The objective of this study was to investigate the inhibitory activity of these agents using four assays of inflammatory aspects of arthritis. METHODS: Crystal-induced neutrophil activation was measured by luminol-dependent chemiluminescence. Synoviocyte proliferation was measured by an MTS assay using HIG-82 rabbit synoviocytes in cell culture. Chondrocyte (cultured primary cells) expression of the matrix metalloproteinases collagenase and stromelysin was measured by Northern Blot analysis. Angiogenesis was measured using the chorioallantoic membrane of the chick embryo. RESULTS: Both agents inhibited neutrophil activation, synoviocyte proliferation and angiogenesis. Curcumin strongly inhibited collagenase and stromelysin expression at micromolar concentrations whereas quercetin had no effect in this assay. CONCLUSION: These studies suggest that curcumin and to a lesser extent quercetin may offer therapeutic potential for the treatment of crystal-induced arthritis or rheumatoid arthritis.

Animals↗
PubMed2004

Camptothecin-loaded films for the prevention of postsurgical adhesions.

OBJECTIVE AND DESIGN: The purpose of this work was to investigate the local application of camptothecin (CPT), a drug with anti-inflammatory, antiproliferative and antiangiogenic properties, as an inhibitor of surgical adhesion formation in rats. METHODS: The anti-adhesion properties of CPT were investigated using the cecal sidewall abrasion model in a total of 92 rats. An adhesion score for each animal was obtained based on the strength and extent of the adhesions. Significance was determined by Students t-test and p values less than 0.05 were considered significant. TREATMENT: The drug was administered by application of carbodiimide crosslinked hyaluronic acid (HA) films containing CPT at concentrations of 0, 0.6, 2.5 and 7.5% w/w at the site of surgical injury. The HA films were characterized by in vitro measurements of drug release rates. RESULTS: In this model the application of HA films alone, or 0, 0.6, 2.5 or 7.5% w/w CPT-loaded HA films, had a significant effect in reducing the mean strength and area of adhesions (3.8 +/- 2.7, 5.6 +/- 0.7, 1.3 +/- 0.7, 0.9 +/- 0.8, 0.7 +/- 1.0, respectively) when compared to those animals in which no film was placed (8.4 +/- 2.5). In addition, a significant difference was observed in the effect of 0.6, 2.5 and 7.5% w/w CPT-loaded films when compared to the HA or 0% CPT-loaded films (p < 0.05). No toxicity was observed in the rats following administration of these films. CONCLUSIONS: CPT loaded films inhibited the formation of adhesions in the rat cecal sidewall abrasion model. HA crosslinked with 2 mM carbodiimide and containing 20% w/w glycerol and 0.6, 2.5 or 7.5% w/w CPT are flexible, mucoadhesive, biocompatible controlled release films that can be used to prevent adhesion formation.

Animals↗
PubMed2004

Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits.

OBJECTIVES: To assess the biocompatibility of controlled release microspheres prepared from different polymeric biomaterials in various size ranges in rabbit synovial joints and based on these data, design and evaluate the efficacy of an intra-articular, paclitaxel-loaded microspheres formulation in rabbit models of arthritis. METHODS: Paclitaxel-loaded microspheres of poly(lactide-co-glycolide) (PLGA), poly(L-lactic acid) (PLA) and poly(caprolactone) (PCL) were prepared in different size ranges and inflammatory responses monitored following injection into healthy rabbit joints. The efficacy of 20% paclitaxel-loaded PLA microspheres (35-105 microm size range) injected intra-articularly into antigen and carrageenan induced rabbit models of arthritis was monitored. RESULTS: Polymeric microspheres in the 35-105 microm size range were biocompatible whereas smaller microspheres (1-20 microm) produced an inflammatory response. Efficacy studies showed that injection of 20% paclitaxel-loaded PLA microspheres significantly reduced all measures of inflammation in the antigen arthritis rabbit model. CONCLUSIONS: Paclitaxel-loaded PLA microspheres in the 35-105 microm size range, released paclitaxel in a controlled manner over several weeks, and may be a potential formulation for the intra-articular treatment of inflammation in arthritic conditions.

Animals↗
PubMed2003

The effect of inhibiting topoisomerase I and II on the anti-apoptotic response associated with pro-inflammatory crystals of calcium pyrophosphate dihydrate in human neutrophils.

OBJECTIVE AND DESIGN: To investigate the ability of various topoisomerase I and II inhibitors to reverse the pro-survival effects of calcium pyrophosphate dihydrate (CPPD) crystals on human neutrophils, thereby identifying potential agents that may promote the resolution of neutrophil accumulation typical of crystal associated inflammatory diseases. MATERIALS AND METHODS: Freshly isolated human neutrophils incubated in the presence of CPPD crystals, with or without the pro-apoptotic cytokine TNF-alpha, were pre-incubated in the presence or absence of the topoisomerase I inhibitors camptothecin, nogalamycin or beta-lapachone, or topoisomerase II inhibitors etoposide, doxorubicin or mitoxantrone. Neutrophil respiratory burst was assessed via chemiluminescence, and two quantitative methods were used for the determination of neutrophil apoptosis; cytoplasmic histone-associated-DNA fragmentation assessment, and endogenous caspase 3 substrate (Ac-DEVD-AMC) cleavage. RESULTS: Beta-lapachone and mitoxantrone effectively repressed CPPD crystal associated respiratory burst, whereas the other topoisomerase inhibitors had no inhibitory or stimulatory effect. Camptothecin and all of the topoisomerase II inhibitors induced neutrophil apoptosis, even in the presence of the CPPD crystals that normally repress TNF-alpha-induced and spontaneous apoptosis. CONCLUSIONS: These results suggest that although topoisomerase II antagonists are distinctively effective agents at reversing the pro-survival effects of crystals on neutrophils, camptothecin was unique as a topoisomerase I inhibitor in that it was significantly more effective as a pro-apoptosis inducer than the topoisomerase II poisons without affecting normal neutrophil activation responses.

Apoptosis↗
PubMed2002

Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations.

A number of hypersensitivity reactions have been attributed to the presence of Cremophor((R)) EL in the current formulation for paclitaxel. This has led to the development of formulations for paclitaxel employing polyether-polyester diblock copolymers as micelle forming carriers. Diblock copolymers of methoxypolyethylene glycol-block-poly(D,L-lactide) (MePEG:PDLLA) were synthesized from monomers of D,L-lactide and MePEG by a ring opening bulk polymerization in the presence of stannous octoate. Up to 25% paclitaxel could be loaded into matrices of MePEG:PDLLA (60:40, MePEG molecular weight of 2000) using the solution casting method. Dissolution of paclitaxel/copolymer matrices in aqueous media resulted in complete solubilization of paclitaxel within the hydrophobic PDLLA core of the micelles. This review article describes the synthetic reaction conditions influencing the degree of conversion of monomer to copolymer, thermal properties, critical micelle concentrations of copolymers, methods of incorporation of paclitaxel into copolymer matrices and subsequent constitution in aqueous media and biological evaluations of micellar paclitaxel.

Animals↗
PubMed2001

Paclitaxel loaded poly(L-lactic acid) microspheres: properties of microspheres made with low molecular weight polymers.

Microspheres were prepared from poly(L-lactic acid) polymers having molecular weights between 500 and 50k g/mol. The polymers were synthesized using two initiator molecules, L-lactic acid oligomer (PLLA-LA) or stearyl alcohol (PLLA-SA). For both PLLA-LA and PLLA-SA polymers, glass (Tg) and melting (Tm) transition temperatures and enthalpy of melting all increased as the polymer molecular weight increased. PLLA-SA showed the greatest change in Tg (-13 to 54 degrees C) as molecular weight increased from 500 to 10k x g/mol, compared to 25 to 55 degrees C for PLLA-LA polymers. Changes in Tm and enthalpy of melting with increasing molecular weight were similar for both PLLA-LA and PLLA-SA. Paclitaxel release from 30% paclitaxel loaded microspheres in the size range of 50-90 microm was affected by these changes in polymer properties as molecular weight increased. As the molecular weight increased from 2k to 50k x g/mol the amount of drug released from microspheres over 14 days decreased from 76 to 11% of the initial drug load. The release profiles were consistent with a diffusion controlled mechanism provided a two-compartment model was employed. According to this model, the total amount of 'available' drug (compartment 1) was released by diffusion in 14 days while the remainder (compartment 2) was confined within the polymeric matrix and could not diffuse out at a measurable rate. Following the in vitro release study, microsphere made from 2k-10k g/mol polymers showed significant signs of disintegration whereas 50k x g/mol polymer microspheres remained intact.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Inhibition of TNF-alpha-induced neutrophil apoptosis by crystals of calcium pyrophosphate dihydrate is mediated by the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways up-stream of caspase 3.

The role of protein kinases in the inhibition of TNF-alpha associated apoptosis of human neutrophils by crystals of calcium pyrophosphate dihydrate (CPPD) (25 mg/ml) was investigated. We monitored the activities of the p44 extracellular signal-regulated kinase 1 (ERK1) and p42 ERK2 mitogen-activated protein (MAP) kinases and phosphatidylinositol 3-kinase (PI3-K)-regulated protein kinase B (Akt) in neutrophils incubated with TNF-alpha and CPPD crystals, separately and in combination, in parallel with the endogenous caspase 3 activity and DNA fragmentation. CPPD crystals were observed to induce a robust and transient activation of ERK1, ERK2, and Akt, whereas TNF-alpha produced only a modest and delayed activation of Akt. In the presence of TNF-alpha, Akt activity was enhanced, and CPPD crystal-induced activation of ERK1 and ERK2 was more sustained than with CPPD crystals alone, but TNF-alpha itself reduced the basal phosphotransferase activities of these MAP kinases. Preincubation with the MAP kinase kinase (MEK1) inhibitors PD98059 (20 ng/ml) and U0126 (250 nM), or the PI3-K inhibitors wortmannin (100 nM) and LY294002 (50 microM) repressed the activation of ERK1, ERK2, and Akt in association with CPPD crystal incubation, in the absence or presence of TNF-alpha. Furthermore, the inhibition of the Mek1/Mek2-->ERK1/ERK2 or PI3-K/Akt pathways reversed CPPD crystal-associated suppression of TNF-alpha-induced caspase 3 activation and neutrophil apoptosis. Together, these results indicate that CPPD crystals function to induce acute inflammatory responses through ERK1/ERK2 and PI3-K/Akt-mediated stimulation of neutrophil activation and repression of apoptosis.

Apoptosis↗
PubMed2000

The suppression of human prostate tumor growth in mice by the intratumoral injection of a slow-release polymeric paste formulation of paclitaxel.

Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmetastatic human prostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a blend of a biodegradable triblock copolymer of a random copolymer of D,L-lactide and epsilon-caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 microl of this paste at room temperature. Changes in tumor progression were assessed using both serum prostate-specific antigen (PSA) levels and tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentration-dependent fashion with an IC50 of 1 nM. Apoptosis was documented using DNA fragmentation analysis. The paste formulation solidified over a period of 1 h both in vivo and in aqueous media at 37 degrees C as the methoxypoly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant released drug at a rate of about 100 microg/day in vitro. In control mice treated with paste without paclitaxel, serum PSA levels increased from 2-8 ng/ml (mean, 4.3+/-2 ng/ml) to 60-292 ng/ml (mean, 181+/-88 ng/ml), and tumor volume increased from 30 to 1000 mm3. In mice treated with a single 100-microl injection 3 weeks after castration (early-phase treatment group), tumors decreased in volume from a mean of 43+/-19 mm3 to nonpalpable, and PSA levels decreased from a mean of 22+/-8 to 2+/-1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after castration (androgen-independent tumors; late-phase treatment group), tumors decreased in volume from a mean of 233+/-136 mm3 to nonpalpable, and serum PSA decreased from 24+/-8 to 9+/-4 ng/ml. Observed side effects of the treatment were limited to minor ulceration at the needle injection site in paclitaxel-treated mice only. The controlled-release formulation can be injected via 22-gauge needles and is effective in inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple nonmetastatic tumors. Paclitaxel may be an effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment.

Animals↗
PubMed2000

Neutrophil activation by plasma opsonized polymeric microspheres: inhibitory effect of pluronic F127.

The phagocytosis of drug-loaded polymeric microspheres by white blood cells, such as neutrophils or mononuclear cells, represents the major clearance mechanism by which this foreign material is eliminated from the body. The process of phagocytosis requires the activation of the white blood cells by the microsphere surface, followed by binding and engulfment. Phagocytosis may result in the removal of the microspheres from the blood or the disease site and an inflammatory response. Therefore, we have studied the level of neutrophil activation by microspheres ( +/- opsonization) manufactured from various biomaterials or polymers. Polymer microspheres with equivalent size distributions were made from poly (DL-lactic acid) (PLA), poly(epsilon-caprolactone) (PCL), poly(methyl methacrylate) (PMMA) or a 50 : 50 blend of PLA: poly(ethylene-co-vinyl acetate) (PLA: EVA). Neutrophils were isolated from human blood and activation of these cells by microspheres was measured by chemiluminescence (CL). All four types of microspheres induced only low levels of CL, however these levels were enhanced significantly if the microspheres were pretreated with plasma or IgG suggesting an opsonization effect. The adsorption of IgG or proteins from plasma was confirmed by polyacrylamide gel electrophoresis (SDS-PAGE). The poloxamer Pluronic F127 inhibited the opsonization effect of IgG and plasma on all four types of microspheres and inhibited protein adsorption as measured by SDS-PAGE. Since neutrophil activation is part of the inflammation process in vivo, these in vitro data suggest that all four types of microspheres are likely to be inflammatory if injected into body compartments containing plasma-derived fluids. Pretreatment of the microspheres with Pluronic F127 may reduce the inflammatory potential of the microspheres.

Biocompatible Materials↗
PubMed2000

Paclitaxel loaded poly(L-lactic acid) microspheres for the prevention of intraperitoneal carcinomatosis after a surgical repair and tumor cell spill.

A controlled release delivery system for paclitaxel was developed using poly(L-lactic acid) to provide local delivery to the peritoneal cavity. Microspheres were made in 1-40 and 30-120 microm size ranges. In an in vitro release study, 30-120 microm microspheres loaded with 10, 20 and 30% paclitaxel exhibited a burst phase of release for 3 days followed by an apparently zero-order phase of release. At all loadings, 20-25% of the original load of paclitaxel was released after 30 days. The effect of microsphere size on retention in the peritoneal cavity was assessed. Control 1-40 microm microspheres were injected intraperitoneally in rats. The rats received either insufflation of the peritoneal cavity using 11 mmHg CO2 or no further treatment. After sacrifice, microspheres with diameters less than 24 microm were observed in the lymphatic system after being cleared from the peritoneal cavity through fenestrations in the diaphragm. Insufflation of the peritoneal cavity had no effect on the size of microspheres that were cleared. Efficacy studies were carried out using 30-120 microm microspheres that were of sufficient size to be retained in the peritoneal cavity. In a model of a tumor cell spill after a cecotomy repair, 100 mg of 30-120 microm microspheres containing 30% paclitaxel were effective in preventing growth of tumors in the peritoneal cavity at both 2 and 6 weeks post-surgery. No gross or histologically evident tumor growth was observed on any peritoneal surfaces or in the surgical wound site. Rats receiving control microspheres all showed tumor cell implantation and growth after 2 weeks.

Animals↗
PubMed2000

The inhibition of spontaneous and tumor necrosis factor-alpha induced neutrophil apoptosis by crystals of calcium pyrophosphate dihydrate and monosodium urate monohydrate.

OBJECTIVE: Spontaneous neutrophil apoptosis may be inhibited by various proinflammatory stimuli. which may result in prolonged lifetimes and responses of these phagocytic cells with the potential for extended inflammation. We investigated the effect of short term incubation of opsonized crystals of monosodium urate monohydrate (MSUM) or calcium pyrophosphate dihydrate (CPPD) on both spontaneous and tumor necrosis factor-alpha (TNF-alpha) induced neutrophil apoptosis. METHODS: Peripheral neutrophils were incubated with plasma opsonized crystals of CPPD or MSUM in the presence or absence of TNF-alpha for 4 h at 37 degrees C. Apoptosis was determined using 3 separate assays: (1) an agarose DNA fragmentation assay, (2) a cytoplasmic histone associated DNA fragmentation assay, and (3) a caspase 3 fluorometric assay. RESULTS: All 3 assays showed similar results. Both MSUM and CPPD crystals inhibited spontaneous apoptosis in neutrophils. TNF-alpha induced high levels of apoptosis in neutrophils. However, co-incubation of the cells with TNF-alpha and crystals resulted in the inhibition of apoptosis to levels below those of control cells. Pretreatment of neutrophils with the protein synthesis inhibitor cycloheximide prevented the inhibition of apoptosis by crystals. CONCLUSION: These data support the concept of crystal induced inhibition of neutrophil apoptosis as part of the pathophysiology of the diseases collectively known as crystal induced arthritis.

Apoptosis↗
PubMed2000

The involvement of phospholipase C in crystal induced human neutrophil activation.

OBJECTIVE: To investigate the involvement of phospholipase C (PLC) in the signal transduction pathway leading to neutrophil activation by inflammatory microcrystals. METHODS: Neutrophil chemiluminescence, superoxide anion generation, and degranulation responses to opsonized crystals were measured in the presence of U73122, a specific inhibitor of PLC. Phospholipase Cgamma2 (PLCgamma2) activity was measured by Western blotting. RESULTS: U73122 was shown to inhibit neutrophil activation induced by plasma opsonized crystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate. The IC50 for inhibition of crystal induced respiratory burst (measured by chemiluminescence) was roughly 3 microM. No inhibition of crystal induced respiratory burst was observed using U73343, an inactive analog of U73122. These results show the pivotal role of PLC in neutrophil respiratory burst activation by both crystals. Superoxide anion generation and degranulation responses of neutrophils to CPPD crystals were also strongly inhibited by U73122 at a concentration of 10 microM, supporting the concept of direct involvement of PLC in signal transduction pathways leading to crystal induced oxidase activation and degranulation responses. CPPD crystals caused a sustained increase in the tyrosine phosphorylation levels of PLCgamma2 in neutrophils. CONCLUSION: We conclude that PLC plays a central role in signal transduction pathways leading to respiratory burst and degranulation responses in neutrophils activated by inflammatory microcrystals, and that PLCgamma2 may be the isoform involved in these pathways.

Calcium↗
PubMed1998

Activation of S6 kinase in human neutrophils by calcium pyrophosphate dihydrate crystals: protein kinase C-dependent and phosphatidylinositol-3-kinase-independent pathways.

Phosphatidylinositol 3-kinase (PI 3-kinase) has been shown previously to be a central enzyme in crystal-induced neutrophil activation. Since activation of the 70 kDa S6 kinase (p70S6K) has been shown to be dependent on PI 3-kinase activation in mammalian cells, and since the former is a key enzyme in the transmission of signals to the cell nucleus, activation of p70(S6K) was investigated in crystal-stimulated neutrophils. Cytosolic fractions from calcium pyrophosphate dihydrate (CPPD)-crystal-activated neutrophils were separated by Mono Q chromatography and analysed for phosphotransferase activity using a range of substrates and probed by Western analysis using antibodies to p70(S6K) and mitogen-activated protein kinase (MAP kinase). CPPD crystals induced a robust, transient activation (peak activity at 2 min) of p70(S6K) that was fully inhibited by pretreatment with rapamycin. This is the first report of the activation of p70(S6K) in neutrophil signal transduction pathways induced by an agonist. This crystal-induced activation of p70(S6K) could also be inhibited by a protein kinase C (PKC) inhibitor (Compound 3), but not by the PI 3-kinase inhibitor wortmannin. CPPD crystals also activated the ERK1 and ERK2 forms of MAP kinase (wortmannin insensitive), PKC (Compound 3 sensitive) and protein kinase B (wortmannin sensitive) in neutrophils. These data suggest that activation of p70(S6K) may proceed through a PI 3-kinase- and protein kinase B-independent but PKC-dependent pathway in crystal-activated neutrophils.

Androstadienes↗
PubMed1998

The antineoplastic ether lipid, s-phosphonate, selectively induces apoptosis in human leukemic cells and exhibits antiangiogenic and apoptotic activity on the chorioallantoic membrane of the chick embryo.

INTRODUCTION: We investigated the cytotoxic and antiangiogenic activity of the ether lipid, 2'-(trimethylammonio)ethyl 4-(hexadecyloxy)-3(S)-methoxybutane-phosphonate (termed s-phosphonate). METHOD: Cytotoxicity was determined using an XTT bioassay. Apoptosis was measured by either DNA fragmentation or immunolabelling techniques. Angiogenesis was measured using the in vivo chorioallantoic membrane (CAM) of the chick embryo. RESULTS: S-phosphonate was selectively cytotoxic towards the human leukemic cell lines, HL-60 and AML-14, whereas leukemic K-562 cells and the murine mast cell line, MC-9, were resistant to this agent at concentrations as high as 50 microM. This selectivity resulted from the induction of apoptosis (or programmed cell death) by s-phosphonate in HL-60 and AML-14 cells but not in resistant K-562 or MC-9 cells. S-phosphonate induced localized antiangiogenic effects and membrane thinning in the CAM. This concentration-dependent antiangiogenic effect was associated with apoptosis in the CAM as measured by DNA fragmentation in extracted CAM tissue. The localized areas of membrane thinning and antiangiogenesis on the CAM caused by s-phosphonate were also the only areas of the membrane in which apoptosis occurred. CONCLUSION: We conclude that s-phosphonate selectively induces apoptosis in human leukemic cells and exhibits antiangiogenic and apoptotic activity on the CAM.

Animals↗
PubMed1997

An investigation of the antitumour activity and biodistribution of polymeric micellar paclitaxel.

PURPOSE: To evaluate in vitro cytotoxicity, in vivo antitumour activity and biodistribution of a novel polymeric (poly(DL-lactide)-block-methoxy polyethylene glycol) micellar paclitaxel. METHODS: Hs578T breast, SKMES non-small-cell lung, and HT-29 colon human tumour cells were exposed, either for 1 h or continuously, to conventionally formulated paclitaxel (Cremophor paclitaxel) or polymeric micellar paclitaxel. After a period of incubation, cytotoxicity was measured using a radiometric system. In the in vivo antitumour study, B6D2F1 mice, bearing P388 leukaemia tumour intraperitoneally (i.p.), were treated with polymeric micellar paclitaxel or Cremophor paclitaxel by i.p. injection. The number of deaths and body weights were recorded. In the biodistribution study, CD-1 mice were given micellar paclitaxel i.p. at a dose of 100 mg/kg. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted by acetonitrile and analysed using HPLC. RESULTS: The polymeric micellar paclitaxel showed similar in vitro cytotoxicity to Cremophor paclitaxel against the tumour cell lines. The polymeric micellar formulation of paclitaxel produced a fivefold increase in the maximum tolerated dose (MTD) as compared with Cremophor paclitaxel when administered i.p. In addition, micellar paclitaxel was more efficacious in vivo when tested in the murine P388 leukaemia model of malignancy than Cremophor paclitaxel when both were administered i.p. at their MTDs. Micellar paclitaxel-treated animals had an increased survival time and, importantly, long-term survivors (20% of those tested) were obtained only in the polymeric paclitaxel formulation group. Biodistribution studies indicated that a significant amount of paclitaxel could be detected in blood, liver, kidney, spleen, lung and heart of mice after i.p. dosing of the polymeric micellar paclitaxel formulation. CONCLUSION: These preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.

Animals↗
PubMed1997

The development of a novel intraperitoneal tumor-seeding prophylactic.

BACKGROUND: Peritoneal tumor dissemination and implantation is a complication of both open and laparoscopic oncologic surgery. This study evaluates the efficacy of paclitaxel-loaded poly(L-lactic acid) microspheres as prophylaxis against intraabdominal tumor seeding. METHODS: 2 x 10(6) 9L glioblastoma cells were introduced into the abdominal cavity of Wistar rats. Fifteen minutes later, the peritoneal cavity was washed with the experimental solutions, and 2 weeks later the presence of tumor implantation was determined. After defining the optimum dose of paclitaxel PLA microspheres in a dose-ranging study, the microsphere formulation was then compared with conventional paclitaxel in four experimental groups (n = 5) as follows: 100 mg of 30% paclitaxel-loaded microspheres; 100 mg PLA microspheres; paclitaxel 4.1 mg; and controls receiving no intraabdominal therapy. RESULTS: Although carcinomatosis developed in all control animals, none in the paclitaxel-loaded microsphere group had biopsy proven cancer. The conventional paclitaxel group (3) showed significant toxicity; only 1 animal survived and had positive histology. CONCLUSIONS: In this animal model of peritoneal carcinomatosis, the paclitaxel-loaded microsphere formulation was more effective than conventional paclitaxel in preventing tumor seeding.

Animals↗