Biomedical subjects

Brian E Gilbert

Publications and source records attributed to Brian E Gilbert.

9 recordsLinked to original sources

PubMed2005

A fullerene-paclitaxel chemotherapeutic: synthesis, characterization, and study of biological activity in tissue culture.

A fullerene-paclitaxel conjugate has been synthesized as a slow-release drug for aerosol liposome delivery of paclitaxel for lung cancer therapy. The conjugate was designed to release paclitaxel via enzymatic hydrolysis and subsequently has shown a half-life of release of 80 min in bovine plasma. A liposome formulation of the conjugate has been prepared using dilauroylphosphatidylcholine (DLPC), and its IC50 is virtually identical to the IC50 for a paclitaxel-DLPC formulation in human epithelial lung carcinoma A549 cells. With both clinically relevant kinetics of hydrolysis and significant cytotoxicity in tissue culture, the conjugate holds promise for enhanced therapeutic efficacy of paclitaxel in vivo.

Aerosols↗

PubMed2005

Antiviral efficacy of VP14637 against respiratory syncytial virus in vitro and in cotton rats following delivery by small droplet aerosol.

VP14637, the lead compound in a series of substituted bis-tetrazole-benzhydrylphenols developed by ViroPharma Incorporated, was evaluated for antiviral efficacy against respiratory syncytial virus (RSV) in vitro in cell culture and in vivo in cotton rats. A selective index of >3000 (> or =2000 times greater than that observed for ribavirin) was determined in the in vitro studies for this compound against both RSV A and B subtypes. In cotton rats, animals given as little as 126 microg drug/kg by small droplet aerosol in divided doses starting 1 day after experimental virus infection with either a RSV A or B subtype consistently had significantly lower mean pulmonary RSV titers and reduced histopathological findings than mock-treated animals or cotton rats given placebo (vehicle-treated animals). No cotton rat treated with aerosols of VP14637 during these studies manifested any evident untoward responses. Thus, VP14637 exhibited good selective antiviral efficacy both in vitro and in vivo.

Aerosols↗

PubMed2004

Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(s)-camptothecin in patients with advanced pulmonary malignancies.

PURPOSE: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. EXPERIMENTAL DESIGN: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 micro g/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. RESULTS: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 micro g/kg/day. At 20.0 micro g/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. CONCLUSIONS: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient's plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 micro g/kg/day (equivalent to 0.5 mg/m(2)/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.

Administration, Inhalation↗

PubMed2004

Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis.

PURPOSE: To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors. METHODS: Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dil-auroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week. RESULTS: Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P< 0.001)in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters,namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining. CONCLUSIONS: Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment.

Aerosols↗

PubMed2004

Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice.

The objective of this study was to assess the effect of cyclosporin A liposome aerosol on the anticancer activity of paclitaxel (PTX) liposome aerosol against renal cell carcinoma (Renca) pulmonary metastases in mice. Cyclosporin A (CsA) was administered as a liposome aerosol for one-half hour before starting one-half hour treatment with PTX liposome aerosol (CsA/PTX), and in a second groups of animals cyclosporin A liposome aerosol was given before PTX for one-half hour and also later by mixing a second dose of cyclosporin A aerosol with PTX aerosol and extending the treatment period to one hour (CsA/PTX + CsA). In one experiment, PTX and CsA/PTX aerosols were significantly more effective compared to untreated controls against renal cell cancer as measured by lung weights and tumor surface areas. CsA/PTX was significantly better that PTX alone as measured by lung weights and tumor area. In a second experiment, tumor areas of PTX and CsA/PTX treated mice were significantly reduced compared to untreated controls and CsA/PTX treated mice had significantly smaller tumor areas than PTX treated mice. In contrast, tumor numbers were not significantly fewer than controls in either therapeutic group. In a third experiment, tumor numbers and tumor areas were significantly fewer in mice treated with CsA/PTX and CsA/PTX + CsA compared to untreated controls. Mice treated with CsA/PTX + CsA had significantly fewer tumors and less tumor area than mice receiving CsA/PTX. While PTX treated mice were not different than untreated controls with respect to tumor numbers or tumor volumes, PTX treated mice had significantly greater tumor numbers and tumor areas than CsA/PTX and CsA/PTX + CsA treated mice. Co-administration of CsA with PTX demonstrated significant dose dependent anticancer effects against renal cell pulmonary metastases in mice. Toxicity manifested by weight loss was associated with the highest dose of CsA.

Animals↗

PubMed2003

Short duration aerosols of JNJ 2408068 (R170591) administered prophylactically or therapeutically protect cotton rats from experimental respiratory syncytial virus infection.

Cotton rats exposed to continuous small droplet aerosols of 2[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]methyl]-6-methyl-3-pyridinol (JNJ 2408068) or its hydrochloric salt for only 15 min, one day prior to virus inoculation or one day after, were significantly protected from pulmonary respiratory syncytial virus (RSV) infection compared to control animals similarly infected but exposed to aerosols of placebo at these times. No evidence of toxicity was seen in any of these animals or in cotton rats administered 10 times the minimum cotton rat efficacious dose (i.e. 10x0.39 mg of active compound per kilogram of body weight) for four continuous days. The marked selective antiviral activity observed in the cotton rats mirrored that seen for these compounds in cytotoxicity and antiviral assays performed against RSV in vitro. Plasma kinetics and tissue distribution of JNJ 2408068 in cotton rats following inhalation were determined in separate experiments performed using conditions similar to those utilized in the in vivo efficacy studies. The data from these experiments indicated that significant levels of the test compound were delivered to the lungs of exposed animals, but that extrapulmonary distribution was limited.

Administration, Inhalation↗

PubMed2003

Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis.

A nonhydrolyzable ether analogue of RRR-alpha-tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR-alpha-tocopheryloxyacetic acid or RRR-alpha-tocopherol ether-linked acetic acid analogue (alpha-TEA), exhibits antitumor activity in vitro and in vivo using a syngeneic BALB/c mouse mammary tumor model (line 66 clone 4 stably transfected with green fluorescent protein). Treatment of cells with 5, 10, and 20 micro g/ml alpha-TEA for 3 days produced 6, 34, and 50% apoptosis, respectively, and treatment of cells with 10 micro g/ml for 2, 3, 4, and 5 days produced 20, 35, 47, and 58% apoptosis, respectively. A liposomal formulation of alpha-TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. Alpha-TEA-treated animals showed a significant decrease in tumor volumes over 17 days of aerosol treatment (P < 0.001). Forty percent of aerosol as well as untreated control mice had visible, macroscopic lung metastases versus none (0%) of the alpha-TEA-treated mice. On the basis of fluorescence microscopic examination of the surface (top and bottom) of flattened whole left lung lobes, an average of 60 +/- 15 and 102 +/- 17 versus 11 +/- 4 fluorescent microscopic metastases was observed in aerosol control and untreated control versus alpha-TEA-treated animals, respectively. Alpha-TEA formulated in ethanol + peanut oil (5 mg/mouse/day) delivered by gavage did not reduce s.c. primary tumor burden; however, fluorescent microscopic lung metastases were significantly reduced (P < 0.0021). In summary, alpha-TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.

Administration, Oral↗

PubMed2002

9-nitrocamptothecin liposome aerosol: lack of subacute toxicity in dogs.

9-Nitrocamptothecin (9-NC) dilauroylphosphatidylcholine (DLPC) liposome aerosol was evaluated for potential toxicity in an 8-wk, subacute toxicity study in dogs. Fourteen adult dogs were divided into 2 groups with 10 animals in the 9-NC-DLPC treatment group and 4 animals in the DLPC-only vehicle control group. 9-NC-DLPC was administered to the animals using an Aerotech II nebulizer flowing at 10 L/min. Full-face exposures for 60 min were conducted for 5 consecutive days a week for 8 wk. The estimated deposited aerosol dose was 24.7 microg/kg/day. Animals in the vehicle control group received aerosolized DLPC only. Body weight, food consumption, urinalysis, in-life observations, hematology, plasma chemistry, and necropsy and histopathology were monitored before and during the treatment period and in a subset of animals for 2 wk following the end of treatment. Animals were observed for signs of pharmacologic and/or toxicologic effects three times on days of dosing and once daily on nondosing days. 9-NC-DLPC liposomes administered as a small-particle aerosol were determined to be nontoxic to dogs when given for 5 days/wk, for a duration of 8 wk. DLPC-only liposome also had no toxic effects.

Administration, Inhalation↗

PubMed2002

Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer.

PURPOSE: Transfer of growth-suppressive genes to lung tumors has therapeutic potential, but effective delivery techniques have not been developed. Here, we investigated gene delivery to lung tumors by aerosolization of adenoviral vectors incorporated into calcium phosphate precipitates. EXPERIMENTAL DESIGN: To investigate the efficacy of this delivery method in normal and neoplastic lung, an adenoviral vector expressing beta-galactosidase was administered by jet nebulization to K-ras(LA1) mice, which develop lung adenocarcinomas through activation of a latent allele carrying mutant K-ras(G12D). Furthermore, we investigated whether aerosolized delivery of Ad-MKK4 (KR), an adenoviral vector expressing dominant-negative mutant mitogen-activated protein kinase kinase 4(MKK4), can block Ras-dependent signaling in K-ras(LA1) mice. RESULTS: After a single administration, beta-galactosidase was detected in lung tissue for up to 21 days, and expression was much greater in tumors than in normal lung tissue. MKK4 was activated in the lungs of K-ras(LA1) mice, and aerosolized treatment with Ad-MKK4 (KR) decreased c-Jun-NH(2)-terminal kinase but not extracellular signal- regulated kinase activity, providing evidence that MKK4 was selectively inhibited. CONCLUSIONS: These findings demonstrate a novel approach to targeting oncogenic pathways in lung tumors by aerosolized gene delivery.

Adenocarcinoma↗