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J A Gibbons

Publications and source records attributed to J A Gibbons.

At least 19 recordsLinked to original sources
PubMed2000

A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with approximately 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees, and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.

Animals↗
PubMed1997

Intestinal absorption screening of mixtures from combinatorial libraries in the Caco-2 model.

PURPOSE: Understanding how chemical structures influence transport across the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationships between structure and transport, six arbitrary mixtures of N-substituted glycine (NSG) peptoids containing 24 physicochemically diverse compounds were evaluated in the Caco-2 model of intestinal absorption. METHODS: Samples were analyzed by HPLC and the areas of the peaks representing the components of each mixture were summed to measure "aggregate" apparent permeability coefficients (Papp), a score of the influence of the common structural element within each mixture towards absorption. Mass spectrometry was used to identify the chemical structure of Caco-2 permeable compounds. RESULTS: Three linear trimeric mixtures were examined and, for each mixture, none of the components was detected in receiver chambers. It was concluded that the components of these mixtures each had a Papp value less than 0.8 x 10(-6) cm/sec, a permeability less than mannitol. Three dimeric mixtures were examined and they exhibited aggregate P(app) values of 9.2 x 10(-6), 14 x 10(-6) and 6.9 x 10(-6) cm/sec. These transport rates reflected the transport of most of the components of each mixture. Furthermore, the components of the dimeric mixtures which were transported at a rate greater than mannitol were apparently transported by passive mechanisms. CONCLUSIONS: This study demonstrated that mixtures can be used to study structure-transport relationships in the Caco-2 model. The information obtained from this type of study will be integrated into the design of future chemical libraries. Other potential uses of chemical mixtures with the Caco-2 model are also discussed.

Biological Transport, Active↗
PubMed1996

Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma.

We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.

Adult↗
PubMed1996

Pharmacologic characterization of CHIR 2279, an N-substituted glycine peptoid with high-affinity binding for alpha 1-adrenoceptors.

We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Quantitation of the renal clearance of interleukin-2 using nephrectomized and ureter-ligated rats.

The objective of this work was to determine the role of the kidneys in the systemic clearance rate (CL) of interleukin-2 (IL-2). Rats received IL-2 by i.v. bolus and the pharmacokinetic data were found to be well described by a two-compartment, first-order elimination model. With administration of 0.2, 0.5 or 1.0 mg/kg of IL-2 (n = 3 per treatment), the median alpha and beta half-lives (T1/2 alpha, 2.3 min; T1/2 beta, 13.2 min, respectively), initial volume of distribution (V1, 93 ml/kg), volume of distribution at steady state (Vss, 198 ml/kg) and CL (16.8 ml min-1 kg-1) did not vary with the dose (P = .05). This demonstration of first-order kinetics suggested that renal CL remains constant over a range of doses. The pharmacokinetic properties of 1.0 mg/kg of IL-2 were examined after either single or double nephrectomy (n = 3 and 4, respectively), sham operation (n = 4) or no renal operation (n = 4; the "controls"). No difference in median T1/2 alpha, T1/2 beta, V1, Vss or CL was detected between control and sham-operated rats nor between single nephrectomy and sham operation. Compared with sham operation, double nephrectomy showed no significant change in V1 or Vss but the T1/2 alpha and T1/2 beta approximately doubled and CL was reduced by 75%. In a separate experiment, ureter-ligated rats were compared with sham-operated rats. With ureter ligation, T1/2 alpha, T1/2 beta, V1 and Vss were unchanged but CL was reduced by 36%.

Animals↗
PubMed1994

Venovenous extracorporeal life support in traumatic bronchial disruption and adult respiratory distress syndrome using surface-heparinized equipment: case report.

Venovenous extracorporeal membrane oxygenation and carbon dioxide removal was utilized to support a patient with traumatic bronchial disruption and associated injuries. With use of surface-heparinized perfusion equipment, low levels of anticoagulation were maintained allowing surgical repair of the bronchial injury and recovery from acute respiratory failure without significant hemorrhage.

Adolescent↗
PubMed1994

Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.

PURPOSE: Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated. PATIENTS AND METHODS: rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy. RESULTS: The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy. CONCLUSION: rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.

Adult↗
PubMed1994

Nonlinear pharmacokinetics of recombinant human macrophage colony-stimulating factor (M-CSF) in rats.

The pharmacokinetics and mechanisms of elimination of recombinant human macrophage-colony stimulating factor (M-CSF) were investigated in rats. Intravenous injections of 0.1, 1 or 10 mg/kg M-CSF were administered and plasma samples were measured for M-CSF by bioassay. Systemic clearance decreased and the shape of the concentration-time curve changed with increasing dose, indicating nonlinear pharmacokinetics. At 10 mg/kg, two half-lives were initially observed, but after about 20 hr the plasma M-CSF suddenly declined with a steep slope. The rapidly declining phase suggested a saturable clearance mechanism that was prominent at low plasma concentrations of M-CSF (below 300 ng/ml) and obscured at high plasma concentrations of M-CSF. The rapid decline of plasma M-CSF occurred at earlier times with multiple daily injections of M-CSF, indicating induction of the saturable clearance mechanism. The rapidly declining phase was inhibited by carrageenan, indicating that saturable clearance might be due to metabolism of M-CSF by macrophages. With ligation of either the renal pedicles or ureters, the apparent half-lives of M-CSF increased by a factor of 2- to 3-fold, while the occurrence of the rapidly declining phase was delayed, but not eliminated. Overall, the results are well described by a two-compartment, first-order elimination model with a parallel Michaelis-Menten elimination pathway. First-order elimination is largely performed by the kidneys and the saturable Michaelis-Menten elimination pathway appears to be mediated by cells of the monocyte-macrophage lineage.

Animals↗
PubMed1992

Benzo[e]pyrene elicits changes in the biochemical activities and chromatographic behavior of murine hepatic cytochromes P-450 that are distinct from those induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The objective of this study was to examine the potential for a specific ligand of carcinogen binding protein (CBP) to induce changes in the overall character of hepatic microsomal cytochromes P-450 (P450) and to compare potential changes with those induced by an Ah receptor ligand. Benzo[e]pyrene (BeP) was previously shown to bind CBP with high affinity and Ah receptor with low affinity. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binds Ah receptor avidly and CBP weakly. Hepatic microsomes were prepared from C57BL/6J (B6) and DBA/2J (D2) mice treated with corn oil, BeP or TCDD. Relative to corn oil controls, pretreatment of B6 mice with BeP or TCDD increased the nmol P450/mg microsomal protein content 26 and 28%, respectively. In D2 mice, nmol P450/mg microsomal protein was increased 23% in the BeP pretreatment, while TCDD pretreatment had no effect relative to the corn oil controls. For the O-alkyl ethers of resorufin, rates of metabolism (per nmol P450) were affected differently in B6 and D2 by BeP pretreatment. Pentoxyresorufin O-dealkylase activity was reduced to 44% of control activity in B6 mice and increased 39% relative to controls in D2 mice. BeP pretreatment had no effect on ethoxyresorufin O-dealkylase activity in B6 mice, while this activity was decreased to 58% of controls in D2 mice. Additionally, benzyloxyresorufin O-dealkylase activity was reduced to 65% of control levels in B6 mice and not affected in D2 mice. Methoxyresorufin O-dealkylase activity was reduced in both strains to an average of 55% of control values. As expected, TCDD pretreatment resulted in increases of all O-dealkylations measured in both strains of mouse. For both inbred strains of mouse, anion exchange chromatography revealed a P450 peak associated with BeP pretreatment that was not present in chromatograms generated with corn oil or TCDD pretreatments. Results of enzyme linked immunosorbant assays also indicated that the pattern of P450 isoenzyme expression associated with BeP pretreatment was distinct from that associated with TCDD pretreatment. Overall, these data show that treatment with a specific ligand of CBP induces changes the biochemical activities and chromatographic behavior of P450 isozymes in murine hepatic microsomes. Moreover, they indicate that changes in P450 occurring after treatment with a CBP ligand are distinct from those changes that are associated with treatment with an Ah receptor ligand (TCDD). Differences between B6 and D2 strains suggest that the hepatic P450 changes occurring in response to pretreatment with a CBP ligand may be influenced by the presence of Ah receptor.

Animals↗
PubMed1991

Benzo[e]pyrene pretreatment of immature, female C57BL/6J mice results in increased bioactivation of aflatoxin B1 in vitro.

Hepatic microsomes were prepared from immature C57BL/6J mice 24 h after receiving intraperitoneal injections of either corn oil, benzo[e]pyrene (BeP, 50 mg/kg) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 4 x 10(-3) mg/kg). The capacity of these hepatic microsomes to bioactivate aflatoxin B1 (AFB1), 2-aminoanthracene (AA), benzo[a]pyrene (BaP), 3-methylcholanthrene (MC), 7,12-dimethylbenzanthracene (DMBA), BeP and pyrene (PY) was measured using strain TA100 in the Salmonella typhimurium/microsome reversion assay. BeP pretreatment of mice resulted in a 33% increase in mutagenic potency (MP) of AFB1 over the corn oil controls and a 70% increase in MP relative to TCDD-pretreated microsomes. With AA, BaP and DMBA as promutagens, BeP pretreatment reduced MP an average of 24%, while TCDD pretreatment increased MP of these 3 promutagens 263% compared to controls. Since the general effects of BeP and TCDD on murine hepatic cytochrome P-450 (P450)-mediated activities in this study were discordant, it appears that changes in P450 activity by BeP pretreatment are not mediated through the Ah receptor.

Aflatoxin B1↗
PubMed1987

Halothane and isoflurane only slightly impair arterial oxygenation during one-lung ventilation in patients undergoing thoracotomy.

Controversy exists as to whether the halogenated inhalation (IH) anesthetics impair arterial oxygenation during one-lung ventilation (1-LV). Accordingly, the authors have answered this question in 12 consenting patients who required 1-LV to facilitate the performance of thoracic surgery, by comparing arterial oxygenation during a prolonged period of IH anesthesia with arterial oxygenation during a prolonged period of intravenous (IV) anesthesia during stable 1-LV conditions. The patients were equally divided into halothane and isoflurane groups. Each patient in each IH anesthetic group underwent the following experimental sequence: step 1, two-lung ventilation (2-LV), 1 MAC IH anesthesia; step 2, 1-LV, 1 MAC IH anesthesia; step 3, 1-LV, iv anesthesia; step 4, 2-LV, iv anesthesia. Stable 1-LV conditions were proven by serial arterial blood gas measurement. Conversion from 2-LV to 1-LV during IH anesthesia (step 1 to step 2) caused a very large and significant decrease in PaO2 (from 484 +/- 49 to 116 +/- 61, and from 442 +/- 58 to 232 +/- 97 mmHg in the halothane and isoflurane groups, respectively) and increase in shunt (from 14 +/- 4 to 44 +/- 9, and from 19 +/- 5 to 31 +/- 8% in the halothane and isoflurane groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

A comparison of synthetic absorbable suture with synthetic nonabsorbable suture for construction of tracheal anastomoses.

This study compares the use of synthetic absorbable suture (SAS, Vicryl) with that of synthetic nonabsorbable suture (SNS, Ticron) for construction of cervical tracheal anastomoses in the dog. Fourteen mongrel dogs underwent resection of one to four tracheal rings. Paired tracheal anastomoses were constructed, using 10 SAS or 10 SNS. After two months each anastomosis was removed and analyzed. All animals survived with intact anastomoses. There were no visible reactions to the SAS. Twenty-six of 70 SNS developed gross suture granulations. Significant stenosis developed in one of seven SAS and in four of seven SNS anastomoses. Histologic examination revealed no residual inflammatory reaction in the SAS specimens, while the SNS demonstrated a spectrum of inflammatory response that directly correlated in intensity with the gross appearance. These findings support the continued evaluation for the use of SAS in clinical tracheobronchoplastic procedures.

Animals↗
PubMed1981

Computerized tomographic diagnosis of paracardiac masses.

Paracardiac masses may alter the cardiac contour seen on roentgenograms of the chest so as to mimic configurations associated with cardiac disease. Recently, the use of computerized transmission tomography has proved valuable as a noninvasive method of distinguishing between intrinsic cardiac disease and paracardiac masses. In some cases, the procedure obviates the need for preoperative cardiac catheterization.

Adolescent↗