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Biomedical subjects

L D Lewis

Publications and source records attributed to L D Lewis.

At least 19 recordsLinked to original sources
PubMed2001

Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo.

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcgammaR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNgamma. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcgammaRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-gamma (IFNgamma) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcgammaRI after being treated with IFNgamma, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.

Animals↗
PubMed2001

Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/neu.

INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a dose escalation study of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcutaneous IFNgamma (50 microg/m(2) to up-regulate FcgammaRI) administered three times a week for 3 weeks. We investigated the pharmacokinetic-pharmacodynamic relationships between MDX-H210 C(max) and AUC and (i) MDX-H210 binding to peripheral blood monocytes and neutrophils, (ii) the peak plasma G-CSF, IL-6, IL-8 and TNFalpha concentrations, and (iii) the observed clinical toxicity. RESULTS: 23 patients (19F:4M; median age 51.5; range 25-72 y) with advanced HER-2/neu positive cancers (19 breast, three prostate and one lung) were studied. Plasma MDX-H210 concentrations over time, circulating numbers of monocytes and neutrophils, percent saturation of monocyte and neutrophil FcgammaRI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNFalpha were measured and clinical toxicity monitored. The E(max) pharmacodynamic model best fitted the relationship of MDX-H210 C(max) and the maximum percent saturation of both monocytes (E(max)=74.6; EC(50)=0.9 microg/ml) and neutrophils (E(max)=66.2; EC(50)=2.3 microg/ml) on the first day of treatment. On the last day of treatment, day 19, these parameters were E(max)=57.0% and EC(50)=0.46 microg/ml for monocytes and E(max)=61.9% and EC(50)=0.26 microg/ml for neutrophils. No positive relationship was defined between the log MDX-H210 C(max) and the log peak plasma IL-6, G-CSF, TNF or IL-8 concentrations on day 1. On day 19 these plasma cytokine concentrations were undetectable post MDX-H210 therapy. There was no consistent relationship between MDX-H210 C(max) and the observed clinical toxicities. CONCLUSIONS: These data suggest that MDX-H210 C(max) and AUC could be related by the E(max) model to maximum percent FcgammaRI saturation on circulating monocytes and neutrophils in the patients studied. After day 1, the post MDX-H210 therapy cytokine response attenuated over time, consistent with desensitization. We did not find a relationship between log MDX-H210 C(max) and peak plasma cytokine concentrations or clinical toxicities.

Adult↗
PubMed2000

Visualization of intravenously administered contrast material in the CSF on fluid-attenuated inversion-recovery MR images: an in vitro and animal-model investigation.

BACKGROUND AND PURPOSE: The FLAIR (fluid-attenuated inversion-recovery) pulse sequence has been shown to be sensitive to abnormalities of the subarachnoid space. Our clinical experience led us to investigate whether intravenously injected contrast material can affect the appearance of the subarachnoid space on FLAIR MR images. METHODS: After noting unexplained high signal in the subarachnoid space on FLAIR images in a patient, we studied two dogs with sequential FLAIR MR imaging after i.v. administration of contrast material. A third dog was studied with a 6-hour delayed FLAIR sequence after triple-dose (0.3 mmol/kg) i.v. contrast administration. CSF was obtained from two animals for measurement of gadolinium concentration. A phantom was developed to determine the lowest concentration at which the effects of gadolinium were evident on FLAIR images in vitro. RESULTS: In all three animals, the appearance of the CSF in the ventricles or subarachnoid space was modified after administration of i.v. contrast. This was most evident on delayed images. The CSF samples showed a gadolinium concentration of 0.007 mmol/L in the dog who received the 0.1 mmol/kg dose and 0.02 mmol/L in the dog who received a triple dose. In our in vitro phantom experiments, gadolinium effects were evident on FLAIR images at a concentration four times lower than those on T1-weighted images. CONCLUSION: I.v. contrast material can cross into the CSF in sufficient concentration to alter the appearance of the subarachnoid space on FLAIR images in normal dogs. Although we encountered two patients with CNS disease in whom enhancement of the CSF was seen on postcontrast FLAIR images, additional investigation is needed in humans to determine whether enhancement may occur at triple dose in healthy subjects.

Aged↗
PubMed1999

Noradrenergic modulation of cognitive flexibility in problem solving.

Stress causes impaired performance on tests of creativity. Drugs that block beta-adrenergic receptors improve test performance in patients with test anxiety. Furthermore, catecholamine precursors (L-DOPA) reduce the flexibility of semantic networks. Our study investigated the effect of noradrenergic system modulation on cognitive flexibility in problem solving. Eighteen normal subjects undertook three problem solving tasks (number series, shape manipulation and anagrams) 45 min after propranolol, placebo and ephedrine. On the task that appeared to rely most heavily on cognitive flexibility (anagrams), subjects who were most able to solve these problems demonstrated significantly shorter solution times (logarithmic scores) after propranolol than after ephedrine. This suggested that the noradrenergic system exerts a modulatory effect on cognitive flexibility in problem solving.

Adolescent↗
PubMed1999

Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173.

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia (>20%) was seen in 3 of 6 study subjects who received 150 mg/day for > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.

AIDS-Related Opportunistic Infections↗
PubMed1998

Induction of cytochrome P4503A by taxol in primary cultures of human hepatocytes.

In primary cultures of human hepatocytes, paclitaxel (Taxol), at pharmacological concentrations, was demonstrated to induce immunoreactive cytochrome P4503A (CYP3A). The magnitude of the inductive response of the hepatocytes to Taxol varied in five separate cultures. In general, exposure to increasing concentrations of Taxol (0.2 to 10 microM) resulted in increases in immunoreactive CYP3A. In four of the cultures, treatment of hepatocytes with the lowest concentration of Taxol tested (0.2 microM) resulted in approximately two-fold increases in CYP3A. In the other culture, however, a six-fold increase in CYP3A was observed at 0.2 microM. Taxol was almost as effective as rifampicin in inducing CYP3A in two of the cultures, but less effective than rifampicin in two other cultures. CYP3A4 mRNA was increased by Taxol. Increases in CYP3A4 mRNA correlated with increases in the levels of immunoreactive CYP3A. These results demonstrate that Taxol is a potent inducer of CYP3A in human hepatocytes. The clinical significance of these findings is discussed.

Adolescent↗
PubMed1997

Effect of Taxol on cytochrome P450 3A and acetaminophen toxicity in cultured rat hepatocytes: comparison to dexamethasone.

The purpose of this study was to determine if Taxol induced CYP3A in primary cultures of rat hepatocytes and, if so, whether induction of CYP3A would increase acetaminophen toxicity. Taxol caused a concentration-dependent increase in the amount of immunoreactive CYP3A and in the steady-state levels of CYP3A1/DEX but not CYP3A2 mRNA. Similar concentration-dependent increases in toxicity as measured by a decrease in protein synthesis were observed after exposure of cells to acetaminophen for 7 hr whether cells were pretreated with Taxol or dexamethasone. Increased release of lactate dehydrogenase occured after 24 hr exposure to acetaminophen, with no further decreases in protein synthesis than those observed at 7 hr. Increases in acetaminophen toxicity correlated with increased covalent binding of acetaminophen to cellular proteins. Triacetyloleandomycin, a selective inhibitor of CYP3A, completely protected the cells against acetaminophen toxicity in both Taxol- and dexamethasone-pretreated cells and prevented the increase in covalent binding of acetaminophen to cellular proteins. These results demonstrate that Taxol, like dexamethasone, induces CYP3A and that increases in this P450 are responsible for increased acetaminophen toxicity.

Acetaminophen↗
PubMed1997

Delayed sequelae after acute overdoses or poisonings: cranial neuropathy related to ethylene glycol ingestion.

A 31-year-old woman came to the hospital with breathlessness, confusion, and a refractory anion gap metabolic acidosis; acute renal failure subsequently developed. Her blood ethylene glycol concentration was 390 mg/L, and she was treated with an intravenous ethanol infusion and hemodialysis. During the tenth and eleventh day after admission bilateral seventh cranial nerve paralysis developed, as well as bilateral dysfunction of cranial nerves II, V, VIII, IX, X and XII. Magnetic resonance imaging of her head showed gadolinium enhancement of the fifth cranial nerve bilaterally and a communicating hydrocephalus. Over the subsequent 11 months she recovered full function of her cranial nerves V, VII, IX, X, and XII, and she had subjective clinical improvement to baseline function in cranial nerves II and VIII. This case serves to introduce a discussion of agents that cause delayed complications after their acute toxic ingestion.

Adult↗
PubMed1997

Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Adolescent↗
PubMed1997

A study of the effects of sumatriptan on myocardial perfusion in healthy female migraineurs using 13NH3 positron emission tomography.

Sumatriptan, a 5-HT1D receptor agonist, is believed to alleviate migraine attacks by extracerebral vasoconstriction. Chest pain associated with myocardial ischemia may occur after sumatriptan administration. We investigated the effect of a single 6-mg subcutaneous dose of sumatriptan on myocardial perfusion (MP) as measured by 13NH3 positron emission tomography (PET) in a randomized, double-blind, placebo-controlled, crossover trial at the Clinical PET Centre, Guy's and St. Thomas' Hospitals, London. Nineteen volunteer female migraineurs, age range 33 to 62 years, at low risk for ischemic heart disease were included. All bad undergone previous treatment with oral or intravenous sumatriptan. Patients were recruited by advertisement and referral from local neurology specialists. Each volunteer underwent two scanning sessions. On each occasion, a baseline dynamic 13NH3 PET scan was acquired followed by a 13NH3 PET scan 10 minutes after subcutaneous injection of placebo or 6 mg of sumatriptan. Regional MP was measured in five myocardial regions using the Patlak system of image analysis. The mean % change from baseline (+/-SD) in global MP after placebo was +9.5% +/- 18.0 and after sumatriptan was +6.6% +/- 18.8 (repeated measures ANOVA for treatment effect p = 0.56). There were no significant differences in MP changes from baseline observed in any of the five myocardial regions (treatment p = 0.32 to 0.84). These data suggest that in healthy female migraineurs, a single 6-mg subcutaneous dose of sumatriptan does not cause a significant change in regional or global myocardial perfusion.

Adult↗
PubMed1997

The role of polymorphonuclear neutrophils (PMNs) in clearance of granulocyte colony-stimulating factor (G-CSF) in vivo and in vitro.

Previous studies have suggested that in vivo granulocyte colony-stimulating factor (G-CSF) pharmacokinetics may change over time. We studied three patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) for metastatic breast cancer after intravenous administration of recombinant human (rh) G-CSF (5 or 16 microg/kg/day). We investigated plasma G-CSF concentrations and absolute neutrophil counts (ANCs/pL) in these patients on three separate days. G-CSF plasma clearance increased with time post-ABMT with no change in the apparent volume of distribution (Vd) of G-CSF. Regression analysis of G-CSF plasma clearance and ANCs revealed a linear relationship, with r2 = 0.85 (p = 0.00025). We further investigated this phenomenon in vitro by estimating pharmacokinetic parameters for rhG-CSF using a model in which polymorphonuclear neutrophils (PMNs) were incubated with rhG-CSF. We found that, at low G-CSF concentrations in vitro, there was an increase in G-CSF clearance with increasing ANCs, but at higher G-CSF concentrations this relationship did not hold. We suggest that this finding resulted from aggregation and polymerization of G-CSF at high concentrations when kept at 37 degrees C for 24-48 hours in vitro. Using fluorescence staining techniques, our data suggest there are changes over time in the amount of G-CSF bound to PMNs. These changes may reflect reexpression or recycling of the G-CSF receptor, and could explain the continuing clearance of G-CSF by PMNs in vitro. The strong positive correlation between G-CSF plasma clearance and ANCs in vivo is compatible with the hypothesis that neutrophils mediate one of the major pathways for rhG-CSF clearance.

Bone Marrow Transplantation↗
PubMed1996

A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles.

1. Ifosfamide demonstrates increased clearance with time when administered daily for 5 days. The objectives of this study were to define whether the increased ifosfamide clearance was sustained between treatment cycles and whether it was reproducible in consecutive treatment cycles. 2. Seven patients with inoperable cancer received 1.5 g m-2 ifosfamide infused intravenously over 0.5 h, each day for 5 days, for two consecutive cycles. Urine and appropriately timed blood samples were collected for up to 24 h post ifosfamide infusion on day 1 and day 5. Plasma ifosfamide concentrations were assayed by gas liquid chromatography and pharmacokinetic parameters were imputed using non-compartmental analysis. 3. The difference in the mean (n = 7) total ifosfamide plasma clearance between day 5 and day 1 of Cycle I was an increase of 56.8 ml min-1 (99.8% CIs + 22.6-->+ 91.4). The difference in the mean (n = 7) total ifosfamide plasma clearance between day 1 of Cycle II and day 5 was a decrease of 61.9 ml min-1 (99.8% CIs -111.2 -->-12.6). The magnitude of the mean increase in total ifosfamide plasma clearance in Cycle II and Cycle I was similar because the difference between these means (0.9 ml min-1, 99.8% CIs -63.7-->+65.3) was not statistically significant. There was no change in the apparent volume of distribution of ifosfamide between the two study days in either of Cycle I or II, or between cycles. 4. The difference in the mean (n = 7) ifosfamide renal clearance between day 5 and day 1 of Cycle I was minus 0.4 ml min-1 (99.8% CIs -8.5-->+8.6); the means +/- s.d. wee 6.3 +/- 2.6 ml min-1 and 6.7 +/- 3.2 ml min-1 respectively. The difference in the mean (n = 4) ifosfamide renal clearance between day 5 and day 1 of Cycle II was -0.2 ml min-1 (99.8% CIs -5.7-->+5.2); the means +/- s.d. were 7.8 +/- 6.1 ml min-1 and 8.0 +/- 6.2 ml min-1 respectively. 5. These data suggest that the increase in total ifosfamide plasma clearance with time in a 5 day fractionated regimen was due to an increase in ifosfamide metabolism which was not sustained over the 21 days between cycles, but was reproducible and of a similar magnitude in the two consecutive treatment cycles studied.

Adult↗
PubMed1995

Clinical trials of bispecific antibody MDX-210 in women with advanced breast or ovarian cancer that overexpresses HER-2/neu.

MDX-210 is a bispecific antibody (BsAb) that recognizes Fc gamma R1 on monocytes and macrophages and the cell surface product of the HER-2/neu oncogene, which is overexpressed on some breast and ovarian cancers. Clinical trials have demonstrated that treatment with MDX-210 is well tolerated and that MDX-210 is both immunologically and clinically active. Optimization of the dose and schedule of MDX-210 and development of combination treatments with cytokines that modulate immune effector cells will greatly enhance the efficacy of this novel BsAb construct for treatment of tumours that overexpress HER-2/neu. We envision that MDX-210 will be effective for treating patients with tumors that overexpress HER-2/neu, especially in the minimal disease setting.

Antibodies, Anti-Idiotypic↗
PubMed1995

Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.

PURPOSE: MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. PATIENTS AND METHODS: Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2. RESULTS: Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. CONCLUSION: MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.

Adult↗