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Biomedical subjects

L D Lewis

Publications and source records attributed to L D Lewis.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1993

Reconceptualizing the psychiatric head nurse role.

The increasing complexity and specialization of psychiatric services mandate changes in the management of people and the delivery of health care. These changes have occurred simultaneous with significant progress in the discipline of psychiatric nursing and its evolvement into expanding areas of clinical expertise, higher levels of education, and growing sophistication in research. Such significant changes require that the role of the psychiatric head nurse be reexamined and reformulated to facilitate its alignment with the current realities of the health care environment. Important considerations in redesigning the psychiatric head nurse role are identified, and an actualization of the new role in one inpatient setting is described.

Education, Nursing, Continuing↗
PubMed1993

A study of self poisoning with oral salbutamol--laboratory and clinical features.

1. The recent increase in asthma mortality coupled with reports of fatal asthma associated with beta-2-agonist therapy, has stimulated interest in the plasma concentrations of beta-2-agonists that produce systemic toxicity. 2. We prospectively studied 17 patients (9 male), mean age 23 years (range 2-72), who attended the emergency departments of hospitals throughout the United Kingdom having recently ingested an overdose of salbutamol. 3. Clinical, laboratory, ECG data, plasma and urine samples were obtained from each patient. Plasma was assayed for salbutamol concentration using a high performance TLC-photodensitometric method. 4. The mean (+/- s.d.) salbutamol dose reported to have been ingested was 89(+83)mg and the mean plasma salbutamol concentration was 166 (range 18-449) ng ml-1. The mean plasma potassium was 2.9 (s.d. +/- 0.6) mM (n = 16). None of the patients in this study developed serious cardiac dysrrhythmias. 5. There were significant correlations between the plasma salbutamol concentration and plasma potassium concentration (r = -0.85; P < 0.00005) and between plasma salbutamol concentration and pulse rate (r = 0.66; P < 0.005). 6. We conclude that in these patients, without respiratory decompensation, suprapharmacological plasma concentrations of salbutamol were tolerated without serious cardiac arrhythmias or any fatalities.

Adolescent↗
PubMed1992

Uroepithelial and nephrotubular toxicity in patients receiving ifosfamide/mesna: measurement of urinary N-acetyl-beta-D-glucosaminidase and beta-2-microglobulin.

The effect of three ifosfamide/mesna regimens on urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and beta-2-microglobulin (beta 2 M) was studied. All regimens produced significant increases in these urinary proteins, indicating nephrotubular damage. In regimen A (n = 15), plasma nitrobenzylpyridine (NBP) alkylating activity area under the curve (AUC) on day 1 correlated with the percentage increase above baseline of maximum urinary NAG activity (r2 = 0.538, P = 0.0022) and maximum beta 2 M concentration (r2 = 0.413, P = 0.0097). In regimen B (n = 5), plasma NBP alkylating activity AUC correlated with the percentage increase above baseline of maximum NAG activity (r2 = 0.843, P = 0.03) and beta 2 M (r2 = 0.78, P = 0.046). In these two regimens the renal exposure to ifosfamide metabolites correlated with the increases in urinary NAG and beta 2 M. The relation of these urinary protein abnormalities to longer term effects on renal function with different ifosfamide/mesna schedules requires further study.

Acetylglucosaminidase↗
PubMed1992

Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure.

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodeficiency virus (HIV)-infected patients would be extremely useful in the more appropriate utilization of ZDV in the treatment of HIV infection. We developed a specific and sensitive combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) procedure for the determination of ZDV, ZDV-monophosphate, ZDV-diphosphate, and ZDV-triphosphate in PBMCs taken from ZDV-treated HIV-infected patients. ZDV and its anabolites were extracted from washed, Ficoll-Paque-isolated PBMCs and then separated by HPLC using a strong anion-exchange column. The anabolites were then hydrolyzed to ZDV with acid phosphatase. ZDV was then measured by using a modified commercially available RIA protocol. Our method was validated by measuring [3H]ZDV anabolites generated in Molt-4 cells radioisotopically and simultaneously by the combined HPLC-RIA procedure. The ZDV determinations correlated well (r2 = 0.97) over the range of 0.037 to 5.2 pmol (10 to 1,400 pg) per assay tube. Furthermore, we defined the stability of ZDV anabolites during ficoll isolation and the recovery after extraction and cleanup. We then measured intracellular parent ZDV and its phosphorylated anabolites in PBMCs from six ZDV-treated HIV-infected patients (PBMCs were taken 2 h after a 300-mg oral dose). The mean concentrations ( +/- standard deviations) of parent and of mono-, di-, and triphosphates were 0.15 +/- 0.08, 1.4 +/-, 0.082 +/- 0.02, and 0.081 +/- 0.03 pmol/10(6) PBMC, respectively (one pmol/10(6) PBMC represents a concentration of approximately 1 microm). Concurrent serum ZDV concentrations were between 1.3 and 7.1 microm. This method should provide a useful tool for evaluating in vivo pharmacokinetics of ZDV anabolites in PBMCs and possibly other cell types, even at the low doses of ZDV currently administered therapeutically.

Cells, Cultured↗
PubMed1992

Ultrastructural changes associated with reduced mitochondrial DNA and impaired mitochondrial function in the presence of 2'3'-dideoxycytidine.

Incubation of Molt-4 cells in 4 microM 2'3'-dideoxycytidine did not produce a significant change in the mitochondrial ultrastructure after 4 days; however, by 12 days, the mitochondrial ultrastructure was distorted, with condensed cristae or vacuolization, or both. Concentration-dependent decreases in both cell growth (mean 50% inhibitory concentration, 4.70 +/- 0.5 microM) and mitochondrial DNA content (mean 50% inhibitory concentration, 0.46 +/- 0.06 microM) occurred after incubation with 2'3'-dideoxycytidine for 4 days.

Cells, Cultured↗
PubMed1991

Ifosfamide pharmacokinetics.

This review examines and details the pharmacokinetics of ifosfamide (a congener of cyclophosphamide) when administered by a number of commonly used chemotherapeutic regimes. The influence of route of administration, schedule of administration and dose on the pharmacokinetics of ifosfamide and its metabolites are discussed. Oral fractionated ifosfamide therapy, which causes an excessively high incidence of neurotoxicity, is similar to intravenous fractionated therapy in that it exhibits a time dependent increase in ifosfamide metabolic clearance. Five g/m2 ifosfamide given intravenously as a short (half hour) or long (24 hr) infusion does not exhibit dose dependent (zero-order) pharmacokinetics. In patients who develop ifosfamide/mesna associated CNS toxicity the pharmacokinetics of parent ifosfamide are not aberrant. This implies that ifosfamide metabolites are more likely to be responsible for the neurotoxicity rather than the parent drug. The development of simple and more specific analytical methodology, will allow further studies of the pharmacokinetics of the active ifosfamide metabolite(s). This may lead to further optimisation of the therapeutic index of ifosfamide treatment.

Administration, Oral↗
PubMed1991

Concomitant Creutzfeldt-Jakob and Alzheimer diseases.

We report a 69-year-old female with cerebral and cerebellar symptomatology of 15-month duration. At autopsy, both panencephalopathic Creutzfeldt-Jakob and plaque-predominant Alzheimer diseases were found. Plaque amyloid was exclusively of the beta/A4 type, but abundant abnormal protease-resistant protein was identified by Western blot analysis of brain extracts.

Aged↗
PubMed1991

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

1. We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens. Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2. After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t1/2,z of 5.4 h (3.6-10.4 h). The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-1. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-1. 3. When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t1/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effects of dietary fiber supplementation on glycemic control in dogs with alloxan-induced diabetes mellitus.

The effect of a high insoluble-fiber (IF) diet containing 15% cellulose in dry matter, high soluble-fiber (SF) diet containing 15% pectin in dry matter, and low-fiber (LF) diet on glycemic control in 6 dogs with alloxan-induced insulin-dependent diabetes mellitus was evaluated. Each diet contained greater than 50% digestible carbohydrate in dry matter. A crossover study was used with each dog randomly assigned to a predetermined diet sequence. Each dog was fed each diet for 56 days. Caloric intake was adjusted weekly as needed to maintain each dog within 1.5 kg of its body weight measured prior to induction of diabetes mellitus. All dogs were given pork lente insulin and half of their daily caloric intake at 12-hour intervals. Mean (+/- SEM) daily caloric intake was significantly (P less than 0.05) less when dogs consumed the IF diet vs the SF and LF diets (66 +/- 3 kcal/kg, 81 +/- 5 kcal/kg, and 79 +/- 4 kcal/kg, respectively). Serum alkaline phosphatase activity was significantly (P less than 0.05) higher when dogs consumed the LF diet vs the IF and SF diets (182 +/- 37 IU/L, 131 +/- 24 IU/L, and 143 +/- 24 IU/L, respectively). Mean postprandial plasma glucose concentration measured every 2 hours for 24 hours, beginning at the time of the morning insulin injection, was significantly (P less than 0.05) lower at most blood sampling times in dogs fed IF and SF diets, compared with dogs fed the LF diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗