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Biomedical subjects

W E Miller

Publications and source records attributed to W E Miller.

At least 55 records · Page 3Linked to original sources
PubMed1997

2-chlorodeoxyadenosine administration to patients with the myeloid blast phase of chronic myelogenous leukemia.

Three patients with chronic myelogenous leukemia (CML) in myeloid blast phase received 2-chlorodeoxyadenosine (2-CdA) at 0.7 mg/kg per course over 5 days every 2-4 weeks for 7, 2 and 5 courses. Each patient had a decrement in their white blood cell count, and in the absolute number and percentage of circulating immature cells following 2-CdA administration. Two patients achieved hematologic responses of 14 and 3 months and survived 19 and 6 months, respectively, while the non-responder died 2 months later. 2-CdA-induced anemia and thrombocytopenia, generally mild and reversible, were observed in all patients. Given the dismal results and considerable toxicities that follow multiagent induction chemotherapy for CML in myeloid blast phase, 2-CdA therapy may represent a reasonable therapeutic alternative, although confirmation is required in larger numbers of patients.

Aged↗
PubMed1996

Prolonged, complete remission after 2-chlorodeoxyadenosine therapy in a patient with refractory essential mixed cryoglobulinemia.

Essential mixed cryoglobulinemia is a systemic disorder in which cutaneous vasculitis and frequently glomerulonephritis are associated with cryoprecipitable serum immune complexes. Typically, the treatment regimen consists of plasmapheresis, high-dose corticosteroids, and cytotoxic chemotherapy, as well as interferon alfa for hepatitis C virus-related cryoglobulinemia. Herein we describe a man with progressive, symptomatic cryoglobulinemia and multisystem organ dysfunction in whom corticosteroid and alkylating therapy failed; however, he had a complete and long-lasting remission after administration of 2-chlorodeoxyadenosine (cladribine).

Aged↗
PubMed1996

Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene.

Two Epstein-Barr virus (EBV)-associated malignancies, nasopharyngeal carcinoma and posttransplant lymphoma, rarely have mutations in the p53 tumor suppressor gene, suggesting that a viral protein interferes with p53 function. The EBV oncogene, LMP1, induces expression of the cellular antiapoptotic genes bcl-2 and A20 and could in this way interfere with p53-mediated apoptosis. Two derivatives of the p53-null epithelial cell line H1299 were prepared, one of which (H1299-p53) stably expressed a temperature-sensitive (ts) p53 protein, and another (H1299-p53+LMP1) which stably expressed both ts-p53 and latent membrane protein 1 (LMP1). At the permissive temperature, the p53 protein in the H1299-p53 cell line transcriptionally activated two of its target genes, the cyclin-dependent kinase inhibitor p21 and the mdm2 gene product, in an LMP1-independent manner. Upon serum withdrawal at the permissive temperature, p53-mediated apoptosis was induced in 50 to 60% of the cells. In the H1299-p53 cell line which stably expressed LMP1, however, only 20 to 25% of the cells underwent apoptosis. While stable expression of LMP1 did not affect levels of bcl-2 family members in these cells, it did induce expression of A20. Stable expression of A20 in the H1299-p53 cell line inhibited p53-mediated apoptosis equivalent to inhibition by LMP1. The induction of A20 may underlie the ability of LMP1 to protect EBV-infected epithelial cells from p53-mediated apoptosis.

Animals↗
PubMed1996

Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy.

PURPOSE: This study was designed to evaluate the absolute bioavailability (F value) of 2-chlorodeoxyadenosine (cladribine; 2-CdA) after multiple oral administrations, and the intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients with malignancy. PATIENTS AND METHODS: Patients with advanced malignancies were eligible. There were two treatment cycles; during cycle 1, patients received 2-CdA solution at 0.28 mg/kg/d orally under fasting conditions for 5 consecutive days concomitantly with omeprazole, and 4 weeks later during cycle 2 patients received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood samples for 2-CdA plasma levels were obtained after drug administrations on days 1 and 5 during each treatment cycle. RESULTS: Ten patients completed cycles 1 and 2. The F value of oral 2-CdA measured on days 1 and 5 was 37.2% and 36.7%, respectively. For both oral and IV multiple administrations, there was no significant accumulation in maximum concentration (Cmax), and the intersubject variabilities (coefficient of variation [CV], approximately 40%) in Cmax and area under the concentration-time curve from 0 to 24 hours [AUC(0-24)] values were comparable for both routes on days 1 and 5. A three-compartment open model was applied to the plasma concentration data after oral and IV administrations and resulted in good agreement between observed and simulated concentration-time profiles. Neutropenia was the principal adverse event observed when 2-CdA was administered orally and IV. CONCLUSION: The F value of 2-CdA after oral administration was approximately 37% and there were no cumulative differences in bioavailability observed on multiple dosing of the drug. The absorption and disposition characteristics of oral 2-CdA were linear and predictable with this dosing regimen.

Administration, Oral↗
PubMed1996

Mobilized peripheral blood progenitor cells (PBPC) in support of tandem cycles of high-dose chemotherapy (HDC).

We evaluated the efficacy, toxicity and feasibility of two cycles of high-dose chemotherapy (HDC), each supported with mobilized peripheral blood progenitor cells (PBPC). Ninety-six patients with metastatic or high-risk cancers received disease-specific HDC regimens. The first cycle consisted of cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2 and carboplatin 1200 mg/m2. Alternatively, some patients received etoposide 1800 mg/m2 substituted for thiotepa. A second cycle was planned 6-8 weeks later and consisted of mitoxantrone 60 mg/m2 with either melphalan 140 mg/m2 or thiotepa 600 mg/m2. PBPC were mobilized with either growth factor alone or cyclophosphamide followed by growth factor(s). Thirty-four of 96 enrolled patients (35%) did not receive the second cycle. The reasons were: patient refusal (15); insurance refusal (three); toxicities of cycle 1 (seven); no response to cycle 1 (four); and inadequate mobilization or poor engraftment, (five). Of the 33 patients who entered cycle 2 with measurable disease, 28 demonstrated further response after cycle 2 (including 10 who entered CR). One patient died of toxicity after each cycle. Hematologic recovery was rapid and complete in most patients. Tandem cycles of high-dose chemotherapy supported by PBPC are feasible and safe, although many patients fail to receive the second treatment. Preliminary evaluation shows evidence of further antitumor efficacy following cycle 2.

Adult↗
PubMed1995

The Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor.

The Epstein-Barr virus (EBV)-encoded LMP1 protein is an important component of the process of transformation by EBV. LMP1 is essential for transformation of B lymphocytes, most likely because of its profound effects on cellular gene expression. Although LMP1 is expressed in the majority of nasopharyngeal carcinoma (NPC) tumors, the effect of LMP1 on cellular gene expression and its contribution to the development of malignancy in epithelial cells is largely unknown. In this study the effects of LMP1 on the expression and tyrosine kinase activity of the epidermal growth factor receptor (EGFR) were investigated in C33A human epithelial cells. Stable or transient expression of LMP1 in C33A cells increased expression of the EGFR at both the protein and mRNA levels. In contrast, expression of the EGFR was not induced by LMP1 in EBV-infected B lymphocytes. Stimulation of LMP1-expressing C33A cells with epidermal growth factor (EGF) caused rapid tyrosine phosphorylation of the EGFR (pp170) as well as several other proteins, including pp120, pp85, pp75, and pp55, indicating that the EGFR induced by LMP1 is functional. LMP1 also induced expression of the A20 gene in C33A epithelial cells. In C33A cells, LMP1 expression increased the proliferative response to EGF, as LMP1-expressing C33A cells continued to increase in number when plated in serum-free media supplemented with EGF, while the neo control cells exhibited very low levels of viability and did not proliferate. Immunoblot analysis of protein extracts from nude mouse-passaged NPC tumors also demonstrated that the EGFR is overexpressed in primary NPC tumors as well as those passaged in nude mice. This study suggests that the alteration in the growth patterns of C33A cells expressing LMP1 is a result of increased proliferative signals due to enhanced EGFR expression, as well as protection from cell death due to LMP1-induced A20 expression. The induction of EGFR and A20 by LMP1 may be an important component of EBV infection in epithelial cells and could contribute to the development of epithelial malignancies such as NPC.

Cell Division↗
PubMed1994

Sequence variation in the Epstein-Barr virus latent membrane protein 1.

The sequence of the latent membrane protein 1 (LMP-1) gene was analysed in Epstein-Barr virus (EBV) isolates from specific regions representing both type 1 and type 2 EBV. A predominant strain marked by an XhoI restriction enzyme polymorphism (REP) within the LMP-1 gene has been identified in type 1 EBV in nasopharyngeal carcinoma (NPC) from Southern China. This polymorphism was also present in type 2 EBV in NPC from Alaska. In this study, the sequence of the LMP-1 gene was determined in these samples representing type 1 and type 2 EBV and was compared with the prototype lymphoid strains. Consistent nucleotide variation in the amino terminus of LMP-1 was identified in strains marked by the XhoI REP. These changes were present in both EBV type 1 and type 2 strains. Three types of sequence variation were detected in the carboxy terminus of LMP-1. The LMP-1 sequences differed in the number of an 11 amino acid repeat element. In the prototype EBV type 1 (B95-8) sequence and in the type 1 Raji and type 2 HR-1 strains, the third repeat element contained an insertion of 5 amino acids that were also the first five unique amino acids after the last partial repeat element. The third variation was a deletion of amino acids 343 to 352 of the B95-8 LMP-1. This deletion was detected in the type 1 Chinese EBV strains, but was not detected in the type 2 Alaskan strains although the Chinese and Alaskan strains have nearly identical amino acid changes at the amino terminus. Numerous other amino acid changes were detected in the carboxy terminus which did not cosegregate with either EBV type, amino acid changes in the amino terminus, or specific geographic regions. These data indicate that EBV strains can be distinguished by sequence differences within LMP-1 and that unlike the divergence between type 1 and type 2 EBV in Epstein-Barr nuclear antigen sequences, different EBV types are nearly identical in LMP-1 sequence.

Amino Acid Sequence↗
PubMed1992

Twenty-four hour blood pressure effect of once-daily lisinopril, enalapril, and placebo in patients with mild to moderate hypertension.

This multicentre, double-blind, parallel-group, placebo-controlled study compared the antihypertensive effects of equal doses of two long-acting angiotensin converting enzyme (ACE) inhibitors. After a two-week, placebo run-in phase, 110 patients with mild to moderate hypertension were randomised to receive 10 mg lisinopril or enalapril, or placebo for 4 weeks. Office BPs were measured at regular intervals throughout the study. Twenty-four hour ambulatory blood pressure (ABP) was measured at baseline and after the first and final doses of study drug. Serum ACE activity and aldosterone were obtained concomitantly with each ABP monitoring. Office BP differences from placebo reached (P less than 0.05) or approached (P less than 0.10) statistical significance at all observations for the lisinopril group but were not significant for any observation in the enalapril group and approached significance on two occasions. After four weeks of treatment, ABP analysis revealed that the lisinopril and enalapril groups, when compared with placebo, had similar and significant systolic and diastolic AUC reductions (P less than 0.01) from baseline over the 24 h dosing interval. During the second half of the dosing interval, 13-24 h post drug administration, the lisinopril group was significantly different from placebo (systolic BP, P = 0.002; diastolic BP, P = 0.005) while the enalapril group was not. Both drugs were well tolerated. The results indicate that monotherapy with 10 mg of lisinopril is as effective as with 10 mg of enalapril, and that ABP monitoring is useful in more precisely depicting the clinical effect of the known pharmacokinetic properties of these two agents.

Adult↗
PubMed1991

Screening for lung cancer. A critique of the Mayo Lung Project.

The National Cancer Institute of the United States recently sponsored three large-scale, randomized controlled trials of screening for early lung cancer. The trials were conducted at the Johns Hopkins Medical Institutions, the Memorial Sloan-Kettering Cancer Center, and the Mayo Clinic. Participants were middle-aged and older men who were chronic heavy cigarette smokers and thus at high risk of developing lung cancer. Screening procedures were chest radiography and sputum cytology, the only screening tests of established value for detecting early stage, asymptomatic lung cancer. In the Hopkins and Memorial trials the study population was offered yearly chest radiography plus sputum cytology every 4 months. The control population was offered yearly chest radiography only. In these trials the addition of sputum cytology appeared to confer no lung cancer mortality rate advantage. The Mayo Clinic trial compared offering chest radiography and sputum cytology every 4 months to offering advice that the two tests be obtained once a year. This trial demonstrated significantly increased lung cancer detection, resectability, and survivorship in the group offered screening every 4 months compared with the control group. However, there was no significant difference in lung cancer mortality rate between the two groups. The statistical power of these trials was somewhat limited. Nevertheless, results do not justify recommending large-scale radiologic or cytologic screening for early lung cancer at this time.

Clinical Trials as Topic↗
PubMed1990

Once-daily lisinopril compared with twice-daily captopril in the treatment of mild to moderate hypertension: assessment of office and ambulatory blood pressures.

This multicenter, double-blind, parallel-group study compared the antihypertensive effects of two angiotensin-converting enzyme inhibitors, lisinopril and captopril, in 70 patients (35 lisinopril, 35 captopril) with mild-to-moderate essential hypertension. Doses of 10, 20, and 40 mg once-daily lisinopril or 25, 50, and 100 mg bid captopril were increased at biweekly intervals until patients responded to treatment, as defined by a decrease in office diastolic pressure to less than 90 mm Hg or at least a 10 mm Hg decrease from baseline. Patients who responded to a 2-week titration dose remained at that dose for another 2 weeks. Blood pressure assessments were made using both office and ambulatory blood pressure monitoring. Area under the curve analysis of ambulatory blood pressure reductions showed significant differences between treatment groups for both systolic (P = .023) and diastolic (P = .007) blood pressures, with lisinopril-treated patients showing the most significant reduction in pressure. Greater reductions (P less than .05) were also noted in patients receiving lisinopril at hours 10 to 12, suggesting two blood pressure troughs for those receiving captopril. Both drugs were well tolerated, and no patients withdrew from either treatment group. The authors concluded that after at least 4 weeks of therapy, once-daily lisinopril administration was more effective than twice-daily captopril administration in reducing blood pressure, when measured by 24-hour ambulatory blood pressure monitoring.

Ambulatory Care↗
PubMed1990

Accuracy of mitral Doppler echocardiographic cardiac output determinations in adults.

The Doppler echocardiographic estimation of cardiac output at the mitral valve site is often underestimated in adults with slow heart rates because the mitral valve remains open in mid-diastole when flow is markedly reduced. Therefore we tested several approaches to this measurement in 17 adults with nonvalvular heart disease who had thermodilution catheters in the right side of the heart. Superior correlations with thermal output values were obtained by a new method that excludes mitral orifice measurements during mid-diastole when flow less than 10 cm/sec (r = 0.94) compared with the standard method (r = 0.89). Also, the new method resulted in significantly less underestimation of thermal cardiac output in patients with heart rates less than 70 beats/min (-10%) compared with the standard method (-34%). In addition, use of a constant maximal two-dimensional echocardiographic mitral orifice correction factor of 0.77 with the new method to account for variations in mitral valve orifice during the cardiac cycle, as opposed to 0.68 with the standard method, resulted in similar results as compared with determining individual correction factors from M-mode echoes. We conclude that: (1) the mitral orifice approach is accurate for measuring cardiac output in adult patients with nonvalvular heart disease; (2) a new method that excludes mid-diastolic mitral orifice measurements is superior to the standard method; and (3) use of a constant two-dimensional echocardiographic mitral valve orifice correction factor obviates the need for M-mode echoes.

Cardiac Output↗
PubMed1988

Nadolol versus diltiazem and combination for preventing exercise-induced ischemia in severe angina pectoris.

Combination beta-blocker and calcium antagonist therapy has been shown to be superior to monotherapy with either class of drugs in the treatment of patients with severe angina pectoris. Some combinations of these agents have resulted in an increased frequency of adverse effects. Although nadolol and diltiazem have low incidences of side effects as monotherapy, little is known about their combination. Thus, 18 patients with angina pectoris despite medical therapy were randomly assigned to 3-week periods of nadolol (160 mg/day), diltiazem (240 mg/day) or their combination. At the end of each treatment period, treadmill exercise testing and rest and peak bicycle exercise 2-dimensional echocardiography were performed. The heart rate-systolic blood pressure product was decreased most at peak treadmill exercise with the combination therapy versus monotherapy with either nadolol or diltiazem (12 vs 14 vs 22 x 10(3), respectively, p less than 0.05). Exercise duration did not differ with any of the 3 regimens, but the number of patients without angina during exercise was lowest with the combination therapy versus nadolol or diltiazem alone (5, 10 and 11, respectively, p less than 0.05); similar results were noted with the number of patients developing 1-mm ST depression on the exercise electrocardiogram (6, 10 and 13, respectively, p less than 0.05). The left ventricular ejection fraction at rest and during peak exercise was similar among the 3 treatments. The therapeutic combination of nadolol and diltiazem is well tolerated and results in less evidence of myocardial ischemia during exercise than monotherapy with either agent.

Aged↗
PubMed1988

Percutaneous placement of the Greenfield vena caval filter.

During the period from August 1986 to August 1987, 50 patients underwent percutaneous placement of a Greenfield vena caval filter from the right femoral vein, left femoral vein, or right internal jugular vein at our institution. All 50 patients had a contraindication to anticoagulation therapy or had complications of anticoagulation for deep venous thrombosis or pulmonary emboli. The percutaneous placement was accomplished in the angiographic suite with use of local anesthesia and was well tolerated by all patients. Only three complications related to the percutaneous approach occurred during the short-term follow-up (3 months to 1 year). These complications were deep venous thrombosis of the leg in two patients and misplacement of the filter in one patient. The three patients tolerated these complications well. We conclude that placement of Greenfield vena caval filters can be readily accomplished by means of percutaneous entry. Our experience demonstrated minimal associated morbidity and no mortality.

Aged↗
PubMed1988

Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure.

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

Percutaneous transluminal angioplasty in the lower extremities: a 5-year experience.

From January 1979 to March 1984, percutaneous transluminal angioplasty (PTA) was used to treat 148 limbs of 135 Mayo Clinic patients with occlusive arterial disease of the lower extremities. The procedure was technically successful in more than 95% of the attempts. The outcome was clinical improvement in 89 limbs and no improvement in 40 limbs; in 19 limbs, PTA was technically successful but the patient was dismissed from the hospital and lost to follow-up before the extent of improvement could be determined. Mean ankle/brachial pressure indices increased after PTA in those with clinical improvement but not in those without improvement. Clinical improvement was less likely to follow PTA in patients with advanced age, diabetes, severe initial symptoms, low ankle/brachial indices, or distal occlusive disease. In patients with improvement after PTA, the mean follow-up period was 33 months; during that time, failure (defined as recurrence of the original symptoms or the need for repeat PTA or operation) occurred at a rate of 6.4% per year. Serious complications occurred after three procedures (2.0%). We conclude that PTA is technically feasible and generally safe for many patients with occlusive arterial disease of the lower limbs.

Aged↗
PubMed1986

Lung cancer screening: the Mayo program.

The National Cancer Institute has sponsored three randomized controlled trials of screening for early lung cancer in large, high-risk populations to determine whether lung cancer detection can be improved by adding sputum cytological screening every 4 months to chest roentgenography done either yearly or every 4 months; and lung cancer mortality can be significantly reduced by this type of screening program, followed by appropriate treatment. Results of the three trials suggest that sputum cytology alone detects 15% to 20% of lung cancers, almost all of which are squamous cancers with a favorable prognosis; and chest roentgenography may be a more effective test for early-stage lung cancer than previous reports have suggested. Nevertheless, results of the randomized trial conducted at the Mayo Clinic showed that offering both procedures to high-risk outpatients every 4 months conferred no mortality advantage over standard medical practice that included recommended annual testing.

Clinical Trials as Topic↗