Biomedical subjects

W E Evans

Publications and source records attributed to W E Evans.

At least 19 recordsLinked to original sources

PubMed1992

Pharmacokinetics of subcutaneous recombinant human granulocyte colony-stimulating factor in children.

Fifteen children (age 1.2 to 9.4 years) with advanced neuroblastoma were treated with myelosuppressive chemotherapy (cyclophosphamide, cisplatin, doxorubicin) followed by 5 (n = 5), 10 (n = 5), or 15 (n = 5) micrograms/kg recombinant granulocyte colony-stimulating factor (rG-CSF) subcutaneously (SC) once daily for 10 days, starting the day after chemotherapy. Serial serum samples obtained on days 1 and 10 were analyzed for G-CSF activity by a specific proliferation assay using NFS-60 cells. G-CSF serum concentration-time data were best described by a one-compartment model, with zero-order absorption and first-order elimination. After SC injection, absorption was prolonged, with peak concentrations of G-CSF (3 to 117 ng/mL) being reached after 4 to 12 hours. The relatively slow absorption, with a mean elimination half-life of 5.8 hours on day 1 and 4.5 hours on day 10, provided measurable G-CSF concentrations for the entire 24-hour dosing interval in all patients at each dosage level. The median apparent clearance of G-CSF on day 10 was significantly higher than on day 1 (0.57 v 0.31 mL/min/kg, P = .02), and was positively correlated with the absolute neutrophil count (ANC) (r2 = .33, P = .003). Systemic exposure to G-CSF was dose-related, but interpatient pharmacokinetic variability yielded overlap in area under the concentration-time curve (AUC) at all three dosage levels. Stepwise regression analysis showed that G-CSF AUC could be predicted by a model that includes rG-CSF dosage and ANC on the day of administration (r2 = .82, P = .0001).

Absorption↗

PubMed1992

Factors affecting in vitro protein binding of etoposide in humans.

Clinical studies have demonstrated that the plasma protein binding of etoposide, a widely used anticancer drug, is extensive (approximately 94%), highly variable among patients (10-fold range), and significantly related to serum albumin and total bilirubin concentration. The present study was designed to more thoroughly evaluate factors likely to affect etoposide protein binding under controlled in vitro conditions where single variables could be changed. Protein binding was determined using an equilibrium dialysis method with tritiated etoposide. The binding of etoposide was similar in serum or plasma, and heparin had no effect on binding. Etoposide binding decreased with increased pH, but no clinically significant difference was noted within the range of physiologic pH. Etoposide binding evaluated in single-source donor plasma was concentration-dependent over a concentration range of 1 to 250 micrograms/mL. Etoposide binding parameters determined in normal human plasma were characterized by a single class of binding sites of moderate affinity (K = 2.88 +/- 0.47 x 10(4)) and high capacity (nP = 5.07 +/- 0.5 x 10(-4); where n is the number of binding sites). The etoposide binding ratio was significantly correlated with albumin concentration (r2 = 99%, p less than 0.05). The characteristics of etoposide binding in a 4.0-g/dL solution of human serum albumin (K = 3.56 +/- 1.22 x 10(4) and nP = 5.58 +/- 0.16 x 10(-4)) suggest that the single class of binding sites is on albumin. Bilirubin caused a significant decrease in K, consistent with competitive binding, but only at higher bilirubin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Bilirubin↗

PubMed1992

Lingual infarction: a review of the literature.

Lingual infarction, although a very rare entity has been reported in 16 cases since 1961. The goal of this article is to alert the physician to the symptoms of tongue claudication to prevent the morbid effects of tongue infarction and blindness due to cranial arteritis. A discussion of the disease and the differential diagnosis is included.

Aged↗

PubMed1992

Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities.

BACKGROUND: The urinary molar concentration ratios of several caffeine metabolites are indicators of specific drug metabolizing enzyme activities. The ratios of 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU) to 1-methylxanthine (1X), AFMU to 1X plus 1-methyluric acid (1U), and AFMU to 1X + 1U + AFMU are indicative of N-acetyltransferase (NAT) activity; the ratios of 1U to 1X and 1U to 1U + 1X indicate xanthine oxidase activity; and the ratio of the sum of 7-demethylated metabolites (AFMU + 1X + 1U) to the precursor for all three compounds, paraxanthine (PX), is a putative indicator of CYP1A2 oxidative activity. Our objective was to discern whether there are race-, gender-, and age-related differences in these indexes of drug-metabolizing activity. METHODS: In 342 normal healthy unrelated subjects, metabolites were measured in urine collected after administration of low-dose caffeine. RESULTS: By two-way analysis of variance, NAT activity was higher in black subjects than in white subjects when assessed as AFMU/(1U + 1X) or as AFMU/(AFMU + 1U + 1X) (p = 0.001 and p = 0.002, respectively), but less so by use of AFMU/1X (p = 0.08). Xanthine oxidase activity, as assessed by 1U/1X or as 1U/(1U + 1X), was lower in black subjects than in white subjects (p = 0.02 and p = 0.001, respectively) and was lower in males than in females (p = 0.001 for both ratios). Females had higher AFMU/1X ratios (p = 0.03) because of higher xanthine oxidase activity. In a model in which AFMU/1X was the dependent variable and race, sex, age, and an index of xanthine oxidase (1U/1X) were independent variables, only race and 1U/1X were significant determinants of this NAT index (p = 0.003 and p < 0.001, respectively). The CYP1A2 ratio was lower in black subjects (p = 0.036) and in females (p = 0.015). CONCLUSION: Racial and gender differences in xanthine oxidase activity render the AFMU/1X ratio less reliable as an assessment of NAT activity in a heterogeneous population compared with the AFMU/(1U + 1X) or AFMU/(AFMU + 1U + 1X) ratios. The observed racial and gender differences in NAT, xanthine oxidase, and CYP1A2 activities may have implications for racial and gender differences in drug effects and carcinogen biotransformation.

Adolescent↗

PubMed1992

Increased teniposide clearance with concomitant anticonvulsant therapy.

PURPOSE: A possible pharmacokinetic interaction between teniposide and anticonvulsant medications was evaluated in pediatric patients. PATIENTS AND METHODS: The systemic clearance of teniposide was determined in six pediatric patients with acute lymphocytic leukemia receiving concomitant therapy with anticonvulsants. Clearance was then compared with a control group of patients treated with the same protocol therapy and matched for age at diagnosis, sex, and race but not receiving anticonvulsants or other agents known to induce hepatic metabolism or alter protein binding of drugs. Eight blood samples were obtained during and after 4-hour infusions of teniposide, and plasma concentrations were measured by a specific high-performance liquid chromatography (HPLC) assay. A two-compartment model was fitted to each subject's data. RESULTS: The mean systemic clearance (range) for the six anticonvulsant-treated patients studied during 22 courses of therapy was 32 mL/min/m2 (range, 21 to 54 mL/min/m2), significantly higher (P less than .001) than the mean value of 13 mL/min/m2 (range, 7 to 17 mL/min/m2) for the control patients studied during 26 courses of therapy. Clearance estimates for control patients were similar to previously published values for pediatric patients. CONCLUSION: These data indicate that the systemic clearance of teniposide is consistently increased two- to three-fold by concomitant phenobarbital or phenytoin therapy. The consequent substantial reduction in systemic exposure may reduce teniposide's efficacy.

Adolescent↗

PubMed1992

Pediatric pharmacokinetics and therapeutic drug monitoring.

Recent advances in pediatric clinical pharmacology have provided a more rational approach to using several medications in children. An increased understanding of the effect of human development, concurrent medications, organ function, and disease states on the absorption, distribution, metabolism, and excretion of drugs has provided a stronger scientific basis for determining drug dosages in children. By measuring drug concentrations and utilizing pharmacokinetic and pharmacodynamic principles, the probability of therapeutic response can be enhanced for a number of medications. Likewise, therapeutic drug monitoring can minimize the risk of adverse effects from many drugs used in children. However, it must be recognized that toxicity can occur in some patients even though plasma drug concentrations are in the therapeutic range; similarly, some patients may not experience a therapeutic effect when plasma drug concentrations are in the same target range. Therefore, achieving the desired plasma concentration of a drug can enhance both the probability of a therapeutic response and diminish the probability of a toxic response. Therapeutic ranges, however, are only intermediate endpoints that must be used in the context of additional criteria to assess the clinical efficacy of any given drug therapy.

Child↗

PubMed1992

Clinical trials of teniposide (VM-26) in childhood acute lymphocytic leukemia.

We describe the development of VM-26 (teniposide) as an effective agent in combination chemotherapy for childhood acute lymphocytic leukemia (ALL). Beginning with its paired use with cytarabine for patients relapsing on conventional therapy, teniposide has shown consistent ability to reduce leukemic cell populations not responsive to other agents. Encouraging results in the treatment of refractory ALL led to the decision to incorporate teniposide into combination chemotherapy for patients with newly diagnosed leukemia. This strategy has yielded higher cure rates for subsets of patients at high risk of treatment failure, including those with initial leukocyte counts of more than 100 x 10(9)/L, and may extend remission lengths for all patients, regardless of risk status. In view of the prolonged marrow aplasia seen with use of teniposide and cytarabine as inducing agents, the optimal role of this combination may be that of "remission reinforcement" therapy. Because of its novel mechanism of action, teniposide affords opportunities to develop new drug combinations that may increase the proportion of long-term ALL survivors still further.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Disposition of antineoplastic agents in the very young child.

Maturation of physiologic process which govern the disposition of pharmacologic agents can yield significant changes in absorption, distribution, metabolism, and elimination of drugs in neonates, infants and children. However, there are very little data concerning the disposition of anticancer drugs in young children. Pharmacokinetic data for six anticancer agents were compared in infants less than 1 year of age and children greater than 1 year of age treated at St Jude Children's Research Hospital. No pharmacokinetic data were available for infants less than 2 months of age. Median methotrexate clearance tended to be lower in four infants (0.26-0.99 years) vs 108 children (1-19 years): 80 vs 103 ml min-1 m-2, respectively (P = 0.01). There was no difference in the median 42 h methotrexate concentration. Teniposide systemic clearance and terminal half-life and cytarabine systemic clearance were not different between the two groups. There was no significant difference in etoposide systemic clearance when normalised to body surface area (ml min-1 m-2), however a significantly lower systemic clearance relative to body weight (ml min-1 kg-1) was observed in two infants, 0.5 to 1 year of age, vs 23 children, 3-18 years of age. Doxorubicin systemic clearance was not significantly different between the two groups when systemic clearance was expressed in ml min-1 kg-1. However, there was a trend toward a lower rate of systemic clearance in ml min-1 m-2 in infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1992

Variability in teniposide plasma protein binding is correlated with serum albumin concentrations.

Teniposide is a widely used anticancer drug that is extensively bound to plasma proteins (greater than 95%). We evaluated the drug's plasma protein binding in nine patients with acute lymphocytic leukemia who were in their first complete remission, and in a second group of nine patients at the time of relapse and subsequently after achieving another complete remission. Plasma protein binding was assessed by equilibrium dialysis, with direct high-performance liquid chromatographic measurement of total and free teniposide. The mean unbound fraction was 0.44% (0.21-0.88%) in the plasma of patients in first remission. It was significantly higher in patients at the time of relapse (mean = 0.86%; range 0.68-1.08%) and after achieving another complete remission (mean = 1.25%; range 0.51-2.11%). Serum albumin values were significantly lower at the time of relapse (mean = 4.6 vs 4.0 mg/dl; p less than 0.014), and decreased further during intensive postremission therapy containing L-asparaginase (mean = 3.2; p less than 0.05). For all 18 patients, a significant negative correlation (r2 = 0.667; p less than 0.001) was found between serum albumin and unbound teniposide, with low albumin being associated with higher unbound fraction. Such patients have higher systemic exposure to unbound (presumably active) teniposide at any given total plasma concentration of the agent.

Adolescent↗

PubMed1992

Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children: long-term results of St Jude total therapy study X.

Long-term follow-up observations are reported on 427 patients who received one of three different intensified therapies in total therapy study X for acute lymphoblastic leukemia (ALL). In the trial for 'standard-risk' ALL, 154 of 309 patients in complete remission were randomized to receive high-dose methotrexate (HDMTX, 1 g/m2) periodically during the first 72 of 120 weeks of standard continuation therapy with 6-mercaptopurine and oral MTX; the remaining 155 patients received 1800 cGy cranial irradiation and intrathecal MTX, followed by 6-mercaptopurine/MTX therapy interrupted from week 36-71 for substitution of two other pairs of drugs. At 9 years of follow-up, significantly higher proportions of patients in the HDMTX group have maintained complete remissions (64 +/- 7%, SE, vs. 52 +/- 6%, p = 0.03), hematologic remissions (73 +/- 6% vs. 62 +/- 6%, p = 0.03), and testicular remissions (94 +/- 5% vs. 80 +/- 8%, p = 0.03); however, the proportion continuing in central nervous system remission has been lower (84 +/- 5% vs 93 +/- 4%, p = 0.02). In the evaluation of teniposide/cytarabine and delayed cranial irradiation for 'high-risk' ALL, 36 +/- 9% of 101 patients are predicted to be event-free survivors at 9 years. Altogether, 217 (51%) of the 427 patients are event-free survivors after at least 7 years of follow-up (median, 9 years); an additional 75 patients are alive and free of leukemia for a median of 6.4 years after successful remission retrieval therapy, boosting the total number of long-term survivors to 292 (68%). These results establish the efficacy of HDMTX for patients with standard-risk ALL and indicate the potential of teniposide/cytarabine for use in multiagent regimens for patients with high-risk disease. The overall survival figure, 68%, affords a benchmark for other studies assessing long-term outcome in ALL.

Child↗

PubMed1992

Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia.

Teniposide, a widely used investigational anticancer drug, is extensively bound to plasma proteins (greater than 95%). The present study evaluated the clearance and pharmacodynamics of total and unbound teniposide in patients with acute lymphocytic leukemia who were either in first complete remission or who had relapsed and achieved a subsequent complete remission. When compared to values of patients in first remission, the mean total systemic clearance of teniposide in relapsed patients was significantly lower at the time remission reinduction therapy was initiated, but increased to values greater than first remission patients after a subsequent remission was achieved. However, the mean clearance of unbound teniposide (ml/min/m2) was 3-fold lower in relapsed patients during reinduction therapy (1224 vs. 4261, P less than .0001), and improved but remained low after these patients achieved a subsequent remission (1965, P = .025). Changes in plasma protein binding accounted for the increase in total clearance when unbound clearance decreased. Continuous therapy with L-asparaginase was the major treatment difference in those patients with hypoalbuminemia and lower clearance of unbound teniposide. In 15 evaluable patients in complete remission, there was a statistically significant (P = .039) linear correlation between the percentage decrease in white blood cell count and the systemic exposure (AUC) to unbound teniposide, with higher exposure associated with a greater decrease in white blood cell count. There was not a significant correlation between the percent decrease in white blood cell count and the dosage given or the systemic exposure to total teniposide.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia.

BACKGROUND AND METHODS: Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. RESULTS: Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. CONCLUSIONS: The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.

Acute Disease↗

PubMed1991

Aspirin alters methotrexate disposition in rheumatoid arthritis patients.

Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis.

Administration, Oral↗

PubMed1991

Concept of maximum tolerated systemic exposure and its application to phase I-II studies of anticancer drugs.

The traditional approach to conducting Phase I studies of anticancer drugs is to select a starting dosage for humans based on preclinical data (e.g., mg equivalent of 1/10 LD10 in mice), then empirically escalate dosages in cohorts of patients until the maximum tolerated dosage (MTD) is established. More recently, NCl and EORTC investigators have advocated the use of pharmacokinetic data from preclinical studies to facilitate more rapid dose escalation (e.g., double the dose until the area under the concentration-time curve [AUC] in humans equals the AUC in mice at the LD10). The present paper describes a strategy which builds on the above approach, by extending the application of pharmacokinetic principles to systematically escalate systemic exposure (AUC) instead of dosage in Phase I trials. Human trials are initiated at whatever patient-specific dosage is required to achieve an AUC equal to 1/10 the AUC in mice at the LD10, such that three patients at the first treatment level might receive three different dosages. If no dose-limiting toxicity is observed, the next cohort of patients receives whatever dosage is required to achieve 2 x AUC of the first dosage level, with AUC escalation continuing until the maximum tolerate systemic exposure (MTSE) is reached. By escalating systemic exposure instead of dosage, one adjusts for interpatient pharmacokinetic variability. This strategy will permit more rapid and precise dosage escalations and, more importantly, it should more precisely establish the maximum level of treatment intensity for future Phase II trials.

Antineoplastic Agents↗

PubMed1991

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Adolescent↗

PubMed1991

Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia.

Thiopurine methyltransferase deficiency, inherited as an autosomal codominant trait, is associated with aberrant mercaptopurine metabolism leading to excessive cellular accumulation of 6-thioguanine nucleotides, the active metabolites of mercaptopurine. We describe a case of severe thiopurine methyltransferase deficiency (activity less than 1 U/8 x 10(8) erythrocytes) in a young girl with acute lymphocytic leukemia. The level of 6-thioguanine nucleotide in the patient's erythrocytes was seven times the population median value, and she had intolerable hematologic toxic effects during postremission therapy with a standard dosage of mercaptopurine (75 mg/m2 per day). Subsequent therapy with 6% of this dosage (10 mg/m2 three times weekly) yielded erythrocytic 6-thioguanine nucleotide concentrations consistently above the population median but not associated with prohibitively toxic effects. This case demonstrates that thiopurine methyltransferase deficiency does not absolutely contraindicate mercaptopurine therapy, and it also provides insight into the mechanism of excessive toxic effects of mercaptopurine sometimes observed in children with acute lymphocytic leukemia.

Child↗

PubMed1991

Lipoprotein analysis in the evaluation of chest pain in the emergency department.

Apolipoproteins were measured in a prospective blinded fashion in blood specimens from patients with chest pain in the emergency department. A definitive diagnosis for the chest pain (non-cardiac-related in 32% and angina or myocardial infarction in 68%) was available in 136 of the 162 patients originally enrolled in the study. Logistic regression and multivariate analysis failed to show any usefulness of apolipoprotein determinations in distinguishing patients with cardiac ischemia from those without it. The clinician's initial impression of the chest pain, the electrocardiogram, a history of previous angina, myocardial infarction, or peripheral atherosclerosis, and male sex were strongly associated with the final diagnosis. We conclude that, although apolipoprotein analysis has proved useful in epidemiologic studies, the most reliable indicators of ischemic pain remain the medical history, the electrocardiogram, and the clinician's overall initial impression.

Aged↗

PubMed1991

Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine.

The disposition of intravenous antipyrine and lorazepam, administered as model substrates for hepatic oxidative metabolism and conjugation, was evaluated in 50 children (mean age, 7.8 years; range, 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012), but was not different when normalized to body surface area. In contrast, lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2, p = 0.036; CLu = 352 versus 485 ml/min/m2, p = 0.010). The mean lorazepam fraction unbound in children was 0.087, which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds, with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.

Adolescent↗