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Biomedical subjects

T Madden

Publications and source records attributed to T Madden.

35 records · Page 2Linked to original sources
PubMed1996

Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.

PURPOSE: To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially. PATIENTS AND METHODS: Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly. RESULTS: Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3. CONCLUSION: When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.

Adult↗
PubMed1996

Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma.

PURPOSE: To determine the efficacy and toxicity of topotecan administered as a 5-day intravenous infusion in patients with advanced ovarian cancer refractory to cisplatin-based chemotherapy. PATIENTS AND METHODS: Thirty patients with advanced epithelial ovarian cancer refractory to cisplatin-based chemotherapy received intravenous infusions of topotecan 1.5 mg/m2 delivered over 30 minutes each day for 5 days. A course was repeated every 21 days. The patient eligibility requirements included age > or = 18 years, Zubrod score < or = 2, measurable disease, adequate hepatic and renal function, neutrophil count > or = 1,500/microL, platelet count > or = 100,000/microL, and anticipated survival > or = 3 months. RESULTS: Twenty eight patients were assessable for response and toxicity. All patients were assessable for survival. The major toxicity from administration of topotecan at this dose schedule was myelosuppression; 21 patients required dose reductions. Four patients had neutropenic fever that required hospitalization, and seven patients required platelet transfusions. Maculopapular pruritic exanthema occurred in 20% of patients; gastrointestinal side effects were mild. No deaths were reported on the study. At dose levels of 1.5, 1.25, and 1.0 mg/m2, 61%, 31%, and 25% of patients, respectively, required dose reductions. Of 28 assessable patients, four (14%; 95% confidence interval [CI], 4% to 34%) achieved a partial response (PR) at a median of 1.4 months and lasting 8.9 months, and 17 had stable disease (SD). The overall median survival time was 10.0 months (95% CI, 8.1 to 13.5). CONCLUSION: Topotecan shows modest clinical activity against cisplatin-refractory ovarian cancer, although the dose-intensity is compromised by the depth of the granulocyte nadir and the duration of granulocytopenia. Further studies of topotecan may necessitate a reevaluation of optimal dose schedule, with the possible incorporation of multilineage cytokines, and its activity in taxane-resistant tumors.

Adult↗
PubMed1996

Phase I clinical and plasma and cellular pharmacological study of topotecan without and with granulocyte colony-stimulating factor.

Topotecan, a semisynthetic water-soluble analogue of camptothecin, inhibits human topoisomerase I (topo I). We performed a Phase I clinical and plasma pharmacological study of topotecan administered by 24-h continuous infusion without and with granulocyte colony-stimulating factor (G-CSF). We also measured topo I-DNA complexes in peripheral blood mononuclear cells (PBMCs) in an attempt to correlate formation of topo I-DNA complexes in patients treated with topotecan with toxicity and/or response. One hundred four courses of topotecan at doses of 2.5-15.0 mg/m2 were administered to 44 patients with solid tumors. The maximum tolerated dose without G-CSF was 10.0 mg/m2; granulocytopenia was the dose-limiting toxic effect. The maximum tolerated dose could not be increased with G-CSF because of severe thrombocytopenia. Plasma pharmacology was obtained in 11 patients treated at 12.5 mg/m2 and 15.0 mg/m2. The topotecan lactone end-infusion plasma levels correlated strongly with the area under the curve. Lactone elimination was biexponential with a mean t1/2alpha of 28 min and a t1/2beta of 3.8 h at 12.5 mg/m2. Topo I-DNA complexes were measured before and after treatment in PBMCs from seven patients. Pretopotecan topo I-DNA complexes were available on two additional patients treated at 15 mg/m2. The mean increase in topo I-DNA complexes at the end of the topotecan infusion was 1.25 times the pretreatment value. There was a statistically significant relationship (P = 0.02) between lack of disease progression and the level of topo I-DNA complexes measured in PBMCs before therapy. For Phase II studies of minimally treated adults with solid tumors, the recommended topotecan starting dose administered by 24-h continuous infusion is 10 mg/m2 without G-CSF.

Adult↗
PubMed1995

Proteases and collagenases of Porphyromonas gingivalis.

Proteases expressed by Porphyromonas gingivalis have been considered as potential virulence factors for these periodontopathic micro-organisms. The introduction of molecular genetic approaches to study these enzymes has clearly demonstrated that these organisms are capable of expressing multiple distinct proteases. Several of these enzymes are apparently expressed as active proteolytic products following processing of larger precursor proteins. In addition, more recent data have suggested a close relationship between some of these enzymes and two other potential virulence factors of these organisms: hemagglutinins and collagenases.

Bacterial Proteins↗
PubMed1995

Dosing of thioTEPA for myeloablative therapy.

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thioTEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean +/- SE plasma concentration of thioTEPA was 124 +/- 63 ng/ml, while that of TEPA was 235 +/- 69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50(s) of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50(s) of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a two-compartment model, the mean thioTEPA Vc was 47.4 +/- 4.7 1/m2, t1/2 alpha 19 +/- 5 min, t1/2 beta 3.7 +/- 0.5 h, and plasma clearance 302 +/- 21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/1 for thioTEPA and 8.9-21.2 mg h/1 for TEPA, while the mean peak concentrations were 0.95-2.08 micrograms/ml for thioTEPA and 0.88-1.90 micrograms/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak > 1.75 micrograms/ml and with combined thioTEPA and TEPA AUC > 30 mg h/1 (5/6 vs 0/9, P = 0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r = 0.74, P = 0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P = 0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.

Adolescent↗
PubMed1994

Nutritional support and prognosis in patients with head and neck cancer.

We retrospectively studied the relationship between nutritional status as indicated by the presence or absence of the cutaneous delayed hypersensitivity response and treatment-related morbidity, disease recurrence, and survival at 2 years in 67 consecutive patients with head and neck carcinoma. Serial nutritional assessments were conducted throughout the course of combined initial antineoplastic treatment and nutritional support. The presence of cell-mediated immunity at the end of treatment was associated with a 2-year survival rate of 100%, whereas patients who were anergic at the end of treatment had a 2-year survival rate of 48% (P < 0.01). Morbidity due to surgical therapy and tumor recurrence rates were also higher in the anergic group (P < 0.01). Prognosis in head and neck cancer is based on many factors, but vigorous nutritional support during initial treatment may have some effect on morbidity, tumor recurrence, and survival time.

Adult↗
PubMed1994

Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation.

PURPOSE: To determine the pharmacokinetics and clinical response of high-dose etoposide in combination with carboplatin for pediatric cancer patients undergoing autologous bone marrow transplant. PATIENTS AND METHODS: Pharmacokinetic parameters for etoposide were determined at doses of 960, 1,200, and 1,500 mg/m2 when given with high-dose carboplatin and followed by autologous marrow rescue. Twenty-nine patients (age 1.6 to 23 years) with refractory or relapsed solid tumors were studied. Etoposide was administered in three divided doses as a 6-hour infusion on alternate days with carboplatin. Etoposide concentrations (n = 14) were determined during and following each of three doses. Patient characteristics, drug dose, and pharmacokinetic parameters were examined as predictors of marrow engraftment as reflected by recovery of granulocytes and platelets. RESULTS: The median values for clearance (Cl) and terminal half-life (T1/2 beta) of etoposide were 14.3 mL/min/m2 (range, 6.8 to 29.6) and 5.9 hours (range, 3.7 to 39). After adjustment for body size, Cl and volume of distribution did not correlate with any laboratory parameter or patient characteristic. However, seven patients who received concomitant anticonvulsant therapy had significantly higher (P < .01) average etoposide Cl values (23.7 mL/min/m2) than 22 patients who did not receive drugs known to alter hepatic metabolism (13.4 mL/min/m2). The median etoposide Cl value in patients who received concurrent carboplatin but no anticonvulsant agents is substantially lower than values previously reported in either children or adults. Higher etoposide concentrations were significantly associated with longer times to recovery of granulocyte and platelet counts. CONCLUSION: Etoposide Cl is significantly higher in patients who receive concomitant anticonvulsant therapy, which is consistent with clinically important hepatic enzyme induction. The lower etoposide Cl associated with high-dose carboplatin suggests that carboplatin may impair etoposide metabolism. Furthermore, high etoposide concentrations appeared to prolong time to recovery of hematopoietic function.

Adolescent↗
PubMed1992

The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer.

Carboplatin disposition was studied in 18 pediatric patients with cancer over a dosage range of 400 to 700 mg/m2 given on an alternate-day schedule (total doses of 1200 to 2100 mg/m2) with high-dose etoposide. Median age was 7.7 years, hepatic functions were normal, and serum creatinine levels were less than or equal to 1.0 mg/dl. Carboplatin pharmacokinetics were determined by atomic absorption spectroscopy. Median pharmacokinetic parameters for ultrafilterable platinum were as follows: clearance 45.8 ml/min/m2 (range, 25.5 to 65.3 ml/min/m2) and a terminal half-life of 3.6 hours (range, 2.1 to 14.2 hours). Carboplatin clearance (CL) values and volume of distribution (VC) were highly correlated to body size (CL = 55 x Body surface area in [BSA, in square meters] - 6.7, r2 = 0.73; VC = 5 x BSA [in square meters] + 0.26, r2 = 0.69). However, carboplatin doses normalized to BSA still resulted in twofold to threefold variability in area under the concentration-time curve. Carboplatin CL was significantly lower in those subjects (n = 9) who had previously received cumulative cisplatin doses of greater than or equal to 960 mg/m2 (p less than 0.05) but was not influenced by age, gender, or diagnosis.

Adolescent↗
PubMed1991

Isolation and characterization of Pseudomonas aeruginosa exotoxin A binding glycoprotein from mouse LM cells.

A Pseudomonas aeruginosa exotoxin A (PE) binding glycoprotein was affinity purified from toxin sensitive mouse LM cells. The binding protein was solubilized with Triton X-100 or Nonidet P-40 and purified on a PE-Sepharose affinity column. Polyacrylamide gel electrophoresis yielded a single band with an estimated molecular mass of greater than 300,000 Da. N-Linked carbohydrate was present, accounting for approximately 10% of the total mass of the molecule. The purified protein specifically bound PE. Incubation of purified protein specifically bound PE. Incubation of purified PE binding protein with toxin reduced toxicity to LM cells. We speculate on the role of this toxin binding glycoprotein in the intoxication process.

ADP Ribose Transferases↗
PubMed1989

Clinical pharmacology of cancer chemotherapy in children.

The pharmacokinetics of most anticancer drugs are highly variable in children, and are commonly different when children are compared to adults. Several recent studies have demonstrated that variability in systemic exposure due to interpatient pharmacokinetic variability, may be related to the probability of oncolytic effects or toxicity for some anticancer drugs. This review has exemplified differences in the clinical pharmacology of several anticancer drugs, when children are compared to adults. Such age-related differences in the pharmacokinetics and pharmacodynamics of these drugs, together with biologic differences between pediatric and adult cancers, provide the rationale for systematically conducting pediatric phase I through IV studies of anticancer drugs and denote the risks of relying on adult trials to identify new therapeutic strategies for childhood cancers.

Adult↗
PubMedDate not supplied

Attitudes toward menopause and aging across ethnic/racial groups.

OBJECTIVE: Attitudes have a potential role to play in the experience of menopause. The objective of this study was to examine the degree to which attitudes toward menopause and aging vary across ethnic groups and menopausal status (ie, premenopausal through postmenopausal). METHODS: More than 16,000 women were interviewed by telephone as part of the Study of Women's Health Across the Nation. They represented five ethnic/racial groups (African American, white, Chinese American, Japanese American, and Hispanic) from seven geographical sites (Boston, MA; Pittsburgh, PA; Chicago, IL; Michigan; New Jersey; and northern and southern California). RESULTS: African American women were significantly more positive in attitude. The least positive groups were the less acculturated Chinese American and Japanese American women. Menopausal status was not a consistent predictor of attitude across ethnic groups. CONCLUSIONS: In general, women's attitudes toward menopause range from neutral to positive. Ethnic groups within the United States vary slightly, but reliably, in their attitudes toward menopause and aging. Factors other than those directly associated with menopausal status seem to play a role in attitude.

Adult↗
PubMedDate not supplied

Cultural values and intergenerational value discrepancies in immigrant and non-immigrant families.

The goal of this research was to explore the generality of developmental processes related to intergenerational value discrepancies across 701 families from immigrant and non-immigrant groups. In a study involving 471 immigrant families (197 Armenian, 103 Vietnamese, and 171 Mexican) and 230 non-immigrant families (95 African American and 135 European American), adolescents and parents reported their endorsement of values pertaining to family obligations. We examined similarities and differences at three levels of analysis, from the general to the group-specific. Results provide evidence for general developmental processes (family obligations were endorsed more by parents than by adolescents in all groups), processes associated with immigration (the intergenerational value discrepancy generally increased with time in the United States), and processes that are unique to each ethnic group.

Adolescent↗
PubMedDate not supplied

The dentist's role in end-of-life care.

Dentists and dental specialists have much to offer in ensuring proper pain management in end-of-life care for terminally ill patients. As the population of the United States ages and devastating disease processes continue to affect many, the need for oral comfort care measures will further increase. In an ideal situation, the dentist will be among those consulted in advance of beginning therapeutic regimens that have significant oral side-effects or for cases in which oral care after treatment has begun is accompanied by greatly increased risk. The objectives for dentists caring for terminally ill patients include ensuring comfort, eliminating sites of infection or potential infection, understanding the patient's preferences enhancing oral function, and, when desired, protecting self-esteem through esthetic maintenance. The provision of adequate pain management and comfort care is an unequivocal ethical obligation for the benefit of these patients. Dentists have a further ethical obligation to share their knowledge with physicians and patients to set a higher standard for comfort care for the terminally ill.

Antineoplastic Agents↗
PubMedDate not supplied

The use of microdialysis in pharmacokinetics and pharmacodynamics.

Microdialysis is a new in vivo sampling technology applied to the study of pharmacokinetics and drug metabolism in the blood and soft tissues of living systems. A small-diameter probe containing a dialysis membrane is implanted into tissue and perfused with a suitable fluid. Low-molecular-weight substances passively diffuse through the semipermeable membrane along a concentration gradient, resulting in the collection of purified dialysate samples. The advantage of this approach over blood sampling and dissection of tissues is the ability to sample blood and extracellular fluid with minimal tissue damage or alteration of fluid balance. Sampling several tissues simultaneously and continuously in animal models allows data to be obtained that more directly reflect interactions of drugs at their sites of activity and detoxification. Techniques such as this will have a tremendous impact on preclinical and clinical pharmacologic research.

Animals↗