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H Rockett

Publications and source records attributed to H Rockett.

5 recordsLinked to original sources
PubMed2000

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine.

PURPOSE: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein alpha1-acid glycoprotein (AAG), which may limit tissue availability. In this phase I-II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. METHODS: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m2 i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. RESULTS: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 microM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 microM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. CONCLUSIONS: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo.

Administration, Oral↗
PubMed1999

Reproducibility and validity of a food frequency questionnaire among fourth to seventh grade inner-city school children: implications of age and day-to-day variation in dietary intake.

OBJECTIVE: To assess the reproducibility and validity of a semiquantitative food frequency questionnaire (FFQ) to classify children and adolescents in terms of daily servings of fruits and vegetables and intake of calories, protein, fat, carbohydrate, dietary fibre, vitamin C, phosphorous, calcium and iron. DESIGN: FFQs were collected in the autumn of 1993 and 1994. Four 24-hour diet recalls were collected during the same 1-year period and their mean was compared to the FFQ diet estimates. SETTING: Low income, inner-city state schools. SUBJECTS: A sample of 109 inner-city fourth to seventh grade students. RESULTS: The 1-year reproducibility of the FFQ, assessed with Spearman correlations, was lower among the fourth and fifth (range: r=-0.26 to 0.40) than the sixth and seventh grade students (range: r=0.18-0.47). After adjusting for day-to-day variation in dietary intake, for most nutrients and foods the correlations between the FFQ and the 24-hour recalls remained greater among the junior high school students (fourth to fifth grade range: r=0.0-0.42; sixth to seventh grade range: r=0.07-0.76). CONCLUSIONS: Inner-city sixth and seventh grade students demonstrated the ability to provide valid estimates of intake of calories, carbohydrate, calcium, phosphorous, iron and vitamin C over the past year. However, children in the fourth and fifth grades experienced some difficulty in completing the FFQ. Our results suggest that, before using this instrument with fourth and fifth grade children, investigators should assess whether study participants can think abstractly and are familiar with the concept of 'average intake'.

Child↗
PubMed1999

Vitamin K intake and hip fractures in women: a prospective study.

BACKGROUND: Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture. However, data are limited on the effects of dietary vitamin K. OBJECTIVE: We investigated the hypothesis that high intakes of vitamin K are associated with a lower risk of hip fracture in women. DESIGN: We conducted a prospective analysis within the Nurses' Health Study cohort. Diet was assessed in 72327 women aged 38-63 y with a food-frequency questionnaire in 1984 (baseline). During the subsequent 10 y of follow-up, 270 hip fractures resulting from low or moderate trauma were reported. RESULTS: Women in quintiles 2-5 of vitamin K intake had a significantly lower age-adjusted relative risk (RR: 0.70; 95% CI: 0.53, 0.93) of hip fracture than women in the lowest quintile (< 109 microg/d). Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis, including calcium and vitamin D intakes, were added to the models. Risk of hip fracture was also inversely associated with lettuce consumption (RR: 0.55; 95% CI: 0.40, 0.78) for one or more servings per day compared with one or fewer servings per week), the food that contributed the most to dietary vitamin K intakes. CONCLUSIONS: Low intakes of vitamin K may increase the risk of hip fracture in women. The data support the suggestion for a reassessment of the vitamin K requirements that are based on bone health and blood coagulation.

Adult↗
PubMed1993

Phase I study of bryostatin 1: assessment of interleukin 6 and tumor necrosis factor alpha induction in vivo. The Cancer Research Campaign Phase I Committee.

BACKGROUND: Many oncogenes have been shown to code for growth factor receptors that are involved in regulation of cell growth and proliferation and can activate transcription via protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, has demonstrated potent antitumor activity in vitro and in vivo in human tumor xenografts. PURPOSE: The aim of this phase I study was to determine the optimal dosage and toxicity profile of bryostatin 1 and its influence on cytokine release in vivo. METHODS: Three successive cohorts consisting of 35 patients with various malignant tumors were treated with bryostatin 1 by intravenous infusion over 1 hour as follows: cohort A--35 micrograms/m2 (three patients) or 50 micrograms/m2 (eight patients) once every 2 weeks; cohort B--25 micrograms/m2 once a week (eight patients); and cohort C--25 micrograms/m2 once a week for 3 weeks, with no treatment during the 4th week (16 patients). Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoradiometric assay and by radioimmunoassay, respectively. RESULTS: The dose-limiting toxicity was grade 3 or 4 myalgia in four of 11 patients in cohort A, in two of eight in cohort B, and in none of 16 in cohort C. Occurrence of myalgia was dose related. There was no significant myelosuppression, apart from a small and transient fall in platelet count. Six patients experienced acute but transient skin flushing, dyspnea, hypotension, and bradycardia, probably related to the bryostatin 1 vehicle. TNF-alpha and IL-6 were detected in plasma at 2 and 24 hours after treatment, respectively, and the levels were dose related (P = .02). Two patients with metastatic malignant melanoma had partial remission after three or four cycles of therapy; remission lasted 6 weeks and 10+ months, respectively. CONCLUSIONS: The dose-limiting toxicity of bryostatin 1 was myalgia. Plasma IL-6 and TNF-alpha concentrations were increased within 24 hours of therapy. Antitumor activity against malignant melanoma was observed early in the course of treatment. IMPLICATIONS: The recommended dosage of bryostatin 1 for phase II studies is 25 micrograms/m2 by intravenous infusion for 1 hour once a week for 3 weeks, with no treatment in the 4th week. IL-6 and TNF-alpha plasma concentrations may be useful in monitoring biological activity of bryostatin 1. Future studies should explore use of this drug with other conventional immune modulators and conventional cytotoxic drugs.

Adult↗