Search PubMed⌕ Search

Biomedical subjects

I Dennis

Publications and source records attributed to I Dennis.

13 recordsLinked to original sources
PubMed1999

Phase I and pharmacokinetic study of DACA (XR5000): a novel inhibitor of topoisomerase I and II. CRC Phase I/II Committee.

DACA, also known as XR5000, is an acridine derivative active against both topoisomerase I and II. In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks. A total of 41 patients were treated at 11 dose levels between 9 mg m(-2) d(-1) and the maximum tolerated dose of 800 mg m(-2) day(-1). The commonest, and dose-limiting, toxicity was pain in the infusion arm. One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction. At the highest dose levels, several patients also experienced flushing, pain and paraesthesia around the mouth, eyes and nose and a feeling of agitation. Other side-effects, such as nausea and vomiting, myelosuppression, stomatitis and alopecia, were uncommon. There was one minor response but no objective responses. DACA pharmacokinetics were linear and did not differ between days 1 and 3. The pattern of toxicity seen with DACA is unusual and appears related to the mode of delivery. It is possible that higher doses of DACA could be administered using a different schedule of administration.

Acridines↗
PubMed1996

A new approach to exploring biases in educational assessment.

This paper presents and illustrates an approach to the study of marking biases based on multi-sample confirmatory factor analysis. This is applied to the marks awarded by two independent markers to the final year dissertations of 197 female and 58 male psychology undergraduates. One of the two markers had supervised the work on which the dissertation was based on a one-to-one basis. The results suggest that about 30 per cent of the variance in the supervisor's mark is attributable to influences which are specific to the supervisor, orthogonal to the merit of the project as assessed by the two markers jointly, and general across each of the four marks awarded by the supervisor. The most plausible interpretation of these influences is that they represent a contamination of the supervisor's mark by personal knowledge of the student. These biases in the supervisor's marking were found to have more influence for male than for female students and to elevate the marks of males relative to those of females to a small but significant extent. It would be unwise to overgeneralize from these findings, but they demonstrate the potential value of this method of studying marking biases.

Adult↗
PubMed1995

General practitioners' tacit and stated policies in the prescription of lipid lowering agents.

BACKGROUND: Research into general practitioners' prescribing behaviour with regard to lipid lowering agents has relied on survey methods which presume that doctors have insight into their prescribing behaviour and can describe it accurately. AIM: This study set out to measure the tacit policies used by general practitioners in prescribing lipid lowering agents and to compare these with their stated policies. METHOD: Effects of 13 separate cues on decisions to prescribe were examined. The cues included cholesterol levels and a number of associated risk factors for coronary heart disease. Doctors rated 130 imaginary cases presented by a computer. Thirty five general practitioners in the Plymouth area participated in the study. Their ages ranged from 31 to 55 years and all but four were men. The raw data in each case was a rating of the likelihood that the doctor would prescribe for the patient described. These were converted into statistical weightings by use of multiple linear regression. The pattern of (standardized) weights constituted the tacit policy for each doctor. Stated policies were measured in a subsequent interview by asking doctors to rate the influence of each cue. RESULTS: Both tacit and stated policies diverged widely between different doctors. Most doctors overestimated the number of cues that had actually influenced their decisions, and many believed that they had taken into account associated factors for coronary heart disease when they had not. On lifestyle related risks doctors were generally less likely to treat overweight people and most stated this as their policy. Most were also less likely to treat smokers but some had the opposite policy. Those less likely to treat smokers were also less likely to treat obese patients. There was also considerable variation in the extent to which the doctors took account of the attitude of the patient to receiving treatment. CONCLUSION: Doctors' policies are highly variable and particularly inconsistent in the treatment of smokers. Relevant risk factors may be ignored--even though they are understood--because the risk assessment involved is too psychologically complex a task to be performed intuitively. Decision aids and clear protocols are needed in this area.

Adult↗
PubMed1993

A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using 31P magnetic resonance spectroscopy.

BW12C79 stabilizes the oxyhemoglobin molecule resulting in a reversible left-shift of the oxygen saturation curve. The activity of a number of bioreductive anticancer drugs, such as mitomycin C, may be enhanced under hypoxic conditions. Twenty-four patients with various malignancies received BW12C79 and mitomycin C. BW12C79 was administered i.v. with a loading dose (20-50 mg/kg) over 1 h followed by a maintenance infusion of 4 mg/kg/h for 5 h. Percentage modification of the oxyhemoglobin (degree of left-shift) was dose related with maximum modification of 56% and was maintained for the duration of maintenance infusion of BW12C79. Hemoglobin electrophoresis showed a fast moving band consistent with the BW12C79-oxyhemoglobin complex. Side effects at the top dose level comprised headache, nausea/vomiting, vein irritation, and myocardial ischemia. One other patient suffered from an acute encephalopathy of unknown etiology a few days following BW12C79. 31P magnetic resonance spectroscopy of exercising calf muscles showed increased breakdown of high energy phosphate stores and a greater reduction in pH. Recovery of the high energy phosphate stores after exercise was slow. These results were consistent with reduced oxygen supply due to either a left shift of the oxygen saturation curve and/or reduced muscle blood flow. BW12C79 did not interfere with the pharmacokinetics of mitomycin C. In conclusion, this phase I study demonstrates the feasibility of achieving a significant left shift in the oxygen saturation curve in cancer patients which is maintained for at least 5 h with acceptable toxicity. The maximum tolerated dose of BW12C79 was 50 mg/kg loading infusion followed by a maintenance infusion of 4 mg/kg/h. Magnetic resonance spectroscopy results were consistent with reduced supply of oxygen to exercising skeletal muscle. BW12C79 may be of potential benefit as an adjunct to bioreductive drugs in the treatment of solid tumors.

Adult↗
PubMed1993

A phase II and pharmacokinetic study with oral piritrexim for metastatic breast cancer.

Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.

Administration, Oral↗
PubMed1993

Improving auditory warning design: quantifying and predicting the effects of different warning parameters on perceived urgency.

The effects of four parameters (speed, fundamental frequency, repetition units, and inharmonicity) on perceived urgency were scaled using an application of Stevens's power law. From the exponents obtained, equal units of urgency change were calculated for three parameters. The units were combined in a set of stimuli, and the order of urgency was predicted. The obtained and predicted orders of urgency were highly correlated. The results also showed that even when equalized by psychophysical techniques, some parameters contribute more to perceived urgency than do others. This may be attributable to the different types of parameters scaled or the proportion of the usable range of each parameter that represents a unit change in urgency. The implication of the work for the design and improvement of auditory warnings is discussed.

Adolescent↗
PubMed1992

Phase I study of BW12C in combination with mitomycin C in patients with advanced gastrointestinal cancer.

The effect of combining the oxyhemoglobin-modifying drug BW12C with mitomycin C was investigated in a Phase I study of 18 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 50 mg/kg to modify the hemoglobin-oxygen saturation curve by up to 48%. The period of maximum modification was then prolonged for up to 3 hr by a maintenance infusion of 4-6 mg/kg/hr. Pharmacokinetics of BW12C and mitomycin C were performed in all patients. Peak levels of BW12C increased from 139 micrograms/ml to 378 micrograms/ml. Plasma half life was independent of dose, with an average of 3.3 hr. BW12C was well tolerated with no severe side effects. Three patients had objective tumour responses.

Adenocarcinoma↗
PubMed1992

Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data.

Flavone acetic acid (FAA) showed impressive effects against murine solid tumours but no activity in clinical studies. The mechanism of action in mice may involve damage to tumour vasculature or immunomodulation, and these effects may be species-specific. Alternatively, concentrations of FAA achieved in mouse tumours may be higher than in human tumours. It is important to resolve this issue since it raises important questions about the relevance of in vitro versus in vivo tumour screens and the development of FAA analogues. As part of a Cancer Research Campaign Phase II study of metastatic melanoma in which 8.4 g m-2 FAA was given as a 6 h infusion, six tumour biopsies were obtained from four patients. FAA tumour concentrations were determined by HPLC and compared with subcutaneous murine solid tumours within the same analytical laboratory. Tumour/plasma percentages (range 26-61%; mean +/- SD, 43.9 +/- 11.4%) were similar to those in mice, as was the area under the curve (AUC) extrapolated to infinity and the AUC above the putative activity threshold of 100 micrograms ml-1. We conclude that the exposure of drug-refractory human melanoma tissue to FAA was comparable to that of sensitive mouse tumours. This suggests that reduced penetration of FAA into human tumours is unlikely to explain the lack of antitumour activity observed in clinical studies and that differences in mechanism of action are predominant.

Adult↗
PubMed1991

Improving auditory warning design: relationship between warning sound parameters and perceived urgency.

This paper presents an experimental study of the effects of individual sound parameters on perceived (psychoacoustic) urgency. Experimental Series 1 showed that fundamental frequency, harmonic series, amplitude envelope shape, and delayed harmonics all have clear and consistent effects on perceived urgency. Experimental Series 2 showed that temporal and melodic parameters such as speed, rhythm, pitch range, and melodic structure also have clear and consistent effects on perceived urgency. The final experiment tested a set of 13 auditory warnings generated by an application of the earlier experimental findings. The urgency rank ordering of this warning set was predicted, and the correlation between the predicted and the obtained order was highly significant. The results of these experiments have a widespread application in the improvement of existing auditory warning systems and the design of new systems, where the psychoacoustic and psychological appropriateness of warnings could be enhanced.

Accidents, Occupational↗