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Biomedical subjects

A Howes

Publications and source records attributed to A Howes.

14 recordsLinked to original sources
PubMed2005

Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours.

This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1-7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.

Administration, Oral↗
PubMed2001

The General Medical Council's Performance Procedures: peer review of performance in the workplace.

The General Medical Council procedures to assess the performance of doctors who may be seriously deficient include peer review of the doctor's practice at the workplace and tests of competence and skills. Peer reviews are conducted by three trained assessors, two from the same speciality as the doctor being assessed, with one lay assessor. The doctor completes a portfolio to describe his/her training, experience, the circumstances of practice and self rate his/her competence and familiarity in dealing with the common problems of his/her own discipline. The assessment includes a review of the doctor's medical records; discussion of cases selected from these records; observation of consultations for clinicians, or of relevant activities in non-clinicians; a tour of the doctor's workplace; interviews with at least 12 third parties (five nominated by the doctor); and structured interviews with the doctor. The content and structure of the peer review are designed to assess the doctor against the standards defined in Good Medical Practice, as applied to the doctor's speciality. The assessment methods are based on validated instruments and gather 700-1000 judgements on each doctor. Early experience of the peer review visits has confirmed their feasibility and effectiveness.

Clinical Competence↗
PubMed2001

Incidental memory and navigation in panoramic virtual reality for electronic commerce.

Recently much effort has been dedicated to designing and implementing World Wide Web sites for virtual shopping and e-commerce. Despite this effort, relatively little empirical work has been done to determine the effectiveness with which different site designs sell products. We report three experiments in which participants were asked to search for products in various experimental e-commerce sites. Across the experiments participants were asked to search in either QTVR (QuickTime Virtual Reality), hypertext, or pictorially rich hypertext environments; they were then tested for their ability to recall the products seen and to recognize product locations. The experiments demonstrated that when using QTVR (Experiments 1, 2, and 3) or pictorial environments (Experiment 2), participants retained more information about products that were incidental to their goals. In two of the experiments it was shown that participants navigated more efficiently when using a QTVR environment. The costs and benefits of using 3D virtual environments for on-line shops are discussed. Actual or potential applications of this research include support for the development of e-commerce design guidelines.

Adult↗
PubMed2001

The assessment of poorly performing doctors: the development of the assessment programmes for the General Medical Council's Performance Procedures.

BACKGROUND: Modernization of medical regulation has included the introduction of the Professional Performance Procedures by the UK General Medical Council in 1995. The Council now has the power to assess any registered practitioner whose performance may be seriously deficient, thus calling registration (licensure) into question. Problems arising from ill health or conduct are dealt with under separate programmes. METHODS: This paper describes the development of the assessment programmes within the overall policy framework determined by the Council. Peer review of performance in the workplace (Phase 1) is followed by tests of competence (Phase 2) to reflect the relationship between clinical competence and performance. The theoretical and research basis for the approach are presented, and the relationship between the qualitative methods in Phase 1 and the quantitative methods in Phase 2 explored. CONCLUSIONS: The approach is feasible, has been implemented and has stood legal challenge. The assessors judge and report all the evidence they collect and may not select from it. All their judgements are included and the voice of the lay assessor is preserved. Taken together, the output from both phases forms an important basis for remediation and training should it be required.

Clinical Competence↗
PubMed2000

Strategic use of familiarity in display-based problem solving.

The authors report 4 experiments that investigated the role of recognition memory and plausibility in a display-based problem-solving task (computer menu search). It was found that both the familiarity of options and their plausibility played a role in determining choices when the correct options could not be recollected. The use of familiarity was adaptive: Participants relied less on familiarity when it was a less valid guide to correct choices. The implications of these findings for theories of problem solving and learning are discussed.

Adolescent↗
PubMed1999

Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer.

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established second-line hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with well-established methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophin-releasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was well-tolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical-pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.

Adult↗
PubMed1999

Bulky, barrel-shaped cervical carcinoma (stages IB, IIA, IIB): the prognostic factors for pelvic control and treatment outcome.

The purpose of this study was to assess the prognostic factors for pelvic control and the treatment outcome in bulky, barrel-shaped cervical carcinomas. Between September 1980 and December 1992, 65 patients with stage IB or stage IIA-B carcinoma of the uterine cervix classified as barrel-shaped or concentrically expanded (i.e., at least 5 cm in greatest diameter) were treated with curative intent. Forty patients had stage IB or stage IIA carcinoma (according to the classification of the International Federation of Gynecology and Obstetrics [FIGO]), and 25 patients had FIGO stage IIB carcinoma. Seventy-two percent of the patients were treated with radiotherapy (RT) alone and 28% with radiotherapy followed by extrafascial hysterectomy (RT + S). The median follow-up time of surviving patients was 68 months (range 33-172). Survival and control rates were calculated by the Kaplan-Meier method. The 10-year actuarial pelvic control rate was 75% for all patients. The likelihood of pelvic control was not affected by FIGO stage, tumor size, patient's age, histologic features, or treatment modality (RT vs. RT + S). The extent of tumor regression following external beam radiotherapy correlated with the likelihood of local control (p = 0.02). For patients treated with RT alone, increased brachytherapy dose was associated with an increased likelihood of local control. The 10-year actuarial overall and cause-specific survival rates were 53% and 68%, respectively, and did not differ significantly between treatment groups. It is concluded that for most patients with bulky cervical carcinoma, RT alone provides good local control and survival. However, for patients with tumors that respond poorly to external beam radiotherapy, local control and survival are poor. More aggressive treatment protocols should be considered for these patients. The routine use of adjuvant hysterectomy is not recommended.

Adult↗
PubMed1997

A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine.

AIMS: The study was designed to investigate the effects of the H2-receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers. METHODS: Twelve healthy volunteers took part in a randomized placebo-controlled cross-over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (-) enantiomers were determined tby h.p.l.c. RESULTS: Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21-23% increase in Cmax of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (p < 0.05) increased the AUC [mean +/- s.d. (95% C.I. of differences in mean)] for unchanged (+/-)-nebivolol [7.76 +/- 3.07 ng ml-1 h with placebo; 11.50 +/- 5.40 (1.75, 8.76) ng ml-1 h with cimetidine], (+)-nebivolol plus its hydroxylated metabolites [73.0 +/- 18.0 ng ml-1 h with placebo; 91.5 +/- 25.7 (1.0, 23.1) ng ml-1 h with cimetidine] and (-)-nebivolol plus its hydroxylated metabolites [101 +/- 32 ng ml-1 h with placebo; 123 +/- 38 (3.3, 27.0) ng ml-1 h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol. CONCLUSIONS: There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.

Adult↗
PubMed1994

Interactions of steroid, methotrexate, and radiation determine neurotoxicity in an animal model to study therapy for childhood leukemia.

Children with leukemia receive CNS therapy to improve long-term survival. Neurotoxic effects, such as cognitive impairment, have been associated with this therapy. A rat model was developed to determine which agent, or combination of agents, in CNS therapy causes neurotoxicity. The agents examined were cranial irradiation (1000 cGy), methotrexate (2 or 4 mg/kg, intraperitoneally), and prednisolone (18 or 36 mg/kg, intraperitoneally). Young Sprague-Dawley rats were exposed to each agent alone or to two- or three-agent combinations. Each therapy had matched controls that received sham radiation and/or intraperitoneal saline. Subsequent to exposure, spontaneous behavior was tested using a computer pattern recognition system, which recorded and classified behavior in a novel environment. Behavioral initiations, total times, and time structures were compared in therapy and control groups. Combined rather than single-agent therapies had more behavioral effects, and these were dose- and sex-dependent. Synergistic interactions between agents caused behavioral deficits, and components of the combination determined the abnormality. Some combinations interacted antagonistically, and thus mitigated behavioral deficits. Prednisolone was clearly pivotal to behavioral outcome. A low prednisolone dose antagonized methotrexate preventing deficits, whereas a higher prednisolone dose altered behavior by enhancing effects of methotrexate and radiation. These findings emphasize that steroids are important in agent interactions. Their role in morbidity associated with leukemia treatment protocols may be equally important as that of methotrexate and cranial irradiation.

Animals↗
PubMed1994

Radiation effects on growth are altered in rats by prednisone and methotrexate.

CNS therapy for childhood leukemia has adverse effects upon growth and cognition. The cause of these deficits is unknown. In a rat model, we determined which agent, or combination of agents, in CNS therapy affected growth. Young Sprague-Dawley rats were exposed to cranial irradiation (1000 cGy), methotrexate (2 or 4 mg/kg, intraperitoneally), or prednisolone (18 or 36 mg/kg, intraperitoneally) alone or in two- or three-agent combinations. Matched control groups received appropriate sham radiation, intraperitoneal saline, or both. Body weight was recorded from 14 through 150 d of age. After the rats were killed at 150 d, body length was recorded and the head and left femur were removed to determine body and craniofacial proportions. Cranial irradiation alone, but not methotrexate or prednisolone alone, stunted growth permanently and altered craniofacial proportions. When these agents were combined, methotrexate and prednisolone modified the growth response to cranial irradiation. Methotrexate given before cranial irradiation prevented radiation stunting in males. This protection was lost when the dose of methotrexate was increased, when prednisolone was added to the combination, or when females were studied. The protection in males was effective against both growth and behavioral deficits. These results indicate that the physical and behavioral side effects of CNS therapy are better understood in the context of dose, sex, and interactions of the agents.

Animals↗
PubMed1993

Preoperative irradiation for unresectable carcinoma of the rectum.

The records of 20 patients with unresectable carcinoma of the rectum who received preoperative radiation therapy (4,300 to 5,580 cGy) in an attempt to facilitate resection were reviewed. Patients were stratified as unequivocally unresectable at the time of diagnosis or borderline resectable. Thirteen of the 20 patients were able to undergo resection with curative intent after radiotherapy. Patients had follow-up examinations for a minimum of five years, and median survival period for all patients was 43 months with a five year survival rate of 40 percent. Patients stratified to unequivocally resectable survived for a median of only 17 months. Three of the 13 patients who underwent a curative resection had a local recurrence in the pelvic area. Sixteen complications occurred in nine of the 17 patients who underwent any sort of resection, with infectious and wound healing complications being most prevalent. The incidence of complications in similar series is discussed and the need for better selection of patients is addressed.

Adult↗
PubMed1990

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on growth and craniofacial proportion.

Many long term survivors of childhood acute lymphoblastic leukemia have short stature, as well as craniofacial and dental abnormalities, as side effects of central nervous system prophylactic therapy. An animal model is presented to assess these adverse effects on growth. Cranial irradiation (1000 cGy) with and without prednisolone (18 mg/kg i.p.) and methotrexate (2 mg/kg i.p.) was administered to 17- and 18-day-old Sprague-Dawley male and female rats. Animals were weighed 3 times/week. Final body weight and body length were measured at 150 days of age. Femur length and craniofacial dimensions were measured directly from the bones, using calipers. For all exposed groups there was a permanent suppression of weight gain with no catch-up growth or normal adolescent growth spurt. Body length was reduced for all treated groups, as were the ratios of body weight to body length and cranial length to body length. Animals subjected to cranial irradiation exhibited microcephaly, whereas those who received a combination of radiation and chemotherapy demonstrated altered craniofacial proportions in addition to microcephaly. Changes in growth patterns and skeletal proportions exhibited sexually dimorphic characteristics. The results indicate that cranial irradiation is a major factor in the growth failure in exposed rats, but chemotherapeutic agents contribute significantly to the outcome of growth and craniofacial dimensions.

Animals↗
PubMed1990

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on behavior.

Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

Animals↗