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Biomedical subjects

D Edwards

Publications and source records attributed to D Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1999

Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials.

We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.

Animals↗
PubMed1999

Helical computed tomography and three-dimensional reconstruction of a bipedicular developmental anomaly of the C2 vertebra.

STUDY DESIGN: A case of bilateral failure of fusion of the C2 neural arch resembling a bipedicular fracture in a 9-year-old boy involved in a motor vehicle accident. OBJECTIVES: To describe the use of helical computed tomography and three-dimensional reconstruction images to identify the defect as congenital. SUMMARY OF BACKGROUND DATA: Congenital defects in the C2 neural arch are rare. Diagnostic difficulties arise when they are discovered during the assessment of patients after trauma, when they may resemble C2 arch fractures. METHODS: Lateral cervical spine radiograph, transverse section computed tomography, and three-dimensional reconstruction images were used to delineate the anatomy of the defect. RESULTS: The three-dimensional reconstruction views showed that normal alignment of the vertebrae was maintained, despite the pedicle defects. CONCLUSIONS: Differentiation of a C2 fracture from a congenital defect may be difficult. Reconstruction in three dimensions from helical computed tomography is a useful adjunct to conventional computed tomography in the evaluation of such patients.

Cervical Vertebrae↗
PubMed1999

On model prespecification in confirmatory randomized studies.

Typically, the primary purpose of confirmatory randomized trials, such as drug trials sponsored by the pharmaceutical industry, is to determine whether there is a treatment effect, and if there is, to estimate the size of the effect. For such studies it is accepted practice to prespecify the statistical model to be used in the primary analysis. The reason for this is a concern that if the model were to be chosen on the basis of the data, the model most favourable to the sponsor might be chosen, with consequent inflation of the type I error. The purpose of this article is to show that, in a sense, this concern is needless. It is shown that if the model is chosen in a blinded fashion and randomization-based tests for no treatment effect are used, then the type I error is controlled. A similar technique to derive unbiased estimates of treatment effect is also described. This approach may be of value when there is uncertainty as to the correct model when the study is being planned.

Bias↗
PubMed1999

Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340.

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.

Animals↗
PubMed1999

Alcohol effects on mood, equilibrium, and simulated driving.

BACKGROUND: The effects of alcohol on simple versus complex psychomotor performance were compared in 18 adults. METHODS: Subjects received ethanol doses of 0.0, 0.5, and 0.8 g/kg in a randomized, double-blind, within-subject design. Forty minutes after finishing their drinking, the subjects completed a 60-min battery of tests that included: 1) a sensory organization posturography test (EquiTest); 2) latency to apply the brake after appearance of a barrier in a driving simulator (brake reaction time); 3) visual analog subjective-effects scales (VAS); 4) the Profile of Mood States (POMS); 5) critical flicker fusion (CFF); and 6) choice reaction time (CRT). RESULTS: Alcohol dose dependently reduced composite equilibrium scores and increased brake reaction time. On the CRT task, total reaction time was significantly increased after the high dose but not the low dose. Alcohol dose dependently increased VAS "dizzy," "high," and "drug effect" ratings. The POMS and CFF were not significantly affected by alcohol. CONCLUSIONS: These data suggest that an ethanol dose that neither influences certain mood states nor impairs simple psychomotor task performance nonetheless may impair equilibrium and complex psychomotor tasks (e.g., driving).

Adult↗
PubMed1998

Mum's the word: mothers' perspectives on communication about sexuality with adolescents.

Mothers' perceptions of the style, content and frequency of their communications with their adolescents about sex and sexuality were examined. We administered semi-structured interviews to 30 mothers of 16-year-olds (16 mothers of sons, 14 mothers of daughters). Despite a uniform assessment that they were effective sexual communicators, mothers varied greatly in their style of sexual communication. Qualitative analyses revealed five communication styles: avoidant, reactive, opportunistic, child-initiated and mutually interactive. These styles differed in who initiated and maintained sexual communication, the comfort level of mother and of teenager, the frequency of sexual communications, the context in which communications took place and the topics discussed and avoided.

Adolescent↗
PubMed1998

Head and neck cancer services: views of patients, their families and professionals.

OBJECTIVES: To explore views of patients, their families and professionals about head and neck cancer services. METHODS: Focus group interviews of 33 patients and relatives and 33 professionals from four hospitals and two patient support groups in SouthEast England. RESULTS: Although patients and relatives were grateful for their care, many thought that some areas could be improved. Many thought that their ward facilities were inappropriate. Patients wanted to have more information about the impact of their treatment and about different treatment options whereas professionals tended to concentrate on giving information about the details of operations. Counselling services were often found to be inaccessible and inappropriate. Administrative difficulties were a major source of frustration for professionals, as were failure of treatment and communication difficulties. Professionals valued joint clinics and a team approach in keeping up to date, in clinical decision making, and in providing mutual support. CONCLUSION: The findings highlight areas that could be improved which would benefit both patients and professionals.

Communication↗
PubMed1998

A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.

In a multicentre, double-blind, parallel-group, placebo-controlled trial, a three-times daily regimen of tiagabine was evaluated as add-on therapy in 154 adult patients with refractory partial seizures. A total of 77 patients were randomised to treatment in each arm. Tiagabine HCl was titrated from an initial dose of 12-30 mg/day over 4 weeks. During the 12-week fixed-dose period, there was a significant reduction in the median 4-weekly seizure rate for all partial seizures and simple partial seizures (P < 0.05 in each case). Furthermore, the proportion of patients with a reduction of 50% or more in all partial seizures was higher in the tiagabine group than in the placebo group (14 versus 6%), though the difference did not achieve statistical significance. The difference with respect to simple partial seizures was significant (21 versus 6%, P < 0.01). The percentage of patients achieving an increase of at least 50% in the proportion of days free of all partial seizures was significantly greater in the tiagabine group compared to placebo (14 versus 4%, P<0.01). Tiagabine did not appear to influence the plasma concentrations of other concomitant antiepileptic drugs and was generally well tolerated, with most drug-related adverse events being mild or moderate in severity. The most common adverse events were dizziness, asthenia, headache and somnolence. Adverse event incidence was similar between tiagabine and placebo groups, except for dizziness which was more common with tiagabine (29 versus 10%, P < 0.01). Tiagabine had no significant effects on laboratory tests or vital signs. The present study shows that tiagabine, at a dose of 10 mg administered three-times daily, which is at the lower end of the usual recommended dose range (30-50 mg/day, tiagabine base), is generally well tolerated and demonstrates efficacy for the treatment of refractory partial seizures.

Adolescent↗
PubMed1998

Multiple genes encoding the conserved CCAAT-box transcription factor complex are expressed in Arabidopsis.

The CCAAT motif is found in the promoters of many eukaryotic genes. In yeast a single complex of three proteins, termed HAP2, HAP3, and HAP5, binds to this sequence, and in mammals the three components of the equivalent complex (called variously NF-Y, CBF, or CP1) are also represented by single genes. Here we report the presence of multiple genes for each of the components of the CCAAT-binding complex, HAP2, 3,5, from Arabidopsis. Three independent Arabidopsis HAP subunit 2 (AtHAP2) cDNAs were cloned by functional complementation of a yeast hap2 mutant, and two independent forms each of AtHAP3 and AtHAP5 cDNAs were detected in the expressed sequence tag database. Additional homologs (two of AtHAP3 and one of AtHAP5) have been identified from available Arabidopsis genomic sequences. Northern-blot analysis indicated ubiquitous expression for each AtHAP2 and AtHAP5 cDNA in a range of tissues, whereas expression of each AtHAP3 cDNA was under developmental and/or environmental regulation. The unexpected presence of multiple forms of each HAP homolog in Arabidopsis, compared with the single genes in yeast and vertebrates, suggests that the HAP2,3,5 complex may play diverse roles in gene transcription in higher plants.

Amino Acid Sequence↗
PubMed1998

The case study as a scientific method for researching alternative therapies.

This article argues that the case study design is a research method capable of providing valuable data and insight into alternative therapies. The background and roots of the case study in medicine and clinical practice are covered, and the status of the case study as a scientific method is examined. The highly regarded randomized controlled clinical trial--though often powerful and useful--is neither feasible nor ideal for understanding the effects of many unconventional treatment approaches. Given the complexity of the factors involved in unconventional therapeutic applications--health beliefs, changing health paradigms, patient/practitioner interactions, multiple treatment modalities, multiple symptom profiles--the case study approach offers an alternative methodological route for investigating and generating findings in this arena. Reliability and validity of data collection, data reduction, and interpretation can be enhanced through steps discussed in this article. As it continues to work with evidence that is currently unorganized, the field of alternative medicine can benefit both in clinical prowess and scientific stature from additional, carefully conducted case studies.

Complementary Therapies↗