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D R Phillips

Publications and source records attributed to D R Phillips.

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

Activity and DNA binding of new organoamidoplatinum (II) complexes.

Two series of organoamidoplatinum (II) complexes were synthesized [Class 1, Pt(NRCH2)2L2 and Class 2, Pt(NRCH2CH2NR2')L(X)] and their antitumour activity examined by a range of in vitro, cellular and animal studies. All Class 1 compounds exhibited activity comparable to cisplatin in mouse leukemia L1210 cells, but were at least 8-fold more active against the cisplatin-resistant L1210/R line. The lead compound 1a (R=p-HC6F4) caused nearly complete tumour regression in the ADJ/PC6 mouse tumour model. Compound 1a exhibited similar DNA reactivity to cisplatin, resulting in virtually identical DNA sequence specificity as cisplatin, and had similar time and concentration dependency of interstrand crosslinks. Compared with cisplatin, la showed 3-fold greater cellular uptake into human ovarian carcinoma 2008 cells, and this was dramatically enhanced to 17-fold in the cisplatin-resistant 2008/R line. The activity of 1a, therefore, appears to be due at least in part to a greater cellular uptake into tumour cells, particularly cisplatin-resistant cells, and once in the cell it reacts with DNA in a similar manner to that of cisplatin. The enhanced uptake and enhanced cytotoxicity of Class 1 compounds, and 1a in particular, may be due to a greater hydrophobicity compared with cisplatin. The activity of the Class 2 compounds, especially in the cisplatin-resistant cell lines, is unusual because they have trans amine ligands, and further study of both classes of compounds is warranted.

Animals↗
PubMed1999

Ageing in rural China: impacts of increasing diversity in family and community resources.

The majority of China's population lives in rural areas and a pattern is emerging of very uneven provision of support for rural elderly people. Local economic conditions and broad demographic trends are creating diversity in the ability both of rural families to care for their elderly kin and in the capacity of communities to support their elderly residents and family carers. In part as a consequence of China's population policy and the 'one-child policy', future Chinese families will have fewer members and be 'older', but they will continue to be regarded emotionally and in policy as the main source of economic and social support for the elderly. The increasing involvement of women in the paid workforce and the changing geographical distribution of family members resulting from work-related migration, are reducing the ability of families to care for their elderly relatives. The availability of resources other than the family for the care of older persons therefore becomes a key issue. Communities in more prosperous, modernising rural areas are often able to provide their elderly residents with welfare and social benefits previously found almost exclusively in urban areas. However, in poorly developed rural areas, provision is either very patchy or non-existent and the local economy cannot support expansion or improvement. A case study in Zhejiang Province illustrates the favourable provision for ageing in a prosperous modernising rural community, in which entitled elderly residents are provided with an impressive array of financial and social benefits. The paper concludes with a consideration of the policy implications of the growing differentiation of the social and economic capacity of rural communities to support their elderly members.

Journal Article↗
PubMed1999

Sequence specificity and reactivity of the binding of phenazine-tethered platinum complexes to DNA.

An in vitro transcription assay was used to probe the sequence specificity of the binding of phenazine-tethered platinum complexes to DNA. It was found that when compared to cis-dichloro(ethylenediamine)platinum(II), the number of RNA polymerase blockage sites was increased by approximately 50% and the blockage sites were broadened by 1-3 nucleotides by the presence of the phenazine ligand. The rate of platination was also enhanced by the presence of the intercalator, and the increase in the kinetics of platination resulted in increased levels of adducts formed (i.e. high drug occupancy) as detected under conditions of active transcription. The level of platination by derivative 3 was 20-fold greater than that of the reference compound, which lacked a tethered intercalating phenazine group.

Antineoplastic Agents↗
PubMed1998

Characterization of covalent adriamycin-DNA adducts.

Adriamycin is a popular antineoplastic agent whose ability to form covalent adducts with DNA has been correlated to cellular apoptosis (programmed cell death) in tumor models. We have isolated and purified this adduct formed under oxido-reductive (Fenton) conditions in Tris buffer. We show by homo- and heteronuclear NMR spectroscopy that the covalent Adriamycin-DNA adduct is structurally equivalent to that resulting from direct reaction with formaldehyde. Covalent linkage of the drug to one of the DNA strands confers remarkable stability to the duplex, indicated by a 162-fold reduction in the rate of strand displacement compared with the complex with noncovalently bound drug. Glyceraldehyde also engenders covalent Adriamycin-DNA complexes, providing a possible relevant biological context for in vivo adduct formation.

Antineoplastic Agents↗
PubMed1998

Atopic eczema and domestic water hardness.

BACKGROUND: The environment plays an important part in the aetiology of atopic eczema, but specific causes are unknown. Exposure to hard water is thought to be a risk factor for eczema. We undertook an ecological study of the relation between domestic water hardness and the prevalence of eczema among Nottinghamshire schoolchildren. METHODS: Questionnaire details of 1-year period and lifetime prevalence of eczema were obtained from parents of 4141 randomly selected primary-school children and 3499 secondary-school children in southern Nottinghamshire. Geographical information systems (GIS) were used to link the geographical distribution of eczema prevalence with domestic water-hardness data (four categories). Adjustment was made for potential confounding by sex, age, socioeconomic status, and access to health care. FINDINGS: Among the primary-school children there was a significant direct relation between both 1-year period and lifetime prevalence of eczema and water hardness, both before and after adjustment for confounders. The 1-year period prevalence was 17.3% (261/1509) in the highest water-hardness category and 12.0% (94/786) in the lowest (adjusted odds ratio 1.54 [95% CI 1.19-1.99] p for trend <0.001). The corresponding values for lifetime prevalence were 25.4% (384/1509) and 21.2% (167/786; adjusted odds ratio 1.28 [1.04-1.58], p for trend=0.02). Eczema prevalence trends in the secondary-school population were not significant (adjusted odds ratio for highest compared with lowest hardness category for 1-year prevalence 1.03 [0.79-1.33], p for trend=0.46; for lifetime prevalence 0.99 [0.83-1.23], p for trend=0.93). Eczema prevalence in primary-school children increased in relation to chlorine content of water, but the trend across four chlorine-content categories was not independently significant after adjustment for confounders. INTERPRETATION: Exposure to hard water in the home may increase the risk of eczema in children of primary-school age.

Adolescent↗
PubMed1998

Upregulation of P-glycoprotein in rat hepatoma rho(o) cells: implications for drug-DNA interactions.

Rat hepatoma cells lacking mitochondrial DNA (rho(o) cells) were used as a model system to examine the possible roles of mitochondrial DNA as a target for the DNA-acting anticancer drug Adriamycin (doxorubicin). The rho(o) cells were 45-fold less sensitive to Adriamycin than the parental rho+ cells containing mitochondrial DNA. Other non-DNA-acting drugs also exhibited similar behaviour, and this was shown to be due to a multidrug resistance (MDR) phenotype in the rho(o) cells. This was indicated by confocal microscopy where rho+ cells exhibited thirteenfold higher cellular levels of Adriamycin than rho(o) cells. Upregulation (tenfold) of P-glycoprotein in rho(o) cells was also confirmed by Northern dot blot analysis. Since the MDR phenotype is present in rho(o) cells and upregulation of P-glycoprotein is maintained in these cells, rho(o) cells are not a good model system for drug-DNA studies (where the drug is susceptible to extrusion by P-glycoprotein), and any such results obtained with this system must be treated with considerable caution.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Tyrosine phosphorylation of the beta3 cytoplasmic domain mediates integrin-cytoskeletal interactions.

Tyrosine phosphorylation of the beta3 subunit of the major platelet integrin alphaIIb beta3 has been shown to occur during thrombin-induced platelet aggregation (1). We now show that a wide variety of platelet stimuli induced beta3 tyrosine phosphorylation, but that this phosphorylation occurred only following platelet aggregation. Several lines of evidence suggest that the beta3 cytoplasmic domain tyrosine residues and/or their phosphorylation function to mediate interactions between beta3 integrins and cytoskeletal proteins. First, phospho-beta3 was retained preferentially in a Triton X-100 insoluble cytoskeletal fraction of thrombin-aggregated platelets. Second, in vitro experiments show that the cytoskeletal protein, myosin, associated in a phosphotyrosine-dependent manner with a diphosphorylated peptide corresponding to residues 740-762 of beta3. Third, mutation of both tyrosines in the beta3 cytoplasmic domain to phenylalanines markedly reduced beta3-dependent fibrin clot retraction. Thus, our data indicate that platelet aggregation is both necessary and sufficient for beta3 tyrosine phosphorylation, and this phosphorylation results in the physical linkage of alphaIIb beta3 to the cytoskeleton. We hypothesize that this linkage may involve direct binding of the phosphorylated integrin to the contractile protein myosin in order to mediate transmission of force to the fibrin clot during the process of clot retraction.

Amino Acid Sequence↗
PubMed1998

An in vitro transcription assay for probing drug-DNA interactions at individual drug sites.

An in vitro transcription assay of drug-DNA interactions has been described and is based largely on the stable lac UV5-initiated transcription complex. This system utilizes a synchronized population of radiolabeled nascent RNA 10 nucleotides long. Reaction of this initiated transcription complex with drug and subsequent elongation of the nascent RNA by Escherichia coli RNA polymerase, reveals blockages at drug binding sites. From these blockages it is possible to obtain four features of the drug-DNA interaction: the sequence of preferred drug binding sites, the relative drug occupancy at each binding site, the drug dissociation rate at each site, and the probability of drug-induced termination of transcription at each site. The unidirectional transcription assay has been extended to a two-promoter, counter-directed system, which yields a bidirectional transcription footprint of drug sites.

Autoradiography↗
PubMed1998

The problem of atopic eczema: aetiological clues from the environment and lifestyles.

Atopic eczema is the most common inflammatory skin disease in children, affecting around 10% of children in the developed world. It can be a distressing condition, influencing children's well-being, personal and educational development, and family life, and it has huge economic implications for health services and individual budgets. Like other atopic diseases such as asthma and hay fever, the prevalence of atopic eczema has increased substantially over the last 30 years, for reasons largely unknown. Although a genetic predisposition to the disease has been implicated, evidence from a range of sources suggests that environmental factors play a crucial role in the disease expression. This paper reviews the epidemiology of atopic eczema, with particular attention to potential environmental aetiological factors and draws evidence from studies in the UK and internationally. First, atopic eczema has been found to vary socially and to be more prevalent in the UK among social class I and II families than among other socio-economic groups. Second, it has been suggested that cross infection from other siblings in large families may have a protective role in atopic disease expression. Third, it has been proposed that an increased risk of atopic eczema may result from decreases in helminthic infestation. Fourth, studies of migrant groups have shown large increases in disease prevalence compared with migrants' country of origin, suggesting clues as to the importance of socio-economic and environmental changes such as those associated with industrialization. Finally, a distinct and consistent geographical pattern of eczema has been observed in the UK which cannot be explained by social class distribution. The various types of study have attempted to identify reasons for differences in prevalence but, to date, no definitive causation has been identified. In some cases, specific risk factors have been suggested and include house dust mites, dietary allergens and irritants. It is argued here that the aetiology is unlikely to be simple or uni-causal and that an understanding of the relationships between the disease and behaviour, lifestyle, home and external environmental factors is crucial. This paper reports the preliminary stages of an interdisciplinary research project involving dermatologists, epidemiologists and health geographers, and calls for investigation into associations between atopic eczema and possible environmental and lifestyle factors. These include behavioural factors, microenvironment factors and macroenvironments.

Causality↗
PubMed1998

Focus groups in dermatology.

Focus groups have considerable potential for study of the attitudes and experiences of patients and health care providers within dermatology. This article describes the use of such groups, using specific dermatological examples.

Attitude to Health↗
PubMed1997

Effect of Ca2+ on GP IIb-IIIa interactions with integrilin: enhanced GP IIb-IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate.

BACKGROUND: Integrilin (eptifibatide), a potent inhibitor of the fibrinogen binding function of GP IIb-llla, has been shown to reduce the thrombotic complications of angioplasty and of acute coronary syndromes. The present study was designed to determine whether the reduced Ca2+ concentrations in plasma anticoagulated with citrate affect Integrilin binding to GP IIb-IIIa and the ex vivo pharmacodynamic measurements for this drug. METHODS AND RESULTS: Lower concentrations of Integrilin were found to inhibit platelet aggregation in plasma anticoagulated with citrate (for ADP, mean+/-SD IC(50)=140+/-40 nmol/L, n=6; Ca2+ =40 to 50 micromol/L) than with PPACK (IC(50)=570+/-70 nmol/L, P<.0001, n=6; Ca2+ approximately 1 mmol/L). Chelation of Ca2+ with EDTA or citrate caused a similar degree of enhancement in the inhibitory activity of Integrilin. Measurements of D3 LIBS epitope expression showed that the enhanced inhibitory activity was caused by enhanced GP IIb-IIIa occupancy by Integrilin. Citrate anticoagulation decreased the amounts of Integrilin required to inhibit the binding of PAC1, a monoclonal antibody that mimics the GP IIb-IIIa binding activity of fibrinogen. Reduced Ca2+ also increased Integrilin inhibition of the binding of biotinylated fibrinogen to purified, immobilized GP IIb-IIIa. CONCLUSIONS: These data suggest that citrate anticoagulation removes Ca2+ from GP IIb-IIIa and enhances the apparent inhibitory activity of Integrilin. This finding indicates that the inhibitory activity of Integrilin is overestimated in blood samples collected with citrate, suggesting that it may be possible to achieve greater antithrombotic efficacy beyond that observed in clinical trials to date with Integrilin.

Antibodies, Monoclonal↗
PubMed1997

Clinical pharmacology of eptifibatide.

Activation of receptor function of platelet membrane glycoprotein (GP) IIb-IIIa leads to the binding of fibrinogen and is the final common pathway to platelet aggregation. Platelet aggregates provide the structural basis for coronary thrombosis, a major cause of ischemic heart disease. GP IIb-IIIa has a narrow tissue distribution, being found only on platelets and their progenitors, and inhibition of its receptor function has emerged as a promising new therapeutic strategy for management of acute ischemic coronary syndromes and acute ischemic complications of percutaneous coronary interventions. Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa inhibitor from the venom of the southeastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. Preclinical pharmacologic studies have established that eptifibatide can inhibit thrombosis effectively, with only modest effects on bleeding time measurements. Pharmacokinetic and pharmacodynamic studies in both animal models and humans have shown that the antiplatelet effect of eptifibatide has a rapid onset of action and that the drug has a short plasma half-life. Furthermore, the rapid reversibility of action of eptifibatide, exemplified by an antihemostatic effect limited to the period of drug administration, was apparent in both healthy volunteers and patients with ischemic heart disease. In clinical trials, eptifibatide has not been found to be immunogenic or to induce thrombocytopenia. These studies have led to the evaluation of eptifibatide in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial, which enrolled 4,010 patients undergoing coronary angioplasty. The combination of a bolus plus either of 2 infusion doses of eptifibatide reduced the incidence of ischemic complications without increasing the risk of bleeding or other complications. Recent pharmacodynamic studies have established that more aggressive dosing of eptifibatide provides greater inhibition of ex vivo platelet aggregation and more robust antithrombotic activity. Higher doses of eptifibatide were therefore selected for the Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, which enrolled patients with unstable angina or non-Q-wave myocardial infarction. The available data suggest that eptifibatide may represent a useful clinical alternative to existing antiplatelet therapies.

Animals↗
PubMed1997

Neutrophil-mediated activation of mitoxantrone to metabolites which form adducts with DNA.

In this study we have shown that phorbol ester-stimulated human neutrophils are able to oxidatively activate mitoxantrone and result in covalent incorporation of the drug into cellular DNA. The use of the myeloperoxidase inhibitor sodium azide confirmed that the activation and covalent binding of mitoxantrone to cellular DNA was due to its metabolism by the haem enzyme myeloperoxidase. Phorbol ester-stimulated neutrophils were also able to oxidatively metabolise mitoxantrone and facilitate extracellular covalent binding of the drug to calf thymus DNA. These results suggest that myeloperoxidase may contribute to the mode of action of mitoxantrone.

Animals↗
PubMed1997

The effect of dilute vasopressin solution on the force needed for cervical dilatation: a randomized controlled trial.

OBJECTIVE: To assess the force needed to mechanically dilate the cervix of a nonpregnant woman after intracervically injecting dilute (0.05 U/mL) vasopressin solution. METHODS: In a randomized, double-blind study, equal amounts of either a dilute vasopressin solution or placebo (normal saline) were injected into the intracervical stroma at 4- and 8-o'clock positions, just beneath the mucosal surface, in 52 women immediately before cervical dilatation in preparation for operative hysteroscopy. When vasopressin solution was used, 20 mL of a dilute solution (4 U of 0.05 U/mL of vasopressin in 80 mL of normal saline) was injected. An electronic strain gauge and load cell were used to measure the peak linear force needed to dilate the cervix from 3 mm to 11 mm, using half-size metal dilators. RESULTS: The mean (+/- standard error of the mean) total peak linear force needed to dilate the cervix from 3 to 11 mm in the treated (vasopressin) and control (placebo) groups was 20.29 +/- 1.22 lb (range 5.54-40.82) and 37.05 +/- 2.55 lb (range 6.11-52.2), respectively, a statistically significant difference. The mean total peak linear force needed to dilate the cervix in the treated group and in the control group in 0.5-mm increments from 3 to 11 mm was 1.14 +/- 0.07 lb (range 0.81-1.69) and 2.08 +/- 0.07 lb (range 1.64-2.43), respectively, also a statistically significant difference. With increasing parity, significantly less force was needed to dilate the cervix from 3 to 11 mm in the treated group than in the control group (P < .001). CONCLUSIONS: Administration of dilute vasopressin solution (0.05 U/mL) to the cervical stroma significantly reduces the force needed to dilate the cervix.

Adult↗
PubMed1997

Experience with laparoscopic leiomyoma coagulation and concomitant operative hysteroscopy.

STUDY OBJECTIVES: To evaluate the experiences of women who underwent laparoscopic leiomyoma coagulation (myolysis) alone and those who had myolysis in conjunction with transcervical endomyometrial resection (TEMR), transcervical electrosurgical resection of submucous leiomyomas (TSR), or both. DESIGN: Continuing, prospective observational study with mean (+/- SEM) follow-up of 36.0 +/- 1.2 months (range 18-54 mo). SETTING: Gynecology department of community and teaching hospitals. PATIENTS: One hundred sixty-seven women with symptomatic leiomyomata. INTERVENTIONS: Women complaining of pressure, pain, or both underwent only myolysis. Those with the additional symptom of chronic menorrhagia underwent TEMR, TSR, or both. Nineteen (11.4%) of the 167 women had elective second-look laparoscopy 6.0 +/- 0.3 months (range 6-8 mo) later to evaluate possible adhesion formation. MEASUREMENTS AND MAIN RESULTS: Main outcome measures were control of symptoms, numbers and types of concomitant and subsequent procedures, changes in uterine and leiomyomata volumes, and number of successful pregnancies. Mean total uterine volume of the 167 women decreased from 620 +/- 28.4 cm3 before leuprolide treatment to 131 +/- 7.2 cm3 by 7 to 12 months postoperatively (p <0.0001). Five (3.6%) women had hysterectomies for persistent or recurrent menorrhagia, pain, pressure, or a combination of symptoms (p = 0.01). Pathologic evaluation revealed adenomyosis, leiomyomata, or both. Of 52 women with chronic menorrhagia, 33 (63.5%) developed amenorrhea and 17 (32.7%) developed hypomenorrhea or eumenorrhea; 2 (3.8%) required repeat TEMR. The two women who desired to retain fertility had uncomplicated full-term pregnancies and uneventful vaginal deliveries. CONCLUSIONS: Myolysis alone or in conjunction with TEMR, TSR, or both obviated the need for major surgery in 162 (97.0%) women. Until further studies are concluded, myolysis should be performed selectively in women contemplating pregnancy.

Adult↗
PubMed1997

Preventing hyponatremic encephalopathy: comparison of serum sodium and osmolality during operative hysteroscopy with 5.0% mannitol and 1.5% glycine distention media.

STUDY OBJECTIVE: To determine whether isotonic 5.0% mannitol is superior to 1.5% glycine in preventing development of hyponatremic encephalopathy. DESIGN: Prospective, comparative study (Canadian Task Force classification II=2). SETTING: Gynecology department of a community hospital. PATIENTS: One hundred twenty-two women undergoing operative hysteroscopy. INTERVENTIONS: Eighteen blood serum chemical indicators analyzed preoperatively and postoperatively in 61 women undergoing operative hysteroscopy with 1. 5% glycine (group 1) were compared with those of 61 women having similar surgery with 5.0% mannitol (group 2). Fluid deficit (difference between input and output volume of distention fluid) was recorded, and differences between presurgical and postsurgical indicators of the two groups (mean difference score) were compared. MEASUREMENTS AND MAIN RESULTS: Mean +/- SEM sodium difference scores of groups 1 and 2 were -1.73 +/- 0.42 mEq/L (range -7.00 to 2.00 mEq/L) and -5.04 +/- 1.07 mEq/L (range -36.00 to 3.00 mEq/L), respectively (p <0.01). Serum osmolality difference scores were -6. 88 +/- 1.36 mmol/L (range -13.00 to -1.00 mmol/L) and -1.87 +/- 0.35 mmol/L (range -3 to 15 mmol/L), respectively (p <0.01). Distention fluid deficits were 0.435 +/- 0.071 L (range 0-2.448 L) and 0.473 +/- 0.084 L (range 0-3.640 L), respectively (p = 0.862). Two women (3.4%) in group 1 and five (8.2%) in group 2 developed postoperative asymptomatic dilutional hyponatremia (p = 0.211), which was the only complication. Two of the five women in group 2 developed severe dilutional hyponatremia. CONCLUSION: We found that 5.0% mannitol distention fluid produces greater postoperative dilutional hyponatremia than 1.5% glycine, but hypo-osmolality does not occur with mannitol. Its use should lessen the risk of hyponatremic encephalopathy.

Adult↗