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Biomedical subjects

S Watson

Publications and source records attributed to S Watson.

At least 37 records · Page 2Linked to original sources
PubMed1999

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

Adolescent↗
PubMed1999

Vinblastine pharmacokinetics in patients with non-small cell lung cancer given cisplatin.

The pharmacokinetics of vinblastine were studied in 16 patients with non-small cell lung cancer after a bolus intravenous dose of 3 mg/m2 given before or after cisplatin (100 mg/m2). Venous blood was collected at 0, 10, and 36 hr for analysis by radioimmunoassay. The mean plasma vinblastine concentration at 10 hr was similar when vinblastine was given before (4.8 ng/ml; 95% CI, 3.2-6.3) or after cisplatin (4.9 ng/ml; 95% CI, 2.7-7.1). Plasma vinblastine concentrations in patients given cisplatin were higher than previously reported in patients given vinblastine alone. Patients with plasma vinblastine concentrations less than 2.75 ng/ml at 10 hr experienced less severe neutropenia (37% fall in neutrophil count; 95% CI, 18-55) than those with levels greater than 2.75 ng/ml (69% fall in neutrophil count; 95% CI, 62-77). In conclusion, the pharmacokinetics of vinblastine predict the severity of neutropenia and may be altered when given in conjunction with cisplatin.

Aged↗
PubMed1999

Structure-based drug design: combinatorial chemistry and molecular modeling.

Drug discovery efforts are shifting to include the rapid synthetic procedures of combinatorial chemistry and the elegance of rational library design. The wealth of computational methods which explore both the receptor structure and the ultimate pharmacophore complementarity, provide novel avenues for chemists to discover new lead compounds or design virtual libraries for screening prior to the synthetic stage. This mini-review provides an overview of a few current methodologies of library generation, highlighting docking procedures which have utility in both the discovery and optimization stages of drug development. Three specific examples of different approaches to the use of docking are provided. These describe the development of inhibitors to the human A3 adenosine receptor and HIV-1 protease, and the evaluation of the activity of novel inhibitors of the redox regulator protein, human thioredoxin.

Chemistry, Organic↗
PubMed1999

Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as potential antitumor agents.

We have reported previously that unsymmetrical disulfide inhibitors of the human thioredoxin/thioredoxin reductase redox system (hTrx/TR) possess antitumor activity. We have broadened the search for more potent inhibitors and evaluated a large range of mono- and bis-disulfide compounds, prepared using parallel syntheses. Reaction of isothioisourea-HCI salts (R') or bis-salts (R) with aromatic or aryl thiols (R") in wells of 96-well plates produced >450 derivatives with the structures R"SSR' and R"SSRSSR". The excellent yield and purity of the disulfides provided sufficient material for evaluations of enzyme inhibition and cytotoxicity. Selection criteria based on the IC50 values for hTrx/TR inhibition and for cytotoxicities of the disulfides identified agents for subsequent scale-up syntheses and in vivo evaluations of antitumor activity. These scale-up studies confirmed the original activities of agents synthesized in the plates and validated the parallel synthetic approach. Structure-activity information derived from the hTrx/TR IC50 data allow for a number of generalizations. The most potent inhibitors of the Trx system contained two heteroatoms ortho to the disulfide moiety in an aromatic functionality. The thioalkylating moieties had greatest activity with one branch point alpha to the disulfide. In the absence of branching, more potent inhibition was observed with the electron withdrawing functionalities. Bis-disulfides showed patterns of activity which depended on chain length, with optimum activity observed when the disulfide units were separated by 3.9 A, a similar distance to that separating the thioredoxin active site cysteine residues. From the agents selected for scale-up syntheses, three disulfide compounds were studied for their antitumor activity in vivo against human tumor xenografts in scid mice. One of the analogues discovered through the combinatorial syntheses/screening for Trx inhibition, 1-phenylethyl 2-imidazolyl disulfide, N1 (ProlX agent PX-C5), has demonstrated excellent in vivo activity against the MCF-7 human breast cancer and the HL-60 human leukemia, thus validating this approach for novel drug discovery.

Animals↗
PubMed1998

Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity.

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.

Angiotensin II↗
PubMed1998

Enhancing motivation for change in treatment-resistant eating disorders.

Denial and resistance to change are prominent features in most patients with anorexia nervosa. The egosyntonic quality of symptoms can contribute to inaccuracy in self-report, avoidance of treatment, difficulties in establishing a therapeutic relationship, and high rates of attrition and relapse. Individuals with bulimia nervosa are typically more motivated to recover, but often ambivalent about forfeiting the ideal of slenderness and the protective functions of binge-purge behavior. Few attempts have been made to assess denial and resistance in the eating disorders, or to examine alternative strategies for enhancing motivation to change. Review of the clinical literature indicates a striking convergence of recommendations across conceptually distinct treatment approaches. Clinicians are encouraged to acquire a frame of reference that can help them understand the private experience of individuals with eating disorders, empathize with their distress at the prospect of weight gain, and acknowledge the difficulty of change. The Socratic method seems particularly well-suited to work with this population because of its emphasis on collaboration, openness, curiosity, patience, focused and systematic inquiry, and individual discovery. Four themes are crucial in engaging reluctant eating-disordered clients in therapy: the provision of psychoeducational material, an examination of the advantages and disadvantages of symptoms, the explicit use of experimental strategies, and an exploration of personal values.

Attitude of Health Personnel↗
PubMed1998

Accuracy of a new wrist cuff oscillometric blood pressure device: comparisons with intraarterial and mercury manometer measurements.

Accurate measurement of arterial blood pressure is of great importance for the diagnosis and treatment of hypertension. Because of the chronic nature of antihypertensive drug therapy, the involvement of the patient in blood pressure control is desirable. Such an involvement, however, is only feasible if simple, user-friendly, and precise blood pressure measurement devices are available. In this study we tested a new wrist cuff oscillometric blood pressure measurement device in 100 consecutive patients undergoing cardiac catheterization. Blood pressures were simultaneously taken intraarterially (axillary artery) and with a mercury manometer and stethoscope or noninvasive measurement device (OMRON R3). Intraarterial measurements were directly compared with two measurements taken in random order with either an arm cuff mercury manometer or the wrist cuff device. Systolic and diastolic blood pressure as assessed with the mercury manometer was higher, especially when compared with the intraarterial and the wrist cuff values, which were comparable. Correlations of blood pressure values with intraarterial measurement were 0.86 systolic and 0.75 diastolic (P < .01) for the wrist cuff and 0.84 systolic (P < .01) and 0.59 diastolic (P < .05) for the mercury manometer measurements. Reproducibility of both measurements was good for the wrist cuff device ([systolic/diastolic]: r = 0.94/0.92; P < .01) and the mercury manometer (r = 0.97/0.88; P < .01). Both methods overestimated high diastolic values, whereas only the wrist cuff underestimated high systolic values. Thus, the new oscillometric wrist cuff blood pressure measurement device measures arterial blood pressure with great accuracy and reproducibility. As compared with intraarterial values, the wrist cuff device overestimated high diastolic and underestimated high systolic blood pressure values. Blood pressure values as measured by the mercury manometer were higher than intraarterial values and those of the wrist cuff. Both noninvasive devices overestimated high diastolic values.

Blood Pressure Determination↗
PubMed1998

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer.

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.

Adult↗
PubMed1998

Ifosfamide-based three-drug combination regimens in non-small cell lung cancer.

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has expanded in recent years, resulting in increased median survival and higher 5-year survival rates in some studies. Few patients with NSCLC can be cured, however, and the median survival time is still modest. Research strategies are aimed at identifying new active single agents, testing their combination in non-cisplatin- and non-carboplatin-containing regimens, and their incorporation into regimens containing more than two drugs, in efforts to improve response and survival and/or reduce toxicity. Several trials of triplet chemotherapy combinations for the treatment of NSCLC have been conducted at the University of Chicago. The three-drug regimen of vinorelbine, paclitaxel, and ifosfamide with granulocyte colony-stimulating factor was evaluated in a phase I trial. Doses of all three drugs were reduced from their standard doses so that toxicity would be manageable, although toxicity was still high. The low response rate (<20%) at the recommended phase II doses led to early closure of this trial. The University of Chicago is also assessing the three-drug combination of carboplatin, paclitaxel, and ifosfamide in patients with stage IIIB and IV NSCLC. The carboplatin and paclitaxel doses are being maintained within their active single-agent range, with the goal of identifying the maximum tolerated dose of ifosfamide when added to this combination. Additional end points include response rates, survival time, and dose-limiting toxicities. This study is ongoing.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

The effects of massage: an holistic approach to care.

In this article the authors review the benefits of massage and its relationship and relevance to more orthodox therapies. Most studies of the effects of massage on patients' wellbeing have been undertaken by non-nursing researchers and the authors suggest that more nurse-based research would make an important contribution to an holistic approach to care. Interest in, and the use of, complementary therapies has been growing over recent years. Massage seems to be of particular interest to nurses, involving as it does the close, intimate contact which nurses are often engaged in as part of their day-to-day work with patients. The benefits, and some of the problems, associated with massage are explored below.

Clinical Nursing Research↗
PubMed1997

The effect of circulating antigen on the biodistribution of the engineered human antibody hCTM01 in a nude mice model.

Clinical studies are currently underway to assess the biodistribution and therapeutic potential of the genetically engineered human antibody hCTM01 directed against polymorphic epithelial mucin (PEM) in patients with ovarian carcinoma. The present study was undertaken to assess the effect of circulating PEM antigen on the biodistribution of the anti-PEM antibody in mice bearing MUC-1 transfected adenocarcinoma cell lines. Tumour xenografts were established from three cell lines: 413-BCR, which expressed antigen on the cell surface and also shed antigen into the circulation, E3P23, which expressed the antigen but did not shed into the circulation, and a negative control (410.4 MUCI). Groups of five mice were injected with 1.0 mg/kg antibody, imaged after 72 h and then sacrificed, followed by assay of tissue uptake. The results showed a clear difference in the tumour and liver uptake, with the non-secreting cell line showing almost twice the tumour uptake and approximately 20% of the liver uptake of the secreting cell line.

Adenocarcinoma↗
PubMed1997

Statistical analysis of data for three British ethnic groups from a new STR multiplex.

Data have been collected from 602 Caucasians, 190 Afro-Caribbeans and 257 Asians of Indo/Pakistani descent who have been profiled using a new six locus short tandem repeat (STR) multiplex. The data have been analysed by conventional significance testing methods: the exact test, homozygosity, and conventional goodness of fit to Hardy-Weinberg proportions. Frequency tables are given and the expected performance in British forensic casework is discussed.

Chromosome Mapping↗
PubMed1997

Patterns of prolapse in women with symptoms of pelvic floor weakness: assessment with MR imaging.

PURPOSE: To show the magnetic resonance (MR) imaging patterns of prolapse and to correlate them with symptoms in patients with constipation or fecal incontinence. MATERIALS AND METHODS: Thirty women underwent MR imaging with fast spoiled gradient-recalled acquisition in the steady state. The women were divided into three groups: 10 were asymptomatic volunteers, 10 had constipation, and 10 had fecal incontinence. Visceral prolapse and the configuration of the pelvic floor muscles were identified at rest and during straining. Visceral descent was compared between the three groups. RESULTS: Visceral prolapse was seen at multiple sites, most frequently in constipated patients. There was significantly greater bladder base descent (P < .01), uterocervical descent (P < .001), and puborectalis muscle ballooning (P < .05) in the group of constipated patients when compared with the group with fecal incontinence or the asymptomatic group. The degree of anorectal junction descent was significantly greater (P < .05) in the group of incontinent patients when compared with the asymptomatic group. CONCLUSION: MR imaging clearly shows pelvic visceral prolapse and pelvic floor configuration on straining. Prolapse frequently involves multiple sites in constipated patients, which is suggestive of global pelvic floor weakness. In contrast, the weakness is frequently posterior in fecally incontinent patients.

Adult↗
PubMed1997

Dynamic MR imaging compared with evacuation proctography when evaluating anorectal configuration and pelvic floor movement.

OBJECTIVE: The aim of this study was to determine the agreement between measurements of the anorectal configuration made with dynamic MR imaging and with evacuation proctography. SUBJECTS AND METHODS: Ten women with constipation were examined sequentially using both standard evacuation proctography and dynamic MR imaging. Correlation and agreement between standard measurements of anorectal configuration at rest and during straining or evacuation of the rectum were evaluated. RESULTS: Significant correlation existed for anorectal junction descent (r = .7, p = .023), change in the anorectal angle (r = .78, p = .008), the position of the rectal axis on straining (r = .62, p = .032), and rectocele depth (r = .82, p = .004). The mean of the measurement differences for anorectal junction descent as measured using the two techniques was -0.23 cm (SD, 1.40 cm). The mean of the measurement differences for change of the anorectal angle was +15.3 degrees (SD, 27.92 degrees). CONCLUSION: Standard measurements of anorectal configuration made using evacuation proctography and dynamic MR imaging show significant correlation. However, in our study statistical agreement was poor for measurement of anorectal junction descent and anorectal angle change as seen on imaging obtained with the two techniques.

Adult↗
PubMed1997

Paclitaxel/carboplatin plus ifosfamide in non-small cell lung cancer.

Chemotherapy has a positive role in managing patients with stage IV non-small cell lung cancer. Randomized studies and meta-analyses comparing chemotherapy with best supportive care have confirmed a significant prolongation of survival for chemotherapy-treated patients. In recent years, several new active agents have been identified. These include the taxanes paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and docetaxel, the antimetabolite gemcitabine, the mitotic spindle inhibitor vinorelbine, and (potentially) the topoisomerase I inhibitors. Combinations of either vinorelbine or paclitaxel with cisplatin have resulted in a significant increase in median survival times compared with both cisplatin and vindesine and cisplatin and etoposide. Paclitaxel combined with either carboplatin or ifosfamide also has been promising. Since even the best current combination regimens result in median survival times of less than 1 year, the identification of more active drugs and combinations remains a high priority. One possible strategy to identify more active regimens may be the combination of three rather than two active agents into a combination regimen. Although the three-drug regimens used in the 1980s appeared to be no more active than two-drug combinations, the advent of additional active compounds with novel mechanisms of action allows this question to be readdressed. Based on this background, we have initiated a phase I/II study of carboplatin and paclitaxel with escalating doses of ifosfamide. The study design and dosing schedule are discussed in this report.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Magnetic resonance imaging of the pelvic floor in patients with obstructed defaecation.

BACKGROUND: Evacuation proctography and measurements of anorectal physiology are frequently used to clarify the pathophysiology of obstructed defaecation. In some patients these tests are normal, despite convincing clinical evidence of defaecatory difficulty. The aim of this study was to determine whether magnetic resonance imaging (MRI) could reveal pelvic floor abnormality in patients with obstructed defaecation. METHODS: Eleven women with obstructed defaecation, in whom evacuation proctography and anorectal physiology were normal, were examined by MRI, using a fast gradient echo sequence. Measurements of pelvic visceral and muscular descent were taken at rest and during straining, and compared with those obtained from 13 asymptomatic volunteers. RESULTS: Patients with obstructed defaecation had significantly greater pelvic visceral descent (P < 0.05), levator muscle descent (P = 0.04), levator plate angle change (P = 0.003) and increase in the area of the pelvic floor hiatus (P = 0.0002) than asymptomatic volunteers. CONCLUSION: MRI demonstrated marked pelvic visceral and levator muscle descent in women with obstructed defaecation, despite normal evacuation proctography and anorectal physiology. MRI should be considered if these examinations have been normal.

Adolescent↗