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Biomedical subjects

L Phillips

Publications and source records attributed to L Phillips.

At least 19 recordsLinked to original sources
PubMed1997

Dose proportionality of cisatracurium.

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration-time data from 131 patients with limited concentration-time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed-effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.

Adult↗
PubMed1997

EVA: a new theoretically based molecular descriptor for use in QSAR/QSPR analysis.

A new descriptor of molecular structure, EVA, for use in the derivation of robustly predictive QSAR relationships is described. It is based on theoretically derived normal coordinate frequencies, and has been used extensively and successfully in proprietary chemical discovery programmes within Shell Research. As a result of informal dissemination of the methodology, it is now being used successfully in related areas such as pharmaceutical drug discovery. Much of the experimental data used in development remain proprietary, and are not available for publication. This paper describes the method and illustrates its application to the calculation of nonproprietary data, log P(ow), in both explanatory and predictive modes. It will be followed by other publications illustrating its application to a range of data derived from biological systems.

Drug Design↗
PubMed1997

Prospective use of population pharmacokinetics/pharmacodynamics in the development of cisatracurium.

PURPOSE: The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. METHODS: Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I-III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. RESULTS: The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. CONCLUSIONS: The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

Adult↗
PubMed1997

Antimicrobial resistance in isolates from inpatients and outpatients in the United States: increasing importance of the intensive care unit.

To compare the occurrence of antimicrobial resistance in hospitals with that in the community, we analyzed data for isolates collected from inpatients and outpatients in eight U.S. hospitals. The percentage of resistant isolates from inpatients was higher than that from outpatients for the following combinations of antimicrobials and organisms: methicillin/coagulase-negative Staphylococcus (49.0% vs. 36.0%, respectively; P < .01); methicillin/Staphylococcus aureus (33.0% vs. 14.5%, respectively; P < .01); ceftazidime/Enterobacter cloacae (26.0% vs. 12.0%, respectively; P < .01); imipenem/Pseudomonas aeruginosa (12.0% vs. 6.5%, respectively; P < .01); ceftazidime/P. aeruginosa (7.8% vs. 4.0%, respectively; P < .01); and vancomycin/Enterococcus species (6.3% vs. 1.4%, respectively; P < .01). There was a significant stepwise decrease in the percentage of resistant organisms isolated from patients in the intensive care unit (ICU), non-ICU inpatients, and outpatients. These results suggest that resources allocated to control antimicrobial resistance should continue to be focused in the hospital, particularly in the ICU.

Ciprofloxacin↗
PubMed1996

G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor.

Insulin-like growth factor I is an autocrine/paracrine factor for vascular smooth muscle cells and is required for angiotensin II- and thrombin-induced mitogenesis. The insulin-like growth factor I-triggered signaling pathway involves autophosphorylation of the beta-subunit of its tyrosine kinase receptor and phosphorylation of insulin receptor substrate-1, the latter providing binding sites for proteins with src homology-2 domains. In rat aortic smooth muscle cells we observed that both angiotensin II and thrombin induced rapid tyrosine phosphorylation of insulin receptor substrate-1. Our results also demonstrated that these mitogens rapidly stimulated phosphorylation of the insulin-like growth factor 1 receptor beta-chain. These data demonstrate a novel interaction between the G-protein coupled angiotensin II and thrombin receptors and the tyrosine-kinase insulin-like growth factor I receptor.

Angiotensin II↗
PubMed1996

Inspiratory muscle endurance in patients with chronic heart failure.

OBJECTIVE: To assess the significance of changes in respiratory muscle endurance in relation to respiratory and limb muscle strength in patients with mild to moderate chronic heart failure using a threshold loading technique. SUBJECTS: 20 patients with chronic heart failure (17 male) aged 63.8 (SD 7.4) years and 10 healthy men aged 63.1 (5.6) years. Heart failure severity was New York Heart Association (NYHA) grade II (n = 11) and NYHA grade III/IV (n = 9). METHODS: Respiratory muscle strength was measured from mouth pressures during maximum inspiratory effort (MIP) at functional residual capacity (FRC) and limb muscle strength was measured using a hand grip dynamometer. Inspiratory muscle endurance was measured using a threshold loading technique. The total endurance duration, the maximum threshold pressure achieved (P-Max), and the inspiratory load (% ratio of P-Max/MIP) were recorded in all subjects. RESULTS: Inspiratory muscles were weaker in patients with heart failure than in the controls [MIP 53.6 (16.5) v 70.9 (20.2) cm H2O, P < 0.05]. Hand grip strength was similar in both subject groups [31.6 (SD) v 36.1 (15.9) dynes]. Total endurance duration was significantly reduced in the patient group [494 (223) v 996 (267) s, P < 0.01], as was the maximal threshold pressure achieved [P-Max 18.5 (6.4) v 30.7 (6.6) cm H2O, P < 0.01]. When expressed as a percentage of MIP, P-Max was also lower in the patients [35.2 (11.8) v 44.8 (11.4)%, P < 0.05]. There was no significant correlation between any measure of endurance and limb muscle strength. CONCLUSIONS: Respiratory muscle endurance is reduced in patients with chronic heart failure. These changes probably reflect a generalised skeletal myopathy and provide further evidence of respiratory muscle dysfunction in patients with this disease. Respiratory muscle endurance needs now to be related to symptoms and the effects of treatment and respiratory muscle training should also be explored.

Chronic Disease↗
PubMed1996

Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis.

BACKGROUND: Peritoneal infection and poor ultrafiltration continue to be the major causes of treatment failure in CAPD. The combined effects of peritonitis and the continuous exposure to dialysis fluid remain the most likely candidates affecting the peritoneum in the long term. The purpose of this study was to observe the effects of peritonitis and dialysis on longitudinal peritoneal function. METHODS: The peritoneal equilibration test (PET) was utilized to quantify longitudinal changes in low-molecular-weight solute transfer (D/P(creat)) and ultrafiltration (UF) in 233 patients treated with CAPD. Of these, 166 represented an unselected cohort (Group 1) studied prospectively from commencing treatment for up to 54 months, and 67 were selected patients (Group 2) with PET data available at commencement of the study, having been on dialysis for a minimum of 18 months. PETs were performed either 6-monthly or following peritonitis episodes. RESULTS: Data on the short-term effect of peritonitis kinetics were pooled for groups 1 and 2. Single, isolated episodes (n = 86) had no significant effect on D/P(creat) or UF, whereas recurrences or clusters of infection (n = 70) caused increases in D/P(creat) and reductions in UF, the significance of which increased with the number of episodes. There were significant correlations between both changes in D/P(creat) and UF with the cumulative dialysate leukocyte count, regardless of infecting organism, suggesting that intensity of peritoneal inflammation is also important. Those organisms associated with greater change in peritoneal kinetics, e.g. S. aureus, Pseudomonas, also had the highest neutrophil counts. The longitudinal changes in peritoneal kinetics were analysed for patients in group 1 only. There was a highly significant increase in D/P(creat) after 6 months treatment; this increased further with time on treatment, reaching further significance at 42 and 48 months. There was an associated reduction in UF. In view of the short-term effects of peritonitis on kinetics group 1 was further subdivided into patients who were either peritonitis free or only experienced isolated infections, group 1a, and those that had multiple infection episodes, group 1b. Treatment drop-out, due to death or technical failure occurred at double the rate in group 1b, who also had significantly higher D/P(creat) and lower UF at 1, 6, 12, 18 and 24 months of treatment. Group 1a subsequently caught up, however, indicating that peritonitis is not the only factor influencing long-term changes in peritoneal kinetics. CONCLUSIONS: These data suggest that solute transfer increases and UF declines with time on peritoneal dialysis. This process is exacerbated and accelerated by peritonitis, and appears to be proportional to the degree of associated inflammation and number of infections in close proximity.

Adolescent↗
PubMed1996

Impact of peritoneal absorption of glucose on appetite, protein catabolism and survival in CAPD patients.

Dietary protein and calorie intake, protein catabolism and peritoneal kinetics were measured in 97 CAPD patients to establish the effect of peritoneal glucose absorption on appetite and survival. There was a large variability in the number of calories obtained from the dialysate, mean 5.89 cal/kg (median 5.43 cal/kg), with a skewed distribution, due to the increased requirement for hypertonic solutions by patients with more rapid glucose absorption and poor ultrafiltration. On average calories derived from peritoneal absorption accounted for 19% of the total energy intake which in itself was well below that recommended. Patients with > 6 cal/kg, obtained from the dialysate (top 20th percentile, n = 19) were compared with those with < 6 cal/kg, but no significant differences in oral protein or calorie intake, protein catabolism or total calorie intake were found. Age, body mass index (BMI) and KT/V were also similar in both groups. Patients were followed-up prospectively for a minimum of 24 months and a comparison made of actuarial survival. Patients with high peritoneal calorie intake tended to survive longer but this was not significantly different (p = 0.25). This study suggests that calories derived from the peritoneum in CAPD patients do not suppress appetite, provide a useful and significant proportion of the total energy intake, that does not cause excessive obesity or have a negative effect on patient survival.

Absorption↗
PubMed1996

The predictive value of KT/V and peritoneal solute transport in CAPD patients is dependent on the type of comorbidity present.

Comorbidity, age, dialysis dose (KT/V(urea)), plasma albumin, and peritoneal function (D/P(creat) were measured cross-sectionally in 228 continuous ambulatory peritoneal dialysis (CAPD) patients, who were then followed up for a mean of two years. Comorbidity, utilizing a semi-quantitative score described previously, was the most powerful predictor of mortality in both univariate and multivariate analysis. Using univariate analysis, all the variables predicted outcome with statistical significance, mortality being associated with lower KT/V and plasma albumin and a higher D/P(creat). On multivariate analysis only comorbidity, age, and KT/V remained independent predictors. Data was further analyzed on the basis of type of comorbid condition. In those patients without comorbid disease (n = 127) neither KT/V, albumin nor D/P(creat) predicted outcome. In patients with clinical evidence of ischemic heart disease the KT/V was a significant predictor of favorable outcome. In those with clinical evidence of left ventricular function, mortality was significantly and independently associated with low plasma albumin, high D/P(creat), and KT/V. It is suggested that the concept of treatment adequacy in CAPD patients must include both measures of dialysis dose and peritoneal function, particularly in the context of the patient's comorbidity.

Adolescent↗
PubMed1995

Lipoteichoic acid-induced neutrophil adhesion via E-selectin to human umbilical vein endothelial cells (HUVECs).

We investigated whether lipoteichoic acid (LTA) induces the expression of E-selectin and neutrophil adhesion to human umbilical vein endothelial cells (HUVECs). LTA (0.01-30 micrograms/ml) induced the expression of E-selectin in a concentration-dependent manner with maximal response at 10 micrograms/ml. The expression level of E-selectin increased from 2 h after stimulation by LTA with the maximal level at 4-8 h. Neutrophil adhesion to LTA-treated HUVECs correlated with the levels of E-selectin expression. In addition, the adhesion was clearly inhibited by anti-human E-selectin monoclonal antibody CY-1787 as well as a sialyl Lewis X (SLeX) oligosaccharide. LTA-induced expression of E-selectin was inhibited by protein kinase C inhibitors, H-7 and staurosporine. These results indicate that LTA induced the expression of E-selectin and neutrophils adhered to HUVECs via E-selectin.

Cell Adhesion↗
PubMed1995

A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group.

BACKGROUND: We evaluated the effectiveness of three treatment strategies for the prevention of a first episode of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). METHODS: In an open-label trial, 843 patients with HIV infection and fewer than 200 CD4+ cells per cubic millimeter received zidovudine plus one of three randomly assigned prophylactic agents, beginning with trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine and followed by a defined sequence of other drugs to be used in cases of intolerance. RESULTS: The estimated 36-month cumulative risks of P. carinii pneumonia were 18 percent, 17 percent, and 21 percent in the trimethoprim-sulfamethoxazole, dapsone, and aerosolized-pentamidine groups, respectively (P = 0.22). The difference in risk among treatment strategies was negligible in patients entering the study with 100 or more CD4+ lymphocytes per cubic millimeter. In those entering with fewer than 100 CD4+ cells per cubic millimeter, the risk was 33 percent with aerosolized pentamidine, as compared with 19 percent with trimethoprim-sulfamethoxazole and 22 percent with dapsone (P = 0.04). The lowest failure rates occurred in patients receiving trimethoprim-sulfamethoxazole, and failures were more common with 50 mg of dapsone than with 100 mg. Toxoplasmosis developed in less than 3 percent of patients. Of the patients assigned to the two systemic therapies, only 23 percent were receiving their assigned drug and dose when they completed the study. The median survival was approximately 39 months in all three groups, and the mortality attributable to P. carinii pneumonia was only 1 percent. CONCLUSIONS: In patients with advanced HIV infection, the three treatment strategies we examined have similar effectiveness in preventing P. carinii pneumonia. Strategies that start with trimethoprim-sulfamethoxazole or with high-dose dapsone, rather than aerosolized pentamidine, are superior in patients with fewer than 100 CD4+ lymphocytes per cubic millimeter.

AIDS-Related Opportunistic Infections↗
PubMed1995

Both MHC and background gene heterozygosity alter T cell receptor repertoire selection in an antigen-specific response.

Many autoimmune diseases are associated with specific class II MHC alleles; however, this association is not complete. One explanation for the variable expression of disease in susceptible individuals is that variability in the TCR repertoire may alter the potential to generate pathogenic autoreactive T cells. The current study was undertaken to examine the possibility that MHC and background heterozygosity, which is the norm in the outbred human population, alters the expressed TCR repertoire and, if so, whether this has an impact on peptide recognition and antigenic specificity. We, therefore, systematically analysed the beef insulin-specific TCR repertoire in inbred BALB/c mice before and after introduction of MHC heterozygosity (BALB/c x BALB.K)F1 mice, or MHC and background gene heterozygosity (BALB/c x A/J)F1 mice. We show that T cells from all three repertoires are predominantly Ad-restricted and recognize the same immunodominant peptide. Despite this, the beef insulin-specific TCR repertoires in F1 mice differ from those seen in BALB/c mice with the most dramatic changes seen in (BALB/c x A/J)F1 mice. These changes are accompanied by subtle differences in the antigenic specificity of the T cells. The results demonstrate that both MHC and background gene heterozygosity affect TCR repertoire selection, suggesting that the variable expression of autoimmune disease in individuals with a susceptible MHC allele may result, in part, from variability in the TCR repertoire introduced by this heterozygosity.

Amino Acid Sequence↗
PubMed1995

Comorbidity, urea kinetics, and appetite in continuous ambulatory peritoneal dialysis patients: their interrelationship and prediction of survival.

Comorbidity, urea kinetics (Kt/V and normalized protein catabolic rate), dietary protein, total calorie intake, and plasma albumin were measured in 97 continuous ambulatory peritoneal dialysis patients followed prospectively for 30 months. Comorbid disease was graded severe in 12 patients, intermediate in 29, and absent in 56. At entry to the study comorbidity was associated with increased age (P = 0.001), lower dietary protein (P = 0.015) and calorie intake (P = 0.02), and a lower plasma creatinine (P = 0.026). Trends toward lower Kt/V and albumin were not significant, and normalized protein catabolic rate was unaffected. Ability of these measures to predict mortality was assessed by univariate and multivariate analysis using Cox's proportional hazard model. On univariate analysis, comorbidity (P < 0.0001), age (P = 0.0001), Kt/V (P = 0.009), plasma albumin (P = 0.009), calorie intake (P = 0.035), and dietary protein intake (P = 0.03) predicted outcome, whereas normalized protein catabolic rate did not (P = 0.46). Multivariate analysis indicated that comorbidity (P = 0.0003) and age (P = 0.0085) were the only independent predictors of outcome. The addition of plasma albumin and Kt/V increased the significance of the Cox model. Further analysis of comorbidity demonstrated the relative importance of vascular disease and left ventricular dysfunction. This study illustrates the profound influence of comorbid disease on mortality in continuous ambulatory peritoneal dialysis patients and suggests that it causes suppression of appetite independent of the dialysis dose.

Adolescent↗
PubMed1995

Chattanooga Creek: case study of the public health nursing role in environmental health.

Public health nurses have two primary roles in protecting their communities from hazardous substances: community assessment and health education. Developing assessment skills in environmental health enables public health nurses to collaborate with other federal, state, and county agencies in identifying public health hazards and making health-based recommendations at hazardous waste sites needing remedial or removal interventions. Community health education empowers communities to minimize their exposure to hazardous wastes in their environment. Methods for community environmental health assessment and interventions are demonstrated in this article by activities conducted at the Chattanooga Creek site in Chattanooga, Tennessee. A thorough assessment and collaborative approach between government agencies, local health professionals, and community members resulted in a successful community health education program and this site's placement on the National Priorities List.

Environmental Health↗
PubMed1995

Isolation of a highly cytopathic lentivirus from a nondomestic cat.

A feline immunodeficiency virus-like virus (FIV-Oma) isolated from a Pallas' cat (Otocolobus manul) is highly cytopathic in CrFK cells, in contrast to the chronic, noncytolytic infection established by an FIV isolate from a domestic cat (FIV-Fca). The virions have typical lentivirus morphology, density, and magnesium-dependent reverse transcriptase activity. The major core protein is antigenically cross-reactive with that of FIV-Fca; however, FIV-Oma transcripts do not cross-hybridize with FIV-Fca. A conserved region of the FIV-Oma pol gene has 76 to 80% nucleic acid identify with the corresponding pol regions of other feline lentiviruses and 64 to 69% identity with those of human, ovine, and equine lentiviruses.

Animals↗