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Biomedical subjects

R A Parker

Publications and source records attributed to R A Parker.

At least 19 recordsLinked to original sources
PubMed1992

Hypocholesterolemic activity of synthetic and natural tocotrienols.

Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

Animals↗
PubMed1992

Using the virus challenge dose in the analysis of virus neutralization assays.

We propose a new basis for adjusting the results of virus neutralization assays. These assays consist of two separate experiments performed in parallel: a virus titration experiment and a serum dilution assay. In the virus titration experiment, one estimates the amount of virus used in the assay (the virus challenge dose). In a typical virus neutralization assay, the virus challenge dose may range over an order of magnitude. In the serial dilution assay, one measures the serum neutralizing activity against a particular virus. Most standard methods use the virus titration results only to ensure that the overall experiment is acceptable; the specific results of the virus titration experiment are not used to adjust the estimate of serum neutralizing activity. Although adjustment based on calibration with reference sera could be done, this seldom occurs in practice. We use results from recent studies of the kinetics and stoichiometry of polio virus neutralization with monoclonal antibodies to develop a method to use results from the virus titration experiment to adjust the serum neutralizing activity directly. Our results also indicate that a simple ad hoc procedure can improve the accuracy of the estimated serum neutralizing activity.

Antibodies, Monoclonal↗
PubMed1992

Ascorbate and phenolic antioxidant interactions in prevention of liposomal oxidation.

Efficient prevention of membrane lipid peroxidation by vitamin E (alpha-tocopherol) may involve its regeneration by vitamin C (ascorbate). Conceivably, the efficacy of antioxidants designed as therapeutic agents could be enhanced if a similar regeneration were favorable; thus, a model membrane system was developed which allowed assessment of interaction of phenolic antioxidants with ascorbate and ascorbyl-6-palmitate. Ascorbate alone (50-200 microM) potentiated oxidation of soybean phosphatidylcholine liposomes by Fe2+/histidine-Fe3+, an effect which was temporally related to reduction of Fe3+ generated during oxidation. Addition of 200 microM ascorbate to alpha-tocopherol-containing liposomes (0.1 mol%) resulted in marked, synergistic protection. Accordingly, in the presence but not absence of ascorbate, alpha-tocopherol levels were maintained relatively constant during Fe2+/histidine-Fe3+ exposure. Probucol (4,4'-[(1-methylethylidine)bis(thio)]bis[2,6-bis(1,1- dimethylethyl)]phenol), an antioxidant which prevents oxidation of low density lipoproteins, and its analogues MDL 27,968 (4,4'-[(1-methylethylidene)bis(thio)]bis[2,6- dimethyl]phenol) and MDL 28,881 (2,6-bis(1,1-dimethylethyl)-4-[(3,7,11- trimethyldodecyl)thio]phenol) prevented oxidation but exhibited no synergy with ascorbate. Ascorbyl-6-palmitate itself was an effective antioxidant but did not interact synergistically with any of the phenolic antioxidants. Differential scanning calorimetry revealed significant differences among the antioxidants in their effect on the liquid-crystalline phase transition of dipalmitoyl phosphatidylcholine (DPPC) liposomes. Both alpha-tocopherol and MDL 27,968 significantly reduced the phase transition temperature and the enthalpy of the transition. MDL 28,881 had no effect while probucol was intermediate. The potential for ascorbate or its analogues to interact with phenolic antioxidants to provide a more effective antioxidant system appears to be dictated by structural features and by the location of the antioxidants in the membrane.

Antioxidants↗
PubMed1992

Hyperhomocysteinaemia: a risk factor for extracranial carotid artery atherosclerosis.

Hyperhomocysteinemia arising from impaired methionine metabolism, and usually due to a deficiency of cystathionine beta-synthase is a significant and independent risk factor for symptomatic vascular disease. It is not known if hyperhomocysteinemia in apparently healthy asymptomatic subjects is associated with atherosclerosis and whether such a relationship is independent of conventional risk factors. The prevalence of asymptomatic extracranial carotid artery atherosclerosis was determined by duplex ultrasound examination in 25 obligate heterozygotes with respect for cystathionine beta-synthase deficiency (whose children were known to be homozygous for this genetic defect) and in 21 controls. Hyperhomocysteinemia was determined by a standard methionine-loading test and conventional risk factors were also recorded. Twelve of 25 obligate heterozygotes and 8 of 21 normal controls had evidence of extracranial carotid artery atherosclerosis. Hyperhomocysteinemia as a genetic trait was not a significant risk marker, but the actual homocysteine level was associated with an increased risk of carotid disease. After adjustment for the effects of other significant risk factors, the odds ratio of hyperhomocysteinemia for carotid disease was 1.038 per unit increase in homocysteine level (P = 0.03). Hyperhomocysteinemia is a weak risk factor for asymptomatic extracranial carotid atherosclerosis and the relative risk associated with this genetic trait is less than that observed in a study of patients presenting with clinical manifestations of vascular disease.

Adult↗
PubMed1992

Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma.

BACKGROUND: Many regimens are used for cutaneous T-cell lymphoma (CTCL), but with advanced disease response rates and patient survival are not adequate with any current therapy. Recently extracorporeal photochemotherapy (ECP) was proposed as an alternative therapy. OBJECTIVE: Our purpose is to present the results of ECP in patients with CTCL refractory to other treatments. METHODS: Patients with CTCL received ECP at 3- to 5-week intervals for at least 6 months. All patients except one were in stage T2 (patch/plaque) or higher. Eight patients had extracutaneous disease involving lymph nodes (six patients), bone marrow (five), or Sézary cells (six). The interval between initial symptoms and diagnosis was 5.9 +/- 1.9 years (mean +/- standard error of the mean) and the interval between diagnosis and ECP was 2.2 +/- 0.4 years. RESULTS: A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in six patients (30%). Four patients (20%) showed stabilization of their disease and five progressed (25%). The only variable that predicted responders versus nonresponders was the number of ECP sessions (p < 0.05 by multivariate logistic regression). In contrast, no separate beneficial effect of adjunctive chemotherapy (p > 0.5) or electron beam therapy (p > 0.1) was found. CONCLUSION: Long-term ECP may be an effective alternative treatment for CTCL refractory to other therapies and is likely to be even more useful when combined with other modalities.

Adult↗
PubMed1992

Association of poor clinical status and heavy exposure to tobacco smoke in patients with cystic fibrosis who are homozygous for the F508 deletion.

We examined the association between clinical status and exposure to tobacco smoke in 44 patients homozygous for the F508 cystic fibrosis mutation. Heavy exposure to tobacco smoke was significantly associated with lower Shwachman scores, poorer results of pulmonary function tests, and a fivefold increase in the number of pulmonary-related hospitalizations during the previous year.

Adolescent↗
PubMed1992

Low-inoculum model of surgical wound infection.

A model of surgical wound infection that uses low inocula of bacteria and closely simulates clinical infection involved inoculating suspensions of Staphylococcus aureus and dextran microbeads into intermuscular sites on the dorsum of guinea pigs, harvesting lesions at 72-96 h, identifying as a positive end point lesions yielding staphylococci on subculture, and using logistic regression for data analysis. Prophylaxis was placebo, ampicillin, or cefazolin, and three representative strains of S. aureus were used. A highly significant correlation (P less than .001) was observed between inoculum sizes and infection rates. Without antimicrobial prophylaxis, ID50 for each strain was less than 10 organisms; with antimicrobials, ID50 was significantly higher. Differences in the virulence of strains and in the efficacy of the antimicrobial regimens also were observed. The model should prove useful for understanding mechanisms of virulence among pathogenic bacteria and for elucidating subtle but important differences in efficacy among antibiotics used in prophylaxis.

Abscess↗
PubMed1992

Improved survival accounts for most, but not all, of the increase in bronchopulmonary dysplasia.

The incidence of bronchopulmonary dysplasia (BPD) increased from 10.6% in 1976 through 1980, to 21.7% (1981 through 1985), and to 32.9% (1986 through 1990) in very low birth weight neonates (1500 g or less) admitted to the Vanderbilt Neonatal Intensive Care Unit, while there was a concurrent decline in incidence of neonatal death (NEOD) during the same periods (26.4%, 18.3%, and 15.9%, respectively). Population changes in risk factors (birth weight, sex, race, location of birth, gestational age, diagnosis of hyaline membrane disease, and 5-minute Apgar score) over time do not account for this increase. To estimate the proportion of the increase in BPD attributable to the concurrent decline in NEOD during these periods, separate logistic regression models for NEOD and BPD were calculated from patients born during 1976 through 1985. These results were used to predict the expected number of cases of NEOD and BPD during 1986 through 1990, assuming that the adjusted incidence of NEOD and BPD remained constant from 1976 through 1985, to 1986 through 1990. The increase in the combined outcome, NEOD/BPD, over the three time periods (34.2%, 36.1%, and 43.5%) remained statistically significant after adjustment for the risk factors listed above. During 1986 through 1990, the predicted number of NEOD was 83 more than the number observed, while the predicted number with BPD was 115 less than the number observed. If all 83 averted cases of NEOD during 1986 through 1990 had developed BPD, then 83 (72%) of the 115 excess cases of BPD could be attributed to averted NEOD. The approximate 95% confidence interval for this estimate was 58% to 87%.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchopulmonary Dysplasia↗
PubMed1991

Population aging patterns: the expansion of mortality.

We used the hypothesis of mortality compression as a framework to examine patterns of mortality from 1962 to 1984. Data from national vital statistics records were used for analysis of the changing age at death for percentiles of the population. Data from the Social Security Administration and the U.S. Census Bureau were used to calculate the force of mortality. The mean age at death for all percentiles, including the oldest groups, has risen during the interval. Examination of the coefficient of variation for the mean age at death suggests that there is a relative increase in the variability of age at death among the oldest old. The available data do not fit a hypothetical sequence of normal density distributions with an increasing mean and declining standard deviation. The force of mortality in those over 85 years appears to be decreasing in a pattern similar to that for those under 85 years. Current mortality patterns suggest an "expansion," rather than compression, of mortality at the oldest ages. Further refinement of these observations, with improved data on mortality among the oldest old, will be helpful in delineating mortality patterns.

Adolescent↗
PubMed1990

The impact of luteal phase inadequacy in an infertile population.

A retrospective analysis of patients evaluated and treated for infertility was performed. Luteal phase inadequacy was diagnosed when the late luteal endometrial biopsy pattern was greater than 2 days out of phase in two cycles; in patients treated with clomiphene citrate therapy was changed if one biopsy was out of phase. One hundred ninety-seven patients underwent 242 biopsies. Among 137 women no treated with clomiphene citrate, 24 (17.5%) had out-of-phase biopsy specimens; 7 of 24 (29.2%) repeat biopsies were out of phase, with luteal phase inadequacy in 7 of 137 (5.1%) women. The probability of an out-of-phase biopsy occurring by chance alone was 4.2 of 137 or 3.1%. No woman was diagnosed to have luteal phase inadequacy as the single infertility factor. Fifty-three pregnancies (41%) occurred in 130 women without luteal phase inadequacy and in 2 of 7 (28.6%) diagnosed to have luteal phase inadequacy with other infertility factors. In clomiphene citrate-treated patients, pregnancy occurred in 15 of 26 (57.7%) with corrected luteal phase inadequacy and in 21 of 34 (61.8%) without luteal phase inadequacy. In this population the diagnosis of luteal phase inadequacy was not made more frequently than by chance alone. Moreover, fecundity in patients with treated luteal phase inadequacy is comparable to that in patients without this diagnosis.

Biopsy↗
PubMed1990

Use of mixture models in determining laboratory criterion for identification of seropositive individuals: application to parvovirus B19 serology.

Selecting the cut-off value to identify infected individuals requires a trade-off between sensitivity and specificity. The standard technique for selecting a cut-off uses results of a population either known or assumed uninfected. Using mixture models, however, it is not necessary to identify an uninfected population. This technique also provides methods to estimate the probability that an individual will be accurately classified. We illustrate this technique in determining cut-off values for the serological diagnosis of human parvovirus B19 infection.

Antibodies, Viral↗
PubMed1990

Increased survival rate in very low birth weight infants (1500 grams or less): no association with increased incidence of handicaps.

The incidence of major handicaps was studied in a selected high-risk population of 1919 very low birth weight (less than or equal to 1500 gm) infants born between 1976 and 1985. Seventy-four percent of these infants were discharged alive. We have handicap information on 632 infants who have been followed for up to 7 years of age; 462 were evaluated at 18 months or later. Patients lost to follow-up represent 55% of the eligible population, but inpatient morbidity factors were available for the entire population and were used to calculate synthetic estimates of handicap rates. The overall incidence of severe major handicaps at 18 months was 18.0% (83/462). Cerebral palsy was found in 7.6%, and 6.5% were mentally retarded (IQ less than or equal to 70). Severe retinopathy of prematurity was present in 5.5%, and 5.4% of the infants had neurosensory hearing loss. Thirty-one infants (6.7%) had more than one handicap, the most common combination being cerebral palsy and mental retardation. Outcome of infants grouped by 250 gm birth weight intervals was compared for two periods (1976 to 1980, and 1981 to 1985); the numbers of survivors in each birth weight group increased during the second period, especially in the 500 to 750 gm and the 751 to 1000 gm groups. The observed incidence of major handicaps decreased from the first 5-year period to the second 5-year period (p less than 0.001). The largest decreases in the observed proportion handicapped occurred in the two lowest birth weight groups. The incidence of multiple handicaps also dropped; again, the two lowest birth weight groups showed the largest decrease. We conclude that an increased survival rate of very low birth weight infants need not be associated with an increased incidence of major handicaps.

Birth Weight↗
PubMed1990

Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia.

To test the hypothesis that alternate-day administration of furosemide will result in a sustained improvement in pulmonary function without causing alterations in electrolyte or mineral homeostasis, we conducted a randomized, double-blind, placebo-controlled study of 11 hospitalized, oxygen-dependent, spontaneously breathing infants with chronic bronchopulmonary dysplasia. Infants were randomly selected to receive either furosemide, 4 mg/kg in two divided doses on alternate days orally, or placebo for 8 days, followed by crossover to the alternate-therapy for an additional 8-day period. The two study periods were separated by a 48-hour washout period. Dynamic compliance, total pulmonary resistance, the concentration of electrolytes in serum, and the concentrations of calcium and creatinine in urine were measured on nontreatment days. Alternate-day furosemide therapy increased dynamic lung compliance by 76 +/- 112% and decreased total pulmonary resistance by 20 +/- 39%, compared with placebo (both variables p = 0.032). Alternate-day furosemide therapy did not result in increased urine output, electrolyte abnormalities, or increased urinary calcium excretion. We conclude that this simplified treatment regimen may be useful in the management of infants with chronic bronchopulmonary dysplasia. The results support our previous speculation that furosemide improves pulmonary function by mechanisms unrelated to its diuretic properties.

Airway Resistance↗
PubMed1990

Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

A series of 9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(alkyltetrazol-5-yl)- 6,8-nonadienoic acid derivatives 1 were synthesized and found to inhibit competitively the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. The analogues having 1N-methyltetrazol-5-yl attached to the C8-position (3a, 4a, R1 = R2 = F) are the most active in suppressing cholesterol biosynthesis in both in vitro and in vivo models: the IC50 for the chiral form of 3a is 19 nM, Ki = 4.3 x 10(-9)M when Km for HMG-CoA is 28 x 10(-6) M;1 the ED50 (oral) value corresponding to the lactone derivative (4a, BMY 22089) is approximately 0.1 mg/kg. Further, BMY 21950 is nearly 2 orders of magnitude more active in parenchymal heptaocytes, from which most of the serum cholesterol originates, than in other cell preparations (such as spleen, testes, ileum, adrenal, and ocular lens epithelial cells; Table III). This apparent tissue specificity may be highly beneficial since the blocking of cholesterol biosynthesis in other vital organs could eventually lead to undesirable side effects. In addition to the chemical synthesis and biological evaluation, a theoretical study aimed at relating the HMG-CoA reductase inhibitory potency to the three-dimensional structure of the inhibitors was undertaken. With a combination of molecular mapping and 3D-QSAR techniques, it was possible to determine a logical candidate for the conformation of the bound inhibitor and to quantitatively relate inhibitory potency to the shape and size of both the binding site and the C8-substituent.

Animals↗
PubMed1990

Association between respiratory syncytial virus outbreaks and lower respiratory tract deaths of infants and young children.

The temporal patterns of respiratory virus isolations from 10 laboratories in the USA were compared with that of deaths of children less than 5 years old from July 1975 through June 1984. Isolations of respiratory syncytial virus (RSV) occurred as yearly winter outbreaks; parainfluenza virus 1 and 2 isolations occurred as well-defined outbreaks every other year in the autumn; parainfluenza virus 3 isolations occurred throughout the year with periodic, increased isolations suggestive of outbreaks; and influenza virus isolations (A, B, or A plus B) occurred as yearly winter outbreaks. After data were controlled for seasonal patterns, RSV isolations were strongly correlated with the winter peaks in lower respiratory tract illness (LRI) deaths of infants 1-11 months old; influenza virus isolations were correlated with the winter peak in LRI deaths of children 24-59 months old. The parainfluenza viruses were not correlated with respiratory deaths. This study supports the idea that RSV is a major contributor to winter peaks in LRI deaths of children 1-11 months old.

Child, Preschool↗
PubMed1990

The use of protriptyline for respiratory failure in patients with chronic airflow limitation.

Treatment of nocturnal hypoventilation in patients with restrictive chest wall disease and respiratory failure, results in improved daytime arterial blood gas tensions, increase in functional ability and longer survival. Success has been achieved with the use of protriptyline which reduces the duration of rapid eye movement (REM) sleep during which nocturnal hypoventilation occurs. Eighteen patients with severe chronic airflow limitation (CAL), took part in a randomized, double-blind, crossover trial of protriptyline and placebo. Seventeen patients completed the study. The use of protriptyline was associated with a fall in the median percentage of total sleep time spent in REM from 16 to 8.8% (p less than 0.01). This was associated with a reduction in the median daytime arterial carbon dioxide tension from 6.4 kPa (range 5.2-8.5 kPa) to 5.8 kPa (range 5.0-8.1 kPa) (p less than 0.01); increased respiratory muscle strength (p less than 0.05), and increased six minute walking distance from a median of 258 m (range 58.5-585 m) to 275 m (range 171-598 m) (p less than 0.02). We found pharmacological treatment of REM-related nocturnal hypoventilation in patients with CAL to be effective, but anticholinergic side-effects, particularly in older male patients, might preclude long-term treatment.

Adult↗
PubMed1990

Selective inhibition of cholesterol synthesis in liver versus extrahepatic tissues by HMG-CoA reductase inhibitors.

Hepatic specificity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase may be achieved by efficient first-pass liver extraction resulting in low circulating drug levels, as with lovastatin, or by lower cellular uptake in peripheral tissues, seen with pravastatin. BMY-21950 and its lactone form BMY-22089, new synthetic inhibitors of HMG-CoA reductase, were compared with the major reference agent lovastatin and with the synthetic inhibitor fluindostatin in several in vitro and in vivo models of potency and tissue selectivity. The kinetic mechanism and the potency of BMY-21950 as a competitive inhibitor of isolated HMG-CoA reductase were comparable to the reference agents. The inhibitory potency (cholesterol synthesis assayed by 3H2O or [14C]acetate incorporation) of BMY-21950 in rat hepatocytes (IC50 = 21 nM) and dog liver slices (IC50 = 23 nM) equalled or exceeded the potencies of the reference agents. Hepatic cholesterol synthesis in vivo in rats was effectively inhibited by BMY-21950 and its lactone form BMY-22089 (ED50 = 0.1 mg/kg p.o.), but oral doses (20 mg/kg) that suppressed liver synthesis by 83-95% inhibited sterol synthesis by only 17-24% in the ileum. In contrast, equivalent doses of lovastatin markedly inhibited cholesterol synthesis in both organs. In tissue slices from rat ileum, cell dispersions from testes, adrenal, and spleen, and in bovine ocular lens epithelial cells, BMY-21950 inhibited sterol synthesis weakly in vitro with IC50 values 76- and 188-times higher than in hepatocytes; similar effects were seen for BMY-22089. However, the IC50 ratios (tissue/hepatocyte) for lovastatin and fluindostatin were near unity in these models. Thus, BMY-21950 and BMY-22089 are the first potent synthetic HMG-CoA reductase inhibitors that possess a very high degree of liver selectivity based upon differential inhibition sensitivities in tissues. This cellular uptake-based property of hepatic specificity of BMY-21950 and BMY-22089, also manifest in pravastatin, is biochemically distinct from the pharmacodynamic-based disposition of lovastatin, which along with fluindostatin exhibited potent inhibition in all tissues that were exposed to it.

Animals↗