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Biomedical subjects

R L Miller

Publications and source records attributed to R L Miller.

At least 19 recordsLinked to original sources
PubMed1995

Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways.

The imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.

Aminoquinolines↗
PubMed1994

Cytokine induction in mice by the immunomodulator imiquimod.

Imiquimod has been identified as a potent antiviral and antitumor agent in animal models. The biological activity associated with imiquimod has been attributed to its induction of interferon (IFN)-alpha. The present studies evaluated imiquimod administered orally for its ability to stimulate production of IFN and other cytokines in mice. The cytokine profile induced by imiquimod was compared with other known immunomodulators. Imiquimod was found to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five consecutive days led to diminished production of IFN in mice as measured after the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated with imiquimod. Imiquimod produced significantly higher levels of IFN but lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide. Polyinosinic acid:polycytidylic acid induced significantly higher amounts of IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor tilorone induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6 production in cultures of mouse spleen and bone marrow cells. These studies demonstrate that imiquimod induces not only IFN but other cytokines as well, all of which may contribute to its biological activity.

Aminoquinolines↗
PubMed1992

Phosphorylation of carbovir enantiomers by cellular enzymes determines the stereoselectivity of antiviral activity.

Two enantiomers of carbovir, a carbocyclic analog of 2',3'-dideoxyguanosine, were compared with respect to their phosphorylation and the phosphorylation of their nucleotides by mammalian enzymes. 5'-Nucleotidase catalyzed the phosphorylation of (-)-carbovir, which is active against HIV (human immunodeficiency virus), but did not phosphorylate (+)-carbovir. (-)-Carbovir monophosphate was 7,000 times more efficient as a substrate for GMP kinase than was (+)-carbovir monophosphate. Pyruvate kinase, phosphoglycerate kinase, and creatine kinase phosphorylated both enantiomers of carbovir diphosphate at similar rates. Nucleoside-diphosphate kinase preferentially phosphorylated the (-)-enantiomer. Both enantiomers of carbovir triphosphate were substrates and alternative substrate inhibitors of HIV reverse transcriptase. Thus, the contrasting HIV-inhibitory activities of carbovir enantiomers were due to differential phosphorylation by cellular enzymes and not due to enantioselectivity of HIV reverse transcriptase.

Antiviral Agents↗
PubMed1992

Cinnamon-induced stomatitis venenata, Clinical and characteristic histopathologic features.

Fourteen new cases of cinnamon-induced stomatitis are reported. Ten of these fourteen cases were first detected on the basis of histopathologic changes, which included hyperkeratosis, chronic lichenoid mucositis with plasmacytic infiltration, and marked chronic perivasculitis. Six cases of false-positive histopathologic findings are presented for comparison. It is recommended that when the histopathologic features described are recognized, cinnamon stomatitis should be considered.

Adult↗
PubMed1992

Delusions and behavioral disturbances in cognitively impaired elderly persons.

OBJECTIVE: To compare cognitive function and the prevalence of selected behavioral problems in delusional and non-delusional dementia patients. DESIGN: Retrospective medical record review. SETTING: An outpatient geriatric assessment center. PARTICIPANTS: 114 consecutive patients with dementia. MAIN OUTCOME MEASURES: Delusions as recorded in a consultation report. RESULTS: Delusions were described in 25.5% of patients. A variety of behavioral disturbances were more common in delusional than non-delusional patients, including agitation, angry or hostile outbursts, urinary incontinence, wandering or pacing, and insomnia. While cognitive function as measured by the MMSE was similar in delusional and non-delusional patients (18.9 +/- 3.8 and 19.2 +/- 5.9, respectively), there was a statistically borderline tendency for delusions to occur more often in patients in the mid-range of cognitive impairment (17 less than or equal to MMSE less than or equal to 23) compared with patients with greater or lesser degrees of cognitive impairment (32% vs 17% respectively). CONCLUSION: Delusions in dementia are associated with a variety of behavioral problems. Further studies are needed to clarify the role of delusions in the development of disruptive behaviors in dementing illness.

Aged↗
PubMed1991

Determination of cocaine, benzoylecgonine and ecgonine methyl ester in plasma by reversed-phase high-performance liquid chromatography.

A combined assay is described for cocaine and its major metabolites, benzoylecgonine and ecgonine methyl ester. The method uses electrochemical and ultraviolet detectors in series. A non-silica column is used with high-pH mobile phase. The three compounds are completely separated from other cocaine metabolites. The assay has been suitable for pharmacokinetic studies of cocaine disposition in animal studies.

Animals↗
PubMed1991

Purification and characterization of 5'-deoxy-5'-methylthioadenosine (MTA) phosphorylase from human liver.

5'-Methylthioadenosine phosphorylase was purified 8000-fold from human liver using a combination of affinity chromatography, chromatofocusing and gel filtration. A 25% overall yield was obtained. The specific activity of the final preparation was 40 mumol of 5'-methylthioadenosine cleaved per hr per mg of protein. The enzyme had an apparent molecular weight of 55,000 daltons, as determined by gel filtration of Superose 12 and Sephadex G-150, with a subunit molecular weight of 30,000 daltons, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The substrate specificity of the purified enzyme was studied in both the direction of nucleoside cleavage and nucleoside synthesis.

Chromatography, Gel↗
PubMed1991

Disposition and pharmacodynamics of methamphetamine in pregnant sheep.

To determine the placental transfer of methamphetamine, its subsequent fetal disposition, and its hemodynamic effects, we administered methamphetamine intravenously to 15 pregnant ewes 3 days after placement of maternal and fetal vascular catheters. Methamphetamine crossed the placenta within 30 seconds of its administration. Although the ewes had higher peak concentrations, the fetuses' longer elimination half-life ultimately led to higher fetal than maternal methamphetamine concentrations. The ratio of fetal tissue to plasma drug concentration 2 hours after administration was highest in the lung, followed by the placenta, kidney, intestine, liver, brain, and heart. Methamphetamine caused a 54% to 63% rise in maternal blood pressure, a 20% to 37% increase in fetal blood pressure, and a drop in fetal oxyhemoglobin saturation and arterial pH. We conclude that methamphetamine, in doses at or below what is commonly abused, has effects that could be detrimental to the health of the mother and her fetus.

Animals↗
PubMed1991

Inhalational administration of cocaine in sheep.

A pipe for administration of inhaled cocaine and its pyrolytic products in laboratory animals was developed and tested. In-vitro trials showed 30.0 +/- 5.2% (mean +/- SE) recovery of cocaine in solvent. Five non-pregnant ewes were instrumented with tracheal T-tubes and vascular catheters. After surgical recovery, ewes received three doses of cocaine (free base) in a randomized fashion; 2 mg/kg and 4 mg/kg both by inhalation, and 2 mg/kg intravenously. Arterial blood samples were collected and assayed for cocaine and its major metabolites by high performance liquid chromatography. Blood pressure and heart rate were continuously recorded. Cocaine administered by inhalation was eliminated with a half-life of 1.6 +/- 0.5 min (mean +/- SE) compared to 3.4 +/- 0.9 following intravenous administration (p less than 0.03). Likewise, clearance values were greater following inhalation, 5532 +/- 1756 ml/min/kg, than following intravenous administration, 163 +/- 20.6 ml/min/kg (p less than 0.04). Both routes of administration led to significant elevations in blood pressure, 7.5% increase after smoking vs 20% increase after intravenous administration. No correlation was found between inhalational dose of cocaine and peak plasma cocaine concentration.

Administration, Inhalation↗
PubMed1991

Guanosine kinase from Trichomonas vaginalis.

A novel guanosine kinase was partially purified from the parasitic protozoan Trichomonas vaginalis. Unlike nucleoside kinases from other sources, the preferred substrate for this enzyme was guanosine (Vmax/Km = 120). The enzyme also catalyzed the phosphorylation of inosine (Vmax/Km = 3), uridine (2), adenosine (0.5), cytidine (0.2), and 2'-deoxyguanosine (0.1). The 2'-deoxyribonucleosides of adenine, hypoxanthine, uracil, cytosine and thymine were not phosphorylated. The Km for ATP was 6.6 microM. The enzyme was extremely labile in the absence of ATP. As a result, only a 20-fold purification with 25% recovery of activity was possible. However, this preparation was free of nucleoside phosphorylase, nucleoside phosphotransferase and the distinct uridine kinase. The enzyme had a broad optimum of pH 6.5-8. It had a molecular weight of 15000.

Animals↗
PubMed1991

Anabolic pathway of 6-methoxypurine arabinoside in cells infected with varicella-zoster virus.

6-Methoxypurine arabinoside (ara-M) exhibits potent activity against varicella-zoster virus (VZV) as a result of ara-M's anabolism to the triphosphate of adenine arabinoside (ara-ATP) in VZV-infected cells. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) enhanced the formation of ara-ATP by inhibiting ara-M demethoxylation. In contrast, deoxycoformycin and coformycin, inhibitors of both adenosine deaminase and AMP deaminase, blocked the formation of ara-ATP and reversed the anti-VZV activity of ara-M. These results indicate that after the initial phosphorylation of ara-M by the VZV-coded thymidine kinase, the monophosphate is demethoxylated by AMP deaminase to form ara-IMP, which is converted to ara-ATP by the sequential actions of the cellular adenylosuccinate synthetase, adenylosuccinate lyase, and nucleotide kinases.

5'-Nucleotidase↗
PubMed1991

A preliminary report: YAG laser treatment in pediatric dentistry.

Pediatric dentistry offers many opportunities to employ lasers. Observations of laser uses with the primary dentition and evaluation of laser anesthesia for permanent premolars are presented in this preliminary report. Soft tissue surgery with children and adolescents is described. Dentin became desensitized with normal pulp test readings and histology when premolars were given laser exposure. Patient acceptance was high. Enamel conditioning for bonding, decay removal, root canal cleansing and exposing unerupted teeth are the most common procedures.

Anesthesia, Dental↗
PubMed1991

Disposition of cocaine in pregnant sheep. I. Pharmacokinetics.

Cocaine abuse by pregnant women is increasingly recognized as causing serious health consequences for mother and newborn. To assess the placental transfer and fetal effects of cocaine, we studied its pharmacokinetics following intravenous administration to the pregnant ewe and fetus. Following bolus doses of 0.5-4.0 mg/kg to ewes, cocaine appeared within 30 s in fetal circulation, with peak concentrations occurring in 4-5 min. The disappearance of cocaine in the fetal plasma paralleled that in maternal plasma, suggesting that a rapid equilibrium of cocaine occurred between maternal and fetal compartments. The mean half-life of cocaine in the fetus across doses (4.4-5.0 min) was similar to that in the ewe (4.0-5.6 min). Plasma clearance of cocaine in the ewe did not appear to vary according to dose. The fetal exposure to cocaine, as indicated by the area under the fetal plasma concentration versus curve, was a linear function of maternal cocaine dose (r = 0.96, p less than 0.01). These results demonstrate rapid placental transfer of cocaine after maternal administration in an animal model and rapid metabolism by mother and fetus.

Animals↗
PubMed1990

Characterization of benzodiazepine receptors with fluorescent ligands.

Fluorescein conjugates of the high-affinity benzodiazepine receptor ligands Ro 15-1788 and Ro 7-1986 were synthesized. The binding of these fluorescent ligands (BD 621 and BD 607) to benzodiazepine receptors was characterized by direct fluorescence measurement. Both the equilibrium dissociation constants (KD) of BD 621 and BD 607 and the maximum number of binding sites (Bmax) estimated by fluorescence monitoring were consistent with values obtained by using radioligand binding techniques. The binding of BD 621 and BD 607 assessed by fluorescence measurement was reversible, abolished by photoaffinity labeling with Ro 15-4513, and unaffected by a variety of substances that do not bind to benzodiazepine receptors. The potencies of chemically diverse benzodiazepine receptor compounds to inhibit fluorescent ligand binding were highly correlated (r = 0.94, P less than 0.001), with potencies obtained from radioligand binding techniques. These findings demonstrate the feasibility of using direct fluorescence measurement techniques to quantitate ligand-receptor interactions.

Animals↗