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Biomedical subjects

A M Miller

Publications and source records attributed to A M Miller.

At least 73 records · Page 4Linked to original sources
PubMed1989

The pharmacodynamic and pharmacokinetic interaction between single doses of flecainide acetate and verapamil: effects on cardiac function and drug clearance.

Flecainide and verapamil are antiarrhythmic agents that may be used in combination. We have examined their pharmacodynamic interaction by M-mode echocardiography and electrocardiography in eight normal male volunteers (24 +/- 1.8 years of age). Flecainide decreased the left ventricular ejection fraction (LVEF) (-4.4 +/- 1.2%, p less than 0.008), but verapamil did not. Neither drug affected cardiac output or vascular resistance. Both drugs increased the PR interval (12 +/- 4 msec, p less than 0.01 for flecainide; 12 +/- 5, p less than 0.04 for verapamil). Flecainide, but not verapamil, increased the QTc interval (23 +/- 8 msec, p less than 0.02). Both drugs also increased the systolic time interval ratio (PEPc/LVETc) (0.074 +/- 0.012, p less than 0.0004 for flecainide; 0.029 +/- 0.008, p less than 0.007 for verapamil). The combination of flecainide and verapamil had additive effects on myocardial contractility and on atrioventricular conduction. Verapamil slightly decreased the plasma clearance of flecainide (7.78 +/- 0.60 ml/kg/min for flecainide alone, 7.34 +/- 0.48 ml/kg/min for flecainide and verapamil together, p less than 0.05). On the other hand, flecainide had no effect on the plasma clearance of verapamil, which suggests that there was little interaction between the two drugs on their pharmacokinetic parameters.

Administration, Oral↗
PubMed1989

Thermal stress reduces serum luteinizing hormone and bioassayable hypothalamic content of luteinizing hormone-releasing hormone in hens.

Studies were conducted to evaluate the effects of acute (24 h) thermal stress on anterior pituitary function in hens. Circulating levels of luteinizing hormone (LH) were measured and the ability of the pituitary to respond to luteinizing hormone-releasing hormone (LHRH) challenge was determined. Moreover, bioassayable hypothalamic LHRH content was assessed by using dispersed anterior pituitary cells. In two separate experiments, circulating levels of LH were reduced in hens exposed to acute thermal stress (35 degrees C). Injection of LHRH did not result in significant differences in release of LH between normothermic and hyperthermic hens. However, the hypothalamic content of bioassayable hypothalamic releasing activity from hyperthermic hens were significantly reduced compared with normothermic hens. Taken together, these data suggest that the reproductive decline in the acutely heat-stressed hen is mediated by reduced LH releasing ability of the hypothalamus.

Animals↗
PubMed1989

Mating-type control in Saccharomyces cerevisiae: isolation and characterization of mutants defective in repression by a1-alpha 2.

The alpha 2 protein, the product of the MAT alpha 2 cistron, represses various genes specific to the a mating type (alpha 2 repression), and when combined with the MATa1 gene product, it represses MAT alpha 1 and various haploid-specific genes (a1-alpha 2 repression). One target of a1-alpha 2 repression is RME1, which is a negative regulator of a/alpha-specific genes. We have isolated 13 recessive mutants whose a1-alpha 2 repression is defective but which retain alpha 2 repression in a genetic background of ho MATa HML alpha HMRa sir3 or ho MAT alpha HMRa HMRa sir3. These mutations can be divided into three different classes. One class contains a missense mutation, designated hml alpha 2-102, in the alpha 2 cistron of HML, and another class contains two mat alpha 2-202, in the MAT alpha locus. These three mutants each have an amino acid substitution of tyrosine or acid substitution of tyrosine or phenylalanine for cysteine at the 33rd codon from the translation initiation codon in the alpha 2 cistron of HML alpha or MAT alpha. The remaining 10 mutants make up the third class and form a single complementation group, having mutations designated aar1 (a1-alpha 2 repression), at a gene other than MAT, HML, HMR, RME1, or the four SIR genes. Although a diploid cell homozygous for the aarl and sir3 mutations and for the MATa, HML alpha, and HMRa alleles showed alpha mating type, it could sporulate and gave rise to asci containing four alpha mating-type spores. These facts indicate that the domain for alpha2 repression is separable from that for a1-alpha2 protein interaction or complex formation in the alpha2 protein and that an additional regulation gene, AAR1, is associated with the a1-alpha2 repression of the alpha1 cistron and haploid-specific genes.

Amino Acid Sequence↗
PubMed1989

Effects of lipoxygenase and glutathione pathway inhibitors on leukemic cell line growth.

We have examined the effects of various inhibitors of the lipoxygenase pathway of arachidonic acid metabolism on the growth of three well-characterized human leukemia cell lines, HL-60, K-562, and KG-1. An intact lipoxygenase pathway, and the synthesis of leukotriene C4 (LTC4), which requires reduced glutathione, is essential for in vitro growth of normal myeloid progenitors (CFU-GM). We tested the effects of nordihydroguiaretic acid (NDGA) and caffeic acid (CA), inhibitors of lipoxygenase; buthionine sulfoximine (BSO), which inhibits glutathione synthesis; and Acivicin, a glutamine antagonist, on these cell lines and compared the effects with those seen on CFU-GM. In semisolid culture, all three cell lines were inhibited by NDGA, CA, and BSO in a dose-dependent manner similar to that in CFU-GM but were relatively resistant to Acivicin. In liquid culture, all three cell lines exhibited relative resistance to inhibition by both BSO and Acivicin, with KG-1 also demonstrating relative resistance to inhibition by NDGA and CA. The inhibition of HL-60 by CA could be completely reversed by the addition of exogenous leukotriene D4. The dependence on the lipoxygenase pathway may be altered to varying degrees in different leukemic lines and may depend on culture conditions. Whether these changes may contribute to the pathogenesis of leukemia or merely represent secondary metabolic changes is yet to be determined.

Buthionine Sulfoximine↗
PubMed1989

Incest: psychological, legal and ethical considerations.

The psychological, legal and ethical considerations in treating victims and prosecuting offenders in the United States are described, and the dilemmas highlighted by the use of a detailed case study of an incest victim.

Adolescent↗
PubMed1989

Regulation of T-lymphopoiesis by arachidonic acid metabolites.

The cloning efficiency of T-lymphocyte progenitor cells (CFU-T) is dependent on mononuclear cell concentration, with a triphasic growth curve. At low plating cell concentrations, hydrocortisone causes a dose-dependent decrease in cloning efficiency, whereas at high cell concentrations hydrocortisone causes increased cloning efficiency. To determine if the biphasic effects of hydrocortisone are through its inhibition of arachidonic acid metabolism, we tested the effects of various arachidonic acid metabolism inhibitors on cloning efficiency. Indomethacin, which inhibits cyclooxygenase, has no effect at low cell plating doses, but increases cloning efficiency at high cell doses. Prostaglandin E2 (PGE2) causes a dose-dependent inhibition of cloning efficiency at all cell doses. Caffeic acid, an inhibitor of lipoxygenase, causes a dose-dependent inhibition of CFU-T, particularly at lower cell concentrations. Leukotriene B4 (LTB4) restored caffeic acid-inhibited growth, as did addition of recombinant interleukins 1 and 2 (IL-1 and IL-2). These results support a regulatory role for arachidonic acid metabolites in T-lymphopoiesis. PGE2, a cyclooxygenase product, is inhibitory, whereas LTB4, a lipoxygenase product, is stimulatory through its role in IL-1 synthesis.

Arachidonic Acid↗
PubMed1988

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function.

STUDY OBJECTIVE: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. DESIGN: Paired study of single followed by multiple oral doses. SETTING: PATIENTS enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. PATIENTS: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. INTERVENTIONS: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Evidence for the role of leukotrienes C4 and D4 as essential intermediates in CSF-stimulated human myeloid colony formation.

Products of the lipoxygenation of arachidonic acid have been shown to induce a variety of effects on cells of myeloid lineage. Colony-stimulating factor causes release of arachidonic acid from cell membranes, which then undergoes oxygenation via the cyclooxygenase and lipoxygenase pathways. Nordihydroguaiaretic acid (NDGA) and 3-amino-1-[m(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755C), compounds that inhibit both the cyclooxygenase and lipoxygenase pathways, cause dose-dependent inhibition of CSF-induced human granulocyte-monocyte colony formation in vitro, with complete inhibition at 20 and 50 microM, respectively. Indomethacin, which inhibits cyclooxygenase but not lipoxygenase, has no effect on colony growth at 50 microM, which is well in excess of the dose needed for complete inhibition of cyclooxygenase. Leukotrienes (LTs) C4 and D4 (5-100 ng/ml) reverse NDGA inhibition of colony growth. At similar concentrations, neither leukotriene B4 or 5-HETE caused reversal of NDGA inhibition. These results support a role for LTC4 and LTD4 as essential intermediates in CSF-stimulated myeloid colony formation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

High-performance liquid chromatographic method for the quantitation of a meta-O-dealkylated metabolite of flecainide acetate, a new antiarrhythmic.

A simple, sensitive and selective high-performance liquid chromatographic method has been developed to analyze meta-O-dealkylated flecainide, a major metabolite of flecainide acetate, in human biological fluids. Sample preparation is accomplished through the use of bonded-phase extraction columns and the samples are chromatographed on a reversed-phase system with fluorescence detection. An external calibration method is used for quantitation and the inter-day and intra-day precision and accuracy are good. The method has been used to determine metabolite levels in samples from healthy subjects and patients with arrhythmias or renal impairment.

Anti-Arrhythmia Agents↗
PubMed1984

Lymphoreticular cells isolated by centrifugal elutriation from a mammary adenocarcinoma. I. Characterization of an in situ lymphocyte suppressor population by surface markers and functional reactivity.

The procedure of centrifugal elutriation was evaluated as a means of purifying large numbers of in situ lymphocytes from enzymatically disaggregated mouse mammary tumors. The eluate obtained at a flow rate of 3.0 ml/min was optimal for high levels of lymphocyte recovery with low levels of contaminating tumor cells, polymorphonuclear leukocytes, and macrophages. The majority of the tumor infiltrating lymphocytes (90%) expressed the Thy 1.2 antigen, while less than 5% possessed surface immunoglobulin. Further analysis of the T lymphocyte population was accomplished by flow cytometric analysis of in situ lymphocytes stained with fluorescein-conjugated monoclonal anti-Lyt 2 antibodies. The results of such studies reveal an increase in the levels of Lyt 2+ lymphocytes within the in situ population. To determine whether these Lyt 2+ cells were functionally active as suppressor cells, the ISL1 were mixed with spleen cells from tumor bearers and then tested for their ability to respond to mitogen and TAA-induced blast transformation of tumor-bearer spleen cells. Removal of macrophages from ISL by Sephadex G-10 columns did not alter the suppression. Treatment with monoclonal anti-Lyt 1 antibody and complement did not affect the inhibition observed. However, treatment of ISL with anti-Lyt 2+ monoclonal antibody and complement resulted in the elimination of the suppressor cell activity. We concluded that within the tumor-infiltrating lymphoreticular cells there is a population of Thy 1.2+ Lyt 2.2+ lymphocytes responsible for the suppression of mitogen and tumor-antigen-induced blastogenesis.

Adenocarcinoma↗
PubMed1984

The yeast MATa1 gene contains two introns.

In the yeast Saccharomyces cerevisiae there are two mating types, a and alpha, which may mate to produce an a/alpha diploid. Mating type is determined by the allele (MATa or MAT alpha) occupying the MAT locus. In a diploid, expression of the MATa1 and MAT alpha 2 genes determines the a/alpha state by regulating the expression of unlinked genes. Previous S1 endonuclease mapping implied that the MATa1 transcript is not processed. We have performed further S1 mapping of this transcript, demonstrating that the MATa1 gene contains two introns, unlike any other characterized nuclear gene in yeast. Both introns contain 5' splice sites and 5'- TACTAACA -3' consensus sequences at the positions predicted by the S1 mapping data. In the splicing-defective rna2 mutant, the mature message disappears rapidly and the precursor RNA accumulates. The RNA processing removes the UGA stop codon which was previously believed to be read-through.

Base Sequence↗
PubMed1984

Quantitation of flecainide acetate, a new antiarrhythmic agent, in biological fluids by gas chromatography with electron-capture detection.

A sensitive and selective gas chromatographic (GC) method for the quantitation of flecainide acetate, a new antiarrhythmic agent, was developed. The unchanged drug and internal standard were separated from biological fluids by a sequence of solvent extractions and then the drug was derivatized. The pentafluorobenzamide derivatives were chromatographed on a 3% SP-2250 glass column and detected with a nickel-63 electron-capture detector. By this method, greater than or equal to 12.5 ng of flecainide/mL can be quantitated in a 1-mL sample of plasma, saliva, or urine. The intraday precision, expressed as the RSD, at plasma levels of 12.5, 25, 50, 100, 200, 300, 400, and 600 ng/mL was 3.4, 6.2, 5.3, 6.4, 1.0, 1.6, 2.0, and 0.5%, respectively; the accuracy, expressed as relative error at these levels was -24.6, -6.9, -6.0, +0.6, +3.8, -0.3, +2.4, and -1.4%, respectively. The interday precision at these levels was 13.8, 13.0, 5.7, 7.6, 8.3, 6.1, 9.0, and 5.4%, respectively. Several other antiarrhythmic agents and one beta-blocker, which might be administered concurrently with flecainide acetate, do not interfere with the assay.

Anti-Arrhythmia Agents↗
PubMed1984

Application of a bonded-phase extraction column for rapid sample preparation of flecainide from human plasma for high-performance liquid chromatographic analysis--fluorescence or ultraviolet detection.

A simple, rapid, selective, and sensitive procedure for the monitoring of flecainide levels in human plasma is described. The drug and the internal standard--a positional isomer of flecainide--are separated from plasma by the use of a disposable extraction column packed with reversed-phase sorbent. The drug and internal standard which are selectively retained on the extraction column are eluted. An aliquot is injected onto a mu-Bondapak phenyl column and eluted with a mixture of acetonitrile and 0.06% phosphoric acid (40:60, vol/vol) at a flow rate of 2 ml/min. The eluted drug and internal standard are measured by a fluorescence detector with excitation and emission wavelengths of 300 and 370 nm, respectively. The linear range is 3-2,000 ng/ml, and the sensitivity limit is 3 ng/ml with 1 ml of plasma. The within-day coefficient of variation was 1.1-4.6% at concentrations ranging from 3 to 1,600 ng/ml. Many drugs given concomitantly with flecainide acetate do not interfere with the assay. The method compares favorably to a well-documented gas-liquid chromatographic method and is suitable for use in plasma drug level monitoring for patient management as well as in pharmacokinetic studies. Similar results were obtained using an alternate detection method (ultraviolet detection at 298 nm).

Chromatography, High Pressure Liquid↗
PubMed1983

High-performance liquid chromatographic method for the quantitation of flecainide, a new antiarrhythmic, in human plasma and urine.

A simple, selective, sensitive, and accurate high-performance liquid chromatographic method for the quantitation of flecainide in human plasma and urine is described. The method is based on initially washing the sample with hexane followed by a single extraction with hexane. The extracted drug and internal standard are chromatographed on a Zorbax TMS column with a mobile phase consisting of acetonitrile-1% acetic acid in 0.01 M pentanesulfonate (45:55, v/v). The eluent is monitored at 308 nm. This method can routinely quantitate plasma or urine flecainide concentrations as low as 22 ng/ml with a 1-ml sample and 11 ng/ml with a 2-ml sample with no interference from endogenous substances and many drugs and their metabolites. The standard curve is linear over a concentration range of 22-1746 ng/ml. The precision and accuracy of the described method are suitable for monitoring flecainide levels in therapeutic, tolerance, and pharmacokinetic studies in humans.

Anti-Arrhythmia Agents↗
PubMed1983

Evidence for the identification of synaptic transmitters released by photoreceptors of the toad retina.

1. When toad retinae were incubated with veratrine, kainic acid, and L-alpha-aminoadipic acid, photoreceptor cells survived and most other neurones died. This preparation of 'isolated' photoreceptor cells accumulated radioactive molecules from the incubation medium and metabolized these into labelled compounds. When a preparation was placed on a filter and superfused, radioactive molecules which were released into the superfusion fluid could be collected and later analysed. Several procedures were used for inducing the release of possible transmitter compounds. Each released compound was chemically identified. 2. Three compounds, aspartic acid, glutamic acid, and N-acetyl histidine, were released when the potassium concentration was increased in media that lacked calcium and contained cobalt. 3. The release of these compounds was further increased when cobalt was removed and calcium returned to the extracellular medium. 4. Two additional compounds, putrescine and cadavarine, were also released during depolarization when calcium was present. 5. The efflux of each of the compounds listed in Section 2 was also increased by homo- and hetero-exchange. For at least aspartate, exchange was sodium-dependent. 6. The post-synaptic effect of released compounds was tested by their ability to increase the efflux of [3H]GABA from 'isolated' horizontal cells. 0 . 1 mM-L-aspartate, or L-glutamate produced an increase in GABA efflux. N-acetyl histidine, putrescine, and cadavarine were ineffective. 7. Isolated photoreceptors and intact retinae were incubated with [3H]aspartate, or [3H]putrescine. Subsequent histology and autoradiography demonstrated that both compounds were selectively accumulated by cones.

Animals↗
PubMed1983

Measurement of flecainide acetate in human plasma by an extraction spectrophotofluorometric method.

A fluorometric method for the quantitation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (R-818, flecainide acetate) in human plasma has been developed. The minimum quantifiable concentration of flecainide acetate by this method is 25 ng/ml with a 2 ml plasma sample; a slightly modified procedure which also requires the use of a microcell in the spectrophotofluorometer further increases the maximum sensitivity to 12.5 ng/ml. The precision, expressed as relative standard deviation is 2.9, 0.7, 5.6, 3.5, and 4.3% for 75, 150, 250, 500, and 700 ng flecainide acetate/ml, respectively. The accuracy, expressed as relative error, is -6.7, -3.3, -0.4, +4.4, and -0.4%, respectively, for the corresponding concentrations specified above. The relative standard deviations for the inter-day variation are 19, 7, 9, 9, 8, 10, 13, 12, and 9% for the 25, 50, 100, 200, 300, 400, 600, 800, and 1000 ng/ml standards, respectively. Preliminary data indicate that propranolol and quinidine interfere with this method while procainamide, disopyramide, hydralazine, methyldopa, diazepam, hydrochlorothiazide, and sulfinpyrazone exhibit little or no interference. The results of the analyses of clinical samples by the fluorometric method agree well with an established GLC method. Thus, the quality of the fluorometric method is considered adequate for estimating plasma flecainide acetate levels during drug therapy in most non-research settings, if careful consideration is given to possible interference by other drugs.

Chromatography, Gas↗
PubMed1982

Induced release and metabolism of arachidonic acid from myeloid cells by purified colony-stimulating factor.

The in vitro incubation of cells from turpentine-induced rat myeloid hyperplastic marrow and peritoneal monocyte/macrophage with 14C-arachidonic acid resulted in the incorporation of the radiolabel into the particulate phospholipids. Challenge of the radiolabeled cells with a highly purified type I CSF (CSF I) from human pancreatic carcinoma cells in continuous culture resulted in the hydrolysis and release of the 14C-arachidonic acid from the cellular phospholipids. The simultaneous challenge of the prelabeled cells with CSF-I and its specific antibody (anti-CSF-I antibody) inhibited the CSF-I induced hydrolysis of 14C-arachidonic acid from the cells. These results confer a specificity on the CSF-I induced release of arachidonic acid from the cellular phospholipids. Our data also demonstrated that the 14C-arachidonic acid released from the cellular phospholipids was further transformed into products of the cyclooxygenation and lipoxygenation pathways by cellular enzyme systems in both populations of cells. Interestingly, our data also indicate that the challenge of the granulocytic hyperplastic marrow cells and the monocyte/macrophage cells with purified CSF-I resulted in a higher generation of lipoxygenase products in the predominantly granulocytic cell population than in the population rich in monocyte/macrophage cells. The biological significance of this observation remains to be further explored. Thus, the CSF-I induced release of cellular arachidonic acid explains, at least in part, the presence of prostaglandins and other metabolites of arachidonic acid that are found in the media of hemopoietic cells incubated with a variety of CSF preparations.

Arachidonic Acid↗