Showing papers by "Research Triangle Park published in 1982"
TL;DR: Acyclovir, an acrylic purine nucleoside analog, is a highly potent inhibitor of herpes simplex virus, types 1 and 2, and varicella zoster virus, and has extremely low toxicity for the normal host cells.
313 citations
TL;DR: The particle mass in the submicrometer mode was correlated with the nitric oxide concentration in the flue gas, which suggests that control of nitricoxide by modification of the combustion conditions may reduce the generation and emission of sub micrometer particles.
Abstract: Measurements of the particle size distribution at the outlets of six coal-fired utility boilers showed a peak at a particle diameter near 0.1 micrometer. This submicrometer mode appears to be a general feature of coal combustion that results from a volatilization-condensation process in the boiler. At the boilers tested, the submicrometer mode contained 0.2 to 2.2 percent of the total fly ash mass. The importance of this mode is greater than its small quantity suggests because particles in the submicrometer size range are often much more difficult to collect with conventional particulate control devices than larger particles. Thus, the submicrometer mode may significantly influence the design and selection of future power plant emission controls. The particle mass in the submicrometer mode was correlated with the nitric oxide concentration in the flue gas. This correlation suggests that control of nitric oxide by modification of the combustion conditions may reduce the generation and emission of submicrometer particles.
260 citations
247 citations
TL;DR: Attachment of Mycoplasma pneumoniae to host cell by means of a specialized terminus initiates infection and monoclonal antibodies to a surface protein (Pl) inhibit this process, and react with a region of the tip covered with peplomer-like particles.
Abstract: Attachment of Mycoplasma pneumoniae to host cell by means of a specialized terminus initiates infection. Monoclonal antibodies to a surface protein (Pl) inhibit this process, and react with a region of the tip covered with peplomer-like particles. Since antibodies against the Pl protein are generated by natural and experimental infection and by immunization, the substance may be an important determinant of protective immunity.
244 citations
TL;DR: The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients.
243 citations
TL;DR: A randomized double-blind, placebo-controlled, multicenter investigation assessed the usefulness of acyclovir in the treatment of immunosuppressed children with chickenpox, finding no evidence of toxicity related to acyClovir.
223 citations
TL;DR: Sensitivity of herpes simplex virus isolates to acyclovir became reduced in two bone-marrow transplant patients treated for established mucocutaneous infections.
223 citations
TL;DR: In this paper, the effect of initiation of ϵ-caprolactone polymerization with mono-and polyfunctional alcohols was investigated, and the resulting linear and starshaped polymers were characterized by measurement of the molecular weight and molecular weight distribution.
Abstract: The effect of initiation of ϵ-caprolactone polymerization with mono- and polyfunctional alcohols was investigated. The resulting linear and starshaped polymers were characterized by measurement of the molecular weight and molecular weight distribution. The polymerizations were characterized by (1) rapid initiation, (2) invariance of the number of growing chains corresponding to the amount of initiator, and (3) a dominant role played by ester interchange reactions.
184 citations
TL;DR: The in vivo-in vitro hepatocyte DNA repair assay is valuable for the detection and study of a variety of genotoxic carcinogens.
Abstract: The in vivo-in vitro hepatocyte DNA repair assay has been shown to be useful in the evaluation of the carcinogenic potential of chemicals. The purpose of this study was to apply this assay to determining the genotoxicity of the compounds from a wide variety of structural classes. Male Fischer-334 rats were treated by gavage or ip injection with compounds dissolved in either corn oil, water, or dimethyl sulfoxide (DMSO). At selected times after treatment, hepatocytes were isolated by liver perfusion and cultured with 3H-thymidine, Unscheduled DNA synthesis (UDS) was measured by quantitative autoradiography as net grains/nucleus (NG); greater than or equal to 5 NG was considered positive. Water, corn oil, or DMSO controls produced -3 to -6 NG with less than or equal to 6% of the cells in repair. All genotoxic hepatocarcinogens tested produced strong positive responses of greater than 15 NG including dimethylnitrosamine, 2-acetylaminofluorene (2-AAF), azoxymethane, 1,2-dimethylhydrazine, benzidine, aflatoxin B1, 2,6-dinitrotoluene, and 2,4-diaminotoluene. The noncarcinogen, 2,6-diaminotoluene, was negative. The mutagen and rat brain carcinogen methyl methanesulfonate (MMS) and the rat pancreatic carcinogen azaserine were also positive. The carcinogens benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene yielded from -2 to -4 NG. This negative response is consistent with their lack of carcinogenic activity in rat liver. MMS produced the greatest amount of UDS 2 hr after treatment whereas 2-AAF did not induce its maximum response until 12 hr post-treatment. The potent hepatotoxin carbon tetrachloride induced a 40-fold elevation in DNA replication 48 hr after a 400 mg/kg dose, but no UDS was observed at 2, 12, 24, or 48 hr post-treatment. The weak hepatocarcinogen safrole induced no UDS suggesting that it is either nongenotoxic or is metabolized to an active form at an extremely slow rate following a single administration. These results demonstrate that this assay is valuable for the detection and study of a variety of genotoxic carcinogens.
180 citations
TL;DR: The metabolic disposition and pharmacokinetics of acyclovir have been studied as part of the clinical evaluation of the drug in humans and Dosage adjustment for various stages of renal impairment are proposed based on the observed relationship between Cltot and Clcr.
179 citations
TL;DR: In this article, a Fourier transform spectrometer operated at 0.25 cm−1 resolution was used in conjunction with a 1260m optical path folded along a base path of 23 m.
TL;DR: Pulmonary structure and function were quantitatively investigated over the lifespan of the Fischer 344 rat by morphometric and physiologic techniques and progressive increases in vital capacity (VC) and total lung capacity (TLC) were demonstrated.
Abstract: Pulmonary structure and function were quantitatively investigated over the lifespan of the Fischer 344 rat by morphometric and physiologic techniques. Male animals 1 week, 6 weeks, 5 months, 14 months, and 26 months of age and female animals 5 months, 14 months, and 26 months of age were studied. All alveolar tissue compartments demonstrated significant increases in volume, surface area, and cell number during the first 5 months of life. From 5 to 26 months of age, remodelling in the epithelial and interstitial compartments continued to take place while the endothelial compartment remained relatively unchanged. In the epithelial compartment the ratio of type II cells to type I cells lining the alveolar surface decreased as age increased. In the interstitial compartment the volume of the noncellular components of the interstitium increased by 39% in males and by 89% in females from 5 to 26 months of age. Physiologic measurements of lung volumes in males at 6 weeks, 14 months, and 26 months demonstrated progressive increases in vital capacity (VC) and total lung capacity (TLC). Morphometric pulmonary-diffusion capacity (DLO2) increased in males from 1 week to 5 months of age and remained relatively unchanged from 5 to 26 months of age in both sexes.
TL;DR: The denuder difference experiment is a relatively simple method of measuring fine particulate nitrate and gaseous nitric acid in the atmosphere while avoiding losses of particulate Nitrate caused by sampling artifacts.
TL;DR: These findings suggest that intracellular concentrations of DNA precursors may be regulated in order to minimize the frequency of genetic change and indicate the existence of important nonDNA targets for the induction of mutation, recombination, chromosome aberrations, etc.
Abstract: In vivo DNA precursor imbalances can have profound genetic consequences in prokaryotes and eukaryotes. In vitro studies have demonstrated that DNA replication fidelity is dependent on correct balances of deoxyribonucleoside triphosphates during DNA synthesis. These findings suggest that intracellular concentrations of DNA precursors may be regulated in order to minimize the frequency of genetic change. In addition, they indicate the existence of important nonDNA targets for the induction of mutation, recombination, chromosome aberrations, etc. In this article, the genetic effects of deoxyribonueleotide pool imbalances are reviewed.
TL;DR: Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure and four chemicals known to produce only fetal toxicity were tested and the screen successfully identified those that reduced weight.
Abstract: Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure. Postnatal growth and viability of prenatally exposed offspring was used as a measure of developmental toxicity. Gravid CD-1 mice were administered maximum tolerated doses of the compounds for up to 5 consecutive days during the period of major organogenesis. The dams were allowed to give birth, and litter size and weight on postpartum d 1 and 3 were recorded and compared with concurrent controls. All 15 compounds that were teratogenic by standard teratology test criteria exhibited some form of developmental toxicity. Four chemicals known to produce only fetal toxicity (reduced weight or supernumerary ribs) were tested and the screen successfully identified those that reduced weight. Finally, of the 9 compounds that show no effect in standard tests, 6 were also negative in the screen and 3 demonstrated either reduced viability or weight.
TL;DR: After one to several hours exposure of monolayer cell cultures to enkphalin, the number of enkephalin receptors measured subsequently in the extensively washed membrane preparations is greatly reduced, which seems to be selective for opioid peptides and is antagonized by a variety of opiate agonists and antagonists.
Abstract: Cultured mouse neuroblastoma cells (N4TG1)1,2 and neuroblastoma–glioma hybrid cells (NG108-15)3–5 contain enkephalin (δ) receptors2. Studies on hybrid cells have indicated that occupation of enkephalin receptors by opiates and opioid peptides leads to a time-dependent inhibition of adeny-late cyclase activity3–5. If exposure of these cells to agonists is continued, the activity of adenylate cyclase gradually returns to normal and increases above normal on removal of opioids, a phenomenon thought to resemble tolerance and dependence in animals. Direct receptor binding studies on neuroblastoma cells have shown no internalization of receptors1. Using rhodamine-conjugated [D-Ala2,Lys6]Leu-enkephalin and image-intensified fluorescence microscopy, enkephalin (δ) receptors in neuroblastoma cells were found slowly to form clusters which do not appear to be internalized6. This is in contrast to many polypeptide receptors7–12 which are internalized after the initial receptor–ligand interactions. This internalization is believed to be related to the so-called down-regulation or desensitization. We now report that after one to several hours exposure of monolayer cell cultures to enkephalin, the number of enkephalin receptors measured subsequently in the extensively washed membrane preparations is greatly reduced. This reduction in receptor number seems to be selective for opioid peptides and is antagonized by a variety of opiate agonists and antagonists. These observations may be important in elucidating the phenomenon of opioid-induced desensitization.
TL;DR: In general, acyclo-GDP had a lower V'max and a higher K'm than either GDP or dGDP, while none of these enzymes showed significantly higher rates of phosphorylation with GDP or acy Clovir diphosphate in herpes simplex virus-infected Vero cells as compared to uninfected Veros.
TL;DR: The Toxicokinetics of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin in Mammalian Systems as mentioned in this paper was the first work to investigate the toxicity of dioxin.
Abstract: (1982). The Toxicokinetics of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin in Mammalian Systems. Drug Metabolism Reviews: Vol. 13, No. 3, pp. 355-385.
TL;DR: The sensitivity of the technique is higher than that of conventional methods of formaldehyde analysis, enabling endogenous formaldehyde to be quantitatively analyzed in tissues, even in samples as small as 20 mg wet weight.
Abstract: A quantitative method is described for the determination of formaldehyde in biological tissues by stable isotope dilution using gas chromatography/mass spectrometry. (13C2H2)Formaldehyde is used as the isotopic diluent. After tissue homogenization, derivatization is carried out in situ with pentafluorophenylhydrazine, followed by extraction and analysis using selected ion monitoring. The sensitivity of the technique is higher than that of conventional methods of formaldehyde analysis, enabling endogenous formaldehyde to be quantitatively analyzed in tissues, even in samples as small as 20 mg wet weight. The effects of exposure to airborne formaldehyde or to airborne methyl chloride on the formaldehyde concentrations of several tissues of Fischer-344 rats are reported.
TL;DR: Four varieties of Gibberella fujikuroi are described on the basis of mating groups, variation in ascospore and perithecial size, phialide type, and microconidial formation.
Abstract: Four varieties of Gibberella fujikuroi are described on the basis of mating groups, variation in ascospore and perithecial size, phialide type, and microconidial formation. The varietal type, G. fu...
TL;DR: These experiments illustrate that mutagenesis by P element insertion and use of cloned P DNA to retrieve the DNA sequences into which insertion has occurred may be a general method for cloning genetically defined loci in Drosophila.
TL;DR: The results suggest that drugs which block both cyclooxygenase and lipoxygenases may be effective antidiarrheals in patients with colitis.
Abstract: Both 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) increased the short-circuit current (Isc) in rabbit colonic mucosa mounted in vitro in Ussing chambers. Measurements of chlorine-36 fluxes indicated that the Isc response to 5-HPETE is due to stimulation of active chlorine secretion. 9-, 11-, and 12-HPETE9s and leukotrienes C4 and B4 produced either very small increases in Isc or no increase. In contrast to results in rabbit colon, no HPETE, HETE, or leukotriene was effective in rabbit ileal mucosa. The effects of 5-HPETE in the rabbit colon were unaffected by mepacrine, but could be partially blocked by indomethacin. These results suggest that drugs which block both cyclooxygenase and lipoxygenase may be effective antidiarrheals in patients with colitis.
TL;DR: It is concluded that opioid peptides are stored in the primary population of large dense-cord vesicles per se, rather than in a minor population of contaminating particles from cells other than sympathetic C-fibers, which has implications for exocytotic release and the physiological role of the opioid peptide intra- and extra-neuronally.
TL;DR: It is shown that communication between asynchronous processes can be expressed as sequences of nondecomposable, basic interaction which in the general case involve multiple message exchanges.
TL;DR: Although dopamine‐β‐hydroxylase and SDR have different subcellular localizations, a physiological role for SDR in β‐Hydroxylation still appears plausible through reduction of cytosolic semidehydroascorbate.
Abstract: The immediate product of ascorbate oxidation coupled to dopamine-beta-hydroxylation is not dehydroascorbate, as previously thought, but rather semidehydroascorbate. For this reason, the possible participation of the enzyme semidehydroascorbate reductase (SDR) in cofactor regeneration was investigated. In the adrenal medulla, the primary subcellular localization of this reductase was shown to be in the mitochondria. Submitochondrial fractionation studies indicated that SDR is an outer membrane protein. Thus, although dopamine-beta-hydroxylase and SDR have different subcellular localizations, a physiological role for SDR in beta-hydroxylation still appears plausible through reduction of cytosolic semidehydroascorbate. The specific activities of SDR in various rat and guinea pig tissues appear to parallel their ascorbate contents, suggesting a similar participation of SDR in ascorbate metabolism in other tissues.
TL;DR: The data support the concept that the potent hypotensive property of this substance readily observed in the rat, is a result of an effect which is platelet-independent and not associated with thrombocytopenia.
TL;DR: In this paper, the role of intestinal microflora in DNT genotoxicity was investigated and extensive DNT-induced DNA repair in rats having the normal complement of gut flora, but not in rats which have no gut flora.
Abstract: Dinitrotoluene (DNT), an important industrial nitroaromatic compound, is a potent hepatocarcinogen in rats. Male Fischer-334 rats fed technical-grade DNT in the diet for 12 months showed a 100% incidence of hepatocellular carcinomas1. However, various in vitro and in vivo short-term tests using several genotoxic end points have failed to show activity with DNT or purified DNT isomers2–6, including unscheduled DNA synthesis (UDS) in primary hepatocytes in vitro7. In the in vivo–in vitro hepatocyte DNA repair assay, which measures chemically induced UDS in hepatocytes isolated from rats treated in vivo8, DNT was found to be a potent UDS inducer9 having a peak of activity 12 h after a single dose. A possible explanation for the discrepancy between the in vivo and in vitro results is that metabolism by gut flora may be required for formation of the proximate or ultimate carcinogenic metabolites of DNT. The importance of biotransformation of toxicants by intestinal microflora has been demonstrated for cycasin10,11 and other xenobiotics12. We have used the in vivo–in vitro hepatocyte DNA repair assay to study the role of intestinal microflora in DNT genotoxicity. We report here extensive DNT-induced DNA repair in rats having the normal complement of gut flora, but not in rats which have no gut flora. These results indicate that metabolism of DNT by gut flora is a necessary step in the genotoxicity of this compound and illustrate the value of the in vivo–in vitro hepatocyte DNA repair assay in assessing the carcinogenic potential of nitroaromatic compounds.
TL;DR: A good correlation between analgesic activity and morphine ( micro) receptor but not enkephalin (delta) receptor binding affinity was obtained, extending the hypothesis that morphine (micro) receptors mediate the major portion of the analgesicActivity of opioids.
TL;DR: Accumulation of protein in lung lavage fluid was used as an indicator of pulmonary damage following exposure of guinea pigs to O 3 and a dose relationship between the amount of protein accumulation in the lung and the concentration of O 3 to which the animals were exposed was observed.
TL;DR: Safety evaluations accompanied placebo-controlled Phase II studies in infected patients who represent future users of acyclovir confirm acyClovir as the safest antiherpes agent to be explored in clinical studies to date.