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PubMed2000

Neutralization of feline infectious peritonitis virus: preparation of monoclonal antibody that shows cell tropism in neutralizing activity after viral absorption into the cells.

Feline infectious peritonitis virus (FIPV) infection of feline macro-phages is enhanced by mouse anti-FIPV monoclonal antibody (MAb). This anti-body-dependent enhancement (ADE) of FIPV infection is dependent on mouse MAb subclass, and MAb of IgG2a subclass has a strong ADE activity. Furthermore, MAb showing strong neutralizing activity in Felis catus whole fetus (fcwf-4) cells and Crandell feline kidney (CrFK) cells shows strong enhancing activity in feline macrophages, indicating that the neutralizing epitope and the enhancing epitope are closely related. In this study, we prepared MAb FK50-4 that showed a strong neutralizing activity in feline macrophages, despite the fact that the MAb belonged to the IgG2a subclass. However, MAb FK50-4 did not exhibit neutralizing activity in CrFK cells or fcwf-4 cells, thus showing a very unusual property. MAb FK50-4 recognized FIPV small integral membrane glycoprotein (M protein). Even when feline macrophages were pretreated with MAb FK50-4 prior to FIPV inoculation, this antibody prevented FIPV infection. This reaction disappeared after treatment of FK50-4 with protein A. The neutralizing activity of FK50-4 was also effective on feline macrophages after the cells were inoculated with FIPV. These findings indicated that the FIPV replication mechanism differs between feline macrophages and CrFK/fcwf-4 cells and that a neutralizing epitope that can prevent FIPV infection of feline macrophages after viral absorption is present on M protein.

Absorption↗

PubMed1997

Aleutian mink disease parvovirus infection of K562 cells is antibody-dependent and is mediated via an Fc(gamma)RII receptor.

Aleutian mink disease parvovirus (ADV) infects macrophages but infection is restricted. Using the human macrophage cell line U937, we reported infection to be antibody-dependent [22,23]. Recently, we learned that the U937 cells were contaminated with the human cell line, K562 [12]. To clarify which cell line actually supported ADV infection, we studied the antibody-dependent enhancement (ADE) of ADV infection in pure lines of U937 and K562. After infection with ADV complexed with mink anti-ADV antibody, up to 10% of the K562 cells, but none of the U937 cells showed evidence of infection. These results indicated that K562 cells, but not U937 cells, were susceptible to ADV. ADV-infected cultures of K562 were sorted by flow cytometry after staining with a murine monoclonal antibody (IV.3) directed against Fc(gamma)RII. Only cells that were IV.3 positive supported ADV gene expression. Also, preincubation of K562 cells with IV.3 blocked ADV infection by more than 90%. These results established that the ADE of ADV in K562 is Fc(gamma)RIIA-mediated.

Aleutian Mink Disease↗

PubMed2004

Linezolid in the treatment of osteomyelitis: results of compassionate use experience.

BACKGROUND: This case series examines osteomyelitis patients enrolled into a prospective, open label, noncomparative, non-randomized compassionate use program. Patients received 600 mg bid iv or po linezolid. PATIENTS AND METHODS: 89 patients were enrolled into the compassionate use program with the diagnosis of osteomyelitis and were evaluated for clinical efficacy, safety and tolerability. Informed consent was obtained from the patients or their guardians and guidelines for human experimentation of the US Department of Health and Human Services and/or those of the investigators' institutions were followed in the conduct of this clinical research. RESULTS: 55 cases of osteomyelitis met the inclusion criteria for clinical assessment. The 55 courses included long bone (53%), diabetic foot (18%), sternal wound (14.5%) and vertebral osteomyelitis (15%). Clinical assessment at longterm follow-up occurred at a median of 195 days after the last dose, and the clinical cure rate in 22 evaluable cases was 81.8% and failure rate 18.2%. The most common clinical adverse drug events (ADEs) were gastrointestinal disturbances. Reduction in hemoglobin/hematocrit and in platelet counts were the most common laboratory ADEs. CONCLUSION: Linezolid iv or po was successful in treating patients with osteomyelitis caused by resistant grampositive organisms or those with intolerance or nonresponsiveness to other potentially effective treatments. Larger comparator controlled studies should be performed to confirm these findings.

Acetamides↗

PubMed1977

Conformation affinity of cross-linked polyacrylic gels towards nucleobases, nucleosides and nucleotides.

By radical copolymerisation of monofunctional acrylic derivatives with 1,4-tetramethylene dimethacrylate, cross-linked polyacrylic gels which show a high affinity towards nucleic acid residues have been synthesised. Using these polyacrlic gels, mixtures of nucleobases, nucleosides and nucleotides can be chromatographically separated to differing extents, in some cases quantitatively. The elution of nucleobases and nucleosides from the gel in the order Cyt, Gua, Thy, Ade (or dC, dG, dT, dA and C, G, U, A, respectively) shows that Ade (dA, A) is retarded to the highest degree from the gel matrix, Cyt (dC, C) to the lowest degree. Further, the results of the separations prove that the affinity of the polyacrylic gels is much stronger towards deoxyribonucleosides than towards ribonucleosides and nucleobases. The affinity of the polyacrylic gels towards nucleobases and nucleosides depends mainly upon their tertiary structure whereas the functional side groups of the polyacrylate matrix do not contribute significantly to the interaction of the gels.

Acrylic Resins↗

PubMed1987

The isolation and characterization of 2-carboxyethyl adducts following in vitro reaction of acrylic acid with calf thymus DNA and bioassay of acrylic acid in female Hsd:(ICR)Br mice.

Reaction of acrylic acid (AA) at pH 7.0 and 37 degrees C for 40 days with 2'-deoxyadenosine (dAdo), 2'-deoxycytidine (dCyd), 2'-deoxyguanosine (dGuo) and thymidine (dThd) resulted in the formation of 2-carboxyethyl (CE) adducts via Michael addition. The alkylated 2'-deoxynucleoside adducts isolated (percent yield after 40 days) were 1-CE-dAdo (5%), N6-CE-dAdo (11%) (via Dimroth rearrangement of 1-CE-dAdo), 3-CE-dCyd (7.5%), 7-CE-Gua (4%), 7,9-bis-CE-Gua (0.9%) (formed by reaction of AA with depurinated 7-CE-Gua during the course of the reaction) and 3-CE-dThd (0.5%). The products isolated following in vitro reaction of AA with calf thymus DNA at pH 7.0 and 37 degrees C for 40 days were (nmol/mg DNA) 1-CE-Ade (9.9), N6-CE-Ade (8.2), 7-CE-Gua (7.2) and 3-CE-Thy (1.9). Compound 3-CE-Cyt was not detected. Thus the adducts formed following in vitro reaction of AA with DNA are identical to those formed by in vitro reaction of the carcinogen beta-propiolactone (BPL) with DNA as reported in an earlier paper. Structures were assigned on the basis of identical UV spectra, Rf values on paper chromatograms and Rt values on HPLC as marker compounds prepared from reactions of BPL with 2'-deoxynucleosides and 2'-deoxynucleotides-5'-monophosphoric acids. AA was assayed for carcinogenic activity by s.c. injection (20 mumol, once a week for 52 weeks) in female Hsd: (ICR)Br mice. Two mice with sarcomas at the site of application were observed out of 30 mice. Malignancies were not observed in solvent and no-treatment controls. The bioassay results reported in this paper and elsewhere in the same strain of mice suggest that AA is a weak carcinogen in female Hsd:(ICR)Br mice.

Acrylates↗

PubMed1992

In vitro reaction of ethylene oxide with DNA and characterization of DNA adducts.

Ethylene oxide (EO) is a direct-acting SN2 alkylating agent and a rodent and probable human carcinogen. In vitro reactions of EO with calf thymus DNA in aqueous solution at neutral pH and 37 degrees C for 10 h resulted in the following 2-hydroxyethyl (HE) adducts (nmol/mg DNA): 7-HE-Gua (330), 3-HE-Ade (39), 1-HE-Ade (28), N6-HE-dAdo (6.2), 3-HE-Cyt (3.1), 3-HE-Ura (0.8) and 3-HE-dThd (2.0). Reference (marker) compounds were synthesized from reactions of EO with 2'-deoxyribonucleosides and DNA bases, isolated by paper and high performance liquid chromatography and characterized on the basis of chemical properties and UV, NMR and mass spectra. In agreement with our earlier studies with propylene oxide (PO) (Chem.-Biol. Interact., 67 (1988) 275-294) and glycidol (Cancer Biochem. Biophys., 11 (1990) 59-67), alkylation at N-3 of dCyd by EO under physiological conditions resulted in the rapid hydrolytic deamination of 3-HE-dCyd to 3-HE-dUrd. The hydroxyl group on the alkyl side chain which forms after epoxide alkylation is mechanistically involved in this rapid hydrolytic deamination. These results may provide important insights into the mechanisms of mutagenicity and carcinogenicity exhibited by EO and other SN2 aliphatic epoxides.

Animals↗

PubMed1977

Effect of a synthetic polypeptide (COP 1) on patients with multiple sclerosis and with acute disseminated encephalomeylitis. Preliminary report.

Three patients with acute disseminated encephalomyelitis (ADE) and 4 patients in the terminal stages of multiple sclerosis (MS) were subjected to treatment with Cop 1, a synthetic copolymer of amino acids, which had previously been shown to have a beneficial effect in the treatment of experimental allergic encephalomyelitis (EAE). Under the treatment, the ADE patients recovered completely within 3 weeks, but 1 of 2 control cases treated with steroids showed complete recovery as well. The MS patients did not show any significant change in their motor function; however, 2 of them showed some improvement in vision and speech capacity. It is too early to conclude whether this improvement is related to the treatment. No side effect was observed in any of the patients treated with Cop. 1.

Acute Disease↗

PubMed1977

Comparison of the genetic activity of aflatoxins B1 and G1 in Escherichia coli and Saccharomyces cerevisiae.

The ability of aflatoxins B1 and G1 to induce back mutations to arg+ in Escherichia coli K-12/343/113 was compared with the induction of mitotic gene conversion to ade+ in the diploid yeast strain Saccharomyces cerevisiae D4, ade-2. In analogy to previous results with other microorganisms, the compounds were not genetically active per se, indicating that under the experimental conditions employed none of the tester strains were able to activate the compounds to mutagenic products. In experiments using liver homogenates (S-9 fraction) of male Golden Syrian hamsters previously treated with phenobarbital, aflatoxin B1 exhibited strong genetic activity both in E. coli and in S. cerevisiae, whereas the mutagenic activity of aflatoxin G1 was markedly lower and could be detected only in the E. coli tester strain. These results correlate the findings that aflatoxin G1 is a less potent carcinogen and mutagen than aflatoxin B1.

Aflatoxins↗

PubMed1985

Transmission and expression of mutations to nalidixic acid resistance among products of protoplast fusion crosses of Candida albicans.

Earlier studies suggested that heritable resistance to nalidixic acid (Nal) induced in the asexual, pathogenic yeast Candida albicans by growth on Nal results from mitochondrial mutation. To determine conclusively whether mutations to Nal resistance are cytoplasmic or nuclear, several stable Nal-resistant (Nalr) mutants exhibiting distinctive differences in degrees of Nal resistance were obtained from each of two doubly auxotrophic strains (Ade-, Thr- and Arg-, His-), both derived from the same wild-type stock. Inheritance of Nal resistance was then assessed in a series of protoplast fusion crosses between complementing auxotrophs. The initial, intact cellular products of a fusion cross are prototrophic heterokaryons which frequently assort single parental nuclei into monokaryotic blastospores containing biparental cytoplasms. Occasional karyogamy within heterokaryons also yields prototrophic hybrid monokaryons which can undergo recombinations for chromosomal markers through spontaneous or induced mitotic crossing-over. Segregation and expression of Nal resistance among non-hybrid, parental-type monokaryons from Nalr X Nals heterokaryons showed that Nalr mutations are nuclear and that their expressions are not noticeably affected by admixture of cytoplasms of sensitive and resistant parental strains. Analyses of heterokaryons and hybrid monokaryons from Nalr X Nals and Nalr X Nalr crosses demonstrated that Nal resistance is recessive to sensitivity, and that independent Nalr mutations arise at one gene in the Ade-, Thr- strain and at a separate, complementing single gene in the Arg-, His- strain. Prior work demonstrated that induction of Nalr mutations in wild-type C. albicans depends profoundly on the (i) carbon and nitrogen, (ii) growth temperature, (iii) contact with particular metabolic inhibitors and (iv) division stage of cells during exposure to Nal. The present observations indicate that the character of cellular auxotrophies can determine the genetic loci at which Nalr mutations can be recovered.

Alleles↗

PubMed1995

Mutagenicity of nitroscanate, an antischistosomal drug.

Nitroscanate (NSC) was found to be a direct acting mutagen in the Ames Salmonella tester strains TA100 and TA98 and this activity increased further in the presence of rat liver S9 mix. It was inactive in TA98NR and TA100NR, and weakly active in TA98/1,8-DNP6. A substantial fall in drug induced mutagenicity by pentachlorophenol, an inhibitor of acetyltransferase, in TA98, TA100 and YG1024 suggests the initial bioconversion of a nitro group to hydroxylamine and its further activation to the ultimate N-acetoxyarylamine. The refrigerated DMSO solution of the drug in the plate incorporation assay and freshly prepared solutions using the pre-incubation procedure indicated a fall in mutagenicity owing to the conversion of NSC to N,N'-bis-4-(p-nitrophenoxy)phenyl thiourea (NFPT). The drastic reduction in mutagenicity in the presence of 4-amino-4'-nitrodiphenyl ether (ANDE) and 4-aminodiphenyl ether (ADE) was also attributed to the conversion of NSC to the corresponding thiourea, a non-mutagen. The negligible mutagenicity of ANDE and its absence in ADE and 4-isothiocyanate diphenyl ether (ITDE) suggests that the mutagenicity of NSC is due to the nitro group, and the -NCS function is responsible for enhanced mutagenicity over nor-isothiocyanate 4-nitrodiphenyl ether (NDE).

Acetyltransferases↗

PubMed1991

Effects of oral administration of a high-molecular-weight crosslinked polyacrylate in rats.

Oral feeding studies of a crosslinked, high-molecular-weight polyacrylate polymer (PA) were conducted to (1) characterize the biological effects following exposure to either 0, 300, 1000, or 3000 mg PA/kg/day for 93 days; (2) characterize the fecal and urinary mineral excretion at these same dose levels; and (3) monitor the absorption, distribution, and excretion (ADE) of radiolabeled PA following a single oral exposure. The subchronic study results indicate that dietary intake of up to 3000 mg/kg/day PA had no adverse histopathology, hematology, body weight, or clinical chemistry effects in rats. Dietary exposure to PA did, however, result in an elevation in urinary excretion of sodium and phosphorus, whereas excretion of magnesium, calcium, and potassium was lowered. A more detailed study demonstrated that although the urinary excretion of these minerals was changed, total recovery of the minerals (feces + urine), except for sodium, was not different from that for controls. An increase in sodium excretion was expected since PA was in the form of a sodium salt. The ADE studies following a single oral dose of PA indicate that the majority of dosed PA (91.9%) was excreted in the feces. As expected, a small percentage (approximately 3.5%) was absorbed, possibly metabolized, and excreted. In summary, the oral administration of high levels of PA resulted in (1) no histological, hematological, or clinical chemistry changes; (2) no alteration in the overall mineral excretion (feces + urine) with the exception of sodium; and (3) primarily fecal excretion of orally administered PA.

Acrylic Resins↗

PubMed1988

Ethylenediaminetetra(methylenephosphonic acid): genotoxicity, biodistribution, and subchronic and chronic toxicity in rats.

Ethylenediaminetetra(methylenephosphonic acid), EDITEMPA, was tested for oral toxicity in rats in a 13-wk feeding study (at doses of 0, 5, 50 and 500 mg/kg/day) and in a chronic feeding study (at doses of 0, 4, 20 and 100 mg/kg/day). EDITEMPA was also tested for genotoxicity in the Ames, mouse lymphoma, unscheduled DNA synthesis, and in vivo cytogenetics assays. Additionally, absorption, distribution and excretion (ADE) studies were conducted following administration of [14C]EDITEMPA to rats by gavage and via the feed and drinking-water. The principal finding in the 13-wk study was mild anaemia in male and female rats given 500 mg/kg/day, which was resolved during a 9-wk recovery period. In the chronic study, there was no substantial evidence of any treatment-related toxicity or carcinogenicity. Differences in survival of control and treated females (noted late in the study) were interpreted to represent unusually good survival in controls; however, a compound-related increase in mortality could not be completely ruled out. Tests for genotoxicity were all negative. ADE studies revealed that [14C]EDITEMPA was poorly absorbed from the gastro-intestinal tract and that most of the absorbed dose was rapidly excreted by the kidneys or sequestered in bone. The gavage route of administration led to four- to six-fold increases in bone EDITEMPA levels as compared with administration in the feed and drinking-water, respectively. These results suggest that no significant toxicity or carcinogenicity concerns arise from EDITEMPA when it is administered in the feed at the concentrations tested. Reversible anaemia was seen only at very high doses and was interpreted as being secondary to EDITEMPA's ability to interfere with iron absorption and utilization. Localization of EDITEMPA in bone indicated a high degree of affinity for mineralizing tissues, consistent with its chelating properties. There was, however, no effect on bone resorption or mineralization. A comparison of human drinking-water levels of 3500 ppm EDITEMPA (based on a no-effect level of 100 mg/kg/day in rats) with the estimated worst-case exposure in humans of 0.01 ppm suggested a safety margin greater than 1 x 10(5).

Administration, Oral↗

PubMed1991

Aluminum chloride stimulates the release of endogenous glutamate, taurine and adenosine from cultured rat cortical astrocytes.

Primary astrocyte cultures derived from neonatal rat cerebral cortex were treated for 5 min with 0.5 mM or 5.0 mM AlCl3, and the incubation medium was analyzed by HPLC for the content of released glutamate (Glu), taurine (Tau), serine (Ser) and the nucleoside adenosine (Ade). At 0.5 mM, AlCl3 stimulated Tau release to about 170% of basal levels, but did not affect the release of the other compounds. Treatment with 5.0 mM AlCl3 enhanced the release of Tau, Glu and Ade, to 800%, 1000% and 250%, respectively, but decreased the release of Ser to 70% compared to basal levels. The enhanced release of these neuroactive compounds from astrocytes may contribute to changes in neural transmission known to accompany exposure to aluminum.

Adenosine↗

PubMed1992

A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial.

Topical aspirin/diethyl ether (ADE) mixture was used to treat 45 consecutive patients with acute herpetic neuralgia (AHN) (n = 28) and with post-herpetic neuralgia (PHN) (n = 17) in an open-label study. Good-to-excellent results were achieved by 93% of AHN patients and by 65% of PHN patients. Earlier treatment yielded better results for the AHN but not the PHN group. The topical treatment seemed to accelerate the healing of acute herpetic skin lesions and possibly modulate the severity of the herpetic infection. Furthermore, a striking reduction in the percentage of AHN patients developing PHN was observed in the treated group, as compared with the disease natural history reported in the literature (4 vs. 50-70%). Treatment tolerance was excellent with no adverse effect observed. In addition to the open trial, a pilot double-blind crossover placebo-controlled study (n = 11) compared the analgesic efficacy of ADE with two other NSAID (indomethacin and diclofenac) drug/ether mixtures. Aspirin (but not indomethacin and diclofenac) was significantly superior to placebo as regards pain relief (P less than 0.05).

Acute Disease↗

PubMed1996

Topical aspirin/diethyl ether mixture versus indomethacin and diclofenac/diethyl ether mixtures for acute herpetic neuralgia and postherpetic neuralgia: a double-blind crossover placebo-controlled study.

The efficacy of topical aspirin/diethyl ether (ADE) mixture in the treatment of acute herpetic neuralgia and postherpetic neuralgia, suggested in a previous open-label study (De Benedittis et al. 1992), has been evaluated in a double-blind crossover placebo-controlled study as compared with two other NSAID (indomethacin and diclofenac) drug/ether mixtures. The study included 37 patients (15 with acute herpetic neuralgia (AHN) and 22 with postherpetic neuralgia (PHN)). Comparative treatment results showed that only aspirin (but not indomethacin and diclofenac) was significantly superior to placebo, as compared with baseline and duration of pain relief (P < 0.05 and P < 0.01, respectively), in both AHN and PHN groups. Good-to-excellent results were achieved by 87% of AHN patients and by 82% of PHN patients treated with the ADE mixture, with no significant differences between the two groups. On the whole, patients with trigeminal involvement, less severe pain and with dysaesthetic quality of pain yielded best results.

Acute Disease↗

PubMed1993

Gene replacement in the lignin-degrading basidiomycete Phanerochaete chrysosporium.

The ability to carry out gene replacements and gene targeting in the lignin-degrading basidiomycete fungus, Phanerochaete chrysosporium, would facilitate studies on the roles and regulation of various components of its lignindegrading system. A plasmid consisting of the P. chrysosporium ura3 gene (encoding orotidylate decarboxylase) interrupted with the Schizophyllum commune ade2 gene (encoding an adenine biosynthetic enzyme) was used to transform the P. chrysosporium ade2 strain to adenine prototrophy with selection on 5-fluoroorotic acid for inactivation of the ura3 gene. Stable Ade+Ura- strains were obtained at a frequency of approximately one transformant per microgram of DNA. In all of the Ade+Ura- transformants examined by Southern analysis, the chromosomal ura3 locus had been replaced by the plasmid insert.

Basidiomycota↗

PubMed2006

The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats.

Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.

Alcohol Drinking↗

PubMed2005

A similarity measure for case based reasoning modeling with temporal abstraction based on cross-correlation.

Adverse drug events (ADEs) are a major limitation of drug safety. They are often caused by inappropriate selection of dose and the concurrent use of drugs modulating each other (drug interaction). Risk assessment and prevention strategies must therefore consider co-administered drugs, individual doses, and their timing. In a new approach we evaluated the performance of cross correlation, commonly used in signal processing, to determine similarities in patient treatments. To achieve this, patient treatments were modeled as groups of vectors representing discrete time intervals. These vectors were cross-correlated and the results evaluated to find clusters in time courses indicating similarity in treatment of different patients. To evaluate our algorithm, we then created a number of test cases. The focus of this article is on each treatment, and its pattern in time and dosage. The algorithm successfully produces a relatively low similarity score for cases that are completely different with respect to their pattern of time and dosage but high scores when they are equal (score of 0.699) or similar (score of 0.528) in their therapies, and thus succeeds in having a relatively high specificity (27/30). Such an approach might help to considerably reduce the problem of false alarms which hampers most existing alerting systems for medication errors or impending ADEs.

Adverse Drug Reaction Reporting Systems↗