Biomedical subjects

M J Moore

Publications and source records attributed to M J Moore.

At least 109 records · Page 6Linked to original sources

PubMed1994

Determination of fostriecin pharmacokinetics in plasma using high-pressure liquid chromatography assay.

Fostriecin is an antitumor antibiotic with marked activity against ovarian, breast, and lung cancer cell lines in the human tumor clonogenic assay. The mechanism of cytotoxicity in vivo is unknown; in vitro it has been shown to inhibit macromolecular synthesis, interact with the reduced folate carrier system, and inhibit topoisomerase II. Phase I testing of fostriecin in a daily for 5 days schedule has begun in cancer patients. A high-pressure liquid chromatographic method to measure fostriecin in plasma samples was developed using sulfaquinoxaline as an internal standard and ultraviolet detection (268 nm). The extraction efficiency is 70% and the sensitivity limit is 100 ng/ml. The pharmacokinetics of fostriecin were determined in six rabbits following intravenous injection of 12 mg/m2. The mean distribution space was 4.44 L/m2 and the mean plasma clearance was 302 ml/min/m2. The elimination half-life was 11.95 +/- 8.55 min. All rabbits exhibited a 10-60-fold increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that resolved within 48 h of drug administration.

Alkenes↗

PubMed1994

Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer.

PURPOSE: This phase II study was designed to assess the effects of mitoxantrone with prednisone in patients with metastatic prostate cancer who had progressed on hormonal therapy. The methods of assessment included quality-of-life analyses, pain indices, analgesic scores, and the National Prostatic Cancer Project (NPCP) criteria. PATIENTS AND METHODS: Patients received mitoxantrone 12 mg/m2 intravenously every 3 weeks plus prednisone 10 mg orally daily. All had a castrate serum testosterone and Eastern Cooperation Oncology Group (ECOG) performance status < or = 3, and had not received prior chemotherapy. Every 3 weeks, analgesic intake was scored, and a present pain intensity (PPI) record and visual analog scale (VAS) describing pain were collected. Every 6 weeks, the European Organization for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire plus a prostate-specific module were completed. A palliative response was defined as a decrease in analgesic score by > or = 50% or a decrease in PPI by > or = two integers without any increase in the other. RESULTS: Twenty-seven patients were entered onto the study. Nine of 25 (36%) assessable patients achieved a palliative response maintained for > or = two cycles (range, two to eight or more). Improvements in mean PPI and VAS pain scores after each cycle of therapy (P < .05) were seen. Quality-of-life analysis showed improvements in social and emotional functioning, and in pain and anorexia. Using NPCP criteria, one patient achieved a partial response (PR) and 12 had stable disease; one of seven patients with measurable disease had a PR. No serious nonhematologic toxicity was experienced, and there were no episodes of febrile neutropenia. CONCLUSION: Mitoxantrone with low-dose prednisone is a well-tolerated treatment regimen that has some beneficial effects on disease-related symptoms and quality of life for patients with advanced prostate cancer.

Aged↗

PubMed1993

Evidence for two active sites in the spliceosome provided by stereochemistry of pre-mRNA splicing.

Excision of introns from nuclear precursors to messenger RNAs (pre-mRNAs) by the spliceosome requires two distinct phosphodiester transfer (transesterification) reactions: exchange of a 3'-5' for a 2'-5' bond in the first step (lariat formation) and exchange of one 3'-5' phosphodiester for another in the second step (exon ligation). We report here determination of the stereochemical course of each step using splicing substrates that contained a chiral phosphorothioate. This has provided strong evidence that both steps occur as single 'in-line' SN2 nucleophilic displacement reactions, analogous to the mechanism of group I self-splicing introns. Additionally, because both steps are strongly inhibited by the RP phosphorothioate diastereomer, but not by SP, the spliceosome probably shifts between two active sites in catalysis of the two steps. Chemical and stereochemical similarities suggest that the catalytic site for the second step of spliceosomal processing is related to that of group I self-splicing introns.

Animals↗

PubMed1993

Drinking and schooling.

We employ the National Longitudinal Survey of Youth data to explore the effect of youthful drinking on years of schooling and on the likelihood of college graduation. Our instruments for youthful drinking include the state beer tax and the minimum purchase age. Reduced form equations are also estimated. Our results indicate that heavy drinking in high school reduces the average number of years of schooling completed following high school. Other things equal, students who spend their high school years in states with relatively high taxes and minimum age are more likely to graduate from college.

Adolescent↗

PubMed1993

A phase II study of methotrexate, vinblastine, doxorubicin and cisplatin plus recombinant human granulocyte-macrophage colony stimulating factors in patients with advanced transitional cell carcinoma.

The use of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) to treat transitional cell carcinoma is associated with high rates of granulocytopenia. To test whether the addition of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) would decrease the hematological toxicity of M-VAC 21 patients were treated with standard dose M-VAC (30 mg./m.2 methotrexate on days 1, 15 and 22, 3 mg./m.2 vinblastine on days 2, 15 and 22, 30 mg./m.2 doxorubicin on day 2 and 70 mg./m.2 cisplatin on day 2) plus 5 micrograms./kg. rhGM-CSF subcutaneously on days 4 to 13. On cycles 1 and 2 of therapy grade III or greater granulocytopenia (less than 1.0 x 10(9)/l.) was noted in 39% and 43% of the patients, respectively, and the majority were able to receive the day 15 and day 22 treatments as scheduled. This was an apparent improvement over our historical experience with M-VAC alone (p = 0.03). By cycle 3 of treatment this beneficial effect of rhGM-CSF was no longer apparent, with 80% of the patients experiencing grade III or greater granulocytopenia and thrombocytopenia also becoming apparent. Seven patients had to discontinue rhGM-CSF because of side effects. It is unlikely that clinically significant escalation of chemotherapy dosages can be achieved with M-VAC and rhGM-CSF.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Elevated ornithine decarboxylase activity, polyamines and cell proliferation in neoplastic and vacuolated liver cells of winter flounder (Pleuronectes americanus)

Liver neoplasms, including hepatocellular and cholangiocellular tumors, commonly occur in winter flounder (Pleuronectes americanus) caught from some chemically contaminated areas such as Boston Harbor. Hydropically vacuolated cells, very often associated with neoplasia in winter flounder liver, appear to represent the first cellular abnormality in animals that later develop frank neoplasms. The proliferative capacity of hydropically vacuolated cells was studied by analyzing both ornithine decarboxylase (ODC) activity and bromodeoxyuridine (BrdU) labeling indices. Liver of winter flounder with vacuolated cellular lesions had ODC activity more than 5- to 12-fold greater than that in liver that lacked such vacuolation, whether caught from Boston Harbor or Georges Bank. Large focal areas of hydropically vacuolated cells dissected from severely affected livers had ODC activity as high or higher than surrounding parenchymal tissue. Significant elevations in hepatic polyamine levels and ratios of putrescine/spermidine were also present in all Boston Harbor animals studied, especially those exhibiting vacuolated cellular lesions, as compared to Georges Bank fish. BrdU labeling techniques indicate that hydropically vacuolated cells, along with perivacuolar small basophilic cells and neoplastic cholangiocytes, appear to have the capacity to synthesize DNA and undergo mitosis. The frequent association of hydropically vacuolated cells with hepatic neoplasia, along with high ODC activity and DNA synthesis capability, suggest that the vacuolated cells and/or perivacuolar basophilic cells may be integral to the development of some neoplastic phenotypes in winter flounder liver.

Animals↗

PubMed1993

A phase II study of 5-fluorouracil, leucovorin and interferon-alpha in advanced pancreatic cancer.

Increased activity against colorectal cancer by 5-fluorouracil (5-Fu) modulation with leucovorin (LV) and/or interferon (IFN) has been reported. In this study 22 patients with measurable advanced pancreatic cancer received 5-Fu 375 mg/m2 and LV 20 mg/m2 by i.v. bolus daily x 5 every 28 days plus IFN-alpha 3 million units/m2 s.c. There were three out of 21 (14%) responses lasting from 4 to 8 months. Sixteen patients (73%) had one or more episodes of grade 3 or greater toxicity (stomatitis, diarrhea or fatigue). While this combination has some activity against pancreatic cancer, its toxicity limits its potential as a palliative treatment.

Adenocarcinoma↗

PubMed1993

Development and validation of a limited sampling strategy for 5-fluorouracil given by bolus intravenous administration.

A wide range of interindividual variability of 5-fluorouracil (5-FU) pharmacokinetics exists after bolus administration. The degree to which this variability in 5-FU exposure impacts upon the response and toxicity of the drug has not been determined. The area under the concentration time curve (AUC) is a commonly used indicator of exposure, but normally requires the collection of 8-10 timed blood samples after i.v. bolus administration. This presents difficulties if large-scale population samplings are required. This study involved the development and testing of a strategy to estimate AUC from a limited number of blood samples in patients with gastrointestinal and breast cancer. The optimal single time point for AUC estimation was 0.17 h (r2 = 0.954). Addition of the 0.75 h time point significantly improved predictability (r2 = 0.983). Addition of a third or fourth time point did not provide further benefit. These models were then tested separately in a group of women who received a higher dose of 5-FU. The two data points model performed significantly better than the single time point model (r2 = 0.70 and 0.85, respectively). The AUC of standard dose 5-FU after bolus administration can be reliably estimated from two timed samples taken 10 and 45 min after injection.

Adult↗

PubMed1993

Face to face.

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Adolescent↗

PubMed1993

Breastfeeding during pregnancy.

Questionnaire data were gathered on the experiences of 57 women who were concurrently pregnant and breastfeeding. Respondents provided information on nursing and weaning patterns, informational and emotional support, and pregnancy history. The main reasons given for continued breastfeeding after conception were the emotional needs of the child or child-led weaning. Forty-three percent of the children continued to breastfeed throughout the pregnancy and tandem nurse after the birth. Mothers who initiated weaning cited breast and/or nipple pain as the principal reason. Most weanings initiated by the children occurred during the second trimester, corresponding with the diminution of breastmilk. The infants born to these mothers were healthy and appropriate for gestational age.

Adult↗

PubMed1992

Site-specific modification of pre-mRNA: the 2'-hydroxyl groups at the splice sites.

A simple and efficient method for synthesizing long, site-specifically modified RNA molecules was developed whereby segments of RNA were joined with the use of bacteriophage T4 DNA ligase. A single hydrogen or O-methyl group was substituted for the 2'-hydroxyl group at either splice site of a nuclear pre-messenger RNA substrate. Splicing of the modified pre-messenger RNA's in vitro revealed that, although a 2'-hydroxyl is not absolutely required at either splice site, the 2'-hydroxyl at the 3' splice site is important for the second step of splicing. These results are compared to previous studies of analogous 2'-hydroxyl groups in the self-splicing Tetrahymena group I intron.

Animals↗

PubMed1992

C-terminal cysteines of Tn501 mercuric ion reductase.

Mercuric ion reductase (MerA) catalyzes the reduction of Hg(II) to Hg(0) as the last step in the bacterial mercury detoxification pathway. A member of the flavin disulfide oxidoreductase family, MerA contains an FAD prosthetic group and redox-active disulfide in its active site. However, the presence of these two moieties is not sufficient for catalytic Hg(II) reduction, as other enzyme family members are potently inhibited by mercurials. We have previously identified a second pair of active site cysteines (Cys558 Cys559 in the Tn501 enzyme) unique to MerA, that are essential for high levels of mercuric ion reductase activity [Moore, M. J., & Walsh, C. T. (1989) Biochemistry 28, 1183; Miller, S. M., et al. (1989) Biochemistry 28, 1194]. In this paper, we have examined the individual roles of Cys558 and Cys559 by site-directed mutagenesis of each to alanine. Phenotypic analysis indicates that both merA mutations result in a total disruption of the Hg(II) detoxification pathway in vivo, while characterization of the purified mutant enzymes in vitro shows each to have differential effects on catalytic function. Compared to wild-type enzyme, the C558A mutant shows a 20-fold reduction in kcat and a 10-fold increase in Km, for an overall decrease in catalytic efficiency of 200-fold in kcat/Km. In contrast, mutation of Cys559 to alanine results in less than a 2-fold reduction in kcat and an increase in Km of only 4-5 fold for an overall decrease in catalytic efficiency of only ca. 10-fold in vitro. From these results, it appears that Cys558 plays a more important role in forming the reducible complex with Hg(II), while both Cys558 and Cys559 seem to be involved in efficient scavenging (i.e., tight binding) of Hg(II).

Alanine↗

PubMed1991

Structure of the detoxification catalyst mercuric ion reductase from Bacillus sp. strain RC607.

Several hundred million tons of toxic mercurials are dispersed in the biosphere. Microbes can detoxify organo-mercurials and mercury salts through sequential action of two enzymes, organomercury lyase and mercuric ion reductase (MerA). The latter, a homodimer with homology to the FAD-dependent disulphide oxidoreductases, catalyses the reaction NADPH + Hg(II)----NADP+ + H+ + Hg(0), one of the very rare enzymic reactions with metal substrates. Human glutathione reductase serves as a reference molecule for FAD-dependent disulphide reductases and between its primary structure and that of MerA from Tn501 (Pseudomonas), Tn21 (Shigella), p1258 (Staphylococcus) and Bacillus, 25-30% of the residues have been conserved. All MerAs have a C-terminal extension about 15 residues long but have very varied N termini. Although the enzyme from Streptomyces lividans has no addition, from Pseudomonas aeruginosa Tn501 and Bacillus sp. strain RC607 it has one and two copies respectively of a domain of 80-85 residues, highly homologous to MerP, the periplasmic component of proteins encoded by the mer operon. These domains can be proteolytically cleaved off without changing the catalytic efficiency. We report here the crystal structure of MerA from the Gram-positive bacterium Bacillus sp. strain RC607. Analysis of its complexes with nicotinamide dinucleotide substrates and the inhibitor Cd(II) reveals how limited structural changes enable an enzyme to accept as substrate what used to be a dangerous inhibitor. Knowledge of the mode of mercury ligation is a prerequisite for understanding this unique detoxification mechanism.

Bacillus↗

PubMed1991

Sarcoptic mite hypersensitivity and skin lesions in slaughtered pigs.

The association between papular skin lesions in slaughtered pigs and hypersensitivity to Sarcoptes scabiei var suis was examined in experimental and field studies, and by the retrospective analysis of monitoring records obtained at slaughter. A causal role for S scabiei was indicated by the production of lesions in experimentally infested pigs, by increased clinical mange in herds having high lesion scores, and by a reduction in the severity of lesions after the implementation of more intensive mange control measures. The specificity of the lesions as an indicator of sarcoptic mite hypersensitivity was estimated to be 0.92 from experimental data and 0.79 from field data. Generalised lesions were rare in mange free pigs, indicating that such lesions were highly specific (1.0 from experimental data, greater than 0.98 from field data) for mange. The assessment of the severity of the lesions in samples of slaughtered pigs appears to be a useful aid to assessing the severity of sarcoptic mange in pig herds.

Animals↗

PubMed1991

Regeneration of rat extensor digitorum longus tendon: the effect of a sequential partial tenotomy on collagen fibril formation.

Alterations in collagen fibril diameter distribution were measured in rat extensor tendons subsequent to two-successive partial tenotomies, 30 days apart. Subsequent to surgery three areas were created. The primary lesion area, consisted of a regenerating window in the central half of the tissue. Secondary lesion areas consisted of strips at the lateral margin of the tissue, removed during the second operation. Between the lesion areas were the non-lesion areas consisting of tissue not removed during surgery. Tissue was examined 40, 60, 120 and 240 days after the initial operation. Within each group, primary and secondary lesion areas remained unimodal in collagen fibril diameter distribution throughout the period of the study. This distribution was initially unimodal in the non-lesion areas but became multimodal by 240 days postoperatively. Both the primary lesion area and non-lesion areas exhibited an increase in frequency of small diameter fibrils between 40 and 60 days postoperatively. It is suggested that all observations may be related to the level of applied stress.

Animals↗

PubMed1991

Seasonality of sarcoptic mange in pigs in South Australia.

Retrospective analysis of records, from July 1987 to June 1991, of 1140 inspections of slaughtered pigs from 154 swine herds in the Pig Health Monitoring Scheme of South Australia was conducted to evaluate patterns of variation in the prevalence and severity of skin lesions typical of sarcoptic mange. An increase in the severity of sarcoptic mange in winter and spring was observed. There was a substantial reduction in the severity of mange over the period of monitoring. These observations support the role of monitoring at slaughter in the management of endemic disease. They provide some basis for refining control programs for mange to improve cost-effectiveness.

Animals↗

PubMed1991

Clinical pharmacokinetics of cyclophosphamide.

Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful anticancer agents, and is also widely used for its immunosuppressive properties. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard. Sensitive and specific methods are now available for the measurement of cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated. Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Longer term complications of cyclophosphamide therapy include infertility and an increased incidence of second malignancies. Cellular sensitivity to cyclophosphamide is a function of cellular thiol concentration, metabolism by aldehyde dehydrogenases to form inactive metabolites, and the ability of DNA to repair alkylated nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.

Aldehyde Dehydrogenase↗

PubMed1991

In vivo effects of anti-idiotype on Plasmodium chabaudi infection in mice.

A polyclonal anti-idiotype was raised in rabbits following immunization with a murine monoclonal antibody which recognized a 250,000 MW antigen of Plasmodium chabaudi-infected erythrocytes. The monoclonal antibody, NIMP M23 (clone 3,) has been shown to protect mice against homologous parasite challenge. Following purification, the anti-idiotype was shown to bind only the immunizing idiotype and to recognize antigen-binding site-associated anti-idiotype. Mice primed with anti-idiotype and challenged with live parasites had an altered course of infection, with significant reduction in their peak parasitaemia levels. Anti-idiotype priming did not induce an antigen-reactive antibody response in vivo but a population of T cells capable of proliferating in vitro to P. chaubaudi-infected red cells was stimulated. These data are discussed in the context of possible idiotypic interaction in murine malaria.

Animals↗