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Biomedical subjects

M J Murphy

Publications and source records attributed to M J Murphy.

At least 19 recordsLinked to original sources
PubMed1995

Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study.

The incidence of nephrotoxicity occurring with the nonionic contrast agent, iohexol, and the ionic contrast agent, meglumine/sodium diatrizoate, was compared in 1196 patients undergoing cardiac angiography in a prospective, randomized, double-blind multicenter trial. Patients were stratified into four groups: renal insufficiency (RI), diabetes mellitus (DM) both absent (N = 364); RI absent, DM present (N = 318); RI present, DM absent (N = 298); and RI and DM both present (N = 216). Serum creatinine levels were measured at -18 to 24, 0, and 24, 48, and 72 hours following contrast administration. Prophylactic hydration was administered pre- and post-angiography. Acute nephrotoxicity (increase in serum creatinine of > or = 1 mg/dl 48 to 72 hours post-contrast) was observed in 42 (7%) patients receiving diatrizoate compared to 19 (3%) patients receiving iohexol, P < 0.002. Differences in nephrotoxicity between the two contrast groups were confined to patients with RI alone or combined with DM. In a multivariate analysis, baseline serum creatinine, male gender, DM, volume of contrast agent, and RI were independently related to the risk of nephrotoxicity. Patients with RI receiving diatrizoate were 3.3 times as likely to develop acute nephrotoxicity compared to those receiving iohexol. Clinically severe adverse renal events were uncommon (N = 15) and did not differ in incidence between contrast groups (iohexol N = 6; diatrizoate N = 9). In conclusion, in patients undergoing cardiac angiography, only those with pre-existing RI alone or combined with DM are at higher risk for acute contrast nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1995

Iatrogenic profound hypoalphalipoproteinaemia: an unrecognised cause of very low HDL cholesterol.

A significant reduction in plasma high density lipoprotein (HDL) cholesterol is a recognised consequence of treatment with probucol. By contrast, fibrate therapy in general has the opposite effect. We report two cases where the combination of probucol and a fibrate led to profoundly reduced plasma levels of HDL cholesterol associated with very low levels of apolipoprotein A-I (apoA-I). In the first, bezafibrate was added to probucol, and in the second, probucol added to a combination of simvastatin and fenofibrate. In both cases, plasma levels of HDL and apoA-I returned towards normal after discontinuation of one or both drugs, indicating that the reduction was reversible.

Adult↗
PubMed1995

HIMeg-1, a cell line derived from a CML patient, is capable of monocytic and megakaryocytic differentiation.

We have characterized HIMeg-1, a subclone of the promegakaryoblastic cell line HIMeg, in terms of its capability of proliferation and differentiation when it is exposed to various agents. We observed that phorbol 12-myristate 13-acetate (PMA) arrested HIMeg-1 growth and induced expression of monocytic surface antigens CD11c and CD14, but not the megakaryocytic surface antigen CD14a. In addition, PMA treatment of HIMeg-1 led to rapid activation of mRNA expression of egr-1, a transcription factor involved in regulating differentiation of hematopoietic progenitor cells. On the other hand, treatment of HIMeg-1 with the activated peripheral blood lymphocyte-conditioned medium (PBL-CM) resulted in greatly enhanced incorporation of 3H-thymidine into newly synthesized DNA. This enhanced 3H-thymidine incorporation appears to be specific to HIMeg-1 since the same concentrations of PBL-CM had little effect on the growth of the megakaryoblastic leukemia cell line SAM-1. The PBL-CM-induced DNA synthesis in HIMeg-1 was associated with activation of CD41a and CD41b surface antigen expression and down-regulation of expression of the erythroid marker glycophorin A and the early myeloid surface antigen CD33. HIMeg-1 capable of responding differentially to PMA and PBL-CM by changing its growth rate as well as its differentiation patterns will provide an ideal model to study the underlying mechanism regulating lineage restriction of hematopoietic progenitor cells.

Antigens, CD↗
PubMed1993

Megakaryocytopoiesis and platelet production: does stem cell factor play a role?

Megakaryocytopoiesis, resulting in the production and release of platelets, is a multistage procession of cellular differentiation and maturation which is regulated by a constellation of cytokines. Since thrombocytopenia is a frequent dose-limiting toxicity of chemotherapy, newly-identified cytokines have been actively investigated for their potential megakaryocyte/platelet-promoting properties. Stem cell factor (SCF, also known as mast cell growth factor, Steel factor or Kit ligand) has been found to synergize with GM-CSF, IL-6, IL-3, IL-11 or Epo to increase the numbers of megakaryocyte-containing colonies (i.e., CFU-Meg, BFU-Meg, CFU-GMM, CFU-GEMM). On the other hand, SCF increased the number of megakaryocytes per colony in the presence of IL-3, GM-CSF or IL-6. SCF also stimulated the proliferation of specific megakaryocytic cell lines (i.e., CMK, M-07e). SCF did not, however, alter megakaryocyte markers or increase cell ploidy. Thus, SCF appears to expand the committed myeloid progenitor compartments, rather than increase the rate of megakaryocyte maturation or the number of platelets released. We describe studies in which SCF stimulated murine CFU-Meg alone and in the presence of IL-3. However, a decrease in cultured cell plating density resulted in ablation of this SCF-stimulation of CFU-Meg colonies. CFU-Meg colony stimulation by SCF was dose dependent, even under serum-free conditions. The effects of SCF in other in vitro and in vivo animal model systems are reviewed.

Animals↗
PubMed1992

Toxicosis in horses after ingestion of hoary alyssum.

Fever, limb edema, and laminitis were observed in horses 18 to 36 hours after they consumed hoary alyssum (Berteroa incana) under field and experimental conditions. Clinical signs were not observed in all horses that had ingested the plant. Diagnosis in the field cases was limited to observation of clinical signs and evidence of plant ingestion in hay or on pasture. In most cases, clinical remission was observed 2 to 4 days after empirical treatment, removal of the plant source, or both.

Animals↗
PubMed1992

Comparison of the in vitro toxicity of 2',3'-dideoxynucleosides to murine hematopoietic progenitor cells.

Four nucleoside analogues, 2',3'-dideoxyinosine (ddI), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytosine (ddC) and 5-fluoro-2',3'-dideoxycytosine (5-F-ddC), were evaluated for their potential in vitro myelotoxic effects on normal murine hematopoietic progenitor cells. Myeloid granulocyte-macrophage colony-forming units (CFU-gm), erythroid burst-forming units (BFU-e) and colony-forming units (CFU-e) and megakaryocytic (CFU-meg) progenitors were exposed to the agents for 1 h prior to culture in Petri dish assays or continuously throughout the entire culture period. At 10 microM, both ddA and ddI were moderately toxic (2-36% colony inhibition) to murine CFU-gm, BFU-e, CFU-e and CFU-meg following either 1 h or continuous exposure. Colony inhibition for the progenitors ranged from 2-31% at 10 microM for 1 h ddC or 5-F-ddC exposure. Continuous exposure to ddC was highly myelotoxic to murine hematopoietic progenitors with 100 microM suppressing colony formation 82-89%. At the same concentration and exposure time, 5-F-ddC inhibited colony formation 56-67%. Our results demonstrate that 1 h and continuous exposures to ddA and ddI were similarly myelotoxic to murine hematopoietic cells regardless of exposure time. In contrast, continuous ddC or 5-F-ddC exposure was more toxic to murine progenitors than 1 h exposure to these agents.

Animals↗
PubMed1992

Pharmacologic validation of human tumor clonogenic assays based on pleiotropic drug resistance: implications for individualized chemotherapy and new drug screening programs.

Because of the bias toward successful cloning of human tumor cells from more advanced malignancies, alternative approaches to clinical correlations of drug resistance are needed to determine the validity of the human tumor clonogenic assay (HTCA) as a clinically useful test. Capitalizing on the prevalence of clinical drug resistance among these advanced malignancies, we have taken an independent approach to testing the validity of HTCAs based upon pharmacologic principles rather than tumor response. A database of results from drug sensitivity/resistance testing in 1,777 HTCAs has been examined retrospectively for specimens exhibiting either the MDR1 or Topo-II pleiotropic drug resistance phenotype. Twenty specimens were identified as MDR1 based upon test results showing resistance to adriamycin, vinca alkaloid, and etoposide. Test results with mitomycin-c confirmed the MDR1 phenotype in eight out of nine of these specimens. Seven out of eight of the confirmed MDR1 samples were resistant to either cis-platinum or alkylating agents or to both. There was no significant difference in the 5-fluorouracil resistance of these MDR1 specimens and the database as a whole, demonstrating the specific nature of this drug resistance phenotype in vitro. One specimen, a squamous carcinoma of the lung, was mitomycin-c sensitive, even though it exhibited all the other drug resistances characteristic of the MDR1 phenotype. Six specimens with the Topo-II phenotype were identified based upon resistance to adriamycin and etoposide with sensitivity to vinca alkaloids. Surprisingly, the Topo-II phenotype showed a strong association with increased cis-platinum resistance and a weaker one with decreased 5-fluorouracil resistance. Thus, 26/30 (87%) of analyzable specimens showed some form of clinically characterized multidrug resistance, illustrating how easily one can obtain 90% accuracy in predicting clinical drug resistance with HTCAs that are heavily biased by a disproportionate number of successful cloning assays with advanced malignancies. The data analysis also shows that prediction of adriamycin resistance based on lack of Topoisomerase II expression will not be very accurate, in contrast to a previous claim. Until cell culture technology can facilitate frequent successes in the cloning of early detected, drug-sensitive lesions, this bias will remain in HTCA databases, and studies comparing HTCA results with clinical response will continue to be uninformative. However, the in vitro identification of pleiotropic drug resistance phenotypes exactly analogous to those previously observed in patients provides pharmacologic validation at least for the prediction of drug resistance as measured by current HTCAs using suprapharmacologic drug concentrations.

Antineoplastic Agents↗
PubMed1992

Comparative in vitro myelotoxicity of FCE 24517, a distamycin derivative, to human, canine and murine hematopoietic progenitor cells.

FCE 24517, a derivative of distamycin A, exhibits an unusual antitumor profile in experimental models. As part of its preclinical development, we evaluated the in vitro myelotoxicity of FCE 24517 to human, canine and murine hematopoietic cells. Marrow cells were exposed to the agent (2.7 x 10(-5) - 2.7 nM) for 4 h and then assayed in capillary (human) or Petri dish (canine, murine) clonal cultures. FCE 24517 inhibited myeloid (CFU-gm), erythroid (BFU-e, CFU-e) and megakaryocytic (CFU-meg) colony formation in a concentration-dependent manner. The progenitor cells were generally similar in their response to FCE 24517 within a species. Comparing the different progenitor cell response to FCE 24517, canine CFU-gm and CFU-e were 26- to 221-fold more sensitive to this drug's toxic effects than their human and murine counterparts. This was demonstrated by extremely low IC70 values for the canine CFU-gm (0.001 nM) and CFU-e (0.007 nM). Murine progenitors displayed 1.3- to 10.9-times higher IC70 values than human CFU-gm, BFU-e and CFU-e following 4 hr exposure to FCE 24517. The data demonstrated that a mouse model may better predict human in vitro myelotoxicity to FCE 24517 than beagle dogs.

Animals↗
PubMed1992

In vitro toxicity of 3'-azido-3'-deoxythymidine, carbovir and 2',3'-didehydro-2',3'-dideoxythymidine to human and murine haematopoietic progenitor cells.

The myelotoxicities of three antiretroviral agents, 3'-azido-3'-deoxythymidine (AZT), carbovir (CBV) and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), were evaluated in vitro with normal human and murine haematopoietic progenitor cells. These studies demonstrated that continuous AZT exposure was more inhibitory to human and murine colony formation than 1 h exposure, with murine and human progenitors similarly inhibited by continuous AZT exposure. These in vitro results on AZT's myelotoxicity correlate with both human and murine in vivo studies. CBV was only moderately toxic to human and murine cells following either 1 h or continuous exposure, with human and murine progenitors similarly suppressed by continuous CBV exposure. 1 h d4T exposure was less toxic to both human and murine marrow cells than continuous exposure and both species were equivalently inhibited when continuously exposed to d4T. In general, CBV was the least toxic agent to human and murine haematopoietic cells and AZT the most toxic. The study establishes CBV and d4T as less myelotoxic agents to human and murine haematopoietic progenitor cells in vitro than AZT which therefore could be considered as alternatives to AZT for the treatment of HIV infection.

Animals↗
PubMed1992

Effects of recombinant cytokines on murine megakaryocyte colony formation in a serum-free fibrin clot culture system.

A convenient serum-free fibrin clot culture system for murine megakaryocyte progenitor cells was developed. The culture and counting of colonies is much easier in this system, when compared with previously reported serum-free culture methods. Recombinant murine interleukin-3 (rmIL-3) stimulated megakaryocyte colony formation in a dose-dependent manner in this system. While recombinant human granulocyte colony-stimulating factor (rhG-CSF) had no effect on megakaryocytopoiesis, recombinant human erythropoietin (rhEpo) and recombinant human interleukin-6 (rhIL-6) augmented megakaryocyte colony formation stimulated by rmIL-3. The depletion of adherent cells and T cells from the cultured bone marrow did not eliminate the synergistic effect of rhEpo and rhIL-6.

Animals↗
PubMed1992

Unilateral renal agenesis in chick embryos: a model for chronic renal insufficiency.

Although renal agenesis and dysgenesis are relatively common and significant birth defects, no animal model to date has been utilized to adequately study these developmental pathologies. Blockage of the migration of the mesonephric duct in Day 2 chick embryos results in unilateral renal agenesis (URA) on the operated side, thus providing a model of chronic renal insufficiency. Embryos with URA respond with an increase in the rate of growth of the remaining meso- and metanephric kidney. The allometric scaling of single (left) kidney weight to total body weight in control embryos is KM = 3.48M0.98 compared to KM = 3.02M1.16 in embryos with URA. In addition, embryos with URA exhibit a progressively polycystic mesonephros with distinct glomerulonephritis and expansion of the renal tubules. These renal changes are insufficient for normal urine (allantoic fluid) production and oliguria persists throughout incubation. While mortality is unaffected by URA in embryos up to Day 14 of incubation, there is a steady increase in mortality after Day 14; no chick embryo with URA lives beyond Day 18 of the 21-day incubation period.

Animals↗