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Biomedical subjects

B R Smith

Publications and source records attributed to B R Smith.

407 records · Page 23Linked to original sources
PubMedDate not supplied

Storage of platelet concentrates after high-dose ultraviolet B irradiation.

Ultraviolet B (UVB) irradiation of platelet concentrates (PCs) may prevent the development of posttransfusion HLA alloimmunization. As irradiation performed in a blood center or a hospital will probably be associated with a variable postirradiation delay before transfusion, the ability to store PCs after UVB irradiation becomes important. The effects have been studied of a UVB dose of 10,000 mJ per cm2, the dose used in our institution for UVB clinical trials, on PCs pooled and stored for up to 96 hours after irradiation. Results showed that after 96 hours of storage, though there were no changes in pH, platelet count, white cell count, percent discharge of lactate dehydrogenase, or beta-thromboglobulin, there were significant decreases in morphology score and osmotic recovery. These changes, however, were not evident after 24 hours of storage. Similarly, there was a 60-percent decrease in immunoreactive membrane glycoprotein (GP) Ib after 96 hours of storage, but these changes were not seen after 48 hours of storage. No changes were seen in levels of GPIIb/IIIa in either group during the 96 hours of storage. On computer-analyzed two-dimensional polyacrylamide gel electrophoresis, PCs irradiated at 10,000 mJ per cm2 and stored for 72 hours had changes in over 50 platelet proteins as compared to those proteins in nonirradiated age-matched control PCs. It can be concluded that UVB irradiation of PCs at 10,000 mJ per cm2 does not lead to significant platelet deterioration after short-term storage (24-48 hours) but is likely to be deleterious after long-term (72-96 hours) storage.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Banks↗
PubMedDate not supplied

Phenotypic and functional analysis of expanded natural killer cell subpopulations in Hodgkin's disease patients treated with lymphoid irradiation.

We have evaluated the immunophenotype and function of presumptive NK cells taken from Hodgkin's disease patients before and after mantle/para-aortic lymphoid irradiation. We find that the lymphoid irradiation appears to induce a relatively stable, generalized expansion of the entire NK cell compartment rather than an increase in any specific NK cell subset. Flow cytometric cell sorting and functional NK cell assays based on immunophenotype demonstrate no significant changes in the phenotypic proportions of individual NK cell subsets and no significant changes in the lytic activity or cytotoxicity spectrum of these NK cells. These changes in the NK cell compartment may play a role in the long-term immunosuppression of these patients.

Cytotoxicity Tests, Immunologic↗
PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.

Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. The disposition of the closed ring lactone has been studied in 26 patients, and the disposition of both lactone and hydroxy acid has been studied in 12 patients. The clearance rate for topotecan lactone was 1220 ml/min/m2, with a range of 300-4760 ml/min/m2. The clearance rate for total topotecan (lactone and hydroxy acid) was 493 ml/min/m2, with a range of 163-815 ml/min/m2. A model for the disposition of lactone and hydroxy acid incorporating both reversible hydrolysis and elimination was developed. We have shown that topotecan is partially hydrolyzed prior to administration in parenteral solutions, and that clearance of the parent compound proceeds in vivo by conversion to hydroxy acid and elimination. Renal clearance accounted for 30 +/- 18% of drug elimination in patients. The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Regulation of hematopoiesis.

Normal hematopoiesis is a well-regulated process in which the generation of mature blood elements occurs from a primitive pluripotent stem cell in an ordered sequence of maturation and proliferation. Regulation occurs at the level of the structured microenvironment (stroma), via cell-cell interactions and by way of the generation of specific hormones and cytokines: erythropoietin, interleukin 3, granulocyte-monocyte colony-stimulating factor (GM-CSF), monocyte-macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin 5, interleukin 4, and other less well-defined factors, including the megakaryocyte growth factors. Understanding of this complex process has revealed insights into the pathophysiology of human disease and provided a theoretical framework for the therapeutic use of bone marrow transplantation and potential gene transfer therapy. Furthermore, ongoing clinical trials suggest that the hematopoietic growth factors may represent a significant new group of therapeutic reagents for patients with hematological and oncologic disease.

Cell Differentiation↗
PubMedDate not supplied

Metabolism of benzo[a]pyrene by the isolated perfused rabbit lung.

The metabolism of benzo[a]pyrene (BP) was studied in the isolated perfused rabbit lung and in rabbit pulmonary microsomes. Pretreatment of rabbits with 3-methylcholanthrene did not increase the metabolism of BP by microsomal preparations, and the pretreatment did not induce cytochrome P-448 in pulmonary microsomes. In the isolated perfused lung, BP was metabolized at a rate of about 6 nmol/min/g of lung. The intermediate arene oxides formed from BP in the isolated perfused lung were metabolized nonoxidatively by epoxide hydrase and glutathione S-transferases. The rates of the latter reactions were at least an order of magnitude less than the overall rate of metabolism. Pretreatment of the animals with 3-methylcholanthrene increased only the apparent rate of the epoxide hydrase reaction. In the isolated perfused lung, BP and some of its less polar metabolites (i.e., quinones and phenolic derivatives) were preferentially partitioned into lung tissue, precluding accurate measurement of metabolic rates by analysis of the perfusion medium alone. Covalent binding of BP-derived radioactivity to lung tissue occurred, but relatively high variability in this parameter in lungs from 3-methylcholanthrene-pretreated animals did not allow measurement of a significant difference from control lungs.

Animals↗
PubMedDate not supplied

Metabolism and biliary excretion of benzo[a]pyrene 4,5-oxide in the rat.

The excretion and biliary metabolites of intravenously administered benzo[a]pyrene 4,5-oxide were studied in the rat at two dose levels. After administration of 4.5 or 0.47 mumol, half of the dose was excreted in the bile in 60 min. Biliary metabolites were separated by reverse-phase high-pressure liquid chromatography and identified by cochromatography with biosynthetic standards, beta-glucuronidase hydrolysis, ultraviolet spectrophotometry and, in the case of the thioether conjugates, identification of the constituent amino acids. The major biliary metabolite was a mixture of isomeric glutathione conjugates. Some cysteine conjugate was also present, but no cysteinylglycine conjugate was detected. Hydration to transbenzo[a]pyrene-4,5-dihydrodiol followed by glucuronidation was also a quantitatively important metabolic pathway. Although benzo[a]pyrene-4,5-dihydrodiol glucuronide was more readily excreted by the liver than was benzo[a]pyrene 4,5-oxide:glutathione conjugate, the rate of glucuronidation of the dihydrodiol was low, resulting in its accumulation in the liver and possible release into the circulation. Therefore, the glutathione S-transferases may provide a more efficient mechanism for the removal of benzo[a]pyrene 4,5-oxide from the body than is provided by expoxide hydrolase.

Animals↗
PubMedDate not supplied

Cefsulodin and ceftazidime, two antipseudomonal cephalosporins.

The microbiologic, pharmacokinetic, and clinical profiles of cefsulodin and ceftazidime are reviewed. Ceftazidime is a broad-spectrum beta-lactamase stable cephalosporin with excellent activity against gram-negative bacilli, including Pseudomonas aeruginosa. Cefsulodin is a narrow-spectrum cephalosporin with activity against Staphylococcus aureus and Ps. aeruginosa. Both antibiotics, which are expected to be marketed in the United States, are superior to currently available cephalosporins against Ps. aeruginosa. Cefsulodin and ceftazidime are administered by the i.m. or i.v. route, are widely distributed in body fluids and tissues, and exhibit relatively low binding to serum proteins. They are eliminated primarily through the urine, and they generally can be administered every 8 to 12 hours, depending upon the type of infection. Cefsulodin has been used successfully in the treatment of various Ps. aeruginosa infections in noncomparative studies. Ceftazidime has been successfully used as a single agent in comparative studies for Ps. aeruginosa infections. Because of its broad spectrum and its activity against penicillin-resistant and aminoglycoside-resistant Pseudomonas, ceftazidime can be used empirically as a single agent in place of combination therapy in patients with cystic fibrosis. Ceftazidime has also been useful as a single agent used empirically for treating febrile episodes in neutropenic patients and for treating hospital-acquired infections in nonneutropenic patients when Pseudomonas cannot be ruled out. Ceftazidime is a useful broad-spectrum antibiotic, particularly in the empiric therapy of nosocomial infections and in patients whose underlying conditions predispose them to Ps. aeruginosa infections. Cefsulodin may prove useful as single-agent therapy of certain infections known to be caused by Ps. aeruginosa, but its empiric use is not encouraged.

Bacteria, Anaerobic↗