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Biomedical subjects

J Fried

Publications and source records attributed to J Fried.

At least 19 recordsLinked to original sources
PubMed1992

Elevation of cardiac output and oxygen delivery improves outcome in septic shock.

Septic shock is characterized by hypoperfusion and tissue energy defects. We prospectively evaluated the therapeutic benefit of augmenting cardiac output and therefore oxygen delivery (DO2) on mortality in patients with septic shock. Twenty-five patients were randomized to a normal treatment (NT) group and 26 patients were randomized to an optimal treatment (OT) group. All patients had a clinically evident site of infection, sepsis as defined by a systemic response to the infection, and shock indicated by systemic hypoperfusion. Patients were treated during the initial 72 h by an algorithm differing only in the end point of resuscitation. The cardiac index (CI) was increased to 3.0 L/min/m2 in the NT group and to 6 L/min/m2 in the OT group. There were no significant differences in cardiorespiratory parameters in the NT and OT groups on entrance into the study. During treatment, CI averaged 3.6 +/- 0.2 L/min/m2 and DO2 averaged 8.6 +/- 0.8 ml/min/kg in the NT group and CI averaged 5.1 +/- 0.2 L/min/m2 and DO2 averaged 12.2 +/- 0.7 ml/min/kg in the OT group (p less than 0.01). A significant correlation between DO2 and survival was observed. Seventy-two percent of the OT patients died vs 50 percent of the NT patients (p = 0.14). Surviving NT patients stayed 13.7 +/- 3 days in the ICU vs 7.4 +/- 0.6 days (p less than 0.05) for the OT patients. Since some of the NT patients were spontaneously hyperdynamic and some of the OT patients did not achieve their desired end point, patients were arbitrarily subsetted using a midpoint CI of 4.5 L/min/m2. The NT less than 4.5 group had a CI of 3.1 +/- 0.2 L/min/m2 and DO2 of 10.9 +/- 1.0 ml/min/kg while the OT group greater than 4.5 L/min/m2 had a CI of 5.7 +/- 0.2 L/min/m2 and a DO2 of 13.8 +/- 0.7 ml/min/kg (p less than 0.01). Mortality in the NT less than 4.5 group was 74 percent as compared with 40 percent in the OT greater than 4.5 group (p less than 0.05).

Albumins↗
PubMed1990

Pyrimethamine: an approach to the development of a male contraceptive.

With the human population of the world currently more than 5.2 billion and growing at an explosive rate, the need for additional forms of readily available contraception appears paramount. To date, contraception techniques in the male have been very limited. The present study demonstrates the ability of pyrimethamine (PYR) to cause spermatogenic arrest and male infertility in mice in a dose-dependent manner. Furthermore, upon cessation of drug administration all animals returned to normal fertility status. It is also suggested that the action of PYR is due to its antifolate action. Thus, PYR represents another approach toward development of a male contraceptive.

Animals↗
PubMed1990

Immunophenotypic analysis of lymphocytes and myeloma cells in patients with multiple myeloma.

The immunological phenotypes of lymphocytes and myeloma cells in 48 patients with multiple myeloma (MM) were analyzed using a panel of monoclonal antibodies (mAbs). Myeloma cells were positive for OKT10, BL3, PCA1 and BA2. In a few cases, they were also positive for the B cell-associated antigens J5, B1 and I2. Eight of 48 cases had more than 15% J5-positive lymphocytes, and some lymphocytes in MM expressed plasma cell-associated antigens (PCA1, BL3, OKT10), suggesting a possible clonal involvement. These observations demonstrate the heterogeneity of surface antigen expression of myeloma cells and suggest that BL3, PCA1, BA2 and J5 may be useful mAbs for purging myeloma cells from bone marrow for autologous transplantation.

Antibodies, Monoclonal↗
PubMed1989

Fatal hemorrhage from an arterio-portal-peritoneal fistula after percutaneous liver biopsy.

Exsanguinating hemorrhage complicated a percutaneous needle biopsy in a 64-yr-old woman with a probable collagen vascular disease. Angiography performed before Gelfoam embolization demonstrated a hepatic arterio-portal venous-peritoneal fistula, a lesion not previously described, to be a cause of the hemorrhage. Although surgery remains the treatment of choice, the role of selective hepatic arteriography and Gelfoam embolization in patients with serious hemorrhage who are poor surgical risks needs evaluation.

Arteriovenous Fistula↗
PubMed1989

Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels.

The present study reports on the selective effects on human platelets and canine saphenous veins of four stable difluorinated analogues and thromboxane A2 (TXA2), in which the characteristic 2,6-dioxa[3.1.1]bicycloheptane structure of TXA2 has been retained. The four compounds differ in their stereochemistry of the 5,6 double bond and/or the 15-hydroxyl group. Only 10,10-difluoro-TXA2 (compound I) with the natural stereochemistry of TXA2 was an agonist in both platelets and canine saphenous veins (EC50 = 36 +/- 3.6 nM and 3.7 +/- 0.8 nM, respectively). (15R)-10,10-Difluoro-TXA2 (compound II), (5E)-10,10-difluoro-TXA2 (compound III), and (5E,15R)-10,10-difluoro-TXA2 (compound IV) were antagonists of platelet aggregation stimulated by compound I (Kd = 98 +/- 46 nM, 140 +/- 42 nM, and 1450 +/- 350 nM, respectively). However, compounds II, III, and IV stimulated contraction of canine saphenous veins (EC50 = 36 +/- 4.4 nM, 31 +/- 6.8 nM, and 321 +/- 50 nM, respectively). All four compounds could displace the TXA2/prostaglandin H2 antagonist 9,11-dimethylmethano-11,12-methano-16-(3- 125I-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2 from its platelet receptor (Kd values = 100 +/- 30 nM, compound I; 280 +/- 60 nM, compound II; 230 +/- 70 nM, compound III; and 1410 +/- 1020 nM, compound IV). These results support the existence of two subtypes of TXA2/prostaglandin H2 receptors and emphasize the importance of the stereochemical requirements of these TXA2 analogues for interaction with these receptors. These stable fluorinated TXA2 analogues should prove useful tools for the further characterization of these and other TXA2/prostaglandin H2 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Early hemodynamic correlates of survival in patients with septic shock.

In this retrospective study, we attempted to identify early in the course of septic shock hemodynamic variables that differ between survivors and nonsurvivors. We examined the records of 78 patients with septic shock from our medical ICU (40 survivors and 38 nonsurvivors). Significant differences were found in cardiac index (CI) (4.07 +/- 0.25 vs. 2.98 +/- 0.25 L/min.m2) and oxygen delivery (DO2) (15.6 +/- 0.7 vs. 12.7 +/- 0.8 ml/min.kg) at 48 h between surviving and nonsurviving patients. Furthermore, an analysis of the relationship between DO2 and VO2 suggests a critical level of DO2 to be 15 ml/min.kg. Although no difference could be detected in initial arterial lactate concentrations, levels at 48 h were significantly different between survivors and nonsurvivors (2.6 +/- 0.2 vs. 4.1 +/- 0.5 mEq/L, respectively).

Adult↗
PubMed1989

Sustained release methylphenidate: pharmacokinetic studies in ADDH males.

Methylphenidate is widely used in the treatment of school-age children with attention deficit disorder with hyperactivity (ADDH). It is available in a short-acting (MPH) and a long-acting (MPH-SR) preparation. Nine males with ADDH participated in a 1-day pharmacokinetic study following a single morning dose of 20 mg. MPH-SR. Data are presented on MPH-SR's half-life (T 1/2), peak concentrations achieved (Cmax) and the time to the peak plasma concentrations (Tmax). Similar data were gathered from a second group of eight ADDH males treated with a higher, single morning dose of standard, short-acting MPH. After adjusting for dose differences, comparisons of the two sets of plasma concentration curves suggest that MPH-SR has a longer Tmax, but that it does not reach the same Cmax as an identical dose of standard MPH.

Adolescent↗
PubMed1988

Ex vivo treatment of myeloma cells by 4-hydroperoxycyclophosphamide and VP-16-213.

To assess the usefulness of 4-hydroperoxycyclophosphamide (4-HC) and VP-16-213 (VP-16) as a purging agent for myeloma cells in bone marrow (BM) ex vivo, myeloma cell lines (SK-RCS-1, RPMI-8226), lymphoma cell line (SK-DHL-2) and normal BM cells were treated at different concentrations of 4-HC or VP-16. Clonogenic tumor cells from all three cell lines could be reduced by more than 4 logs, when treated alone or as a mixture with irradiated normal BM cells at a 4-HC concentration of 60 microM. Under similar conditions, approximately 1% of the normal BM myeloid progenitor granulocyte-macrophage colony-forming cells survived. These observations support the use of 4-HC for purging myeloma cells for autologous BM transplantation.

Bone Marrow↗
PubMed1988

Cell-mediated toxicity of interleukin-2-activated lymphocytes against autologous and allogeneic human myeloma cells.

We studied the sensitivity of human myeloma (plasma cell leukemia) toward autologous and allogeneic lymphokine-activated killer (LAK) cells. Fresh plasma cell leukemia (PCL)-derived peripheral blood mononuclear cells (PBMC) and PBMC from 3 normal donors were cultured in the presence of recombinant interleukin-2 (rIL2; 1,000 U/ml) for subsequent use as cytotoxic effectors against fresh and continuously cultured myeloma cells. Target cell lysis was measured in a 4-hour 51Cr radioisotope release assay. At an effector to target (E:T) ratio of 50:1, rIL2-induced PCL-PBMC lysed 48 +/- 19% (mean +/- 1 SD) of autologous myeloma targets, as compared to 89 +/- 5, 95 +/- 15, and 100 +/- 9% lysis of standard LAK-sensitive Daudi cells and allogeneic myeloma cell lines SKO-007, and RPMI-8226, respectively. Normal PBMC-derived rIL2-induced (LAK) cells exhibited a slightly lower cytotoxic reactivity against allogeneic targets (61 +/- 9, 60 +/- 6, and 81 +/- 8% cytolysis of SKO-007, RPMI-8226, and Daudi cells, respectively, at a 50:1 E:T ratio). Cytotoxicity against myeloma (PCL) of autologous PCL-derived killer cells could be significantly (at least 2-fold) enhanced when rIL-2-induced effector cells were preincubated for 18 h in the presence of recombinant Interferon-alpha rIFN-alpha; 1,000 U/ml). In summary, our results indicate the potential antitumor efficacy of rIL2- and rIL2 + rIFN-alpha-activated killer cells in human myeloma (PCL).

Cells, Cultured↗
PubMed1988

Elimination of myeloma cells from bone marrow by using monoclonal antibodies and magnetic immunobeads.

The efficacy of immunomagnetic beads to purge human myeloma cells from bone marrow ex vivo was evaluated. The optimal conditions for purging were studied first by using three myeloma cell lines: RPMI-8226, SKO-007, and SKMM-2. Myeloma cells labeled with the vital fluorescent dye Hoechst 33342 were admixed with normal bone marrow cells, and two monoclonal antibodies reactive with the myeloma cells (PCA-1 and BL-3) were added alone or in combination with the cells. Magnetic beads coated with goat antimouse immunoglobulin G were then added, and the tumor cells to which beads were attached were separated from the mixture with a magnet. The efficacy of tumor cell removal was dependent on the bead-to-tumor ratio; a ratio of more than 500 was optimal in the presence of excess normal marrow cells. The combination of monoclonal antibodies PCA-1 and BL-3 increased the tumor cell removal as compared with either antibody alone. Two cycles of treatment were more effective than one cycle was. Under optimal conditions, 2.3 to 4 logs of tumor cells could be removed from the mixture containing 10% myeloma cells without a significant loss of normal hematopoietic progenitors as measured by CFU-GM, CFU-GEM, and BFU-E. When the efficacy of this procedure was tested on fresh bone marrow from patients with multiple myeloma (MM) by using the combination of PCA-1, BL-3, and J-5, 1.6 to 2.5 logs of tumor cells could be removed by one cycle of treatment, even from marrows containing less than 10% myeloma cells. These observations support the use of monoclonal antibody combinations and immunobeads as a reliable and nontoxic method to eliminate contaminating myeloma cells ex vivo in preparation for autologous bone marrow transplantation in patients with MM.

Antibodies, Monoclonal↗
PubMed1987

Discrepancy between flow cytometric analyses of CALLA using two monoclonal antibodies.

Both the J5 and BA-3 monoclonal antibodies are considered to be specific for epitopes on the common acute lymphoblastic leukemia antigen (CALLA). Flow-cytometric analyses of three cell lines and one normal bone marrow sample using these antibodies as CALLA markers demonstrated that J5-labeled cells were always brighter than those labeled with BA-3, and that the ratio of their fluorescence intensities varied widely in the different systems. Furthermore, one of the lines, RPMI 8226, while positive for J5, appeared to be negative when labeled with BA-3, except for a slight displacement of the fluorescence distribution relative to the control. A possible explanation for the observed results is that the BA-3 binding epitope or epitopes on CALLA may vary in their number and/or accessibility to the antibody. These observations suggest that the use of a single monoclonal antibody to detect a cell surface antigen may be misleading, particularly when a negative result is obtained.

Antibodies, Monoclonal↗
PubMed1985

Incidence of involvement of the B and T lymphocyte lineages in chronic myelogenous leukemia.

Peripheral blood specimens were obtained from 22 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) (16 in chronic phase, 2 in an accelerated phase, and 4 in blast crisis). Studies were performed to determine the frequency of the presence of the Ph1 chromosome in cells of lymphoid lineages. Rosetted (E+) lymphocytes (T lymphocytes) from nine patients in chronic phase and one patient in blast crisis were stimulated with T cell growth factor interleukin 2 (IL-2) and/or phytohemagglutinin (PHA). All ten patients had sufficient T lymphocyte metaphases for analysis and of a total of 461 metaphases examined, only one contained the Ph1 chromosome. Nucleated cells of density less than 1.077 g/mL were infected with Epstein-Barr virus (EBV). Following infection, cell lines were established from individual colonies attached to egg albumin-coated Lab-Tek slide chambers (clonal cell lines) or from suspension culture in 96-well tissue culture cluster dishes (nonclonal cell lines). Cell surface and intracellular marker analysis confirmed the B lymphocyte phenotype of all the cell lines examined. B lymphoblastoid cell lines were established from 16 of the 22 patients. All lines from 12 patients were Ph1-negative. From two chronic phase patients, both Ph1-positive and Ph1-negative lines were established. From one patient in an accelerated phase, only Ph1-positive lines were established. From another patient in blast crisis (of myeloblastic phenotype), only Ph1-positive lines were established initially; however, five months later, after the patient had been treated with mitoxantrone, only Ph1-negative lines were derived from this patient. Based on these results, it appears that most B cells and mature T cells in most CML patients are Ph1-negative, but that about 25% of patients have predominantly Ph1-positive B cells or a mixture of Ph1-positive and Ph1-negative B cells that are capable of growing as established cell lines after transformation with EBV.

Adolescent↗
PubMed1979

Prostaglandin F2 alpha and its 13-dehydro analogs: comparative luteolytic effects in vivo.

Prostaglandin F2 alpha (PGF2 alpha) was identified as a luteolytic hormone in sheep (Nature, New Biol. 238, 129, 1972). Attempts to use PGF2 alpha for the pharmacological control of luteolysis in normal cycling sheep met with only partial success due to the rapid clearance of PGF2 alpha from the blood. In addition treated animals showed moderate to severe cardiovascular and gastrointestinal side effects. Accordingly, experiments were carried out to determine whether PG analogs might be more effective as pharmacological luteolytic agents. These compounds, which consisted of a number of the 13-dehydro analogs of PGF2 alpha, were administered to both sheep and monkeys either directly into the ovary or into the systemic circulation to examine them respectively for direct luteolytic activity and for resistance to metabolism. In addition in both the sheep and the monkey smooth muscle activity of the analogs was determined by recording uterine contractions in vivo. Several 13-dehydro analogs including some 16-fluoro derivatives were shown to have luteolytic activity equal to, or in some cases greater than, PGF2 alpha itself. Furthermore most of these compounds showed a marked resistance to the 15-OH-PG-dehydrogenase enzyme in vivo as evidenced by their luteolytic activity when infused intravenously. In terms of uterine contractions, several luteolytic analogs showed markedly diminished smooth muscle activity, and in some cases, complete absence of activity. These results suggest that the receptors governing the luteolytic effect on the one hand, and the smooth muscle effect on the other, possess different structural specificities. Recent studies which we have carried out on the effect of PGF2 alpha on corpus luteum (CL) blood flow support this conclusion. CL capillary blood flow was continuously monitored by means of a miniaturized Geiger-Müller probe inserted through the center of the CL in both the in situ and the autotransplanted ovary of the sheep. Capillary blood flow was measured by the clearance rate of 85Krypton injected periodically into the ovarian artery before and during the induction of luteolysis with PGF2 alpha. It was concluded that the initiation of luteolysis is not dependent on a smooth muscle effect of PGF2 alpha on the capillaries of the CL, a finding which supports the results with the synthetic analogs devoid of smooth muscle activity. More recently, in the primate model used (Macaca fascicularis) we have demonstrated that certain metabolically stable analogs are luteolytic when given intravenously, subcutaneously, or orally. These results demonstrate a rational approach to both drug synthesis and biological evaluation and suggest that a once-a-month contraceptive agent, based on a luteolytic analog of PGF2 alpha, devoid of smooth muscle activity (side effects) and metabolically stable in the bloodstream may become a reality.

Animals↗