Biomedical subjects
N L Kobrinsky
Publications and source records attributed to N L Kobrinsky.
Modulation of membrane transport of alkylating agents and amino acids by an analog of vasopressin in murine L5178Y lymphoblasts in vitro.
The synthetic vasopressin analog 1-deamino-8-D-arginine vasopressin (dDAVP) has been shown to influence a wide range of cell-membrane-related events. Accordingly, the effect of dDAVP on membrane transport of various alkylating agents and amino acids was evaluated in L5178Y lymphoblasts in vitro. dDAVP stimulated melphalan uptake but conversely inhibited uptake of nitrogen mustard, choline (the natural transport substrate for the nitrogen mustard carrier), and leucine. No effect on the uptake of cyclophosphamide or glutamine was observed. Increased melphalan uptake was due to effects on both substrate influx and efflux. The effect of dDAVP on melphalan influx was particularly complex: dDAVP stimulated melphalan influx by amino acid transport system ASC but inhibited influx by system L, resulting in a net increase in unidirectional drug influx. Melphalan efflux was inhibited by dDAVP. Decreased uptake of nitrogen mustard, choline and leucine was due, at least in part, to decreased substrate influx. However, the mechanisms of inhibition were dissimilar: inhibition of substrate influx was non-competitive for choline but competitive for leucine. In conclusion, dDAVP induced diverse but apparently specific effects on membrane transport of several alkylating agents and amino acids. Since the accumulation of alkylating agents such as melphalan within tumor cells is a major determinant of cytotoxicity, dDAVP may have a role as a biological response modifier.
1-Desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery. A randomized, double-blinded, controlled trial.
To evaluate the effect of 1-desamino-8-D-arginine vasopressin (desmopressin) on blood loss in surgery, we conducted a randomized, double-blind trial of the drug in 35 patients with normal hemostatic function who were having spinal fusion with Harrington rod instrumentation. Seventeen patients were designated to receive 10 micrograms/m2 of desmopressin, and 18, to receive a placebo. Preoperative testing showed that desmopressin increased factor VIII coagulant activity, von Willebrand antigen concentrations, glass bead platelet retention, and prothrombin consumption and decreased the partial thromboplastin and bleeding times (p less than or equal to 0.0003). During surgery, desmopressin reduced blood loss by 32.5% (547 mL; 95% confidence interval [CI], 19 to 1075; p = 0.015) and reduced the need for concentrated erythrocyte transfusions by 25.6% (0.86 units; 95% CI, 0.08 to 1.65; p = 0.022). After surgery, desmopressin reduced the duration of treatment with analgesic agents by 13.1% (34.0 hours; 95% CI, -5.2 to 72.7; p = 0.105), presumably by decreasing bleeding in the surgical wound. When adjusted for the origin of the scoliosis by two-way analysis of variance, this effect was even more evident (p = 0.014). Multiple regression analysis showed that the best three predictors of blood loss in surgery and transfusion requirements were the bleeding time, glass bead platelet retention, and the use of desmopressin.
In vitro stability and compatibility of daunorubicin, cytarabine, and etoposide.
The continuous infusion of cytarabine, daunorubicin, and etoposide offers several theoretical advantages over bolus infusion in the treatment of acute nonlymphocytic leukemia. To date, this approach has been limited by the need for three separate iv lines. The in vitro stability and compatibility of these three agents were therefore evaluated. Solutions of 200 mg of cytarabine, 25 mg of daunorubicin, and 300 mg of etoposide per 750 ml of 5% dextrose and 0.45% saline were prepared alone and in combination. The solutions were evaluated visually, spectrophotometrically, and by high-pressure liquid chromatography (HPLC) twice daily for 72 hours. Precipitates or color changes were not noted. Changes in the patterns of the spectral scans and chromatographs were not observed. Concentrations of the drugs as assessed by HPLC were stable over the 72-hour period of observation for both individual and combined drug preparations. In conclusion, cytarabine, daunorubicin, and etoposide are stable and compatible in vitro for at least 72 hours. These drugs can therefore be administered together by continuous infusion using a single iv line.
Absent factor VIII response to synthetic vasopressin analogue (DDAVP) in nephrogenic diabetes insipidus.
To study the effect of 1-deamino-8D-arginine vasopressin (DDAVP) on the factor VIII response in nephrogenic diabetes insipidus (NDI), 0.30 microgram/kg DDAVP was given to 2 unrelated NDI patients, 3 obligate carriers, and 20 controls. Factor VIII coagulant activity (FVIIIC) and factor VIII related antigen (FVIIIR:Ag) responses were absent in both NDI patients and were decreased by approximately 50% in the carriers by comparison with controls. These results show that the vasopressin receptor defect in NDI is not confined to the kidney but is equally expressed in other tissues including the vascular endothelium and hepatic sinusoids, the respective sites of FVIIIR:Ag and FVIIIC production. A decreased factor VIII response may help in identifying carriers in families at risk.
Endothelial cells suppress granulocyte clusters and stimulate large granulocyte colonies in culture.
Endothelial cells have been shown to produce granulopoietic colony stimulating activity (CSA) under the regulatory control of a humoral factor, MRA produced by blood monocytes. An endothelial cell-derived granulopoietic inhibitory factor has also been described. To further define these apparently paradoxical observations, human bone marrow mononuclear cells were co-cultured with umbilical cord derived endothelial cells in a plasma clot system in vitro. To enhance the sensitivity of the assay for growth effects attributable to the endothelial cells (or their products) alone, an exogenous source of CSA (e.g. a peripheral blood leukocyte feeder layer) was not used. On day ten of culture, less than or equal to 1% endothelial cells markedly stimulated the growth of early granulocyte progenitors (large diaminofluorine positive (DAF+) GM-CFUc) (p less than .01) and a linear dose response relationship was confirmed (p less than .001). Late granulocyte progenitors (DAF+ clusters) were coincidently suppressed by less than or equal to 2% endothelial cells (p less than .01). No effect of endothelial cells on intermediate progenitors (small GM-CFUc) was demonstrated at any concentration. Similar effects were observed with the addition of 5% to 30% endothelial conditioned medium (ECM) (p less than .01). When cohort cultures were evaluated serially, suppression of clusters was observed by day four and stimulation of large GM-CFUcs by day six. These varied effects on different stages of granulocyte differentiation suggest that endothelial cell derived CSA(S) may be of biological relevance in the regulation of granulopoiesis.
Shortening of bleeding time by 1-deamino-8-D-arginine vasopressin in various bleeding disorders.
To evaluate the effect of 1-deamino-8-D-arginine vasopressin (DDAVP) in various bleeding disorders, 10 micrograms/m2 DDAVP was administered to subjects with von Willebrand disease (13), platelet function defects (12), von Willebrand disease and platelet defects together (8), or isolated prolongation of the bleeding time (5). DDAVP shortened the bleeding time similarly in all patient groups. Shortening of the bleeding time was also observed in 2 patients with aspirin-induced platelet defects and in 2 normal subjects. DDAVP administration was associated with falls in the platelet count, mean platelet volume, and partial thromboplastin time, and rises in platelet adhesion, factor VIII coagulant activity, factor VIII related antigen, and von Willebrand factor activity. The basal bleeding time was the only predictor of the magnitude of the bleeding-time correction. Normal haemostatis was achieved with DDAVP plus epsilon-aminocaproic acid and no blood product support during operations in 18 patients with bleeding disorders.
Improved hemophilia A carrier detection by DDAVP stimulation of factor VIII.
We studied the differential increase in FVIIIc and FVIII R:Ag after the intravenous infusion of 0.30 micrograms/kg DDAVP in 20 obligate hemophilia A carriers and in 20 female controls. FVIIIc increased in carriers (59.5 +/- 23.1 to 137.5 +/- 45.9) and in controls (98.0 +/- 20.7 to 259.9 +/- 57.4) (P less than 0.001), but the magnitude of the FVIIIc increase in carriers was less than that in controls by 51.9% (P less than 0.001). FVIII R:Ag increased comparably in carriers (105.2 +/- 30.4 to 171.9 +/- 25.4) and controls (92.1 +/- 33.0 to 165.2 +/- 20.6). Using the post-DDAVP instead of the standard FVIIIc/FVIII R:Ag ratio, hemophilia carrier detection was increased from 85% (with 10% false positive and 20% false negative assignments) to 95% (with 5% false positive and 5% false negative assignments). Toxicity associated with DDAVP infusion correlated linearly with doses greater than 10.5 +/- 1.3 micrograms/m2 (P less than 0.02) and with total doses greater than 17.0 +/- 4.5 micrograms (P less than 0.02). The use of DDAVP improves carrier detection in factor VIII-deficient hemophilia.
Anthracycline cardiomyopathy.
Life-threatening irreversible cardiomyopathy is a major complication of anthracycline therapy, particularly in the pediatric population. The pediatric cardiologist, in concert with the primary oncologist, should therefore play a major role in the care of patients receiving these agents and in clinical trials involving their use. Many risk factors and their relationships to drug pharmacokinetics, mechanisms of action, and toxicity have been identified. These data provide a rational basis for present-day recommendations regarding anthracycline administration and dosage scheduling. They furthermore provide potential avenues for clinical investigation aimed at improving the therapeutic index of these agents: alpha-tocopherol, cytochrome Q10, and other free radical scavengers may decrease the deleterious effects of free radical generation on the myocardium without apparent interference with tumoricidal effect. The cardiac glycosides may decrease cardiac toxicity by specific myocardial exclusion. Anthracycline analogs have been designed to specifically inhibit myocardial binding and/or free radical generation. Clinical trials involving these agents are difficult to interpret because of variability in front end risk factors and dosage schedules in the study population. Furthermore, the relatively low (5 to 10%) incidence of affected patients implies the need for large numbers to demonstrate a statistically significant benefit. Pediatric protocols addressing these issues are urgently needed. Guidelines for present-day management and future studies are outlined.
Hematopoietic dysplasia and marrow hypocellularity in children: a preleukemic condition.
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Acute megaloblastic anemia induced by high-dose trimethoprim-sulfamethoxazole.
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Acute nonlymphocytic leukemia.
The discovery of cytosine arabinoside, and then the anthrocycline antibiotics, 6-thioguanine, vincristine, cyclophosphamide, and other drugs, has added to the armamentarium of known effective agents. The use of combination chemotherapy, the recognition of the need during induction for virtual marrow aplasia to obtain a remission, and recognition of the predilection of the disease for the central nervous system requiring prophylaxis constitute major advances. The impediment to long-term survival is the lack of effective maintenance therapy.
Autosomal recessive muscular dystrophy in Manitoba Hutterites.
A slowly progressive type of muscular dystrophy affecting 11 known members of several Southern Manitoba Hutterite colonies is described. Though encompassing the facial characteristics of the facio-scapulo-humeral type and the proximal distribution of the limb-girdle type, it was felt that this disease represents a distinct type of muscular dystrophy with autosomal recessive inheritance. Since all "affected" colonies can be traced to one founding colony in South Dakota, the disease may have been introduced from Europe between 1874 and 1879. Furthermore, normal fertility and a high degree of inbreeding in a genetically isolated population have contributed to the maintenance of the disease in the population.
Endocrine effects of vasectomy in man.
Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and free testosterone index (FTI) were measured serially in 11 fertile men, ages 25 to 40, 4 weeks before to 40 weeks after elective vasectomy. During the 1st week postvasectomy there was a significant fall in FSH levels (P less than 0.001) and FTI (P less than 0.05), with recovery by 2 weeks. This acute response may be due to general surgical stress. Thereafter, the over-all mean FSH level was significantly (P less than 0.05) below the prevasectomy level; over-all levels of LH, T, and FTI did not change. We speculate that this decline in mean FSH levels is compatible with the existence of an as yet unidentified T-independent testicular factor influencing FSH production.
Treatment of cavernous hemangioma with vincristine.
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