Nathan L. Kobrinsky

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.

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.

Perioperative management of patients with Von Willebrand's disease

This review focuses on the pathophysiology of the Factor VIII molecule as it relates to Von Willebrand’s disease. Three major categories of Von Willebrand’ s disease are identified. The perioperative diagnosis and management of all categories are reviewed. 1-Deamino-8-D-argnine vasopressin (DDAVP) is presented as an alternative to the transfusion of blood and blood products for the management of a bleeding diathesis.RésuméCette revue met l’emphase sur la pathophysiologie du facteur VIII relié à la maladie de Von Willebrand. Trois catégories majeures de la maladie de Von Willebrand sont identifiées. Le diagnostic périopératoire et la conduite face à ces trois catégories sont revus. Le 1-deamino-8-D-arginine vasopressine (DDAVP) est présenté comme une alternative à la transfusion sanguine et les dérivés du sang pour la conduite lors d’une diathèse hémorragique.

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.

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.

Prevention of insulin-dependent diabetes mellitus by 2′-deoxycoformycin in the BB Wistar rat

The effect of the adenosine deaminase (ADA) inhibitor 2-deoxycoformycin (dCF) on the development of insulin-dependent diabetes mellitus (IDDM) was assessed in the BB Wistar rat. Sixty-one male rats were treated from days 30 to 120 with 0, 0.5, 1.0 or 1.5 mg dCF/kg/week. The incidence of IDDM was 78% in the controls and was significantly (P < 0.01) decreased in rats receiving 1.5 mg dCF/kg/week (32%), but not in rats receiving lower doses of the drug. However, for those rats that became diabetic the mean time to the development of IDDM was unchanged in animals receiving dCF compared with control. dCF treatment did not produce significant weight loss in the animals or gross changes in the thymus, spleen or kidneys. Although the protective effect of dCF against IDDM was likely produced by immunosuppression, the different dCF dosages had similar effects on ADA suppression in spleen or thymus and on dATP accumulation in these organs.

INCREASED NAUSEA AND VOMITING INDUCED BY NALOXONE IN PATIENTS RECEIVING CANCER CHEMOTHERAPY

To evaluate the role of endogenous opiates in chemotherapy-induced nausea and vomiting, the narcotic-antagonist naloxone was administered to six pediatric patients receiving cancer chemotherapy. Naloxone was administered by continuous intravenous infusion after randomized, double-blind controlled assignment at a dose of 0, 10 or 40 ug/kg/hour for 12 hours. Each patient was studied for four consecutive and identical courses of chemotherapy (eight courses for each naloxone dose, or 24 courses in all). A dose-related increase in nausea (nausea score 2.5 ± 2.24, 3.83 ± 2.73 and 5.75 ± 2.86 per 12 hours, p=.003), vomiting (emetic events 6.0 ± 7.50, 8.08 ± 6.71 and 10.3 ± 8.91 per 12 hours, p=.035) and patient aversion (course preference rank 1.5 ± 0.45, 2.83 ± 1.17 and 3.25 ± 0.42 per four courses, p=.014) was observed. The infusion of naloxone in the absence of chemotherapy vas without effect. These results support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting, and further, suggest that narcotic agents may lye effective anti-emetics in, this setting.

DDAVP (1-DESAMINO-8-D-ARGININE VASOPRESSIN) DECREASES OPERATIVE BLOOD LOSS IN PATIENTS UNDERGOING HARRINGTON ROD SPINAL FUSION SURGERY

To evaluate the effect of l-desamino-8-D-arginine vasopressin (DDAVP) on surgical blood loss, 35 hemostatically-normal subjects received 10 μg/M2 DDAVP or placebo by randomized double-blind assignment prior to Harrington rod spinal fusion. On preoperative testing, DDAVP increased factor VIII coagulant activity, von Willebrand antigen, platelet adhesiveness and prothrombin consumption and decreased the partial thromboplastin time and the bleeding time (p<.0003). At surgery, the drug reduced blood loss by 32.3% (1681 ± 901 ml in the placebo group vs. 1134 ± 593 ml in the treated group, p=.03) and similarly, reduced the requirement for concentrated red cell transfusions by 26.5% (3.36 ± 1.64 units in the placebo group vs. 2.50 ± 0.97 units in the treated group, p=.04). Post-operatively, the drug reduced the duration of analgesia from 201.5 ± 83.0 hours in the placebo group to 149.0 ± 64.0 hours in the treated group (p=.01), presumably by decreasing bleeding into the surgical wound. By multivariate regression analysis, the best three predictors of surgical blood loss (p=.024) and transfusion requirements (p=.008) were the bleeding time, platelet adhesiveness and the use of DDAVP. In conclusion, DDAVP shortens the bleeding time and decreases operative blood loss in hemostatically normal subjects.

1590 ABSENT FACTOR VIII RESPONSE TO DDAVP IN NEPHROGENIC DIABETES INSIPIDUS (NDI)

Patients with NDI are resistant to the anti-diuretic effects of ADH. If this resistance [is due to a generalized defect of the ADH receptor, then other end-organ responses should be absent. DDAVP, a synthetic analog of ADH, increases factor VIII coagulant activity (FVIIIc) and factor VIII related antigen (FVIIIR:Ag) in normal subjects. Therefore, if NDI is due to a generalized receptor defect, the factor VIII response to DDAVP should be absent in affected patients and decreased in obligate carriers. Two unrelated NDI patients, three obligate carriers and twenty controls were studied. Each received 0.30 μg/kg DDAVP. Pre and one-hour post infusion FVIIIc and FVIIIR:Ag levels were determined:FVIIIc and FVIII:Ag responses were absent in both patients (P < .01), and were decreased in two of three obligate carriers. These data confirm that NDI is a generalized defect of the ADH receptor. Further, a decreased factor VIII response may aid in identifying carriers in kindreds at risk.