A randomized, double-blind, dose-response study of ondansetron in the prevention of postoperative nausea and vomiting.

STUDY OBJECTIVE: To determine the dose-response relationship of ondansetron in preventing postoperative nausea and vomiting (PONV) in women undergoing elective surgery. DESIGN: Prospective, randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: 175 women aged 18 to 80 years scheduled for elective surgery. INTERVENTIONS: One of six doses of ondansetron (0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg, 16 mg) or placebo was given prior to the induction of general anesthesia with propofol. Maintenance was with nitrous oxide, isoflurane, opioid, and muscle relaxant. MEASUREMENTS AND MAIN RESULTS: The study period began when the patient emerged from anesthesia. Nausea scores were recorded on a 0 to 10 scale at multiple time points during the 24-hour study period. Patient satisfaction via a visual analog scale (VAS) was determined at 1 and 24 hours after awakening. Rescue medication was given for severe nausea, three emetic episodes within 15 minutes, or if requested by the patient. The primary efficacy variable was the need for rescue antiemetic therapy. The dose-response curve (by logistic regression) of the percentage of patients not rescued versus dose indicated an ED50 of 0.54 mg (95% confidence interval 0.03-1.05 mg). Fewer patients required rescue in the 4 mg dose group compared with lower doses. However, the difference reached significance only in comparison with the 0.5 mg dose group. Survival analysis of the need for rescue, and nausea score versus time curves, also both suggested the superiority of the 4 mg dose compared with lower doses. In addition, there was a highly significant correlation between the lack of need for rescue and satisfaction with anesthesia at 24 hours after emergence. CONCLUSION: The recommended dose of ondansetron for PONV prophylaxis in women remains 4 mg.

Peripheral blood stem cell collection with reduced platelet loss to the patient/donor.

Apheresis procedures that optimize peripheral blood stem cell (PBSC) harvesting also result in a significant loss of platelets to the patient/donor because of their similar densities. We compared the percent drop in platelet count and hemoglobin concentration in the patients before and after PBSC collection using two different collection chambers with the CS-3000. A modified plateletpheresis procedure was utilized. Seven patients underwent 38 PBSC collections during steady state hematopoiesis using the standard A-35 collection chamber. At the end of the procedure, a second low-speed centrifugation of the PBSC concentrate was performed in the manual mode, with siphoning out and return of the PRP to the patient through a transfer pack. For 14 patients who underwent 113 PBSC collections, a small volume collection chamber (SVCC) was substituted for the A-35 chamber and the second centrifugation step was omitted. These patients were also primed with 4 g/m2 of cyclophosphamide. The percent drop in platelet count in the patients after the collection procedures was significantly less in the SVCC group (20.4 +/- 9.1 vs. 36.0 +/- 12.3, P = 0.000), even after correction for the difference in the volume of blood processed between the two groups (3.2 +/- 1.4 vs. 3.9 +/- 1.3, P = 0.006). The percent drop in hemoglobin concentration was also less with the SVCC both before (5.4 +/- 3.8 vs. 11.7 +/- 3.0, P = 0.000) and after (0.8 +/- 0.6 vs. 1.3 +/- 0.3, P = 0.000) correction for the difference in the volume of blood processed.(ABSTRACT TRUNCATED AT 250 WORDS)

A leukocyte lipid up-regulates the avidity of lymphocyte function-associated antigen-1.

An acidic lipid termed leukocyte adhesion lipid (LAL) was isolated from PMA stimulated lymphoid and myeloid cell lines HL60, Jurkat, K562 and U937 but not from unstimulated cells or PMA treated Cos7 cells. LAL treated peripheral blood leukocytes (PBL) adhered strongly to IL-1 beta activated human umbilical vein endothelial cells (HUVEC), and the interaction could be inhibited by antibodies to intercellular adhesion molecule (ICAM-1) or lymphocyte function-associated antigen-1 (LFA-1). Leukocytes treated with LAL maintained the high avidity state of LFA-1 for at least 1 hr whereas the avidity of LFA-1 in PMA treated cells declined after 30 min. LAL was stable to heat (100 degrees C, 10 min), alkaline phosphatase and proteinase K treatments. Chemical analysis suggested that LAL contained unsaturated lipids. Our findings provide evidence for the involvement of lipids in LFA-1 activation.

Spermine dialdehyde, a novel ex vivo purging agent for both allogenic and autologous bone marrow transplantations.

The use of ex vivo purging agents has shown to be beneficial for both allogeneic and autologous bone marrow transplantations. We have shown previously that spermine dialdehyde (SDA), an oxidized product of spermine, when used in phosphate-buffered saline (PBS) preferentially inhibits T-cell proliferation while sparing myeloid cells. Lethally irradiated mice were rescued by reconstitution with SDA-treated allogeneic marrow and showed no sign of graft-vs-host disease (GVHD). In this paper, we show by HPLC analysis that SDA degraded rapidly in PBS but remained intact in saline. Administered in saline, SDA was more inhibitory on leukemic cell lines than normal myeloid or T-cells. Lethally irradiated mice receiving a syngeneic bone marrow leukemic cell mixture treated ex vivo with SDA in saline did not manifest leukemia. Thus, the preferential inhibitory effect of SDA and its degraded products in different buffers suggest that SDA could act as a novel purging agent for both allogeneic and autologous bone marrow transplantations.

Role of aldehyde dehydrogenase in the biological activity of spermine dialdehyde, a novel immunosuppressive/purging agent.

The antitumour and immunosuppressive activities of spermine dialdehyde (SDA), a synthetic, oxidized form of spermine, were examined using L1210 cell lines and murine bone marrow cells. SDA acted as a high affinity substrate for aldehyde dehydrogenase (ADH) derived from different sources, with kinetic profiles similar to other aldehyde substrates. The murine leukaemic, cyclophosphamide-resistant L1210/CPA cells, having high levels of intracellular ADH activity, were less sensitive to SDA compared to ADH deficient L1210/O cells as measured by [3H]-thymidine incorporation in proliferation studies. Furthermore, pretreatment of L1210/CPA cells with the ADH inhibitor, diethyl aminobenzaldehyde (DEAB), resulted in potentiation of the SDA response. Murine bone marrow cells were more resistant to SDA than splenic T cells. However, addition of DEAB to bone marrow cultures potentiated the sensitivity of progenitor cells to SDA, as measured by colony formation. The results indicate that levels of ADH in the target tissues would determine the potency of SDA and subsequently offer selectivity and specificity to the therapeutic potentials of this putative purging agent.

Concentration of bone marrow mononuclear cells using a programmable blood cell separator.

Bone marrow was collected from adult patients with various solid tumors who consented to participate in a study of myelo-ablative chemotherapy followed by autologous bone marrow rescue. Twenty marrow suspensions were processed by using standard Procedure 3 (PRO-3) for lymphocytapheresis without modification. A modified Procedure 1 (M-PRO-1) for plateletpheresis was employed for processing 34 marrow suspensions. For PRO-3, mononuclear cell (MNC) recovery was 68 +/- 22% of the starting marrow suspension (baseline), in a concentrate volume of 234 +/- 53 ml. MNC represented 59 +/- 27% of the total WBC count of the concentrate. The residual volume of RBC was 49 +/- 47 ml. For M-PRO-1, MNC recovery was 63 +/- 22% of the baseline in a concentrate volume of 200 +/- 8 ml. MNC comprised 94 +/- 7% of the total WBC count of the concentrate. RBC contamination was 7 +/- 3 ml. Hematopoietic recovery, defined as the post-transplant days when a sustained granulocyte count of 500/microL and a platelet count of 50,000/microL were achieved, was similar in the two groups and comparable to other reports utilizing other methods and equipment for bone marrow concentration. Personnel time was significantly reduced compared to other procedures for bone marrow concentration due to increased automation. Although there was no significant difference in MNC recovery between the two groups (P greater than 0.5), M-PRO-1 was clearly superior to PRO-3 because of the consistently high degree of purity of the MNC in the concentrate and minimal RBC contamination.(ABSTRACT TRUNCATED AT 250 WORDS)

Ex vivo spermine dialdehyde treatment prevents lethal GVHD in a murine bone marrow transplantation model.

Spermine dialdehyde (SDA), an oxidized product of spermine which irreversibly suppresses T cell and NK cell activities, was evaluated as an ex vivo purging agent in the prevention of graft-versus-host disease (GVHD) in mice transplanted with SDA-treated allogeneic bone marrow. In this model, lethally irradiated C3H (H-2k) mice received BALB/c (H-2d) bone marrow and spleen cell mixtures which had been treated ex vivo for 10 min with SDA. Mice receiving SDA-treated cells survived past 100 days whereas mice in the control group died between days 25-35 suffering from severe GVHD. Surviving mice from the SDA-treated groups exhibited full chimerism at day 120. In vitro assays indicated that SDA inhibited T cell and NK cell activities at concentrations that spared myeloid cell growth. When a minimum number of bone marrow cells were used for reconstitution, SDA-treated marrow reconstituted lethally irradiated mice as effectively as control marrow suggesting that SDA had little impact on early myeloid cells which are required for engraftment. SDA may have clinical application as a purging agent in allogeneic bone marrow transplantation.

Peripheral blood-derived stem cell collections for use in autologous transplantation after high dose chemotherapy: an alternative approach.

Peripheral blood-derived hematopoietic stem cells (PBHSC) can be utilized to reconstitute hematopoiesis in patients after high dose myeloablative chemotherapy. We have performed PBHSC reinfusion in 18 patients who have or had a history of tumor involving the bone marrow or a hypocellular bone marrow. The PBHSC were collected by continuous flow leukapheresis and subsequently cryopreserved. A median of 31.9 X 10(9) (range 18 X 10(9)-67.2 X 10(9)) mononuclear cells or a median of 4.85 X 10(8) mononuclear cells/kg (range 2.7 X 10(8)-11.0 X 10(8)) were collected. Fifteen patients had in vitro assays of granulocyte-monocyte colony-forming cells (CFU-GM) performed with a median of 2.7 X 10(4) (range 0-11.5 X 10(4)) CFU-GM/kg. To date, of the 18 patients collected, all have undergone high dose chemotherapy and PBHSC reinfusion. For the evaluable patients, granulocyte recovery (greater than 500 X 10(6)/ml) has occurred in a median of 15 days and platelet recovery (greater than 50 X 10(9)/ml without transfusion support) has occurred in a median of 43 days. Four patients have had prolonged thrombocytopenia and still require platelet transfusion at 80+, 97+, 124+, and 270+ days. PBHSC collection is safe and effective for hematopoietic reconstitution after high dose chemotherapy in the majority of patients; however incomplete hematopoietic reconstitution has been observed in 4/18 evaluable patients. This procedure requires further investigation.

Central nervous system side effects of beta-adrenergic blocking agents with high and low lipid solubility.

beta-adrenergic blocking agents have undesirable effects believed to be mediated through the central nervous system (CNS). If these effects are due to direct CNS action, less lipid soluble agents ought to have fewer effects. Accordingly, several formal psychological tests of items such as mood, motivation, and anxiety were used in a double-blinded crossover study in 17 hypertensive subjects taking equipotent beta blocking agents with high (propranolol) and low (atenolol) lipid solubility. Patients had less negative effects (p less than 0.05) on 12 of 21 items evaluated with atenolol compared to propranolol while peripheral beta blockade [beta 1, exercise heart rate (HR), and blood pressure (BP)] was equivalent. These results suggest that the mental changes which accompany beta blockade therapy are mediated directly in the CNS and that less soluble drugs can be expected to have fewer CNS effects.

Pricing and performance in health maintenance organizations: a strategic management perspective.

Innovative, consumer-oriented pricing strategies have contributed to the impressive growth of health maintenance organizations (HMOs). In a national study of HMO marketing directors, the relationships between strategic management style and (1) the relative importance of pricing in competitive marketing strategy, (2) the effectiveness of price strategy planning, and (3) financial performance are examined. The findings indicate that HMOs practicing effective price planning also perform well on an overall basis. Insight into the content and substance of HMO pricing strategies is also provided.

Management styles and marketing strategies: an analysis of HMOs.

The results of a recently conducted national study indicate that a variety of strategic management styles are being pursued by HMOs, and that relationships exist between these styles and marketing strategies. The findings themselves have strategic relevance for HMOs and other health service providers.

Survival with localized carcinoma: radical prostatectomy vs radiation therapy.

The charts of all patients receiving radical surgery and radiation therapy for cancer localized to the prostate in the years 1950 to 1977 in the State of Connecticut were reviewed. Long-term survival rates at ten and fifteen years were considerably better in those patients treated with radical surgery.

Measured and predicted atmospheric transmission in the 4.0-5.3-microm region, and the contribution of continuum absorption CO(2) and N(2).

High resolution measurements of atmospheric transmission of sunlight from space to altitudes of 12.2 km, 8.53 km, and 5.48 km made over Johnston Island are reported. The spectral region covered is 4.0-5.3 microm. Comparisons of the measured transmission with theoretically synthesized transmission curves are presented. It is shown that the sharp spectral features due to molecular line-by-line absorption can be predicted accurately while the modeling of the continuum absorption features needs further development. A discussion of the current models for CO(2) and N(2) continuum absorption is presented. An alternative mechanism is proposed for continuum absorption, which is based on the spectral properties of atmospheric van der Waals molecular complexes such as CO(2).N(2) and N(2).N(2) dimers.