A pilot study of ranolazine in patients with intermittent claudication.

AIM: This pilot study provides preliminary information regarding safety and changes in exercise performance during treatment with ranolazine extended-release in patients with reproducible claudication during exercise treadmill testing (ETT). METHODS: We enrolled 45 patients with documented peripheral arterial disease, reproducible claudication on ETT, and ankle-brachial indices <0.85 at rest that decreased by at least 0.15% or 20% immediately postexercise. Randomized patients received double-blind treatment with either ranolazine 1 000 mg b.i.d. (n=22) or placebo (n=23) for 4 weeks. RESULTS: Compared with baseline, peak walking time (PWT) increased (mean+/-SEM) by 53+/-34 s with ranolazine (P=0.13) and by 41+/-33 s with placebo (P=0.22). Pain-free walking time during ETT increased by 62+/-18 s with ranolazine (P=0.002) and 36+/-18 s with placebo (P=0.045). Supplemental analyses, excluding patients with baseline exercise duration (16 min and (12 min, showed additional improvement with ranolazine on PWT. CONCLUSIONS: Ranolazine was well tolerated and these data provide a rationale for proceeding with a definitive trial.

Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure.

OBJECTIVES: To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND: Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS: On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS: Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS: Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation.

Oral ganciclovir is effective in preventing cytomegalovirus (CMV) disease in HIV-infected patients despite a bioavailability of only 6-9%. To determine safety, pharmacokinetics, and the influence of acute gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability and antiviral effect of oral ganciclovir after marrow transplantation, CMV seropositive patients received oral ganciclovir (1000 mg 3 times per day) from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose (intravenous and oral) and steady-state oral pharmacokinetic profiles and weekly trough levels were performed. Twenty-one patients received oral ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state pharmacokinetic profiles and seven had single-dose profiles. The absolute bioavailability was similar in patients with or without acute GI-GVHD (7.2 vs. 6.9%). At steady state, the extent and rate of absorption of oral ganciclovir were comparable in these same patient subgroups (area under the curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough CMV antigenemia, viremia, or plasma polymerase chain reaction positivity occurred in eight of 21 (38%) patients (four of seven with GVHD and four of 14 without). Drug discontinuation because of GI adverse effects was required in six of 21 (29%) patients. Neutropenia occurred in two of 15 (13%) patients who had received oral ganciclovir for more than 10 days. In conclusion, the bioavailability of oral ganciclovir seems similar to that reported in other settings. The presence of acute GVHD of the GI tract did not appear to adversely affect absorption of oral ganciclovir. The use of oral ganciclovir was limited by the presence of GI intolerance in the early posttransplant period. The efficacy of oral ganciclovir in preventing CMV infection in marrow transplant recipients is being assessed in a separate randomized controlled trial.

Safety of blood donations following a natural disaster.

To evaluate the relative safety of blood donations given in response to a major disaster, donor demographics and infectious disease test results were compared for donations made during the 10 days following the October 17, 1989, San Francisco Bay Area earthquake and those made during the preceding 6 months. These comparisons were made for donations given to the regional blood center in the area that was immediately affected by the disaster (Irwin Memorial Blood Centers) and for those given in an unaffected region (Los Angeles/Orange Counties Region, American Red Cross Blood Services). The rate of donation increased more than 200 percent during the 5 days following the earthquake in both the disaster-affected and unaffected regions. Both the disaster-affected and unaffected regions observed significant increases in the proportions of donations by first-time donors, by persons aged 20 to 39 years, and by women. The rates of confirmed positivity for infectious disease markers for post-earthquake donations did not differ significantly from rates for homologous donations given during the preceding 6 months, particularly when the rates were adjusted for the increased representation of first-time donors. Approximately 39 percent of post-earthquake first-time donors gave blood again within the following 6-month period. It is concluded that donations given after major disasters are essentially as safe as routine donations and that active efforts to recruit these donors again can be undertaken without reservation.

Donor room personnel attitudes toward autologous donors.

Patients with serious illnesses who donate their blood for autologous use create anxiety for many phlebotomists. Donor room staff were surveyed at three donor centers, using confidential questionnaires, to identify their concerns and to evaluate factors associated with reduced anxiety toward autologous donors. Among respondents (n = 93), 58 percent had patient care experience within the last 5 years, which correlated with diminished concern about phlebotomizing cardiac patients (r = .21; p = 0.04). Fifty-seven percent of respondents had drawn blood from greater than 50 autologous donors. Surprisingly, the experience of drawing blood from relatively large numbers of autologous donors did not correlate with increased confidence in phlebotomizing pediatric, cardiac, and elderly patients (r = -.04; p = 0.75). Those respondents who felt that they had adequate medical support agreed with more liberal donor criteria and were more confident about phlebotomizing pediatric, cardiac, and elderly patients (r = -.32; p = 0.001). Those respondents who believed most strongly in the benefits of autologous transfusion had the least anxiety toward donors who were medically more complex (r = .39; p = 0.0001). It is concluded that, contrary to what might be expected, phlebotomizing large numbers of autologous donors does not reduce the anxiety of staff members when they encounter donors with complex medical problems. Factors that do reduce anxiety include dependable physician and other medical support services, previous experience in direct patient care, and knowledge of the benefits of autologous transfusion.

Moderate and severe reactions during autologous blood donations are no more frequent than during homologous blood donations.

Because autologous donation is permitted for donors who do not meet homologous blood donation standards, referring physicians and blood center personnel may be concerned about autologous donor reactions. Small studies have determined that mild reactions do not occur more frequently, but the incidence of rarer, more serious, moderate and severe reactions is unknown. We therefore studied the frequency of reactions during 10,200 autologous and 219,307 concurrent homologous donations at four blood centers. No significant difference was seen for severe reactions: autologous 0.039% (4/10,200), homologous 0.037% (82/219,307) (p = 0.79); moderate reactions: autologous 0.19% (19/10,200), homologous 0.22% (473/219,307) (p = 0.60) or mild reactions: autologous 2.26% (231/10,200), homologous 2.26% (4946/219,307) (p = 0.98). We conclude moderate and severe donation reactions do not occur more frequently among autologous donors who are preselected by referring physicians and screened by blood center personnel.

Selective generation of erythroid burst-promoting activity by recombinant interleukin 2-stimulated human T lymphocytes and natural killer cells.

Because T lymphocytes and natural killer (NK) cells produce a variety of growth factors and interleukin 2 (IL2) modulates the activity of both, we assessed the ability of IL2 to stimulate human T cells and NK cells to produce hematopoietic growth factors detectable in clonogenic marrow culture. Human recombinant interleukin 2 (rIL2) added directly to cultures of human bone marrow that had been depleted of monocytes or depleted of both monocytes and T cells caused no significant alteration of myeloid (CFU-GM) or erythroid colony formation. Conditioned media harvested from rIL2-stimulated (greater than 100 U/mL) peripheral blood mononuclear cells, T cells, Leu-2 cells, and Leu-3 cells all had erythroid burst-promoting activity (BPA) but lacked myeloid colony-stimulating factor (GM-CSF) or CFU-GM-inhibitory activity. These T cells were IL2 receptor-negative, and the addition of anti-IL2 receptor monoclonal antibody (anti-Tac) to T cell cultures did not abrogate this IL2-stimulated BPA production. In addition, Percoll gradient-enriched, large granular lymphocytes (LGL) were separated by fluorescence-activated cell sorting into Leu-11+ (NK) cells and Leu-11- (low-density Leu-4+ T) cell fractions. rIL2 stimulated LGL, Leu-11+ and Leu-11- cells to produce BPA but not detectable GM-CSF or CFU-GM-inhibitory activity. Leu-11+ (NK) cells were Tac-negative from days 0 through 14 of culture. We conclude that rIL2 at high concentrations stimulated T cells, Leu-2 and Leu-3 cell subsets, LGL, and NK cells to produce BPA but not GM-CSF and that this stimulation may be mediated by an IL2 receptor distinct from Tac or by an epitope of the IL2 receptor not recognized by the anti-Tac antibody.