Renal sparing by amphotericin B colloidal dispersion: clinical experience in 572 patients.

Data from five clinical trials of amphotericin B colloidal dispersion (ABCD) in the treatment of invasive mycoses were pooled to analyze the renal sparing effects of ABCD. Serum creatinine levels at baseline and either during or at end of treatment were available for 499 of 572 patients (87.2%). The median cumulative dose of ABCD administered to the 499 evaluable patients was 4,050 (range: 30-74,250) mg, and the median duration of treatment was 18 (range: 1-407) days. For the entire group of evaluable patients, the median change in serum creatinine during treatment with ABCD was -0. 1 mg/dl; for the subgroups of patients enrolled in the trials because of amphotericin B toxicity or preexisting renal impairment, the median changes in serum creatinine were -0.3 and -0.2 mg/dl, respectively. There was no trend of increasing serum creatinine with increasing cumulative dose of ABCD (correlation coefficient = -0. 016). ABCD was prematurely discontinued in 19 of 572 patients (3.3%) because of elevated serum creatinine levels. Unlike conventional amphotericin B, ABCD is not associated with dose-dependent nephrotoxicity.

Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial.

PURPOSE: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis.

To assess the efficacy and safety of amphotericin B colloidal dispersion (ABCD), 82 patients with proven or probable aspergillosis who were treated in clinical trials with ABCD were compared retrospectively with 261 patients with aspergillosis who were treated with amphotericin B at six cancer or transplant centers from January 1990 to June 1994. The groups were balanced in terms of underlying disease; ABCD recipients were younger and more likely to have preexisting renal insufficiency than were amphotericin B recipients (40.7% vs. 8.7%, respectively), and amphotericin B recipients were more likely to be neutropenic at baseline than were ABCD recipients (42.5% vs. 15.9%, respectively). Response rates (48.8%) and survival rates (50%) among ABCD-treated patients were higher than those (23.4% and 28.4%, respectively) among amphotericin B-treated patients (P < .001 for both comparisons). Renal dysfunction developed less frequently in ABCD recipients than in amphotericin B recipients (8.2% vs. 43.1%, respectively; P < .001). Multivariate analysis revealed that treatment group was the best predictor of response, mortality, and nephrotoxicity (ABCD: relative risk [RR] = 3.00, P = .002; RR = 0.35, P < .001; and RR = 0.13, P = .001; respectively). This retrospective study suggests that in the treatment of aspergillosis ABCD causes fewer nephrotoxic effects than amphotericin B and the efficacy of ABCD is at least comparable with that of amphotericin B.

Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of ganciclovir for prevention of cytomegalovirus (CMV) infection and disease. DESIGN: A randomized, placebo-controlled, double-blind trial. SETTING: University-affiliated bone marrow transplant center. PATIENTS: Cytomegalovirus-seropositive allogeneic bone marrow transplant recipients. INTERVENTIONS: Random assignment to receive either a placebo or ganciclovir at a dose of 2.5 mg/kg body weight every 8 hours for 1 week before transplant and then at a dose of 6 mg/kg once per day, Monday through Friday, after transplant when the post-transplant neutrophil count reached 1.0 x 10(9)/L. MEASUREMENTS: Cytomegalovirus infection (positive culture, seroconversion, positive histologic findings), CMV disease (pneumonia, gastroenteritis, the wasting syndrome), and study-drug toxicity. RESULTS: Cytomegalovirus infection developed in 25 of 45 placebo patients (56%) but in only 8 of 40 ganciclovir patients (20%) (P < 0.001). Cytomegalovirus disease may also have occurred less often in the ganciclovir patients (4 of 40 patients [10%] versus 11 of 45 patients [24%]; P = 0.09). The probability of CMV disease occurring within the first 120 days after transplantation was 0.29 among the placebo patients but only 0.12 among ganciclovir patients (P = 0.06). Reversible neutropenia was the only appreciable toxicity related to ganciclovir and required interruption of the study drug after transplant in 25 of 43 ganciclovir patients (58%) and in 13 of 47 placebo patients (28%) (P = 0.005). Overall survival was similar in both the placebo patients (29 of 45 [64%]) and ganciclovir patients (28 of 40 [70%]; P > 0.2). CONCLUSIONS: Prophylactic ganciclovir, started before transplant and continued after recovery of the post-transplant neutrophil count, reduces the incidence and severity of CMV infection in CMV-sero-positive bone marrow transplant recipients but is frequently associated with neutropenia.

Ganciclovir treatment of cytomegalovirus colitis in AIDS: a randomized, double-blind, placebo-controlled multicenter study.

The efficacy and safety of ganciclovir therapy for cytomegalovirus (CMV) colitis in patients with AIDS was examined in a double-blind, placebo-controlled study. Sixty-two patients at four university medical centers were enrolled. All had biopsy-proven CMV colitis with diarrhea, fever, and weight loss. Other pathogens were excluded. Ganciclovir (5 mg/kg) or placebo was administered every 12 h for 14 days. A significant reduction in CMV-positive colonic and urine cultures was seen with ganciclovir (P = .034 and P < .001, respectively) compared with placebo. Colonoscopy scores were improved significantly more with ganciclovir than with placebo (P = .042). New extracolonic CMV disease developed in 7 (23%) of 30 placebo patients and in 3 (9%) of 32 ganciclovir patients in only 14 days (P = .026). Ganciclovir-treated patients maintained body weight, while placebo patients had a mean loss of 1.5 kg. Overall, ganciclovir appears of some benefit in treating CMV colitis in patients with AIDS.

Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive. METHODS: Bone marrow--allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival. RESULTS: Between assignment to the study drug and day 100 after transplantation, CMV disease developed in only 1 of the 37 patients assigned to receive ganciclovir (3 percent), but in 15 of the 35 patients assigned to receive placebo (43 percent, P less than 0.00001). The ganciclovir recipients had rapid suppression of virus excretion; 85 percent had negative cultures after one week of treatment, as compared with 44 percent of the placebo group (P = 0.001). The principal toxic reaction was neutropenia; 11 ganciclovir recipients had an absolute neutrophil count below 0.75 x 10(9) per liter, as compared with 3 placebo recipients (P = 0.052). Treatment was discontinued in 11 ganciclovir recipients and 1 placebo recipient because of neutropenia (P = 0.003). After treatment was stopped, the neutrophil count recovered in all patients. Overall survival was significantly greater in the ganciclovir group than in the placebo group both 100 days and 180 days after transplantation (P = 0.041 and 0.027, respectively). CONCLUSIONS: Early treatment with ganciclovir in patients with positive surveillance cultures reduces the incidence of CMV disease and improves survival after allogeneic bone marrow transplantation.

Relationship between inappropriate admissions and days of care: implications for utilization management.

A critical issue for utilization management programs is how much of the hospitalization should be reviewed and whether information relative to the admission provides information about the subsequent days of stay. This study evaluates the relationship between the appropriateness (defined as overutilization of acute, inpatient services) of admissions and all days of stay in a probability sample of 6,063 hospitalizations from 50 Department of Veterans Affairs medical centers (VAMCs). Results suggest that preadmission reviews in hospital-based utilization management programs may eliminate not only unnecessary admissions but also, in most cases, completely inappropriate hospitalizations. In addition, except where inpatient-appropriate surgeries are not performed in a timely manner, review of the rest of the stay may not be an efficient use of time and resources.

Electrical activity from the superior pharyngeal constrictor during reflexive and nonreflexive tasks.

The purpose of this investigation was to determine, in a quantitative manner, which, if any, nonswallowing tasks produce significant levels of activation in the superior pharyngeal constrictor muscle of normal human subjects. Bipolar hooked wire electrodes were inserted in the superior pharyngeal constrictor muscle of 15 healthy subjects. Electrode placement was controlled. Each subject performed two reflexive tasks, six voluntary tasks requiring phonation, and four nonspeech voluntary tasks. The electromyogram (EMG) was rectified and integrated. The resulting number was then transformed by taking its natural logarithm. An ANOVA was performed and a linear model was estimated. The magnitude of the EMG activity was related to the location of the electrodes. The largest values were recorded in the lateral-superior placement, followed by the lateral-inferior, medial-inferior and medial-superior. The superior pharyngeal contrictor was found to be a muscle activated primarily during reflexive activity. There was a general trend in the amplitude of EMG activity in relationship to task. Swallowing produced the greatest amount of activity and a gag produced about 60% of the activity produced by the swallow. Two tasks, production of the work /hok/ in which the phoneme /k/ was stressed, and a "modified Valsalva," which was actually a hard /k/ held for several seconds, produced the next greatest level of EMG.