Once-daily administration of didanosine in combination with anti-retroviral zidovudine in previously untreated patients]

25 HIV-infected antiretroviral-naive adults were included in a 24-week study to evaluate the efficacy and the tolerability of a zidovudine/didanosine combination therapy in which didanosine was administered once daily (200 mg if weight < 60 kg, 300 mg if weight > 60 kg) and zidovudine twice daily (500 mg/day if weight < 90 kg, 600 mg/day if weight > 90 kg). 5 patients discontinued their treatment early: 3 had poor compliance and 2 presented adverse events. Evaluation of treatment efficacy was based on CD4+ T cell enumeration and HIV RNA level quantitation in plasma (NASBA). Baseline values were 278 CD4+/mm3 and 5.42 log RNA copies/ml. Mean changes from baseline were +102 CD4+/mm3 and -2.14 log RNA copies/ml at week 8 and +156 CD4+/mm3 and -2.07 log RNA copies/ml at week 24. HIV RNA in plasma was lower than the detection limit (2.60 log RNA copies/ml) in 55% of patients at week 8 and in 30% at week 24. No major adverse events such as neuropathy or pancreatitis were observed. Once-daily administration of didanosine in combination with twice-daily administration of zidovudine is a well tolerated regimen that appears to be as effective ad the conventional zidovudine/didanosine combination regimen.     

Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients

This study was designed to investigate the interaction between high-dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open-label, randomized, three-period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC0-12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady-state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.     

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.     

Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study

PURPOSE: This multicenter, randomized phase III clinical trial evaluated the efficacy of etoposide plus carboplatin (EC) versus etoposide plus cisplatin (EP) in good-risk germ cell tumor (GCT) patients. PATIENTS AND METHODS: Between October 1986 and December 1990, 270 patients with good-risk GCTs were randomized to receive four cycles of either EP or EC. The etoposide dose in all patients was 100 mg/m2 on days 1 through 5. EP patients received cisplatin at 20 mg/m2 on days 1 through 5 and therapy was recycled at 21-day intervals. For EC patients, the carboplatin dose was 500 mg/m2 on day 1 of each cycle and the EC recycling interval was 28 days. RESULTS: Two hundred sixty-five patients were assessable: 131 patients treated with EC and 134 treated with EP. One hundred fifteen of 131 assessable patients (88%) treated with EC achieved a complete response (CR) versus 121 of 134 patients (90%) treated with EP (P = .32). Sixteen patients (12%) treated with EC relapsed from CR versus four patients (3%) treated with EP. Therefore, 32 patients (24%) who received carboplatin experienced an event (incomplete response [IR] or relapse) compared with 17 of 134 patients (13%) who received cisplatin (P = .02). At a median follow-up of 22.4 months, event-free and relapse-free survival were inferior for patients treated with EC (P = .02 and P = .005, respectively). No difference in overall survival was evident (P = .52). CONCLUSION: Two-drug therapy with EC using this dose and schedule was inferior to therapy with EP. Cisplatin remains as the standard platinum analog in the treatment of patients with good-risk GCTs. Carboplatin should be restricted to investigational trials in GCT.     

Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis

BACKGROUND: Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. The fluoroquinolone agent ciprofloxacin is active in vitro against these strains of bacteria, but has not been routinely used to treat acute childhood infections because of concern that quinolones may cause arthropathy in children. We undertook a randomised double-blind study to test the effects of ciprofloxacin treatment in children with shigella dysentery. METHODS: We compared the efficacy and toxic effects of ciprofloxacin suspension (10 mg/kg every 12 h for 5 days, maximum individual dose 500 mg) with those of pivmecillinam tablets (15-20 mg/kg every 8 h for 5 days, maximum individual dose 300 mg). We enrolled 143 children aged 2-15 years with dysentery of 72 h or less duration. Patients stayed in hospital for 6 days, and were followed up 7, 30, and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentery on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. FINDINGS: 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 (80%) of 60 patients who received ciprofloxacin and in 39 (65%) of 60 patients who received pivmecillinam (p=0.10). Treatment was bacteriologically successful in all of the patients receiving ciprofloxacin, and in 54 (90%) of the patients receiving pivmecillinam (p=0.03). Joint pain after treatment began in 13 (18%) of 71 patients who received ciprofloxacin and 16 (22%) of 72 patients who received pivmecillinam (p>0.2), and no patient had signs of arthritis. INTERPRETATION: In our trial, ciprofloxacin suspension and pivmecillinam had the same clinical efficacy. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. We conclude that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.     

Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations

Prospective clinical studies about photocoagulation of extrafoveolar choroidal neovascularizations in focal hemorrhagic chorioretinopathy (CR) have demonstrated that the risk of visual loss years after successful treatment is related to the development of retinal pigment epithelium (RPE) atrophy around the laser scar. The reason for this event was thought to be late damage of RPE cells due to the laser treatment. However, because RPE atrophy can also be seen in untreated patients, a prospective study was started to test this pathogenetic hypothesis and to analyze the pathogenetic factors and prognostic importance of RPE atrophy in focal hemorrhagic CR. Eighty-eight patients (52 women, 36 men, 15-45 years old; mean follow-up 62 months; 26 patients treated by photocoagulation) with focal hemorrhagic CR were reexamined. Fifty-two patients (15 treated by photocoagulation and 37 untreated) showed clinically visible RPE atrophy. In these 52 patients the initial and final visual acuity, the amount of initial subretinal fluid (34.6% < 500 microns, 50% 500-750 microns, 15.4% > 750 microns) and the amount RPE atrophy (23.2% < 500 microns, 53.6% 500-750 microns, 23.2% > 750 microns) were analyzed. The development of RPE atrophy was dependent on the time of follow-up (36 patients without RPE atrophy, mean follow-up 29 months; 52 patients with RPE atrophy, mean 84 months, P < 0.001). Of the 52 patients with RPE atrophy, 15 were treated by photocoagulation. The distribution of RPE atrophy was similar to what was found in the 37 untreated patients (P = 0.4). With pronounced RPE atrophy, a decrease in final visual acuity was seen (RPE atrophy < 500 microns, mean visual acuity 0.5; 500-750 microns mean visual acuity 0.3; > 750 microns, mean visual acuity 0.1; P = 0.005). Increased RPE atrophy was also associated with a higher incidence of visual loss (p = 0.009). The amount of RPE atrophy was not dependent on the time of follow-up (P = 0.3), but only correlated with the initial amount of subretinal fluid (atrophy < 500 microns: subretinal fluid < 500 microns 15.4%, 500-750 microns 7.7%, > 750 microns 0%; atrophy 500-750 microns: subretinal fluid < 500 microns 19.2%, 500-750 microns 32.7%, < 750 microns 1.9%; atrophy > 750 microns: subretinal fluid < 500 microns 0%, 500-750 microns 9.6%, > 750 microns 13.5%; P < 0.0001). Because RPE atrophy in focal hemorrhagic CR was seen in patients both with and without photocoagulation therapy, laser treatment cannot be the causative factor. With increased follow-up the risk of the development of RPE atrophy increases in all patients. The resulting amount of RPE atrophy was only dependent on the initial amount of subretinal fluid. If the fovea is included in the exudative detachment, there is a higher risk of long-term visual loss.     

Multiple resistance modulators combined with carboplatin for resistant malignancies: a pilot study

BACKGROUND: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers. METHODS: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m2 in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m2). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m2. RESULTS: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m2, but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses < or = 300 mg/m2, although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers. CONCLUSIONS: Acceptable doses for phase II studies are carboplatin 300 mg/m2, 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m2/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m2 p.o. q6h x 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m2 p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m2 suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m2 i.v. right after carboplatin), novobiocin 600 mg/m2 p.o. q12h x 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m2/day plus ketoconazole 700 mg/m2/day x 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.     

Prevention of emesis by tropisetron in children receiving combined chemotherapy with cisplatin

We evaluated the antiemetic efficacy of tropisetron, a 5-HT3 receptor antagonist, during its use in 15 children with malignant disease who received cisplatin (CDDP) either alone (1/15) or in combination (14/15) with other cytostatic drugs. Tropisetron was given to 15 children (8 boys and 7 girls, ranging from 6 months to 17 years of age) with miscellaneous neoplasms. Generally, tropisetron (5 mg/m2/day, maximum 5 mg/day) was administered intravenously the first day of CDDP-based chemotherapy and orally for 4 subsequent days of chemotherapy. The dose of tropisetron was reduced to 0.2 mg/kg/day in children less than 1 year of age and/or those weighing less than 10 kg. Vomiting and nausea were controlled completely in 8 of 15 (53.3%) children on day 1 with a single intravenous infusion of tropisetron. Partial control was observed in 40% of patients on day 1. Complete control of delayed nausea and vomiting ranged between 40% and 80% in patients over days 2 to 5. The results obtained during administration of tropisetron confirm that it is a valid, safe, and manageable antiemetic for the treatment of malignant disease in pediatric patients.     

Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease

BACKGROUND & AIMS: Azathioprine (AZA) and 6-mercaptopurine (6-MP) are used in pediatric patients with ulcerative colitis and Crohn's disease to reduce disease activity, maintain remission, prevent relapse, and lower corticosteroid dosage, but their long-term side effects remain to be studied. The aim of this study was to analyze the safety of AZA and 6-MP and steroid reduction in this age group. METHODS: The investigators' database identified 118 patients who received either drug; 23 were excluded (single visit, noncompliance, or therapy < 1 week), leaving 95 patients, with a mean (+/-SD) age of 14.2 +/- 4.4 years. Medical files were reviewed for adverse side effects: fever, pancreatitis, infections, gastrointestinal intolerance, aminotransferase level increase, leukopenia, and thrombocytopenia. Prednisone doses before and after immunomodulatory therapy were compared. RESULTS: AZA or 6-MP was tolerated in 51 of 95 patients (54%) without adverse reaction; 27 of 95 (28%) experienced side effects that responded to dose reduction (23 patients) or spontaneously (4 patients), most commonly increased aminotransferase level (13.7%). Cessation of therapy was needed in 17 of 95 patients (18%), including recurrent fever (4), pancreatitis (4), gastrointestinal intolerance (4), and recurrent infections (3). Mean prednisone dose decreased from 24.3 to 8.6 mg/day. CONCLUSIONS: AZA and 6-MP were well tolerated in 82% of patients; of these, prednisone reduction occurred in 87%. However, 18% required discontinuation because of hypersensitivity or infectious side effects.     

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone)

The sulfone derivative of the non-steroidal anti-inflammatory drug (NSAID), sulindac, has been reported to inhibit mammary and colon tumor formation in rodent models of chemically-induced carcinogenesis. Unlike its parent compound, this metabolite lacks cyclo-oxygenase inhibitory activity. A tumor induction protocol, consisting of NNK administration in the drinking water over several weeks to model chronic human exposure, was used to test whether the sulfone (called FGN-1) could inhibit the formation of primary lung tumors in mice. A total of 150 female, AIN76A-fed, A/J mice received 9 mg of NNK each. Concentrations of FGN-1 that had been previously determined not to affect body weight gain were added to the food at levels of 0, 250, 500 and 750 mg/kg of diet (30 mice/group) starting 2 weeks before NNK administration and continuing for 22 weeks. At that time pleural surface tumors were counted. Tumor incidence decreased significantly from 96 % in the control diet and 93% in the 250 FGN-1 mg/kg diet to 63 and 67% in the 500 and 750 mg FGN-1/kg diet groups, respectively (P < 0.001 by chi-square analysis). Lung tumor multiplicity decreased from 18.1+/-3 tumors/ mouse (mean+/-SEM, control diet) to 12.3+/-3 (250), 5.3+/-1 (500) and 2.1+/-1 (750) (P < 0.0005 by post hoc ANOVA). In previous studies using this carcinogenesis protocol, the maximum tolerated dose of sulindac inhibited lung tumor multiplicity by no more than 50% with no effect on incidence. This dose-dependent reduction in tumorigenesis by a non-toxic dose of FGN-1 indicates a strong chemopreventive activity against experimental induction of lung carcinogenesis. The greater potency of the sulfone over sulindac and its lack of toxic side effects because of its inability to affect cyclo-oxygenase activity suggests that clinical testing in individuals at high risk for lung cancer should be considered.     

Phase I study of cyclophosphamide (NSC 26271) by 72-hour continuous intravenous infusion

A phase I clinical study of cyclophosphamide administered by 72-hour continuous intravenous infusion was conducted in 13 patients with various types of advanced solid tumors to evaluate the drug's toxicity and efficacy. The initial dosage of 300 mg/m2/day X 3 days repeated at 3-week intervals was progressively increased by 150 mg/m2/day-increments to a maximum dosage of 750 mg/m2/day. The dose-limiting toxicities were hematologic and gastrointestinal. Neutropenia was more severe than was thrombocytopenia. The lowest granulocyte count less than 500/mm3 occurred during more than half of the treatment courses at doses of 600 mg/m2 and higher. Severe nausea and vomiting were observed in patients during three of four treatment courses at the 750 mg/m2 dose level. None of the patients had microscopic hematuria or symptoms suggestive of cystitis. Partial response occurred in a patient with parotid cancer metastatic to the lung. Disease stabilization occurred in four patients, while six patients had progression of disease. The recommended starting dosage of cyclophosphamide by continuous intravenous infusion for phase II trials is 600 mg/m2/day X 3 every 3 weeks for patients with good bone marrow reserve.     

Phase I study of UFT plus leucovorin in advanced colorectal cancer: a double modulation proposal

Twenty-six patients with advanced colorectal cancer were treated with UFT and leucovorin (LV). On day 1, patients received LV 500 mg/m2 in IV infusion, followed by 15 mg/12 h for 13 days. On days 1 to 14, patients took oral UFT twice daily. Three cycles were given every 28 days, unless grade III-IV toxicity appeared. The initial dose of UFT (200 mg/day) was increased until 800 mg/day. Dose limiting toxicities were stomatitis, diarrhea and epigastralgia. The maximum tolerated dose of UFT was 390 +/- 10 mg/m2. Three out of 24 evaluable patients achieved a partial response and 1 a complete response with UFT doses of 260 to 390 mg/m2. These results warrant confirmation in phase II studies.     

Antifungal prophylaxis with itraconazole in neutropenic patients with acute leukaemia

The efficacy of antifungal prophylaxis with itraconazole capsules and its serum concentrations were evaluated in patients intensively treated for acute leukaemia. A consecutive group of patients without systemic antifungal prophylaxis (January 1993 to August 1994, period 1) was compared with another consecutive group of patients (period 2) who received itraconazole capsules (September 1994 to April 1995 400 mg/day, from May 1995 onwards 600 mg/day). All patients admitted with acute leukaemia and standard or high-dose chemotherapy were included into the study. Clinical endpoint was mortality from proven fungal infection. Seventy-six patients and 148 courses of cytotoxic chemotherapy were analysed in the control group as well as 47 patients and 112 treatment courses in the intervention group. Antifungal prophylaxis led to a significant decrease of mortality from invasive fungal infections (8.8%-0.9%, P = 0.005). The median trough concentration of itraconazole of all measurements was 520 ng/ml (range 230-793) in patients who received 400 mg/day and 760 ng/ml (370-1200) in patients receiving a dosage of 600 mg/day (P = 0.002). These findings suggest that itraconazole is an effective drug for antifungal prophylaxis but also that a considerable number of patients do not reach the desired trough levels (>500 ng/ml) with itraconazole capsules.     

5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer

The aim of this Phase III, balanced randomised trial was to compare continuous intravenous infusion (CVI) of 5-FU with bolus (B) administration for metastatic colorectal cancer (CRC). One hundred and fifty-five non-pretreated patients were randomised to receive CVI 5-FU at a dose of 750 mg/m2/day (d), 7 d every 21 d (n = 77), or bolus 5-FU 500 mg/m2/d x 5 d every 28 d (n = 78). Incremental dose escalation at 50 mg per step was recommended in the absence of toxicity. All the patients had measurable metastatic disease (M), particularly, liver and a good performance status (WHO grade 0-1). Dose intensity was significantly higher in CVI than in the bolus group: 1369 mg/m2/week versus 558 mg/m2/week (P = 0.0001). Grade II-IV stomatitis was more frequent in the CVI group (31% versus 9%; P < 0.0001) as was hand and foot syndrome (14% versus 3%; P < 0.001). Diarrhoea (22% versus 12%) and grade III granulocytopenia (2% versus 6%) were comparable. Responses were more frequent in the CVI (26%) than in the bolus group (13%) (P < 0.04); progression-free survival was higher for the CVI group (P = 0.04), but there was no statistical difference in overall survival (median: 10 months (m) compared to 9 m), and 1 year survival (SD) 42% (6%) versus 40% (6%). In the multivariate analysis, survival was better for patients with a good PS, well-differentiated adenocarcinomas and a primary tumour without serosal extension. In conclusion, with a higher dose intensity, CVI 5-FU improved tumour control, but not overall survival.     

Food advertising on British children''s television: a content analysis and experimental study with nine-year olds

No unanimous consent has been reached about treatment guidelines of cryptococcosis in the setting of AIDS, as well as about optimal fluconazole dosing in both initial and suppressive therapy. In order to evaluate the relationship between fluconazole dosing and clinical and microbiological outcome of AIDS-related cryptococcosis, a retrospective study was carried out on 30 consecutive patients. Among the 12 subjects treated with fluconazole doses < 400 mg/day, an unfavorable course was significantly more frequent (early mortality, poor clinical and microbiological response, appearance of early relapses) compared with the 18 patients who received daily doses > or = 400 mg, while no differences were observed between the two treatment groups according to known risk factors for a poor prognosis. When assessing maintenance treatment (22 evaluable cases), the 15 patients receiving oral fluconazole at doses < 200 mg/day showed earlier disease relapse and mortality as opposed to the 7 individuals treated with high-dose fluconazole (> or = 200 mg/day), in the absence of significantly different risk factors for disease recurrence. Our experience pointed out a significant difference in clinical activity of fluconazole in AIDS-related cryptococcosis according to its daily dosing, and suggested 400 and 200 mg as the threshold daily dose for an effective initial and suppressive therapy, respectively, since the probability of treatment failure seemed greater with low-dose drug administration, after controlling data for prognostic markers of disease severity. Controlled studies are warranted, comparing high-dose fluconazole with standard regimens containing amphotericin B in the treatment of AIDS-associated cryptococcosis, and identifying the best fluconazole dosing for both acute-phase and maintenance treatment.     

Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients

OBJECTIVE: The authors studied the risk of tardive dyskinesia for older patients in the early stages of treatment with typical neuroleptics. METHOD: They examined the cumulative incidence of tardive dyskinesia 1, 3, 6, 9, and 12 months after the institution of neuroleptic therapy among 307 psychiatric outpatients over age 45. The patients' median dose was 68.4 mg/day of chlorpromazine equivalent. RESULTS: In the patients who had never received neuroleptics at baseline (N = 87), the mean cumulative incidence of tardive dyskinesia was 3.4% and 5.9% at 1 and 3 months, respectively. There was no significant difference in the 12-month cumulative incidence of tardive dyskinesia among patients who had been neuroleptic-naive at baseline (22.3%) and the 89 patients who had received neuroleptics before baseline for 1-30 days (24.6%); however, the 131 patients who had received neuroleptics before baseline for more than 30 days tended to have a greater cumulative 12-month incidence of tardive dyskinesia (36.9%). CONCLUSIONS: The risk of tardive dyskinesia in older outpatients is high, even with relatively short treatment with low doses of conventional neuroleptics.     

Randomized study of two doses of didanosine in children infected with human immunodeficiency virus

2'3'-Dideoxyinosine (didanosine) is a nucleoside analog active in vitro against human immunodeficiency virus. Few data are available regarding its use for the treatment of children. In a single-center, randomized, open-label trial, we compared two dosages of didanosine (120 vs 270 mg/m2 per day) for at least 6 months in 34 children infected with human immunodeficiency virus who had become resistant to or were intolerant of zidovudine. Serum levels of didanosine 1 hour after administration were significantly different in the two groups and remained stable with time. There was a significant reduction in human immunodeficiency virus-p24 antigenemia and quantitative cellular viremia with time but no difference between the two groups. The intensity of the biologic response, however, was significantly higher in the patients who had more than 50 CD4+ cells 10(6)/L at inclusion. No pancreatic or neurologic toxic effects were observed. In five children, liver function abnormalities developed that are unusual in this setting, and the death of one child from unexplained hepatocellular failure suggests that didanosine may be hepatotoxic. Three of these five children had preexisting liver disease. Although no definite conclusion can be made as to the optimal dose, there were no major differences between the two administration schedules in terms of biologic effects and tolerability.     

A simple prognostic index for patients with acute renal failure requiring dialysis. French Multicentric Prospective Study on Furosemide in Acute Renal Failure Requiring Dialysis

The probability of death in patients with acute renal failure (ARF) remains high. A valid prognostic index available on patient admission and during follow-up could be helpful for decision making. In this study, 94 ARF patients requiring dialysis (not responding to a previous single dose of furosemide 15 mg/kg) were included. On admission, patients were classified according to a Simplified Acute Physiology Score (SAPS) of < or = 15 or > 15. The prognostic value of 11 risk factors was analyzed. Only 6 in 11 risk factors were significant by univariate analysis: age (> 55 years) (0.02), mechanical ventilation (0.008), oliguria (< 500 mL/day during the first 5 days) (0.02), sepsis (0.001), shock (0.007), and serum bilirubin (> 30 mumol) (0.001). Only oliguria and sepsis were significant risk factors by multivariate analysis. Overall mortality rate was 41%. Mortality rate was higher in patients with SAPS > 15 (65%) than in those with SAPS < or = 15 (22%) (0.001). Patients with > 3 risk factors showed a significantly higher mortality rate than patients with < 3 risk factors (all patients disregarding SAPS) (0.001). Considering the worst combination of risk factors by univariate analysis, mortality prediction was 56% if oliguria, sepsis, and high serum bilirubin were present, and reached 80% if an older age was added (four risk factors). Ventilation increased probability of death to 92% (five risk factors). If all six risk factors were present, the probability rose to 96%. The corresponding observed mortality rate was 32% for three risk factors, 70% for four, 81% for five and 100% for six risk factors. The results suggest that probability of death in ARF requiring dialysis can be correctly estimated when more than three significant risk factors are present. If confirmed, they could avoid using a more complex severity scoring system in patients with ARF requiring dialysis.     

Isotretinoin for acne vulgaris--10 years later: a safe and successful treatment

The purpose of this study was to assess the long-term benefit of isotretinoin in otherwise therapy-resistant acne. We also assessed risk factors which might influence the long-term outcome. We studied 88 patients (mean age 20.8 years), most of whom had suffered from acne for many years (mean 7.4 years). They received isotretinoin in an initial dose of 0.5 or 1.0 mg/kg/day. The dose was subsequently adjusted according to response and side-effects. Most patients only required 4 months' therapy to produce at least 85% clinical improvement. The patients were seen up to 10 years post-therapy (mean 9 years). Sixty-one patients were still virtually clear of disease. Of the others, 16% required further treatment with conventional antibiotics and 23% required a second course of isotretinoin. Of those who relapsed, 96% did so within 3 years of stopping therapy. The patients' age, sex, and duration of acne did not influence outcome. However, in patients with predominantly truncal acne, especially when severe, there was an increased incidence of relapse. Sebum excretion is known to correlate with acne severity, but the long-term degree of sebum suppression was found not to be related to relapse. The dose schedule, in particular cumulative dose, was an important factor in determining relapse rate. Those patients who received 0.5 mg/kg daily, or a cumulative dose of < 120 mg/kg, had a significantly higher relapse rate than patients receiving a larger dose. We did not elicit any long-term systemic or biochemical side-effects. We conclude that isotretinoin is a safe and effective therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the efficacy of treatment of Kawasaki disease before day 5 of illness

We evaluated the efficacy of treating Kawasaki disease earlier than Day 5 of illness with a standard dose of immunoglobulin and aspirin. We performed a case-control study of patients with Kawasaki disease admitted to Princess Margaret Hospital from 1994 to 1999. Patients with pretreatment coronary aneurysm or those treated after day 10 of illness were excluded. All patients received immunoglobulin (2 g/kg) and aspirin (80-100 mg/kg/day) until fever subsided for 48 hours. Immunoglobulin retreatment was given for persistent fever 48 hours after the first dose of immunoglobulin or recrudescent fever. The case group consisted of 15 patients who received treatment earlier than day 5 of illness, and the control group consisted of 66 patients who were treated on or after day 5. Patients' sex, age, duration of posttreatment fever, need for additional immunoglobulin, and coronary artery status were noted. Treatment efficacy was assessed by the duration of posttreatment fever and the prevalence of coronary artery aneurysms. Eighty-one patients were included in this study. There were 15 patients in the case group and 66 in the control group. No significant difference was noted in age and sex between the case and control groups. Thirty-three percent (5/15) and 8% (5/66) of the case and control groups, respectively, had persistent/ recrudescent fever 48 hours after the first dose of immunoglobulin that required retreatment ( p = 0.017). Thirteen percent (2/15) and 5% (3/66) of the case and control groups, respectively, had coronary aneurysms ( p = 0.158). Treatment of Kawasaki disease before day 5 of illness was associated with persistent/recrudescent fever that required retreatment. However, there was no significant increase in the prevalence of coronary aneurysm if retreatment was given.