Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity.
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Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36-73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min(-1) mg(-1) protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoretical range 0-20) was twice as high in patients with marked DD (below 100 pmol min(-1) mg(-1) protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min(-1) mg(-1) protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile. (+info)
Itraconazole oral solution as prophylaxis for fungal infections in neutropenic patients with hematologic malignancies: a randomized, placebo-controlled, double-blind, multicenter trial. GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche dell' Adulto.
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To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species. (+info)
Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group.
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A randomized, double-blind trial comparing oral fluconazole (400 mg daily) with placebo as prophylaxis for adult patients receiving intensive cytotoxic therapy for acute leukemia or autologous bone marrow transplantation was conducted in 14 Canadian university-affiliated hospitals. Although fluconazole prophylaxis did not obviate the need for parenteral antifungal therapy compared with placebo (81 [57%] of 141 vs. 67 [50%] of 133, respectively), its use resulted in fewer superficial fungal infections (10 [7%] of 141 vs. 23 [18%] of 131, respectively; P = .02) and fewer definite and probable invasive fungal infections (9 vs. 32, respectively; P = .0001). Fluconazole recipients had fewer deaths attributable to definite invasive fungal infection (1 of 15 vs. 6 of 15, respectively; P = .04) and achieved more frequent success without fungal colonization (52 [37%] of 141 vs. 27 [20%] of 133, respectively; P = .004; relative risk reduction, 85%) than did placebo recipients. Patients benefiting the most from fluconazole prophylaxis included those with acute myeloid leukemia who were undergoing induction therapy with cytarabine plus anthracycline-based regimens and those receiving marrow autografts not supported with hematopoietic growth factors. Fluconazole prophylaxis reduces the incidence of superficial fungal infection and invasive fungal infection and fungal infection-related mortality among patients who are receiving intensive cytotoxic chemotherapy for remission induction. (+info)
The evolution of antibiotic therapy for neutropenic patients.
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Considerable progress has been made in the treatment of infections in neutropenic patients during the past three decades. A major contribution to this progress has been the discovery of effective new therapies and their prompt administration. Unfortunately, successful therapy of each important pathogen has resulted in the emergence of new pathogens, usually with unique patterns of antibiotic susceptibility. Unfortunately, antibiotic resistance has become an increasing threat in recent years, raising the possibility of infections that will be difficult to eradicate. Fortunately, there are new classes of antimicrobials that hold promise for therapeutic success in the future. (+info)
Protein kinase C mediates experimental colitis in the rat.
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Protein kinase C (PKC) plays an important role in the cell signal transduction of many physiological processes. In contrast to these physiological responses, increases in PKC activity have also been associated with inflammatory disease states, including ulcerative colitis. The objective of this study was to examine the role of PKC as a causative mediator in initiation of experimentally induced colitis in the rat. Colitis was induced in rats by intrarectal (0.6 ml) instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 75 mg/kg in 50% ethanol) or the PKC activator phorbol 12-myristate 13-acetate (PMA; 1.5-3.0 mg/kg in 20% ethanol). Gross and histological mucosal damage, mucosal neutrophil infiltration, mucosal PKC activity, and PKC protein content for PKC isoforms alpha, beta, delta, and epsilon were assessed 2 h to 14 days after an inflammatory challenge. Both PKC activity and mucosal injury increased significantly within 4 h of TNBS treatment. PKC activity was maximal at 7 days and declined at 14 days, whereas mucosal damage became maximal at 1 day and declined after 7 days. In contrast, neutrophil infiltration as assessed by myeloperoxidase activity only increased 12 h after TNBS treatment, became maximal 1 day after TNBS administration, and declined thereafter. PKCbeta, -delta, and -epsilon were increased in response to TNBS, whereas PKCalpha protein content was decreased. The PKC antagonists staurosporine and GF-109203X (25 ng/kg iv) reduced TNBS-induced changes in mucosal PKC activity and the degree of mucosal damage. In contrast, neutropenia induced by antineutrophil serum treatment did not significantly affect the degree of injury or mucosal PKC activity. Furthermore, activation of mucosal PKC activity with PMA also induced mucosal damage, which was also inhibited by pretreatment with a PKC antagonist. In conclusion, these results suggest that increases in PKC activity play a causative role in TNBS-induced colitis. The PKC-mediated response to TNBS does not appear to involve neutrophil infiltration. (+info)
A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration.
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2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing. (+info)
Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.
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PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks. (+info)
Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell transplant recipients: use of high-resolution computed tomography.
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PURPOSE: To obtain statistical data on the use of high-resolution computed tomography (HRCT) for early detection of pneumonia in febrile neutropenic patients with unknown focus of infection. MATERIALS AND METHODS: One hundred eighty-eight HRCT studies were performed prospectively in 112 neutropenic patients with fever of unknown origin persisting for more than 48 hours despite empiric antibiotic treatment. Fifty-four of these studies were performed in transplant recipients. All patients had normal chest roentgenograms. If pneumonia was detected by HRCT, guided bronchoalveolar lavage was recommended. Evidence of pneumonia on chest roentgenograms during follow-up and micro-organisms detected during follow-up were regarded as documentation of pneumonia. RESULTS: Of the 188 HRCT studies, 112 (60%) showed pneumonia and 76 were normal. Documentation of pneumonia was possible in 61 cases by chest roentgenography or micro-organism detection (54%) (P < 10(-6)). Sensitivity of HRCT was 87% (88% in transplant recipients), specificity was 57% (67%), and the negative predictive value was 88% (97%). A time gain of 5 days was achieved by the additional use of HRCT compared to an exclusive use of chest roentgenography. CONCLUSION: The high frequency of inflammatory pulmonary disease after a suspicious HRCT scan (> 50%) proves that pneumonia is not excluded by a normal chest roentgenogram. Given the significantly longer duration of febrile episodes in transplant recipients, HRCT findings are particularly relevant in this subgroup. Patients with normal HRCT scans, particularly transplant recipients, have a low risk of pneumonia during follow-up. All neutropenic patients with fever of unknown origin and normal chest roentgenograms should undergo HRCT. (+info)