Scintigraphic imaging of bacterial and fungal infection in granulocytopenic rats.
(9/458)
Scintigraphic imaging in granulocytopenic patients can be very useful to detect and localize infections, which often do not show localizing signs and symptoms. We studied the potential of 99mTc-labeled polyethylene glycol (PEG)-coated liposomes and 99mTc-labeled IgG to image bacterial and fungal infection in a granulocytopenic rat model. 67Ga-citrate was used as a reference agent. METHODS: 99mTc-PEG-liposomes, 99mTc-hydrazinonicotinate (HYNIC)-IgG or 67Ga-citrate was administered to granulocytopenic rats with a Staphylococcus aureus abscess or with unilateral invasive pulmonary aspergillosis. Imaging and biodistribution studies were performed. RESULTS: All agents visualized the S. aureus infection from 1 h after injection onward. However, only with 99mTc-PEG-liposomes and with 99mTc-HYNIC-IgG did activity in the infectious foci increase with time up to 24 h. 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG showed significantly higher accumulation in the infectious focus compared with 67Ga-citrate (1.33+/-0.31 and 1.40+/-0.16 percentage injected dose per gram [%ID/g], respectively, versus 0.31+/-0.04 %ID/g 24 h after injection; P<0.05). At 24 h after injection, abscess-to-muscle ratios were highest for 99mTc-liposomes (72.1+/-19.1), followed by 99mTc-HYNIC-IgG (18.3+/-3.3) and 67Ga-citrate (4.4+/-0.7). In pulmonary aspergillosis, both 99mTc-PEG-liposomes and 99mTC-HYNIC-IgG showed significantly higher uptake in the infected lung than did 67Ga-citrate (3.6+/-0.4 and 8.3+/-0.8 %ID/g, respectively, versus 1.3 %ID/g at 24 h after injection; P<0.05). CONCLUSION: 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG performed better than did 67Ga-citrate in the localization of peripheral bacterial infection and fungal infection in the lung in granulocytopenic rats. The high focal uptake and high target-to-nontarget ratios of 99mTc-PEG-liposomes and 99mTc-HYNIC-IgG indicate that both radiopharmaceuticals may become valuable agents to image infection in granulocytopenic patients. (+info)
Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections.
(10/458)
Agranulocytosis is a rare complication of antithyroid drugs, and the aetiologies of community-acquired, life-threatening infections in patients taking these drugs have not previously been systematically described. Of 5653 hyperthyroid patients treated with antithyroid drugs at National Taiwan University Hospital between January 1987 and December 1997, 13 (0.23%) developed agranulocytosis with life-threatening infections. The most common presentations were fever (92%) and sore throat (85%). Initial clinical diagnoses were acute pharyngitis (46%), acute tonsillitis (38%), pneumonia (15%) and urinary tract infection (8%). Positive blood cultures from six patients yielded Pseudomonas aeruginosa (3), Escherichia coli (1), Staphylococcus aureus (1), Capnocytophaga species (1). Two patients died of uncontrolled infection, thyroid storm and multiple organ failure. Cases of antithyroid-drug-induced agranulocytosis in the English language literature are reviewed; Gram-negative bacilli, including Klebsiella pneumoniae (4 patients) and P. aeruginosa (3), were the most common pathogens in clinical isolates. Our observation and review suggest that broad-spectrum antibiotics with anti-pseudomonal activity should be given to patients with antithyroid drug-induced agranulocytosis who present with severe infection. (+info)
Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin.
(11/458)
The aim of the study was to evaluate the effectiveness and safety of a combined treatment modality including systemic chemotherapy with 5-fluorouracil (FU), leucovorin, cisplatin and external beam radiotherapy in patients with locally advanced pancreatic cancer. Systemic chemotherapy consisted of FU 400 mg m(-2) and leucovorin 20 mg m(-2) both given as intravenous bolus injection on days 1-4, plus cisplatin 20 mg m(-2) administered as 90-min infusion on days 1-4. Treatment courses were repeated every 4 weeks x 6 unless prior evidence of progressive disease. Radiation therapy using megavolt irradiation of > or = 6 MV photons with a 3- or 4-field technique was delivered during the second and third chemotherapy course, that was reduced in dose by 25%. Between October 1994 and July 1996, a total of 38 patients were entered onto this trial, all of whom were assessable for toxicity and survival. Eighteen of these (47%) had objective remissions to combined radiochemotherapy, including four CR (11%), 13 (34%) had stable disease and seven patients (18%) showed tumour progression during treatment. The median progression-free interval of the entire study population was 10 months (range 3-32), and median overall survival was 14.0 months (range 3-45+ months); 53% of all patients were alive at 12 months, and 18% of patients were alive at 24 months respectively. Severe haematological side-effects comprised neutropenia in 18%, thrombocytopenia in 8% and anaemia in 11%. The most frequent non-haematological side-effects were nausea/vomiting (WHO grade 3: 18%), and diarrhoea (grade 3: 13%). This combined radiochemotherapy regimen was tolerable and effective in patients with locally advanced pancreatic cancer. Since therapeutic results, in fact, compare favourably with other series, including surgical treatment of potentially resectable tumours, further evaluation of combined treatment modalities in the neoadjuvant setting seems warranted. (+info)
Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine.
(12/458)
AIMS: To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR-related excess hospital stay in medical inpatients. METHODS: Structured data regarding patient characteristics, 'events' (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer-supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by 'event monitoring' to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. RESULTS: The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease-unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR-related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR-related excess hospital stay accounted for 8. 6% of hospital days. CONCLUSIONS: These data demonstrate the feasibility of the developed 'event monitoring' system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients. (+info)
Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract.
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PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing. (+info)
Bioactivation and covalent binding of hydroxyfluperlapine in human neutrophils: implications for fluperlapine-induced agranulocytosis.
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The use of fluperlapine and the structurally related clozapine has been associated with the induction of agranulocytosis in humans. Unlike clozapine, fluperlapine is relatively resistant to chemical and biochemical oxidations. In this study we demonstrated that 7-hydroxyfluperlapine, the major metabolite of fluperlapine in humans, is oxidized to a reactive intermediate by HOCl and by myeloperoxidase in the presence of H(2)O(2) and Cl(-). This reactive intermediate was identified as an iminoquinone species with a M + 1 ion at m/z 324 by mass spectrometry. The iminoquinone intermediate was trapped by N-acetyl-L-cysteine (NAC) as well as GSH. NMR spectra of the NAC adducts indicated that the NAC was bound to the 6 and 9 positions of the aromatic ring. This is the same orientation as the binding of nucleophiles to the reactive metabolite of clozapine. We were able to use an antibody against clozapine to demonstrate that 7-hydroxyfluperlapine, but not fluperlapine itself, covalently modifies human myeloperoxidase. Furthermore, we demonstrated that 7-hydroxyfluperlapine is metabolized by activated neutrophils to a reactive intermediate that covalently binds to neutrophils. In the presence of NAC or GSH, such covalent binding was inhibited and the NAC or GSH adducts were formed. Thus, the reactivity and even the orientation of the binding of the reactive metabolite of 7-hydroxyfluperlapine is very similar to that of clozapine. These results provide a mechanism for the formation of a reactive metabolite of fluperlapine similar to clozapine that may explain its ability to induce agranulocytosis. (+info)
Blood dyscrasias in clozapine-treated patients in Italy.
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BACKGROUND AND OBJECTIVE: Clozapine is a dibenzodiazepine derivative that is more effective than standard neuroleptic drugs in refractory schizophrenic patients, but its introduction in some countries was delayed by its propensity to cause blood dyscrasias. However, over the last ten years, different reports have clearly demonstrated that agranulocytosis and neutropenia can be easily prevented by means of strict hematologic surveillance. This article reviews the results of the first five years of the Italian Clozapine Monitoring System (ICLOS). DESIGN AND METHODS: The hematologic parameters of 2,404 patients registered between 1995 and 1999 were collected in a central database, before the patients began clozapine-treatment, weekly for the first 18 weeks, and then monthly throughout the duration of therapy. On the basis of conventional criteria, different risk levels have been identified with total leukocyte <3. 0x10(9)/L and/or an absolute neutrophil count <1.5x10(9)/L leading to immediate discontinuation of the drug. RESULTS: The analysis shows that 0.9% of the patients developed neutropenia and 0.7% agranulocytosis, mainly during the first 18 weeks of clozapine treatment. Drug discontinuation led to the normalization of hematologic parameters in all cases, and the use of growth factors reduced the risk of infectious complications. Transient leukocytosis and eosinophilia were also observed but these did not have any serious clinical effects. INTERPRETATION AND CONCLUSIONS: The ICLOS study confirms that regular hematologic monitoring is highly effective in minimizing the incidence of clozapine-associated blood dyscrasias. The lower than initially expected rates of agranulocytosis and associated deaths are encouraging in view of the benefits of this drug in treatment-resistant schizophrenia and other neurologic disorders. (+info)
Phase II study of 3-hour infusion of high dose paclitaxel in refractory and relapsed aggressive non-Hodgkin's lymphomas. Groupe d'Etude des Lymphomes de l'Adulte.
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BACKGROUND AND OBJECTIVE: The first clinical studies of paclitaxel as a single agent for the treatment of relapsed or refractory low or intermediate grade non-Hodgkin's lymphomas (NHL) yielded controversial results regarding the response rates observed, mainly related to the dose and schedule of administration used. To obtain additional data concerning the efficacy and toxicity of paclitaxel in intermediate and high grade NHL we initiated a phase II study using a 3-hour infusion of high doses of paclitaxel. DESIGN AND METHODS: The eligibility criteria included patients with relapsed or refractory aggressive NHL, a performance status < or = 2 (WHO index), a platelet count > or = 100,000/microL, a neutrophil count > or = 2,000/microL, measurable disease, and adequate hepatic function. Patients were excluded if they were infected with HIV, had a left ventricular ejection fraction < 50%, or prior peripheral neuropathy. Paclitaxel was administered as a 3-hour infusion at a dose of 250 mg/m2 every 3 weeks for a maximum of 6 courses. RESULTS: Of 45 eligible patients, 42 received a total 73 courses of paclitaxel. Forty patients were assessable for response (89%), and 42 for toxicity (93%). Six patients (15%) achieved a partial (n = 4) or a complete remission (n = 2). Responses were observed in intermediate grade (n = 4) as well as in high grade lymphoma (n = 2). The main factor influencing the response to paclitaxel was the median duration of response to previous chemotherapy regimens which was 3 times longer in patients who responded to paclitaxel (16.3 months) than in patients who did not respond to paclitaxel (5.2 months) (p<0.05). The most common serious side effects were related to the hematologic toxicity of paclitaxel, and included grade IV granulocytopenia in 20 cases (48%), grade III/IV thrombocytopenia in 14 cases (33%) and grade III-IV anemia in 13 cases (31%). INTERPRETATION AND CONCLUSIONS: Despite frequent manageable hematologic toxicity, paclitaxel is usually well tolerated at a dose of 250 mg/m2 given by a 3-hour infusion. However, the clinical efficiency as a single therapy seems modest in relapsed or refractory aggressive lymphoma. (+info)