Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,2,2-Trifluoroethanol (TFE) produces bone marrow and small intestine toxicity resulting in leukopenia, loss of intestinal dry weight, and consequent lethal septicemia in male Wistar rats. Its metabolic pathway, based on serum and small intestine time courses of substrate and metabolites, was determined to be TFE in equilibrium 2,2,2-trifluoroacetaldehyde (TFAld)----trifluoroacetic acid (TFAA). Administered TFE and TFAld were not toxic per se, since their toxicity and metabolism were inhibited by pyrazole. TFE and TFAld were equipotent at equimolar doses thus precluding the oxidative reaction, TFE to TFAld, from being the toxic step. Since equimolar TFAA exhibited no toxic effects, an oxidative intermediate on the pathway from TFAld to TFAA, most likely F3C-C+(OH)2, must thus be the toxic moiety. The intermediate TFAld is stable in serum, as determined by a novel assay developed for its analysis in biological systems, and can be transported to the target tissues, bone marrow, and small intestine, after formation probably in the liver. On the basis of the more rapid metabolism of TFE to higher levels of TFAld in the small intestine and bone marrow than in the serum, the closer correspondence of bone marrow and small intestine metabolite ratios than serum ratios at high and low doses of TFE to the corresponding ratios of toxicity, and the decreased toxicity of TFAld when administered ig versus ip, the formation of the toxic metabolic intermediate of TFE probably occurs in the target tissues.
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PMID:2,2,2-Trifluoroethanol intestinal and bone marrow toxicity: the role of its metabolism to 2,2,2-trifluoroacetaldehyde and trifluoroacetic acid. 337 17

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.
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PMID:A phase I and pharmacokinetic study with 21-day continuous infusion of epirubicin. 347 90

Thirty-five patients with previously untreated, advanced, measurable metastatic colorectal carcinoma were treated with a 12-week course of continuous 5-fluorouracil (5-FU) and weekly cisplatin. Twenty of 32 evaluable patients responded (five complete and 15 partial responses), for an overall response rate of 63% (90% confidence limits, 43%-75%). Toxicity was generally mild and reversible and included mucositis (40%), painful erythema of the palmar and plantar skin (30%), diarrhea (21%), nausea and vomiting (15%), and leukopenia (6%). One patient died of sepsis secondary to mucositis and myelosuppression. This program is a well-tolerated outpatient regimen for metastatic colorectal carcinoma. The response rate is higher than expected for 5-FU and cisplatin and suggests clinical therapeutic synergism at this dose rate and schedule.
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PMID:Pilot trial of prolonged continuous-infusion 5-fluorouracil and weekly cisplatin in advanced colorectal cancer. 355 89

Interferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I-II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0 X 10(6) IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table. Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.
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PMID:Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial. 359 2

Four cases of midfacial necrotizing lesions are reported. All patients were males with ages ranging from 25 to 76 years. The relationship between subjective symptoms and laboratory data prior to therapy (leukopenia, elevated ESR, increment of IgA and IgG), as well as between fever crisis with sweats and chills and the progression of the lesions were pathognomonic clinical signs for us. In all cases, paranasal sinus and nasopharynx were involved. Middle ear, eye and kidney involvement was present in 2 cases, and joints lesions only in one. Three patients died (2 of sepsis and one from hemorrhage) despite therapy. A pleomorphic cellular infiltrate with atypical lymphocytes and a tendency to angiocentricity was found in these cases. Such features and PAP positivity to beta and kappa chains led us to consider these lesions as an extranodal B-lymphocyte lymphoma-like. In the fourth case the histological picture was that of a necrotizing granuloma with clustered giant cells. This patient, treated only with prednisone, had a total remission of his symptomatology up to 11 years after the onset of the disease.
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PMID:Midfacial granuloma syndrome. A clinic and pathological report on four patients. 361 71

Thirty-six patients with stage III-IV ovarian cancer, bulky disease, were treated with adriamycin and cyclophosphamide administered in two different dosages. Three or four cycles of chemotherapy were administered before the first surgery to facilitate the surgical debulking. After surgery, 6 additional cycles of chemotherapy were administered, and a second look was performed. Clinical CR + PR was observed in 19/30 (63%) evaluable patients after the first part of chemotherapy, but pathologic CR + PR was confirmed in only 13 (43%) patients. After the second part of chemotherapy and the second surgery, 5/30 (17%) patients had pathologic CR and 3/30 (10%) showed residual disease. The two regimens demonstrated similar activity (67% vs 56% clinical CR + PR) but a very different toxicity. In fact, 50% of patients treated with higher doses showed severe leukopenia and 25% severe thrombocytopenia, and 2/13 died of sepsis. The significant activity of adriamycin plus cyclophosphamide in ovarian cancer was confirmed, and increasing the dosage of the two drugs did not increase their activity but only their toxicity.
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PMID:Chemotherapy and surgery in the treatment of ovarian cancer bulky disease. 370 93

Allopurinol has been shown to ameliorate the myelotoxicity of 5-fluorouracil (5-FU) given as an infusion. To study the potential effectiveness of allopurinol in modifying the toxicity of 5-FU given as a bolus, 8 adult patients with metastatic malignancies were given 11 courses of bolus 5-FU with allopurinol. Allopurinol was administered at a dose of 900 mg/day orally beginning a week prior to the 5-FU therapy and continued a week after the last dose of 5-FU was administered. Three patients received a total of 5 courses of 600 mg/m2 of 5-FU via bolus injection for 4 consecutive days every 28 days. Six patients were given 6 courses of 800 mg/m2 of 5-FU via bolus injection in the same schedule. Gastrointestinal toxicity was mild and no significant neurotoxicity was documented. However, severe myelosuppression occurred at the 800 mg/m2 dosage which led to marked leukopenia in 5 of the 6 patient courses and thrombocytopenia in 1. Gram-negative sepsis developed in 3 of the leukopenic patients with 2 resultant deaths. Allopurinol does not appear to allow clinically significant dose escalation of bolus 5-FU given on this schedule.
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PMID:Failure of allopurinol to provide clinically significant protection against the hematologic toxicity of a bolus 5-FU schedule. 372 83

Ceftriaxone has a very long serum half-life and enhanced in vitro activity against common pediatric pathogens. Therefore we evaluated the efficacy and safety of once daily ceftriaxone therapy in 57 children with serious infections including: meningitis (26 patients); ventriculitis (3); pyelonephritis (7); osteomyelitis (6); abscess (4); septic arthritis (3); sepsis (2); and miscellaneous infections (6). The most common isolates were Haemophilus influenzae (23), Escherichia coli (9) and Staphylococcus aureus (8). Ceftriaxone was given intravenously or intramuscularly in a dose of 50 mg/kg for non-central nervous system (CNS) infections. Patients with CNS infections received an initial dose of 100 mg/kg followed by 80 mg/kg 12 hours later and once daily thereafter. In a limited number of patients no major differences in serum ceftriaxone concentrations were found after intravenous or intramuscular injection. Of 57 patients with pathogens isolated 55 were completely cured; in one patient with Klebsiella pneumoniae ventriculitis, intraventricular gentamicin was briefly added to the regimen. Another patient with an anaerobic liver abscess recovered after metronidazole was administered. In three patients a delayed response to ceftriaxone was noted. One patient with previous recurrent infections had a second episode of H. influenzae meningitis 22 days after cessation of therapy. Clinical side effects were noted in 10 of 71 patients (including 14 treated patients who had negative cultures). Seven patients had diarrhea, one each had fever or rash and one had fever, rash and arthralgia. Laboratory side effects in 16 of 71 patients included eosinophilia (7), thrombocytosis (7), elevated liver enzymes (4) and leukopenia and neutropenia (2).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Once daily ceftriaxone for central nervous system infections and other serious pediatric infections. 372 39

A phase II study of acute leukemia with mitoxantrone (MIT) was conducted by the Tokai Blood Cancer Study Group. The drug efficacy was evaluable in 31 cases (14 of ALL and 17 of ANLL) out of 37 entered at 13 institutions. Five cases were for first induction remission and 26 cases for re-induction remission; ages ranged from 7 to 69 (median: 43); 18 males and 13 females. MIT dosage was intravenous injection of 3-6 mg/m2/day X 5 consecutive days as a rule. Of the 14 cases of ALL, 2 achieved CR and 3, PR; the efficacy rate was 36%. Of the 17 cases of ANLL, 4 achieved CR and 3, PR: the efficacy rate was 41%. Of the 5 first induction remission cases, 3 achieved CR, and 1, PR, the efficacy rate being 80%, whereas out of the 26 re-induction remission cases, 3 achieved CR, 5 PR, and the efficacy rate was 31%. In 3 of 6 cases of CR, large cumulative doses of anthracyclines such as DNR 140 mg plus ACR 410 mg, DNR 360 mg plus ADR 120 mg plus ADR 120 mg, and DNR 240 mg plus ADR 540 mg, had been administered previously in each case. As to complications, sepsis and other infections were observed at the rates of 15% and 32%, respectively, from which it was inferred that in therapy with mitoxantrone, leukopenia should be observed carefully. The major non-hematological toxicity was gastrointestinal symptoms, but the degree was mild. From the results of this trial, it was concluded that mitoxantrone was an effective form of therapy for acute leukemia. Further clinical trials on mitoxantrone in combination with other drugs are scheduled.
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PMID:[Phase II study of mitoxantrone in patients with acute leukemia]. 374 Aug 58

Twenty-two patients with metastatic colorectal cancer were treated with a regimen of 5-fluorouracil 600 mg/m2 (maximum, 1.0 g) i.v./week and folic acid 140 mg/m2 i.v. given 1 h prior to the 5-FU. This study was undertaken in an attempt to confirm the in vitro finding that inhibition of thymidylate synthetase by 5-fluorouracil is prolonged by the presence of folates. There were four partial responses (18%) with mean duration 4 months. Dose-limiting toxicity was enteritis, seen in 12 patients (58%), and causing hospitalization in seven patients. Enteritis was shown to be due to the folic acid in most patients. Two patients died from leukopenia, enteritis, and sepsis. Mean serum folate levels at the time of 5-FU injection were 36 microM. This regimen is no more effective than 5-FU alone and has significantly more serious toxicity. Further investigation of this regimen is not recommended.
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PMID:5-Fluorouracil and high-dose folic acid treatment for metastatic colon cancer. 382 92


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