Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tallimustine binds to the minor groove of DNA where it alkylates the N3 position of adenine and may interfere with gene transcription. We conducted a phase II trial of Tallimustine given at a dose of 750 micrograms/m2 intravenously every 4 weeks in patients with small cell lung cancer progressing or relapsing following cisplatin or carboplatin-based chemotherapy. We treated 14 eligible patients with a performance status 0, 1 or 2, bi-dimensionally measurable disease and adequate end-organ function. The main toxicity was neutropenia with a median granulocyte count of 0.1 x 10(9) per liter (range 0-3.9) and four patients (27%) developing febrile neutropenia. In addition, most patients (93%) experienced lethargy. No objective responses were seen. A mixed response was seen in one patient and three others had stable disease for a median of 3.7 months. We conclude that Tallimustine is an ineffective agent in previously treated small cell lung cancer.
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PMID:Tallimustine is inactive in patients with previously treated small cell lung cancer. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. 895 81

Three dogs became lethargic and had poor appetites within 2 months after anticonvulsant treatment was initiated to control seizures. Dogs were neutropenic, thrombocytopenic, and anemic and had splenomegaly. Sensitivity to phenobarbital and related anticonvulsants may induce life-threatening leukopenia, thrombocytopenia, and anemia in dogs. Phenobarbital-induced neutropenia in these 3 dogs may have posed a risk for developing bacteremia. It is important for clinicians to be aware of adverse effects so that adequate precautions can be taken. A baseline hemogram should always be obtained before starting anticonvulsant treatment, and periodic hemograms should be obtained to monitor animals. Furthermore, client education should include instructions on recognizing signs of bacteremia, thrombocytopenia, and anemia.
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PMID:Neutropenia and thrombocytopenia in three dogs treated with anticonvulsants. 952 40

Acivicin is a glutamine analogue antimetabolite that inhibits several glutamate-dependent synthetic enzymes. Previous studies of this agent administered on a 72-h continuous i.v. infusion schedule every 3 weeks demonstrated a high rate of severe, albeit reversible, central nervous system (CNS) toxicity at the 30 mg/m2/day dose level. Animal studies have shown that the CNS toxicity of acivicin can be prevented by a concomitant infusion of amino acids postulated to block drug uptake in the CNS by a saturable transport system that is common to endogenous amino acids. This study evaluated the feasibility of escalating acivicin doses in cancer patients by administering acivicin with a concomitant 96-h i.v. infusion of a mixture of 16 amino acids (Aminosyn, 10%). Twenty-three patients with advanced malignancies were treated with acivicin on a 72-h continuous infusion schedule at doses ranging from 25 to 60 mg/m2/day every 3 weeks. Reversible, dose-limiting CNS toxicity, characterized by lethargy, confusion, and decreased mental status, occurred in the two patients enrolled at the 60 mg/m2/day dose level, precluding further dose escalation. The maximum tolerated dose (MTD) and recommended dose for additional evaluation of acivicin on this schedule is 50 mg/m2/day. Other toxicities observed were dose-related neutropenia that was grade 4 in four patients (four courses), complicated with fever in three of those patients, and grade 3-4 thrombocytopenia in three patients (three courses). Pharmacokinetics studies performed in 15 patients revealed that the acivicin plasma Css increased from 0.44 microg/ml (range, 0.28-0.59 microg/ml) at the 25 mg/m2/day to 1.06 microg/ml (0.64-1.5 microg/ml) at the 50 mg/m2/dose level. Acivicin Css at the MTD was not significantly higher than previously reported values with single-agent acivicin on the same schedule of administration at the MTD of 25 mg/m2/day dose level (0.60 microg/ml; range, 0.43-0.81 microg/ml). Neurotoxicity did not correlate with acivicin Css, but relationships between exposure to acivicin and the occurrence of both neutropenia and thrombocytopenia were well described by a sigmoidal Emax model. This trial demonstrated that concomitant infusions of amino acid can prevent acivicin-induced CNS toxicity, which allows the dose of acivicin to be escalated 2-fold above previously tolerable doses; however, this effect did not translate in a significant increment in acivicin Css.
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PMID:A Phase I and pharmacological study of the glutamine antagonist acivicin with the amino acid solution aminosyn in patients with advanced solid malignancies. 982 40

Following intravenous inoculation with horse blood-infected with the agent of human granulocytic ehrlichiosis (HGE) from a human fatality, two rhesus macaques (Macaca mulatta) exhibited pyrexia and lethargy on days 4-12 postinfection (PI). Hematology revealed neutropenia, thrombocytopenia, and anemia, with ehrlichial morulae in monocytes and neutrophils on days 4-12. Blood was polymerase chain reaction (PCR)-positive on days 4-12 and bone marrow was PCR-positive on day 11. There was a minor increase in gamma-glutamyl transpeptidase on day 12 and serum interferon-gamma levels increased by day 18. Seroconversion occurred on day 20 PI to a titer of 100 by day 22. Western blot bands characteristic of HGE included 25-, 44-, 80-, 94-, 105-, and 125-kD bands. There was generalized lymphohistiocytic infiltration in the liver, spleen, lymph nodes, and other tissues. The liver had focal hepatocyte apoptosis. There was HGE DNA (by PCR) only in the spleen. Comparable findings were not observed in a monkey that received uninfected horse blood as a control. This animal model of human disease is important for further studies of HGE diagnosis, management, and pathogenesis.
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PMID:A simian model of human granulocytic ehrlichiosis. 1040 32

Advanced soft tissue sarcomas (ASTS) refractory to therapy with doxorubicin and/or ifosfamide are highly resistant to therapy with other cytotoxic agents. The efficacy and safety of raltitrexed ('Tomudex') was assessed in patients with ASTS refractory to one or two doxorubicin- and/or ifosfamide-containing regimens in eight centers of the EORTC STBSG group. Raltitrexed was given at 3 mg/m2 as a 15 min i.v. infusion once every 3 weeks. Among the 23 patients [mean age 54 (range 25-73) years] included, 22 patients (15 males and seven females) were eligible and evaluable for response to therapy and 21 were evaluable for toxicity. Patients had previously received chemotherapy in metastatic phase (n=16), as adjuvant treatment (n=5) or both (n=1). The primary tumor was located in the trunk (n=11), in the limbs (n=8) or in the head and neck (n=3). Most patients (n=13) received two courses of raltitrexed (range 1-8). The best response was stable disease in five (23%) patients, while disease progression was noted in 17 patients (77%); the median time to disease progression was 6 weeks. The treatment was well tolerated with only one patient experiencing grade 4 neutropenia and thrombocytopenia, one patient experiencing grade 3 nausea, one lethargy, one headache, and one asthenia. Only one patient experienced febrile neutropenia. Raltitrexed as monotherapy is not an effective treatment for patients with ASTS who failed conventional chemotherapy with doxorubicin and ifosfamide.
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PMID:Phase II study of raltitrexed ('Tomudex') for patients with advanced soft tissue sarcomas refractory to doxorubicin-containing regimens. 1063 Mar 54

Amiodarone is a class III antiarrhythmic drug used in dogs with dilated cardiomyopathy and ventricular tachyarrhythmias. Hepatopathy is one of the more commonly reported adverse effects of amiodarone use in people. We describe 4 dogs that developed hepatopathy associated with amiodarone administration; 2 dogs also developed neutropenia. Three dogs had clinical signs of anorexia and lethargy; 1 did not show signs until impaired liver function had developed. Clinical signs or biochemical abnormalities developed 1.5-8 months after amiodarone treatment was started. Clinical signs resolved within 2 weeks of discontinuing amiodarone, but biochemical abnormalities did not resolve for 6-8 weeks. The delay between onset of liver disease and overt clinical signs suggests that serial evaluation of liver enzyme activities following amiodarone use in does is important.
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PMID:Hepatopathy in 4 dogs treated with amiodarone. 1066 24

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.
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PMID:Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy. 1071 27

To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175-350 mg m(-2) followed by raltitrexed 2.6 mg m(-2). Level VI was irinotecan 350 mg m(-2) plus raltitrexed 3.0 mg m(-2), level VII was irinotecan 400 mg m(-2) plus raltitrexed 2.6 mg m(-2); 261 courses were administered. Only one patient at dose levels I-V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m(-2) and raltitrexed 3.0 mg m(-2).
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PMID:Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma. 1090 62

Balamuthia mandrillaris is a newly described pathogen that causes granulomatous amebic encephalitis, an extremely rare clinical entity that usually occurs in immunosuppressed individuals. We report a case of pathologically proven Balamuthia encephalitis with unusual laboratory and radiologic findings. A 52-year-old woman with idiopathic seizures and a 2-year history of chronic neutropenia of unknown cause had a subacute illness with progressive lethargy, headaches, and coma and died 3 months after the onset of symptoms. Cerebrospinal fluid (CSF) glucose concentrations were extremely low or unmeasurable, a feature not previously described (to our knowledge). Cranial magnetic resonance imaging scans showed a single large temporal lobe nodule, followed 6 weeks later by the appearance of 18 ring-enhancing lesions in the cerebral hemispheres that disappeared after treatment with antibiotics and high-dose corticosteroids. The initial brain biopsy specimen and analysis of CSF samples did not demonstate amebae, but a second biopsy specimen and the postmortem pathologic examination showed Balamuthia trophozoites surrounded by widespread granulomatous inflammation and vasculitis. The patient's neutropenia and antibiotic use may have caused susceptibility to this organism. Amebic meningoencephalitis should be considered in cases of subacute meningoencephalitis with greatly depressed CSF glucose concentrations and multiple nodular lesions on cerebral imaging. Arch Neurol. 2000;57:1210-1212
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PMID:A case of Balamuthia mandrillaris meningoencephalitis. 1092 4

The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.
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PMID:A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly. 1109 9


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