Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan appears to be relatively unaffected by the most common multidrug resistance mechanisms, may potentiate cytotoxicity of alkylators, has good penetration into the central nervous system, is active against a variety of neoplasms, and has myelosuppression as its paramount toxicity. We present our experience with a myeloablative regimen that includes topotecan. Twenty-one patients with poor-prognosis tumors and intact function of key organs received topotecan 2 mg/m2 by 30-min intravenous (i.v.) infusion on days -8, -7, -6, -5, -4; thiotepa 300 mg/m2 by 3 h i.v. infusion on days -8, -7, -6; and carboplatin by 4 h i.v. infusion on days -5, -4, -3 with a daily dose derived from the pediatric Calvert formula, using a targeted area under the curve of seven mg/ml* min ( approximately 500 mg/m2/day). Stem cell rescue was on day 0. The patients were 1 to 29 (median 4) years old; 18 were in complete remission (CR) and three in partial remission (PR). Early toxicities were severe mucositis and erythema with superficial peeling in all patients and a seizure, hypertension, and renal insufficiency followed by veno-occlusive disease in one patient each. Post-transplant treatment included radiotherapy alone (four patients) or plus biological agents (11 patients with neuroblastoma). With a follow-up of 6+ to 32+ (median 11+) months, event-free survivors include 10/11 neuroblastoma patients (first CR), 4/5 brain tumor patients (second PR or CR), 1/3 patients with metastatic Ewing's sarcoma (first or second CR), and a patient transplanted for multiply recurrent immature ovarian teratoma; a patient with desmoplastic small round-cell tumor (second PR) had progressive disease at 8 months. Favorable results for disease control, manageable toxicity, and the antitumor profiles of topotecan, thiotepa, and carboplatin, support use of this three-drug regimen in the treatment of neuroblastoma and brain tumors; applicability to other tumors is still uncertain.
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PMID:Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. 1160 67

The asymmetrical breakdown of the blood-brain barrier (BBB) was studied in female rats. Paw preference was assessed by a food reaching test. Adrenaline-induced hypertension was used to destroy the BBB, which was evaluated using triphenyltetrazolium (TTC) staining of the brain slices just after giving adrenaline for 30 s. In normal rats, the whole brain sections exhibited complete staining with TTC. After adrenaline infusion for 30 s, there were large unstained areas in the left brain in right-pawed animals, and vice versa in left-pawed animals. Similar results were obtained in seizure-induced breakdown of BBB. These results were explained by an asymmetric cerebral blood flow depending upon the paw preference in rats. It was suggested that this new method and the results are consistent with contralateral motor control that may be important in determining the dominant cerebral hemisphere in animals.
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PMID:Blood brain barrier in right- and left-pawed female rats assessed by a new staining method. 1248 93

Although the standard of care for patients with glioblastoma multiforme (GM) remains postoperative radiotherapy (RT) in combination with chemotherapy (CT), the optimal regimen awaits verification. A phase I study was performed to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of topotecan (Hycamptin), given concurrently with RT, in patients with previously untreated glioblastoma multiforme (GM) of the brain. Thirty-six patients with histologically confirmed GM were enrolled. After surgery or stereotactic biopsy, patients received conventional external cranial RT (59.4 Gy/33 fractions in 6.6 weeks). Two cycles of topotecan were administered at days 1 and 4 of each week. Each cycle consisted of 30-min intravenous infusion 30-60 min before RT. The dose of topotecan was escalated in three dose increments from 1.0 to 1.25 and 1.5 mg/m(2) on a twice a week schedule among different patient groups. Three dose levels of topotecan were tested. Ten patients accrued to level 1 (topotecan dose 1 mg/m(2)/day, twice a week). No grade 4 toxicities were seen. Grade 2/3 hematologic toxicity was observed in 4 patients. Of the 11 patients included at level 2 (topotecan dose 1.25 mg/m(2)/day twice a week), 3 presented with grade 3 leucopenia and 2 with grade 3 thrombocytopenia. Of the 15 patients accrued to level 3 (topotecan dose 1.5 mg/m(2), twice a week), six had episodes of grade 4 leucopenia and two developed grade 4 thrombocytopenia. No other serious, early non-hematologic or late toxicities were seen at 21 months median follow-up time (range 6-36 months). From the cases included at level 2 and 3, five patients experienced episodes of grade 2/3 asthenia (13.8%), headache 9 (25%), confusion 5 (13.8%), seizure 4 (11%), and cutaneous erythema 3 (8.3%). The DLTs of topotecan given concurrently with RT were mainly hematological and the MTD was determined at the 1.25 mg/m(2)/day, twice a week dose level. A phase II chemoradiation study using the above recommended MTD dose of topotecan is ongoing, to establish the response rates, the local failures and the median survival of the above patients.
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PMID:Phase I study of weekly topotecan combined to concurrent external cranial irradiation in adults with glioblastoma multiforme of the brain. 1820 94

One major aim in quantitative and translational neuroscience is to achieve a precise and fast neuronal counting method to work on high throughput scale to obtain reliable results. Here, we tested the isotropic fractionator (IF) method for evaluating neuronal and non-neuronal cell loss in different models of central nervous system (CNS) pathologies. Sprague-Dawley rats underwent: (i) ischemic brain damage; (ii) intraperitoneal injection with kainic acid (KA) to induce epileptic seizures; and (iii) monolateral striatal injection with quinolinic acid (QA) mimicking human Huntington's disease. All specimens were processed for IF method and cell loss assessed. Hippocampus from KA-treated rats and striatum from QA-treated rats were carefully dissected using a dissection microscope and a rat brain matrix. Ischemic rat brains slices were first processed for TTC staining and then for IF. In the ischemic group the cell loss corresponded to the neuronal loss suggesting that hypoxia primarily affects neurons. Combining IF with TTC staining we could correlate the volume of lesion to the neuronal loss; by IF, we could assess that neuronal loss also occurs contralaterally to the ischemic side. In the epileptic group we observed a reduction of neuronal cells in treated rats, but also evaluated the changes in the number of non-neuronal cells in response to the hippocampal damage. In the QA model, there was a robust reduction of neuronal cells on ipsilateral striatum. This neuronal cell loss was not related to a drastic change in the total number of cells, being overcome by the increase in non-neuronal cells, thus suggesting that excitotoxic damage in the striatum strongly activates inflammation and glial proliferation. We concluded that the IF method could represent a simple and reliable quantitative technique to evaluate the effects of experimental lesions mimicking human diseases, and to consider the neuroprotective/anti-inflammatory effects of different treatments in the whole brain and also in discrete regions of interest, with the potential to investigate non-neuronal alterations. Moreover, IF could be used in addition or in substitution to classical stereological techniques or TTC staining used so far, since it is fast, precise and easily combined with complex molecular analysis.
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PMID:The Isotropic Fractionator as a Tool for Quantitative Analysis in Central Nervous System Diseases. 2754 77