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Biomedical subjects

Edward A Neuwelt

Publications and source records attributed to Edward A Neuwelt.

28 records · Page 2Linked to original sources
PubMed2004

Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model.

Cisplatin (CDDP) is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for CDDP ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving CDDP. Long Evans rats were treated with CDDP 6 mg/kg delivered to the aorta via a retrograde right external carotid artery infusion, 15 min after intravenous (IV) infusion of saline (n=8) or NAC 400 mg/kg (n=8), such that the vertebral arteries were perfused. Subsequent groups were similarly treated with NAC 30 min before (n=7) and 4 h after (n=7) CDDP. Auditory brainstem response (ABR) thresholds were tested at 4-20 kHz, 7 days after treatment and compared to baseline ABR values. The NAC-treated rats exhibited no significant change from baseline values at all time intervals, while the saline-treated rats showed marked ototoxicity, especially at higher frequencies. Furthermore, the rats treated with NAC 15 min before CDDP exhibited less overall toxicity to CDDP, as evidenced in weight loss 7 days post-treatment (mean for saline=-39.63 g; mean for NAC=-21.13 g; p=0.0084). These data show that treatment with NAC can prevent CDDP-induced ototoxicity in rats.

Acetylcysteine↗
PubMed2004

Mechanisms of disease: the blood-brain barrier.

OBJECTIVE: The blood-brain barrier (BBB) is often perceived as a passive membrane. However, evidence has demonstrated that the BBB plays an active role in normal homeostasis and in certain disease processes. METHODS: Approximately 300 peer-reviewed publications that discussed normal or abnormal BBB function were reviewed. RESULTS: The role of the BBB and how it contributes to disorders of the central nervous system vary, depending on the specific disease process. CONCLUSION: In health and disease and extending to old age, endothelial cells, neurons, and glia constitute a neurovascular unit that regulates the BBB. Advances toward penetrating the BBB must account for both normal and abnormal functions of the neurovascular unit.

Blood-Brain Barrier↗
PubMed2003

Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002.

Under the sponsorship of the International Extranodal Lymphoma Study Group, a Multidisciplinary Workshop on primary CNS lymphoma (PCNSL) with over 50 participants from Europe, North America, Israel, and Australia was held as part of the Eighth International Conference on Malignant Lymphoma in Lugano, Switzerland (June 12 to 15, 2002). The main purposes of the Workshop were to exchange the latest scientific information, to analyze methodologic issues in the design of clinical trials, to reach a consensus on treatment recommendations and prognostic factors, to discuss clinical and molecular targets for future studies, and to establish an international collaborative group to conduct laboratory and clinical investigations in PCNSL. This article summarizes the contents of the Workshop, analyzes the current knowledge on the most relevant biologic and clinical issues in PCNSL, and focuses on fundamental challenges to be addressed in future studies.

Animals↗
PubMed2003

BR96-DOX immunoconjugate targeting of chemotherapy in brain tumor models.

An immunoconjugate of doxorubicin (adriamycin) and a tumor-specific monoclonal antibody, BR96-DOX (now SGN-15) targets chemotherapy to cells that express the LewisY antigen. This immunoconjugate is internalized into lysosomes in antigen-expressing cells, with release of free doxorubicin after hydrolysis of the acid-labile linker. We review our studies using BR96-DOX in a human small-cell lung carcinoma intracerebral xenograft model in nude rats. We have found that the immunoconjugate is effective against intracerebral tumors when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). Enhanced delivery of BR96-DOX with BBB opening can work together with radiotherapy to increase antitumor efficacy, which is maximally effective if immunoconjugate is administered prior to radiotherapy. In heterogeneous brain tumors, enhanced delivery of BR96-DOX significantly reduced tumor volumes, but local release of doxorubicin by targeting antigen expressing cells shows modest cytotoxicity against adjacent non-expressor cells. Although BR96-DOX is not effective against glioma cells tested, it does provide a model for drug-immunoconjugate therapy of gliomas. Our studies in a rat brain tumor model point out the importance of optimized delivery, antigenic heterogeneity, and bystander effect for brain tumor therapy. We review additional studies of drug-mAb immunoconjugates pertinent to the treatment of gliomas.

Animals↗
PubMed2002

Chemotherapeutic dose intensification for treatment of malignant brain tumors: recent developments and future directions.

Despite a large amount of research on malignant brain tumors over the past 70 years, the prognosis for most tumor types is poor. One current focus of research is increasing dose intensity of chemotherapeutic agents. Various ways to increase dose intensity include high-dose chemotherapy followed by stem cell rescue (eg, bone marrow transplant), blood-brain barrier disruption or use of RMP7 to increase transvascular drug delivery, local delivery of chemotherapeutic agents (convection enhancement or clysis, antibody conjugates, and biodegradable polymers), chemoprotective agents, and tumor sensitizers. Improved identification of patients likely to respond to a given regimen may also increase the effectiveness of chemotherapy. We also discuss approaches to improve the design of nonrandomized trials by identifying and controlling potential confounding variables. This will improve the quality of individual studies and perhaps the comparability across studies.

Antineoplastic Agents↗
PubMed2002

Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement.

PURPOSE: To evaluate the safety and efficacy of intravitreal methotrexate in the management of primary central nervous system lymphoma (PCNSL) involving the eye. DESIGN: Retrospective noncomparative interventional case series. PARTICIPANTS: Sixteen human immunodeficiency virus-negative white patients (5 males and 11 females, aged 30-76 years) with intraocular B cell lymphoma treated with intravitreal methotrexate at Oregon Health & Science University or Hadassah University Hospital between August 1995 and September 2000. INTERVENTION: Patients were treated with intravitreal methotrexate (400 micro g/0.1 ml) according to a standard induction-consolidation-maintenance regimen and monitored by serial examinations, including measurement of visual acuity, slit-lamp biomicroscopy, and dilated funduscopy. MAIN OUTCOME MEASURES: Clinical response to intravitreal chemotherapy, number of injections for clinical remission, visual acuity, complications during study period, length of survival from diagnosis, and cause of death. RESULTS: Time of follow-up from commencement of the methotrexate injections was 6 to 35 months (median, 18.5 months). Twenty-six of 26 eyes (100%) were cleared clinically of malignant cells after a maximum of 12 methotrexate injections. A second remission was induced in three patients, who were treated with a further course of intravitreal chemotherapy after their tumor recurred within the eye. Complications that occurred during the period of treatment and follow-up included cataract (73% of 26 eyes), corneal epitheliopathy (58% of 26 eyes), maculopathy (42% of 26 eyes), vitreous hemorrhage (8% of 26 eyes), optic atrophy (4% of 26 eyes), and sterile endophthalmitis (4% of 26 eyes). No patient had irreversible loss of vision that could be definitely attributed to the intravitreal injection of methotrexate. CONCLUSIONS: Intravitreal chemotherapy with methotrexate is effective in inducing clinical remission of intraocular tumor in PCNSL with acceptable morbidity. Further study is indicated to determine whether this approach extends life expectancy.

Adult↗
PubMed2002

Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001.

OBJECTIVES: To summarize the findings relevant to otolaryngology from the annual meeting of the Blood-Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001. STUDY DESIGN: Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included. RESULTS: Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity. CONCLUSIONS: The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.

Animals↗
PubMed2002

Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors.

BACKGROUND AND PURPOSE: Ultrasmall superparamagnetic iron oxide particles result in shortening of T1 and T2 relaxation time constants and can be used as MR contrast agents. We tested four hypotheses by evaluating MR images of intracranial tumors after infusion of two iron oxide agents in comparison with a gadolinium chelate: 1) Ferumoxtran in contrast to ferumoxides can be used as an intravenous MR contrast agent in intracranial tumors; 2) ferumoxtran enhancement, albeit delayed, is similar to gadolinium enhancement; 3) ferumoxtran-enhanced MR images in contrast to gadolinium-enhanced MR images may be compared with histologic specimens showing the cellular location of iron oxide particles; 4) ferumoxtran can serve as a model for viral vector delivery. METHODS: In 20 patients, ferumoxides and ferumoxtran were intravenously administered at recommended clinical doses. MR imaging was performed 30 minutes and 4 hours after ferumoxides infusion (n = 3), whereas ferumoxtran-enhanced MR imaging (n = 17) was performed 6 and 24 hours after infusion in the first five patients and 24 hours after infusion in the remaining 12. MR sequences were spin-echo (SE) T1-weighted, fast SE T2- and proton density-weighted, gradient-recalled-echo T2*-weighted, and, in four cases, echo-planar T2-weighted sequences. Representative regions of interest were chosen on pre- and postcontrast images to compare each sequence and signal intensity. RESULTS: Despite some degree of gadolinium enhancement in all tumors, no significant T1 or T2 signal intensity changes were seen after ferumoxides administration at either examination time. Fifteen of 17 patients given ferumoxtrans had T1 and/or T2 shortening consistent with iron penetration into tumor. Histologic examination revealed minimal iron staining of the tumor with strong staining at the periphery of the tumors. CONCLUSION: 1) Ferumoxtran can be used as an intravenous MR contrast agent in intracranial tumors, mostly malignant tumors. 2) Enhancement with ferumoxtran is comparable to but more variable than that with the gadolinium chelate. 3) Histologic examination showed a distribution of ferumoxtran particles similar to that on MR images, but at histology the cellular uptake was primarily by parenchymal cells at the tumor margin. 4) Ferumoxtran may be used as a model for viral vector delivery in malignant brain tumors.

Adult↗
PubMed2002

Targeted delivery in primary and metastatic brain tumors: summary report of the seventh annual meeting of the Blood-Brain Barrier Disruption Consortium.

The November 2000 NIH report of the Brain Tumor Progress Review Group identified delivering and targeting therapeutic agents as a priority in the treatment of malignant brain tumors. For this reason, the seventh annual Blood-Brain Barrier Disruption Consortium meeting, partially funded by an NIH R13 Grant, focused on recent advances in targeted delivery to the central nervous system, clinical trials for primary and metastatic brain tumors using enhanced chemotherapy delivery, and strategies to lessen the toxicities associated with dose intensive treatments, using thiols.

Antineoplastic Agents↗