Energy transduction: inhibition of cockroach feeding by naphthoquinone.

1,4-Naphthoquinones inhibit feeding of Periplaneta americana by complexing with sulfhydryl groups of receptor protein in sensory neurons, by oxidizing the sulfhydryl groups, and by being reduced.

A phase I study of SR-2508 and cyclophosphamide administered by intravenous injection.

SR-2508, a less lipophilic ane neurotoxic analogue of the nitroimidazole, misonidazole, has exhibited significant chemosensitization properties in preclinical studies with alkylating agents. A phase I trial was carried out to assess toxicity and possible pharmacological interactions of the combination of short infusions of SR-2508 and cyclophosphamide (CP). Patients were randomly assigned to receive either CP alone followed in 3 wk by CP + SR-2508, or CP + SR-2508 followed by CP alone. All additional courses were CP + SR-2508. The maximum tolerated dose of the combination was determined by dose escalation of SR-2508 while the dose of CP remained fixed, initially 1.0 g/m2, and then a second maximum tolerated dose was determined with CP at 1.6 g/m2. One hundred seventeen evaluated courses were administered to 39 patients, the majority of whom had received prior treatment. Somewhat unexpectedly, reversible grade 4 granulocytopenia was the dose-limiting toxicity occurring in four of five evaluable first combination courses at level 6 (SR-2508, 11.3 g/m2; CP, 1.0 g/m2), the initial maximum tolerated dose. SR-2508 enhanced CP-induced myelosuppression as exhibited by the significant difference (p less than 0.001) between the 27 paired courses (CP versus CP + SR-2508) for WBC nadirs over levels 1 to 6. The neurotoxicity encountered was similar to that seen in past clinical trials, being reversible, mild, and usually peripheral in nature. There was one treatment-related death (neutropenic sepsis) on study. No other significant toxicity was seen. SR-2508 exhibited linear pharmacokinetics over the dose range studied. The SR-2508 area under the concentration-time curve increased linearly with dose (r = 0.858; p less than 0.001). No other parameters were dose related. Neither drug appeared to affect the pharmacokinetics of the other, and CP pharmacokinetic values were consistent with those from prior studies. Due to the interaction noted between the two agents and the preclinical data suggesting preferential enhancement of antitumor efficacy under this combination, phase II study appears warranted.

Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.

PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Glucose uptake by gliomas after treatment. A positron emission tomographic study.

Positron emission tomographic scanning with fludeoxyglucose F 18 (18F-fluorodeoxyglucose) was used to study acute changes in gliomas after chemotherapy. In six experimental subjects, scans were obtained before and at days 1, 7, and 30 after treatment. Five control patients with gliomas who did not undergo chemotherapy had two scans, 1 month apart. Ratios were calculated between peak tumor regional cerebral metabolic rate for glucose and contralateral white matter. The percent change in ratios relative to each patient's baseline scan was calculated. Ratios in three stable controls remained unchanged over the study interval; in two controls it increased 155% and 36% and both died of tumor progression. In experimental subjects, ratios increased 20% to 100% 24 hours after chemotherapy and then decreased until at 28 days they varied between 22% above and 35% below baseline. The increased fludeoxyglucose F 18 uptake at 24 hours could be from uncoupling oxidative phosphorylation or shunting glucose to ribose phosphates for salvage nucleoside synthesis.

Defining the role of radiosurgery in the management of brain metastases.

The role of stereotactic radiosurgery in the management of recurrent and newly diagnosed brain metastases was evaluated prospectively. From December 1988 to March 1991, 58 lesions in 40 patients were treated with accelerator-based stereotactic radiosurgery. All patients were followed for a minimum of 6 months or to death. The primary purpose was to determine the impact of radiosurgery on local control and its subsequent effects on quality of life. An overall tumor control rate of 82% with a complete response rate of 43% were achieved. As anticipated, the response rate for smaller tumors was substantially better than that for larger tumors (78% for lesions < 2 cm3; 50% for lesions > or = 10 cm3). Although the overall in-field progression rate was 18.5%, only 1/23 (4%) complete responders subsequently recurred. The in-field failure rate is highly comparable with recently published surgical data. Progression outside the brain was noted in two-thirds of patients. One quarter of the deaths were neurologic. The median survival for this minimally selected patient population was 6.5 months. Stereotactic radiosurgery was also associated with improved quality of life as measured by Karnofsky score, neurologic function, and steroid dependence. Long-term steroid dependence was encountered in only four patients. We conclude that stereotactic radiosurgery can be used effectively in patients with brain metastases. In this series, a high tumor response rate was achieved which was associated with improved quality of life.

Stereotactic radiosurgery for glioblastoma multiforme: report of a prospective study evaluating prognostic factors and analyzing long-term survival advantage.

PURPOSE: Prospective evaluation of the toxicity and efficacy of radiosurgery with external beam radiotherapy in the management of newly diagnosed glioblastoma. METHODS AND MATERIALS: From 5/89 to 12/92, 31 out of 51 patients with glioblastoma multiforme underwent radiosurgery, in addition to 54 Gy in 1.8 Gy/fraction following biopsy (n = 12) or resection (n = 19). Eligibility required supratentorial glioblastoma, tumor not > 4 cm in > 1 axis, age > 18 years, and location > 1 cm from optic chiasm. Patient characteristics were: age 20-78 years (median = 57); 22 male, 9 female; Karnofsky score 20-90 (m = 70), and volume of 2.3-59.7 c.c. (m = 17.4). Eighteen patients were treated with 1 collimator, 5 with 2, 7 with 3, and 1 with 4; peripheral isodoses were 40-90% (m = 72.5) and minimum and maximum tumor dose ranges were 10-20 (m = 12) and 15-35 Gy (m = 18.75). Patients were followed clinically and radiographically every 8-12 weeks to analyze survival, quality of life, and toxicity. RESULTS: With a follow-up of 12-171 weeks, 8 out of 31 (26%) patients are alive. Median survival is 42 weeks. Twelve and 24-month actuarial survival are 38 and 28%. Comparison of the 2-year survival with previous Radiation Therapy Oncology Group patients was carried out using a nonparametric recursive partitioning technique and the observed vs. expected values are 28 vs. 9.7% (p < 0.05). Extent of resection and performance status were associated with improved survival in a multivariate analysis. No significant acute toxicity was encountered. Four patients (13%) developed clinically significant necrosis verified by biopsy or positron emission tomography scan at 9-59 weeks after radiosurgery. CONCLUSION: The improvement in median survival in broadly selected glioblastoma patients treated with radiosurgery is difficult to determine, but the 2-year survival may be superior. Future randomized trials of radiosurgery are recommended, and ad hoc use of this modality should be discouraged.

Early changes in tumor metabolism after treatment: the effects of stereotactic radiotherapy.

Four patients with intracranial neoplasms, two with malignant gliomas and two with brain metastases, were treated with stereotactic radiotherapy. Patients received between 15 and 27.5 Gray of photon irradiation to the central tumor target point; the 80% isodose line covered the periphery of the tumor as determined by contrast enhanced computed tomography. Patients underwent a sequence of three Positron Emission Tomographic scans using [18F]-fluorodeoxyglucose (PET-FDG)--a baseline scan the day before treatment, and follow-up scans 1 and 7 days after treatment. Ratios between the maximal tumor regional cerebral metabolic rate for glucose (rCMRGlu) (T*) and the contralateral remote white matter rCMRGlu (RW), that is, the glucose uptake ratio (T*/RW), were calculated. The percent change in ratios relative to each patient's baseline scan were calculated. Ratios increased 25% to 42% 1 day post-radiotherapy, then decreased to between 10% above and 12% below the baseline value 7 days post-radiotherapy. The T*/RW increased acutely after stereotactic radiotherapy in a fashion similar to that previously described following chemotherapy with a complex multi-drug regimen. A common metabolic pathway may underlie the increase in T*/RW after these different treatments.

Comparative patch clamp studies on the kinetics and selectivity of glutamate receptor antagonism by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 1-(4-amino-phenyl)-4-methyl-7,8-methyl-endioxyl-5H-2,3-benzodiaze pine (GYKI 52466).

The glutamate antagonistic effects of NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline] and GYKI 52466 [1-(4-amino-phenyl)-4-methyl-7,8-methyl-endioxyl-5H-2,3-benzodiaze pine] were compared on inward current responses of cultured superior collicular and hippocampal neurones with the whole cell patch clamp technique. Both NBQX (8 microM) and GYKI 52466 (33 microM) selectively reduced responses to AMPA [(S)-alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid, 50 microM] and kainate (50 microM) whilst having little effect on responses to NMDA (N-methyl-D-aspartate, 100 microM). The effects of the two antagonists on the kinetics of AMPA (50 microM) responses were, however, very different--NBQX dramatically slowed the rise time of responses so that peak currents (IC50 60.4 +/- 4.2 nM) were markedly more effected than desensitized plateau currents (IC50 706 +/- 99 nM) whereas GYKI 52466 antagonized plateau responses (IC50 4.44 +/- 0.21 microM) somewhat more than peak responses (IC50 6.87 +/- 0.46 microM) and had only marginal effects on kinetics. In fact, low concentrations of NBQX (50-250 nM) actually potentiated plateau AMPA responses--an effect likely to be due to a reduction in the degree of AMPA-induced desensitization. Similar effects on response kinetics, were seen with kainate such that the IC50s for NBQX in antagonizing initial and plateau components of current responses to kainate 400 microM were 18.1 +/- 2.9 nM and 298 +/- 27 nM respectively whereas the IC50s for GYKI 52466 against kainate 50 microM were 17.3 +/- 1.8 microM and 15.5 +/- 3.3 microM respectively. These differences are likely to be due to the different modes of action of the two antagonists--NBQX shifted kainate concentration responses curves to the right in a parallel fashion indicative of competitive antagonism whereas the effects of GYKI 52466 were largely noncompetitive. There was, however, some indication for a small allosteric influence of GYKI 52466 on the affinity of the glutamate recognition site of the AMPA/kainate receptor. Estimation of Kbs using the Cheng-Prussoff relationship revealed little difference in the affinity of NBQX in antagonizing plateau responses to AMPA (Kb 23.2 nM) and kainate (Kb 57.1 nM) and indicate that the effects of these two agonists are mediated at a common receptor under the experimental conditions used. Moreover, the differential effects of NBQX on peak and plateau components of AMPA (50 microM) responses was associated with a desensitization-induced, paradoxical increase in the agonist affinity and was probably not due to any change in the affinity of NBQX.(ABSTRACT TRUNCATED AT 400 WORDS)

Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan).

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-D-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2-33 microM) concentration-dependently antagonized responses to NMDA 100 microM with an IC50 of 2.92 +/- 0.05 microM. In contrast, current responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA 50-100 microM) and gamma-amino butyric acid (GABA 10 microM) were unaffected by Memantine 8 microM. Memantine 8 microM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1-100 microM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1-100 microM) also selectively antagonized responses to NMDA (40 microM) in the cortical wedge preparation with IC50 of 12.9 +/- 1.5 microM.

Neuropeptide degradation by large vessel and microvessel-derived endothelial cells in vitro: cell surface catabolism of thyrotropin releasing hormone (TRH).

Cell surface ectopeptidase activity of purified, cultured large vessel and microvessel-derived endothelial cells (EC) was studied. Degradation of thyrotropin releasing hormone (TRH), and production of cyclo-His-Pro was significantly increased (P less than 0.001) in large vessel EC compared with microcapillary EC. Since the rate of catabolism in the microvascular capillary bed is 5 times less than that in the large vessel wall, peptide concentrations are likely maintained longer in close proximity to their site of biosynthesis, where they are presumably most active.

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) of brain tumors.

In summary, PET and SPECT are versatile imaging modalities capable of providing dynamic information regarding the metabolism and physiology of brain and brain tumor. PET and SPECT are useful adjuncts to MRI and CT scanning in the important clinical areas of presurgical estimations of tumor grade. In addition, PET can be used to differentiate tumor necrosis from recurrence noninvasively, which is important for patient management. PET also may prove useful in early assessments of metabolic and physiologic changes in brain tumors following treatment and in monitoring drug delivery to tumor. Studies of drug delivery to and metabolic and physiologic responses of brain and brain tumor to treatment provide a quantitative handle on tumor response and patient prognosis. The ability to acquire such quantitative data may lead in the future to more efficient brain tumor treatment algorithms and to the development of more effective treatment protocols.

Rasmussen encephalitis: epilepsia partialis continua secondary to chronic encephalitis.

Rasmussen encephalitis is a disease consisting of chronic encephalitis with progressive neurologic deficits and focal intractable seizure activity. The etiology is unknown, but pathologic specimens revealed changes consistent with viral encephalitis. Even though neuro-imaging techniques, such as positron emission tomography and magnetic resonance imaging, offer the prospect of specific, presurgical diagnostic criteria, the initial diagnosis usually is made on a clinical basis. Treatment modalities, including a wide variety of antiepileptic drug therapies and surgical interventions, may result in significant physical and mental impairments. We summarize the clinical presentation, diagnostic considerations, and different treatment protocols in a patient with this rare and debilitating disorder.

Blood flow asymmetry in carotid occlusive disease.

Patterns of anterior border zone (ABZ) and middle cerebral artery (MCA) cerebral blood flow (CBF) asymmetry were readily seen during both normocapnic room air (RA) and induced hypercapnic (CO2) inhalation using fluoro-methane and a multislice, high-resolution positron scanner. Wilcoxon two-sample rank testing showed symptomatic-over-nonsymptomatic CBF ratios for unilateral greater than 75% carotid stenosis patients (n = 8) to be 1.05 +/- 0.07 (p less than 0.008 as compared with control of 0.97 +/- 0.02) ABZ RA, 0.98 +/- 0.11 ABZ Co2, 0.98 +/- 0.04 MCA RA, and 0.98 +/- 0.06 MCA CO2. Unilateral carotid occlusion patients (n = 8) had ratios of 0.90 +/- 0.16 ABZ RA, 0.81 +/- 0.19 (p less than 0.002) ABZ CO2, 0.90 +/- 0.12 and 0.89 +/- 0.13 for MCA RA and CO2, respectively (both p less than 0.008 as compared with control 0.99). These preliminary results suggest an upgrade of autoregulation (ie, very high ratio) in the ABZ of high-grade stenosis patients during normocapnia. CBF was preferentially higher on the symptomatic side and then either did not increase or paradoxically fell in response to hypercapnia. In comparison, carotid occlusion patients had low ABZ and MCA ratios during normocapnia, also unable to increase with hypercapnia. The fall in ratios from normocapnia to hypercapnia indicates that these areas, already subject to maximal vasodilation, fail to increase CBF or actually become hypoperfused following induced hypercapnia. These results aid in understanding the concept of "hemodynamic significance."

Tumors of the spine and spinal cord.

OBJECTIVES: To provide an overview of spinal cord neoplasms with a focus on location, histology, pathophysiology, diagnosis, treatment and nursing assessment and management. DATA SOURCES: Published books and peer-reviewed articles. CONCLUSIONS: Tumors of the spine and spinal cord are rare, and they can have grave implications for the patient. The key in the management of spinal cord tumors is their timely diagnosis and treatment to preserve function. IMPLICATIONS FOR NURSING PRACTICE: A thorough nursing assessment and timely intervention can have a positive impact on the outcome of patients with tumors of the spine and spinal cord.

Changes in glucose uptake by malignant gliomas: preliminary study of prognostic significance.

Sequential positron emission tomographic scans with [18F]-2-fluorodeoxyglucose (PET-FDG) were performed on 14 patients with malignant gliomas. All patients had prior brain irradiation. Five patients received adjuvant eight-drugs-in-one-day chemotherapy (experimental subjects) and 9 did not (control subjects). Ratios between the maximal tumor regional cerebral metabolic rate for glucose (rCMRGlu) and the contralateral white matter rCMRGlu, the glucose uptake ratio, were determined. Percent changes in the ratio 1 day after chemotherapy in experimental subjects, and 30 days after the baseline scan in controls, were of prognostic significance. In both groups, patients with the largest percent changes in rCMRGlu had the shortest survival. In contrast, the baseline glucose uptake ratio did not predict length of survival.

Cultured brain endothelium inhibits the cytocidal action of natural killer cells on glioma.

The killing of GL26 and YAC-1 cells by natural killer cells (NKC) is reduced in the presence of a monolayer of endothelial cells. This reduction in cytotoxicity correlates with the degree of adhesion between the tumor cells and the endothelial monolayers. The cytotoxicity of NKC toward glioma was 10% when carried out on plastic, but a monolayer of endothelium derived from brain inhibited the cytotoxicity by about 90%. Endothelium from thoracic duct and lung also inhibited cytotoxicity by about 90%, endothelium from aorta inhibited by 55% and that from ovary by only 45%. Cytotoxicity of NKC toward YAC-1 (a control NK target) was 40% on plastic, but a monolayer of endothelium from thoracic duct inhibited the cytotoxicity by 75%. Endothelium from brain and lung inhibited cytotoxicity by about 60%, aorta by 50%, and ovary by 40%. Interactions between tumor cells and the host-organ microvascular endothelium appear to protect neoplastic cells from natural surveillance mechanisms and may play a role in the formation of metastatic tumor deposits.