Seizures induced by aminooxyacetic acid in mice: pharmacological characteristics

Systemic (s.c.) administration of aminooxyacetic acid (AOAA) in mice triggered clonic convulsions with a CD50 (convulsive dose) of 68 mg/kg (range 54-86). AOAA also induced clonic convulsions in mice subjected to intracerebroventricular administration of the drug with a CD50 of 0.04 mumols (range 0.028-0.06). At the onset of convulsions induced by systemic AOAA (CD97;150 mg/kg), the GAD activity in the frontal cortex and hippocampus was not affected. GABA mimetic drugs, progabide and gabaculine, had no effect on convulsions induced by AOAA. Convulsions induced by systemic administration of AOAA were blocked by diazepam, phenobarbital, and valproate. Ethosuximide, trimethadione, acetazolamide, diphenylhydantoin, and carbamazepine remained ineffective. L-Phenylisopropyladenosine was also found to protect mice against AOAA-induced convulsions, whereas atropine and baclofen had no effect. The seizures induced by intracerebroventricular administration of AOAA (CD97; 0.1 mumols) were blocked by coadministration of preferential N-methyl-D-aspartate antagonists, D-(-)-2-aminophosphonoheptanoic (AP7), 3-[+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic (CPP), and kynurenic acid (KYNA); preferential quisqualate/kainate antagonists, 6-cyano-7-nitro-quinoxaline-2,3-dione and gamma-D-glutamylaminomethylsulphonic acid, remained inactive in the range of dosages sufficient to block seizures induced by quisqualic acid or kainic acid. The antagonistic action of antiepileptic drugs effective against seizures induced by excitatory amino acids (diazepam and valproate), and drugs acting on excitatory amino acid receptors (AP7, CPP, and KYNA) upon seizures induced by AOAA suggests an involvement of excitatory neurotransmission in the convulsant action of the drug.     

Iotrol versus metrizamide in lumbar myelography: a double-blind study

In a prospective, randomized, double-blind study, 49 patients underwent lumbar myelography using iotrol (24 patients) or metrizamide (25 patients). The diagnostic imaging adequacy of iotrol was comparable with that of metrizamide. After iotrol myelography, adverse reactions were fewer, less severe, and of shorter duration than were those following metrizamide myelography. Thirteen of 24 patients (54%) receiving iotrol reported some adverse reactions compared with 24 of 25 patients (96%) receiving metrizamide. Five moderate and one severe adverse reaction occurred in the group receiving iotrol. Fourteen moderate and eight severe adverse reactions occurred in the group receiving metrizamide. Thirty-eight patients underwent electroencephalography both before and after myelography (19 iotrol and 19 metrizamide). None of the EEGs obtained after iotrol myelography changed from baseline, while seven of the EEGs obtained after metrizamide myelography showed changes from baseline. Iotrol was judged superior to metrizamide as a contrast medium in this patient population.     

A data adaptive reprojection technique for MR angiography.

Inability to detect vessel overlap and vascular loops can compromise the interpretation of magnetic resonance angiograms. A data-adaptive ray tracing (DART) technique was developed to produce the appropriate variations in signal intensity at points of vessel overlap in order to simulate the standard angiographic representation of vessels. In this technique a threshold is utilized to identify vessels in the image slices composing a 3D angiographic data set. A mask, which defines regions slightly larger than the vessel boundaries, is obtained by blurring the vessel information surviving the initial threshold. This mask is converted to binary form prior to multiplication by the original angiographic data set. Following application of an additional threshold to the masked data, line integrals through the regions defined by the mask are performed to obtain an angiographic signal proportional to the integrated vessel signal as in conventional angiography. This integrated reprojection is then uniquely combined with a maximum intensity pixel (MIP) reprojection to produce the final DART image. The application of the DART technique to 2D time-of-flight and 3D phase-contrast angiograms successfully enabled the identification of over-lapping vessels and vascular loops. DART was also found to produce less vessel narrowing than the MIP technique.     

Magnetic resonance imaging of rabbit brain after intracarotid injection of large multivesicular liposomes containing paramagnetic metals and DTPA

A procedure has been developed for the preparation of large (10- to 80-microns-diameter) multivesicular liposomes that contain magnetic resonance contrast agent (DTPA and either manganese or gadolinium). Blue dextran was observed to induce the formation of the large liposomes with dioleoylphosphatidylcholine and cholesterol (1:1 molar ratio) and with dipalmitoylphosphatidylcholine and cholesterol (1:1 molar ratio). The formation of the large liposomes is dependent upon mixing the blue dextran with the lipid films at temperatures above the transition point of the lipids. Tracer amounts of 153Gd were added to the aqueous phase to permit quantitation of the recovery of encapsulated materials. Liposomes that were prepared using equimolar ratios of phospholipid and cholesterol were stable in serum for more than 12 h. The ultrastructure of the large multivesicular liposomes reveals the existence of individual vesicles (greater than 2 micron diameter) bound together by a multilamellar coating. When injected into the internal carotid artery of the rabbit, the large liposomes became entrapped in the vascular bed primarily in the frontal and occipital regions of brain. The resulting emboli may provide a means to deliver drugs to a specific site in brain, such as a tumor, if the vascular bed of the site can be cannulated precisely.     

Influence of aminophylline and strychnine on the protective activity of excitatory amino acid antagonists against maximal electroshock-induced convulsions in mice

Summary Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene — a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED₅₀ values of aminophylline were 55.7 and 98.4mg/kg i.p. However, aminophylline (up to 100mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl-enedioxy-5H-2, 3-benzodiazepine (GYKI 52466 — a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock — the ED₅₀ values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28mg/kg s.c., respectively.An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.     

Muscle relaxant action of excitatory amino acid antagonists

Antagonists of neuronal excitation induced by dicarboxylic amino acids were tested in genetically spastic rats of the Han-Wistar strain. These animals exhibit an increased muscle tone which can be measured as a spontaneous tonic activity in the electromyogram of the gastrocnemius-soleus muscle. Compounds that block excitation due to N-methyl-D-aspartic acid reduced the spontaneous activity measured in the electromyogram in a dose-related manner. The most potent compounds, 2-amino-7-phosphonoheptanoic and kynurenic acids were effective muscle relaxants when given either intraperitoneally or intracerebroventricularly. 2-Amino-5-phosphonopentanoic acid possessed much weaker muscle relaxant activity, while L-glutamic acid diethylester was inactive by either route. The results suggest that blockade of N-methyl-D-aspartic acid receptors results in a myorelaxant effect. Specific antagonists of excitation at N-methyl-D-aspartic acid receptors may provide a new class of muscle relaxants.     

Chymopapain chemonucleolysis: correlation of diagnostic radiographic factors and clinical outcome

The therapeutic response to treatment of lumbar disk herniation with chymopapain chemonucleolysis is significantly influenced by the criteria used for patient selection. Although careful clinical selection of patients reduces the frequency of treatment failure, some patients do not achieve satisfactory relief of pain with chemonucleolysis. In an attempt to identify objective pretreatment radiographic findings that might refine selection criteria and further reduce the failure rate of chemonucleolysis, a retrospective correlation of pretreatment radiographs and clinical responses was made of 200 consecutive chemonucleolysis patients. Marked improvement in sciatica occurred in 79.9% and 79.3% of patients at early and late follow-up, respectively. There was a significantly higher response rate, however, in patients who had definite radiographic evidence of focal disk herniation and in those patients with definite radiographic evidence of nerve-root compression (marked nerve-root deviation, nerve-root flattening or edema, root-sleeve amputation) by disk material. Those patients with a preinjection disk height greater than the mean had a slightly better response rate (91.1%) than those whose disk height was smaller than the mean (80.0%). Most cases of treatment failure could be attributed to an incorrect radiographic diagnosis, treatment of patients with equivocal diagnostic studies, the presence of "free" disk fragments, and causes of nerve-root compression unresponsive to chymopapain.     

Role of muscarinic cholinergic mechanisms in the substantia nigra pars reticulata in mediating muscular rigidity in rats

Summary Bethanechol chloride (5–25 g), when injected into the substantia nigra pars reticulata (SNR) of rats, produced muscular rigidity in a dose-dependent way, and in addition, catalepsy and ipsilateral posture. The effects of bethanechol in the dose of 25 g were prevented by coadministration of 10 g scopolamine hydrochloride. Injections of 25 g betanechol or 10 g scopolamine into the reticulata only slightly affected the muscular rigiditiy produced by 15 mg/kg i.p. morphine hydrochloride. The results suggest that muscarinic cholinergic mechanisms in the substantia nigra pars reticulata, although effective by themselves, affect by expression of at least one striatal functional alteration, the muscular rigidity, in a less effective way than GABAergic or endogenous opioid mechanisms do.     

Pre-irradiation chemotherapy in children with high-grade astrocytoma: Tumor response to two cycles of the ‘8-drugs-in-1-day’ regimen

SummaryPurpose This study was undertaken to evaluate the radiographie response to two cycles of chemotherapy prior to irradiation in newly diagnosed children with high-grade astrocytomas.Patients and methods. One hundred and thirty children less than 21 years of age with newly-diagnosed highgrade astrocytoma were treated with the eight-drugs-in-one-day chemotherapy regimen as part of a phase III multi-institutional Childrens Cancer Group (CCG) trial. Computerized Tomographic (CT) or Magnetic Resonance Image (MRI) scans, obtained after two cycles of chemotherapy had been administered, were compared with post-operative scans to determine treatment response. Scans were evaluated by institutional radiologists, and were reviewed centrally by a single neuroradiologist.Results Of 79 patients with evaluable post-operative residual tumor on CT or MRI scans, 26 (33%) were determined on institutional evaluation to have had an objective response. However, central review of scans documented responses on only 14/79 (18%). A significantly higher response rate on central review was observed for those children 36 months of age or less at study entry than for older children (33% v 11%; p < 0.001). However, a higher disease progression rate was also observed for those children 36 months of age or less than for older children (21% v 2.6%; p < 0.001).Conclusion In this study, the largest yet reported in newly-diagnosed children with high-grade astrocytomas, the chemotherapy regimen has activity in younger children. The differences in response rates reported by institutional and central review highlight the difficulties inherent in assessing response to brain tumor therapy. However, the study does demonstrate the consistent ability of radiologists to identify disease progression within the institutional and central reviews.