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

A concern for the possible role of the blood-brain barrier (BBB) in the epilepsies was based on ultrastructural studies that demonstrated increased micropinocytosis in cerebral capillaries during seizures. Continued interest in the structure of the BBB has led to the demonstration that, in human psychomotor epilepsy, there is a thickening of the capillary basement membrane. These studies also suggest that an increase in capillary mitochondria and interendothelial tight junctions may characterize seizure-traumatized brain regions. These studies forecast an increased interest and understanding of the ultrastructural events associated with capillaries in seizure states. Additional focus on the BBB comes from the clinical use of anticonvulsant drug levels in the control and treatment of seizures. Debate as to whether free drug levels are appropriate continues. The brain capillary is the interface between blood-borne drug and the target site, and thus an increased understanding of the events associated with brain-plasma exchange has been sought. The concept that only that fraction of drug that is freely dialyzable is available for equilibration across the BBB is not supported by recent studies, which demonstrate that protein-bound ligands are able to dissociate and gain access to the brain in the course of a single capillary transit. It has been established that albumin-bound fatty acids, steroids, and anticonvulsant drugs more readily distribute into tissues than previously believed. Thus, traditional free drug hypotheses need to be expanded to account for the fact that dissociation constants measured in vitro are not the same as those measured in vivo. The BBB also regulates nutrient availability to the brain, and under normal conditions excess substrate is made available to the brain for metabolism. Indirect evidence is available to suggest that during seizures, BBB transport may indeed be the rate-limiting step. Specifically, glucose availability to the seizing brain may be restricted to such a degree that brain glucose utilization rates are no longer independent of plasma glucose levels. If it can be proven that BBB transport is the rate-limiting step during seizures, then it would be possible to augment brain glucose utilization rates by increasing plasma glucose levels. In addition, a depression of brain glucose utilization could be achieved by inducing hypoglycemia. It is not fully understood whether BBB rate limitation would persist postically, nor is it known whether BBB alterations may be global or restricted to the seizure focus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epilepsy and the blood-brain barrier. 308 37

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as 10x the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracisternal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracisternal inoculation of a cephalosporin resistant strain of E. cloacae. Untreated rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurotoxicity of beta-lactam antibiotics. Experimental kinetic and neurophysiological studies. 324 57

In the course of a large prospective study aimed at evaluating the efficacy of Valproic Acid (VPA) in persons with intractable seizures, six patients that were on a steady dose of diphenylhydantoin (DPH) were exposed to different steady doses of VPA. The changes observed in the serum levels of total, free, and percentage of free DPH are reported here. There were no consistent changes in the serum levels of total DPH, but when serum levels of DPH, obtained before VPA was added to the therapeutic plan, were considered, it was found that the total DPH decreased in those patients with the higher baseline levels while it increased in those with the lower baseline levels. There also was an increase in the absolute total and the percentage of free DPH in most instances. The data suggested that the changes occurred soon after VPA was added and remained constant in the same patient as long as the total dose of VPA did not change. The data also suggested that VPA most probably interfered through a dual mechanism, displacement of albumin-fixed DPH, and decreased liver clearance of DPH. The interpersonal variability was such that only broad generalizations are possible. There is a need to measure free DPH in patients on VPA.
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PMID:Effect of different doses of valproic acid on the serum levels of total and free diphenylhydantoin. 392 46

The inability of most chemotherapeutic agents to adequately penetrate the blood-brain barrier (BBB), in either normal brain or tumor-infiltrated brain, is a major factor limiting the use of chemotherapy in central nervous system malignancy. This barrier, however, can be opened in a reversible manner by the intra-arterial administration of hyperosmotic agents such as mannitol. It has been suggested that the intravenous administration of dimethyl sulfoxide (DMSO) or 5-fluorouracil (5-FU) can accomplish the same thing in a less invasive manner. We have not been able to confirm these findings. DMSO was administered to 25 rats intravenously at concentrations ranging from 25 to 90% or into the internal carotid artery at a concentration of 30%. The penetration of methotrexate, Evans blue-albumin, and hexosaminidase A was then evaluated at intervals ranging from 1.5 to 3.5 hours after administration. Significant barrier opening was not observed in animals receiving intravenous DMSO. Barrier modification, albeit generally modest, was obtained in animals receiving intracarotid DMSO, but this may have been the result of grand mal seizures, inasmuch as 5 of 6 of these animals had such seizures. Several of the animals receiving i.v. DMSO also had seizures, and all animals developed varying degrees of hematuria. Similarly, 5-FU was administered at a dose of 30 mg/kg i.v. and the permeability of the BBB to either Evans blue-albumin or methotrexate was evaluated. No increased permeability of the BBB to these two markers was observed. In summary, osmotic BBB opening in our hands remains the most consistent and reliable means available to open the BBB in a reversible fashion. Neither intravenous DMSO nor 5-FU seems to increase the delivery of chemotherapy or protein tracer to the central nervous system, and the use of DMSO can result in seizures and hematuria.
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PMID:Inability of dimethyl sulfoxide and 5-fluorouracil to open the blood-brain barrier. 621 98

Edema formation and blood-brain barrier permeability was studied in animals with epileptic seizures induced by subcutaneous injection of kainic acid. Brain edema was most pronounced between 3 and 24 h after kainic acid injection. It was reflected by massive swelling of perineuronal and perivascular astroglia. Three hours after kainic acid perivascular astroglia swelling resulted in disturbance of local microcirculation in the affected brain areas. In addition, compression of drainage veins by the edematous brain induced focal perivenous hemorrhages similar to herniation damage in human brain edema. Tracer studies with sodium fluorescein, Evans blue, albumin and horseradish peroxidase revealed only a mild increase in the permeability of cerebral vessels, topographically unrelated to areas of brain edema. This finding indicates the presence of cytotoxic brain edema in kainic acid-induced epileptic brain damage. Treatment of brain edema with dexamethasone did not influence the incidence and severity of kainic acid-induced epileptic brain damage. However, in 54% of animals injected with kainic acid, lesions were completely prevented by treatment of brain edema with mannitol. The present results indicate that brain edema plays an important role in the pathogenesis of epileptic brain damage following systemic kainic acid intoxication. It is suggested that in this model of limbic epilepsy the brain edema is due to the massive ionic imbalance elicited in the affected brain regions by the kainic acid-induced persistent neuronal excitation.
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PMID:The role of brain edema in epileptic brain damage induced by systemic kainic acid injection. 652 75

The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines.
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PMID:The protective influence of the locus ceruleus on the blood-brain barrier. 674 91

Paired serum and cerebrospinal fluid specimens from 19 patients with SLE and central nervous system dysfunction were studied with respect to cerebrospinal fluid IgG index (a measure of intrathecal IgG synthesis), isoelectric focusing using immunoperoxidase staining techniques to detect oligoclonal IgG, and determination of the cerebrospinal fluid/serum albumin quotient (Q albumin) as a measure of blood-brain barrier integrity. Twenty-five patients without neurologic disease and 70 patients with a variety of non-SLE neurologic disorders were also studied for comparison. Of most interest was the observation that 42 percent of the patients with SLE had cerebrospinal fluid oligoclonal IgG, usually in association with elevation of the cerebrospinal fluid IgG index. In addition, two of the cerebrospinal fluid specimens that exhibited oligoclonal IgG also had increased titers of alpha-interferon. Q albumin was normal (under 9.0) in 12 of 13 patients with SLE, who had seizure, psychosis, or cranial neuropathy as principal central nervous system manifestations (mean +/- SD = 5.3 +/- 2.4), but was significantly elevated (mean +/- SD = 27.4 +/- 18.8, p less than 0.001) in five of six patients with diffuse, major central nervous system injury, for example, encephalopathy with coma, transverse myelopathy, paraparesis. Blood-brain barrier impairment was not correlated either with presence of circulating immune complexes or with other clinical or serologic evidence for extra-central nervous system disease activity. Taken together, the data suggest that, within the limitations of the techniques used, impairment of the blood-brain barrier in SLE may be secondary to the central nervous system lesion, rather than a result of systemic immune complex injury. In addition, substantial evidence is provided for an ongoing humoral immune response within the central nervous system in this disorder, which, in certain patients, may be associated with the production of intrathecal alpha-interferon.
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PMID:Intrathecal IgG synthesis and blood-brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. 683 7

The pathophysiology of postictal pulmonary edema was investigated by inducing seizures with bicuculline in nine paralyzed, halothane-anesthetized sheep and measuring of pulmonary lymphatic flow, pulmonary arterial and left atrial pressures, and lymph and plasma albumin concentration. Pulmonary microvascular pressure and transcapillary albumin conductance were calculated. Seizures transiently (less than 15 min) elevated microvascular pressure in all animals; lymph flow increased greater than twofold in response to the increased hydrostatic driving force. However, the elevation in lymph flow, with a stable lymph-to-plasma protein ratio and doubled transcapillary albumin conductance, persisted for the duration of the experiment, more than 3 h after microvascular pressure returned to base line. These changes were neurally mediated because they were blocked by cervical spinal cord transection in four additional animals.
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PMID:Elevated pulmonary lymph flow and protein content during status epilepticus in sheep. 706 Dec 83

Young female guinea pigs were fed various doses of penitrem A very 3 days for 3 weeks. Guinea pigs fed penitrem A had muscle tremors, seizures, and ataxia, and total weight gains were less than those of control guinea pigs. Histologic examination of multiple tissues and electron microscopic examination of liver and kidney revealed no differences between guinea pigs fed penitrem A and controls. Sera harvested at necropsy from guinea pigs fed penitrem A and control guinea pigs did not differ significantly in mean values of two liver enzymes (ornithine carbamoyltransferase and sorbitol dehydrogenase), complement, total protein, and differential proteins (albumin; alpha 1, alpha 2, beta, and gamma globulins). Results of this study indicate that penitrem A causes only central nervous system dysfunction; evidence of cytotoxicity for extraneural tissues was not found.
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PMID:Experimental intoxication of guinea pigs with multiple doses of the mycotoxin, penitrem A. 721 13

The relationship between serum concentrations and cerebrospinal fluid (CSF) concentrations of cefazolin, and the association between these concentrations and neurotoxic reactions, were investigated. Samples of serum and spinal fluid were drawn simultaneously from six patients at the steady state on various dosages of cefazolin sodium for different conditions. The dose, dosing interval, number of doses, results of renal function tests, and signs of neurotoxicity, such as muscle twitches, confusion, and seizures, were recorded. The concentrations of cefazolin in the serum and CSF, total serum protein, and percent albumin were determined. Five of the six patients given multiple doses of cefazolin sodium had notable CSF accumulation of the drug (11.3 +/- 2.7% of the serum concentration). Three patients experienced generalized focal-motor seizures during their therapy. Neurotoxicity was found to be associated with renal dysfunction and multiple-dose therapy leading to serum concentrations greater than 360 micrograms/ml and CFS concentrations greater than 34 micrograms/ml. Cefazolin will penetrate into the CSF in patients receiving multiple-dose therapy of the drug. To avoid neurotoxicity, careful attention should be paid to the recommended dosage regimens, the impact of renal dysfunction on drug clearance should be recognized, and serum assays should be performed when necessary.
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PMID:Effect of multidose therapy on cerebrospinal fluid penetration of cefazolin. 729 44


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