Allergy to Carbamazepine: Parallel In Vivo and In Vitro Detection

Summary: Purpose: Five to 20% of patients discontinue antiepileptic drug (AED) therapy because of adverse reactions. Careful reintroduction, however, may be considered if true drug allergy can be ruled out. Definitive assessment of such immunologically mediated reactions requires demonstration of either specific antibodies or sensitized lymphocytes. Methods: We investigated whether skin patch tests (PTs) and in vitro lymphocyte proliferation assays (LPAs) were suitable for detection of allergy to carbamazepine (CBZ) and the possibly cross-reactive oxcarbazepine (OCBZ). Data of 65 patients displaying a wide range of possibly allergic side effects to CBZ were available for analysis. Data of CBZ users without any side effects and healthy volunteers served as controls. Both PTs and LPAs were done with CBZ, OCBZ and three metabolites [CBZ-10,11-epoxide (CBZ-E), 10-monohydroxy-CBZ (MHD), and 10,11-dihydroxy-CBZ (DIOL)]. Results: Positive PTs with CBZ were seen in 20% and with OCBZ in 14% of the patients. Positive LPA results with CBZ and OCBZ, respectively, were found in 40 and 19%. Both tests were positive in 14 and 7% of the patients. Cross-reactivity to OCBZ was seen in -40% of CBZ-reactive patients in both PTs and LPAs. Conclusion: These data illustrate the additional value of LPAs in the detection of CBZ allergy while showing that a major part of side effects to CBZ and OCBZ is not immunologically mediated, according to PTs and LPAs.     

Synthesis of Quercetin-Metal Complexes,In Vitro and In Silico Anticholinesterase and Antioxidant Evaluation,and In Vivo Toxicological and Anxiolitic Activities

Neurotoxicity Research - The level of acetylcholine, a neurotransmitter essential for processing memory and learning, is lower in the brains of patients with Alzheimer’s disease due to the...     

Cycloheximide Reduces the Effects of Anoxic Insult In Vivo and In Vitro

In vivo and in vitro techniques were utilized to examine the influence of a protein synthesis blocker, cycloheximide (CHX), on the damaging effects of anoxia in the rat. CHX administered 1 h before transient (30 min) forebrain ischaemia increased the survival of animals, decreased body weight loss and reduced the occurrence of delayed degeneration in the CA1 pyramidal region. The same dose of CHX injected 1 h after ischaemia induced status epilepticus, a decrease in survival rate, and did not reduce weight loss or CA1 damage in any of the surviving rats. Electrophysiological techniques were then used to determine the effects of various periods of anoxia and aglycaemia (AA) on CA1 field excitatory postsynaptic potentials (EPSPs) in hippocampal slices incubated in the presence or absence of CHX. In CHX-treated slices, recuperation of EPSP amplitude (45±16%) was significantly greater than in control slices (9±9%) following an AA episode of 3 min 45 s. No difference was seen in the percent recuperation of EPSPs in the control and CHX-treated slices after shorter or longer episodes of AA. From these studies, it appears that CHX protects against the damaging effect of ischaemia in vivo or AA in vitro.     

Interaction Between Uridine and GABA-Mediated Inhibitory Transmission: Studies In Vivo and In Vitro

Na+-independent [3H]gamma-aminobutyric acid (GABA) binding to membrane preparations from frontal cortex, hippocampus, and thalamus is competitively inhibited by the in vitro addition of a naturally occurring pyrimidinic compound, uridine. Moreover, the intraperitoneal injection of uridine produces a dose-related decrease in the cerebellar content of cyclic GMP and antagonizes its increase elicited by bicuculline. The pyrimidinic compound also shows an antagonism toward bicuculline-induced seizures. The relationship between the anti-convulsant actions of uridine and GABA-mediated inhibitory neurotransmission is discussed in terms of an activation of GABA receptor function by the naturally occurring pyrimidinic compound.     

In sickness and in health

Shortage of manpower in the mental health professions makes it critically incumbent upon clinics to explicitly formulate their treatment responsibilities and to carefully appraise the efficiency with which they discharge their assigned tasks. A state of unhappiness is not necessarily a form of mental illness. Priority should be given to treatment of emotional and behavior disorders which have social impact. Clinics need to be sensitively open to the implications of research findings in reviewing their treatment methods and in striving for an effective flexibility in procedures. The clinic and client should have an explicit contract, not an implicit marriage.A version of this paper was given as an invited address at the annual meeting of the Wisconsin Association of Mental Health Clinics, June, 1965.     

In ethanol

Slide-mounted tissue sections of brain were incubated with several reversibly binding [³H]ligands to label receptors. Exposure of these labeled, mounted tissue sections to ethanol solutions for dehydration resulted in a substantial loss of receptor bound ligands in all cases, even when the tissues were fixed with formaldehyde vapors before exposure. Thus, serious problems can be introduced into in vitro labeling autoradiographic procedures by exposure of sections to aqueous or organic media.     

Kynurenic Acid in the Quinolinate-lesioned Rat Hippocampus: Studies In Vitro and In Vivo

The present study was designed to examine the cellular localization and biosynthetic machinery of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid in the lesioned rat hippocampus. Seven days after an intrahippocampal injection of 120 nmol quinolinic acid, which causes massive neurodegeneration in the dorsal hippocampus, kynurenic acid tissue levels and the activity of kynurenic acid's anabolic enzyme, kynurenine aminotransferase, were increased by 92% and 67%, respectively, as compared to controls. The steady-state levels of extracellular kynurenic acid, examined by microdialysis in unanaesthetized rats, were also increased in the lesioned tissue (from 93.6 +/- 10.2 to 207.6 +/- 18.6 fmol/30 microl dialysate). Using microdialysis, three compounds which are known to decrease kynurenic acid production from its bioprecursor l-kynurenine in brain slices and in vivo were tested for their ability to reduce the levels of endogenous kynurenic acid. In unlesioned tissue, aminooxyacetic acid (300 microM), veratridine (50 microM) and glutamate (5 mM), all administered through the dialysis probe, decreased extracellular kynurenic acid concentrations by 30 - 40%, i.e. to a lesser degree than in previous experiments in which kynurenine was used as a bioprecursor. Only the effect of veratridine was abolished in the quinolinate-lesioned hippocampus. These data indicate that kynurenic acid is produced in and liberated from astrocytes, and that aminooxyacetic acid and glutamate (but not veratridine) exert their action by directly affecting glial kynurenic acid biosynthesis. The results also suggest the existence of two distinct intracellular kynurenic acid pools, which are responsible for kynurenic acid storage and rapid kynurenic acid mobilization, respectively. Taken together, these features of kynurenic acid neurobiology may be of relevance in the control of excitatory amino acid receptor function under physiological and pathological conditions.