Drug-induced Disturbances Research Articles

Rare neurologic sequelae: A case report of toxic metabolic encephalopathy caused by carbamazepine-induced hypovolemic hyponatremia

Metabolic or secondary encephalopathies originate from non-cerebral organ system failures, often with multifactorial origins. Toxic-metabolic encephalopathy (TME) results from acute cerebral dysfunction due to metabolic disruptions, including drug effects. TME leads to altered consciousness, from delirium to coma, necessitating intensive care and mechanical ventilation. This study delves into TME, a reversible brain pathology triggered by extracerebral factors, notably drug-induced disturbances. Clinical presentation involves nonspecific altered consciousness, sometimes with asterixis or myoclonus. Carbamazepine (CBZ), a common antiepileptic medication, is linked to hyponatremia, defined by serum sodium levels below 135 mmol/l. The complexity of AED-induced hyponatremia is explored through a comprehensive patient analysis, revealing an array of symptoms including altered mentality, seizures, respiratory distress, and even coma or death. The case study dissects a patient's experience with toxic-metabolic encephalopathy secondary to CBZ-induced hypovolemic hyponatremia. This underscores the need for vigilant monitoring and management of adverse drug reactions, spotlighting the intricate interplay of drug-induced metabolic encephalopathies within clinical practice. The study reinforces the importance of awareness and tailored management strategies to enhance treatment outcomes for individuals with epilepsy.

Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Clostridium difficile Colitis while Dysregulating the Inflammatory Response.

Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile-infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4+ cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses.IMPORTANCEClostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.

Validation of an Automated Patch-Clamp Screening Assay on Human Kir2.1 Cardiac Ion Channels

The Kir2.1 potassium channel underlies the IK1 current which is a main contributor to the diastolic resting potential of cardiac myocytes. These currents are also involved in the shaping of the initial depolarization and final repolarization of the action potential (AP). Drug-induced disturbances of Kir2.1 function can increase the duration of the AP and produce dangerous arrhythmias. Here we have developed a functional cell-based assay on an automated electrophysiology platform to complete a panel of pre-clinical cardiosafety tests for early discovery compounds. CHO cells stably expressing the human KCNJ2 gene product under the control of a tetracycline-inducible promoter were recorded on a QPatch HTX platform. Series of incrementing voltage steps from a −20 mV holding potential elicited large, non-inactivating negative inward currents at membrane potentials below the K+-equilibrium potential, with strong rectification above. Enhancing the external [K+]o concentration resulted in greater inward and outward currents, and a cross-over of the outward currents on the I-V curves. The zero-current potential shifted by 56 ± 6 mV per ten-fold variation of [K+]o, in good agreement with the Nernst equation prediction. Addition of millimolar concentrations of Ba2+or Cs+ dose- and/or voltage-dependently blocked the inward currents as described for native IK1 currents. Pharmacological studies using a step-ramp voltage protocol allowing stable recordings for 30 min demonstrated inhibitory activity in the low micro-molar range for the methoxybenzyl-methanamide Kir-inhibitor ML133 and the pentamidine-derivative PA-6, although these compounds did not exhibit selectivity over hERG channels as claimed.

15th Annual Meeting of the Safety Pharmacology Society: Focus on traditional sensory systems

IntroductionThis report summarizes and comments key talks on the five traditional senses (ear, vestibular system, vision, taste, olfaction, and touch) which were delivered during the 2015 Annual Meeting of the Safety Pharmacology (SP) Society. Areas coveredThe functional observational battery (FOB) can detect major candidate drug liabilities only on ear, touch and vision. Anatomy, physiology, pharmacology, and pathology notions on each sensory system introduce speaker talks. Techniques for evaluating drug effects on hearing functions are reviewed. Nonclinical approaches to assess vestibular toxicity leading to balance deficits are presented. Retinal explants studied with multielectrode arrays allow the identification of drug liability sites on the retina. Routinely performed Safety Pharmacology assays are not powered to address candidate drug-induced disturbances on taste and smell. This weakness needs correction since unintended pharmacological impairment of these sensorial functions may have serious health consequences. Neuropathy produced by chemotherapeutic agents may cause multiple sensorial perception distortions. ConclusionsSafety Pharmacology studies should ensure the safety of any candidate drug on the five sensorial systems.

Domperidone

Domperidone (antinausea/vomiting agent) was recently shown by several groups to increase sudden cardiac death (SCD). Drug-induced disturbances of cardiac repolarization may be a major mechanism. Experiments were executed in isolated female rabbit hearts perfused for 150 minutes with domperidone 30, 60, or 100 nM. Domperidone significantly prolonged the action potential duration: +9% at 30 nM, +32% at 60 nM, and +48% at 100 nM. Domperidone induced significant disturbances of repolarization in 83% of hearts at 60 nM and in 100% at 100 nM, including early afterdepolarizations and polymorphic ventricular tachycardia. Maximum therapeutic free drug plasma concentration of domperidone (19 nM) yields a safety index of only ∼2.5, that is, 12-fold below the accepted minimum. Gastrointestinal benefits and risks for SCD were derived from the literature. The defined daily dose of domperidone (30 mg/day) fails to show unequivocal gastrointestinal benefits beyond a placebo effect. In contrast, 5 of 5 population-based studies show that oral domperidone significantly increases the odds ratio for SCD to 2.8 (1.53-6.21) and it increases sharply above 30 mg/day. Because domperidone has placebo-like benefits but is associated with increased SCD and a narrow safety margin, it should not be used in medicine.

Cardiolipin and oxidative stress: Identification of new short chain oxidation products of cardiolipin in in vitro analysis and in nephrotoxic drug-induced disturbances in rat kidney tissue

Cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane. Alteration of CL, namely by oxidative modifications, has been related with various pathological conditions, and with cell apoptosis. Their location, in the mitochondria, makes them even more likely to be oxidized, since that there is a considerable production of ROS in the inner mitochondrial membrane. In spite of the importance of CL oxidation and its biological consequence, there is a limited knowledge of the oxidation products of CL. In this study, mass spectrometry coupled with liquid chromatography (LC–MS) was used to identify the specific oxidative modifications of tetra-linoleoyl CL induced by the OH • generated under Fenton reaction conditions (H 2O 2 and Fe 2+). Short chain products (with fatty acyl shortened) formed during CL oxidation were identified for the first time and were further characterized by LC-ESI-MS/MS. The short chain products identified resulted from β-cleavage of alkoxyl radicals at C9 and C13. These products were identified as [M−2H] 2− at m/z 691 and 719, with C13 and at m/z 685, 693 and 701, with C9 shortened fatty acyl chains. Detailed analysis of the fragmentation pathways of these precursor ions allowed to identify the MS/MS product ions which allow the unequivocal assignment of the oxidized cardiolipin species, very valuable for their detection in biological samples. Some of these products, namely, the CL short chain product at m/z 685 and 693 were detected in the mitochondria of kidneys obtained from rats treated with gentamicin. Gentamicin is an aminoglycoside antibiotic that induces nephrotoxicity and that has been associated with mitochondrial dysfunction and lipid peroxidation.

Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines

By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow-up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug-induced disturbances, non-convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow-up period.

A better understanding of drug-induced taste disturbances may improve management of the condition

A better understanding of drug-induced taste disturbances may improve management of the condition

Drug-induced conduction disturbances and prognosis after cessation of the culprit drug

Drug-induced conduction disturbances and prognosis after cessation of the culprit drug

Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats

Ventilation of the lungs is mediated by neurons of the respiratory network in the lower brainstem. The activity of rhythmogenic respiratory network neurons seems to depend greatly on cellular levels of the second messenger cAMP. Accordingly, depression of breathing in (preterm) infants associated with clinical administration of opioids and prostaglandins results likely from a fall of cAMP in these cells caused by G i/o proteins that are activated via μ-opiate or EP 3 prostanoid receptors, respectively. Typically, such drug-induced depression of infant breathing is treated with high doses of methylxanthines that have notable adverse effects. It was the aim of our study to investigate whether clinically applicable blockers of cAMP-hydrolyzing phosphodiesterase-4 counteract the inhibition of the respiratory network associated with a drug-induced fall of cAMP. For this purpose, inspiratory-related cervical nerve activity was measured in isolated brainstem-spinal cord preparations from newborn rats. Respiratory frequency was depressed by >80% (from >5 bursts/min to <1 burst/min) with nociceptin (1 μM) which decreases cAMP via a G i/o protein-coupled opioid-like receptor. The nociceptin-induced respiratory depression was reversed by the activator of adenylyl cyclase, forskolin (5–25 μM) and the phosphodiesterase-4 blockers rolipram (0.1–1 μM) and RO-201724 (1–5 μM). Blocking phosphodiesterases 3 and 5 with milrinone (25–100 μM) and zaprinast (25–100 μM), respectively, was not effective. The results indicate that phosphodiesterase-4 blockers are strong stimulants of the respiratory network. We hypothesize that these or related agents may be potent tools for a treatment of drug-induced disturbances of breathing in (preterm) infants.

Refining detection of drug-induced proarrhythmia: QT interval and TRIaD

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or I(Kr), hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.

Behaviorally Fractionated Reaction Time to an Omitted Stimulus: Tests with Visual, Auditory, and Tactile Stimuli

Two experiments tested the adequacy of behavioral criteria to fractionate reaction time (RT) into independent premotor (cognitive) and motor components. Healthy participants performed an omitted stimulus reaction time task in which they responded to the termination of a train of lateralized visual, auditory or tactile stimuli. Exp. 1 with 48 participants (24 men) showed premotor RT was independent of motor RT in each sensory modality and did not differ as a function of side of presentation or sex. Repeated tests administered in Exp. 2 (N= 12) also showed no significant association between the behaviorally fractionated measures. These results are comparable to those obtained using muscle potential to fractionate RT and suggest behaviorally fractionated premotor and motor RT could be a reliable, useful tool in the assessment of cognitive and motor processing in different sensory modalities of healthy people or those with brain injury, disease, or drug-induced disturbances.

Metabolomics: an emerging post-genomic tool for nutrition

The post-genomic era has been driven by the development of technologies that allow the function of cells and whole organisms to be explored at the molecular level. Metabolomics is concerned with the measurement of global sets of low-molecular-weight metabolites. Metabolite profiles of body fluids or tissues can be regarded as important indicators of physiological or pathological states. Such profiles may provide a more comprehensive view of cellular control mechanisms in man and animals, and raise the possibility of identifying surrogate markers of disease. Metabolomic approaches use analytical techniques such as NMR spectroscopy and MS to measure populations of low-molecular-weight metabolites in biological samples. Advanced statistical and bioinformatic tools are then employed to maximise the recovery of information and interpret the large datasets that are generated. Metabolomics has already been used to study toxicological mechanisms and disease processes and offers enormous potential as a means of investigating the complex relationship between nutrition and metabolism. Examples include the metabolism of dietary substrates, drug-induced disturbances of lipid metabolites in type 2 diabetes mellitus and the therapeutic effects of vitamin supplementation in the treatment of chronic metabolic disorders.

Gonadal morphology and sex hormones in male and female Wistar rats after long-term lamotrigine treatment

Drug-induced disturbances in reproductive hormones and gonadal morphology have been observed both in patients with epilepsy and in non-epileptic animals. Less is known about the influence of newer antiepileptic drugs including lamotrigine on reproduction. Lamotrigine is now increasingly used both in epilepsy and psychiatric disorders. Sixty-five Wistar rats were fed by gastric tube either 5 mg kg −1 lamotrigine solution (males=15, females=20) or 0 (vehicle control, males=15, females=15) twice daily for 90 days. In males, no significant differences were found in body or testicular weight. Testicular atrophy was observed in one control animal and in two of the rats receiving lamotrigine. No morphological changes were seen in the other organs investigated (liver, kidney, pancreas, brain, lymphatic tissue, heart). None of the animals showed over-expression of p53. No significant differences were observed between the control rats and the male rats receiving lamotrigine regarding testosterone, FSH and LH. In females, no changes in ovarian morphology or alterations in other tissues were observed. Serum testosterone, FSH, LH, insulin and progesterone remained unchanged in the lamotrigine treated animals, while serum estrogen was significantly reduced.

Plasma leptin in treated patients with schizophrenia

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or IKr, hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.

Pavlovian psychopharmacology: the associative basis of tolerance.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms.

Drug anticipation and drug addiction. The 1998 H. David Archibald Lecture.

Environmental cues associated with drug use become capable of eliciting withdrawal symptoms, craving and relapse to drug self-administration. The phenomenon, although noted almost 150 years ago, has repeatedly been confirmed in epidemiological and experimental studies. Drug tolerance, which is closely correlated with withdrawal symptoms and craving, is also modulated by drug-associated environmental cues. The contribution of predrug cues to withdrawal and tolerance is emphasized in a Pavlovian conditioning analysis of drug administration. Drug-induced disturbances are modulated by homeostatic responses elicited by pharmacological stimulation. According to the conditioning analysis, we learn to anticipate the drug effect; corrective response (conditional compensatory responses) occur in the presence of situations and events that have been associated with the drug in the past. These conditional responses, seen in anticipation of drugs, importantly contribute to drug tolerance, failures of tolerance (enigmatic overdoses), and withdrawal symptoms. I review evidence indicating that a complete analysis of drug withdrawal and tolerance requires an appreciation of the contribution of Pavlovian conditioning.

Acute Hyponatremic Encephalopathy After a Cerebrovascular Accident

A 66-year-old hypertensive male with acute intracerebral hemorrhage developed acute hyponatremic coma 3 days after the addition of enalapril and a combination of amiloride and a thiazide diuretic to his hypotensive regimen. The patient recovered consciousness and serum sodium normalized 2 days after fluid restriction and withdrawal of both medications. Three weeks later, upon inadvertent reinstitution of enalapril and indapamide, severe hyponatremic encephalopathy promptly recurred; recovery was again rapid following fluid restriction and withdrawal of both medications. This temporal relationship establishes the thiazide diuretic or the angiotensin converting enzyme inhibitor or both as the cause of the profound symptomatic hyponatremia in this patient. Results of simultaneous serum and urine osmolality assays on several occasions were consistent with a decrease in free water clearance, a result of either increased antidiuretic hormone (ADH) secretion or potentiation of its peripheral action, and thiazide-induced natriuresis. The use of a thiazide diuretic in the presence of either of these aberrations of ADH homeostasis most likely explains the profound and rapid development of hyponatremia. Drug-induced disturbances in serum osmolality are a potentially reversible cause of deterioration of the mental state in a patient with an acute cerebrovascular accident.

Drug-induced disorders of glucose metabolism. Mechanisms and management.

Glucose homeostasis is maintained by a balance between the release and action of insulin, and the counterregulatory responses mediated principally by glucagon, catecholamines, growth hormone and cortisol. Hence, the effects of a drug on glucose metabolism may be mediated by any of these agents singly or in combination. Host factors, such as inherent glucoregulatory mechanisms, concurrent diseases, organ function and concomitant medications also increase the risk of drug-induced disturbances of glucose homeostasis in susceptible individuals. By far the most important agents causing hypoglycaemia are insulin and the sulphonylureas. Alcohol (ethanol), over-zealous glycaemic control, hypoglycaemic unawareness, detective counterregulation especially in insulin-dependent diabetes mellitus (IDDM), and renal and liver impairment are all important predisposing factors. Although antihyperglycaemic agents such as metformin and alpha-glucosidase inhibitors do not cause hypoglycaemia alone, they may enhance the hypoglycaemic effects of potent hypoglycaemic agents such as insulin and sulphonylureas. On the other hand, the potential hypoglycaemic effects of ACE inhibitors, alpha-blockers, lipid-lowering agents and recombinant human insulin-like growth factor demonstrated in experimental settings, are of potential therapeutic interest. Iatrogenic hypoglycaemia and intensive insulin treatment are associated with hypoglycaemic unawareness which may be obviated by meticulous avoidance of hypoglycaemia. Effective patient education remains an important preventive measure. Oral glucose is used to treat mild hypoglycaemic episodes while more severe episodes are treated by intravenous glucose or glucagon. Nasal glucagon and theophylline are other experimental measures to improve recovery from hypoglycaemia. In refractory hypoglycaemia due to hyperinsulinaemia such as during sulphonylurea overdosage or quinine treatment, the long-acting somatostatin, octreotide, may suppress insulin release and restore euglycaemia. Diuretics, beta-blockers, sympathomimetics, corticosteroids and sex hormones are commonly prescribed drugs which may have adverse effects on carbohydrate metabolism especially in patients with diabetes mellitus or those who are at risk of developing glucose intolerance. Pentamidine was frequently associated with dysglycaemia due to its pancreatic beta-cell cytotoxic effects but is now used less often to treat Pneumocystis carinii pneumonia in immunosuppressed patients. Despite the large number of anecdotal reports of drug-induced disturbances of glucose metabolism, many of the so-called adverse drug reactions were either idiosyncratic or coincidental. Nevertheless, they emphasise the complex nature of glucose homeostasis and its potential interactions with drugs, host factors and disease states. An understanding of these relationships may allow more critical interpretation of these clinical observations, better prediction of drug induced adverse effects on carbohydrate metabolism and the implementation of more rational therapy. Hence, the hypoglycaemic effects of a drug may be turned to a therapeutic advantage in patients with glucose intolerance. Similarly, the hyperglycaemic effect of a drug may help to treat refractory hypoglycaemia.

Amino acids as the source of considerable excitation in cerebral cortex

A number of different factors contributed to the rationale for providing a critical review of the field of excitatory amino acids in the cerebral cortex at this time. In addition to the recent growing realisation by clinicians that the excitatory amino acids are linked critically to a number of neurological conditions, including neurodegenerative syndromes such as Alzheimer's disease, cortical damage due to stroke and cerebral ischemia, epilepsy, amyotropic lateral sclerosis, and schizophrenia, the recent cloning and membrane reconstitution of specific receptors known as AMPA, NMDA, kainate, and metabotropic receptors and their known subunits have prompted a surge of renewed interest in this important family of synaptic transmitter molecules. Moreover, recent advances in our understanding of the molecular events involved in growth promotion in the early stages of the development of the cortex have shown that both NMDA and non-NMDA receptor subtypes perform important roles in certain aspects of target selection and neurite outgrowth, in cone stimulation and guidance, and in spine formation and morphological alterations. A recent explosive growth in interest in the possible roles of nitric oxide and related short-lived radicals in plasticity, disease, and synaptic transmission also is related closely with the actions of excitatory amino acids. All these relatively new advances have transpired in parallel with ongoing work that has extended our appreciation for the roles of excitatory amino acids in the areas of synaptic plasticity (long-term potentiation, long-term depression, receptive field reorganisation following drug-induced or peripheral sensory disturbances, such as denervation or amputation), in processes of normal transmission at functionally and electrophysiologically identified neurones of the cerebral cortex, and in distinct proposed roles for cortical glia. A greater appreciation of the diverse types and properties of the burgeoning family of receptors for the metabotropic receptor also contributed to our desire to feature that aspect of the field in the context of glia and neurones of the cerebral cortex. That part of the field of neuroscience concerned with the functions of excitatory amino acids has grown so large over the past 10 years or so, that a review paper focusing on the contributions to a specialized meeting devoted solely to cerebral cortex could easily be supported by material comprising a sufficient body of communications from top-quality research laboratories. The present account endeavours to summarize and discuss the biochemical characteristics, physiological roles, pharmacological properties, clinical relevance, developmental involvements, and anatomical-morphological aspects pertaining to the excitatory amino acid transmitters in cerebral cortex.