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PubMed1989

Bepridil: a pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia.

In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.

Angina Pectoris↗
PubMed1996

Pharmacological model of catecholamine depletion in the hypothalamus of fetal and neonatal rats and its application.

1. The present study aimed to develop a pharmacological model of catecholamine (CA) depletion in the hypothalamus during the period of its morphofunctional development, i.e. in fetal and neonatal rats of both sexes. 2. In the first series of experiments, pregnant females and, hence, fetuses were systemically treated daily from the embryonic day (E) 13 to E20 with the inhibitor of the CA synthesis alpha-methyl-m-tyrosine. The CA concentrations were subsequently measured in the fetal hypothalamus at E21 by high performance liquid chromatography with electrochemical detection (HPLC-ED). In the second series of experiments, neonatal rats were injected with neurotoxin, 6-hydroxydopamine and/or alpha-methyl-m-tyrosine daily from the 2nd postnatal day (P2) to P10. 3. The HPLC-ED assay of hypothalamic catecholamines (CA's) at E21 and P11 showed that both in fetuses and neonates, alpha-methyl-m-tyrosine caused more than 50% depletion of hypothalamic noradrenaline and adrenaline, while the dopamine (DA) level remained unchanged. The combined treatment of neonatal rats with alpha-methyl-m-tyrosine and 6-hydroxydopamine resulted additionally in a 25% decreased level of DA. 4. The influence of CA deficiency on the developing hypothalamic CA system was further evaluated by measuring [3H]DA uptake by nervous tissue in vitro. 5. The CA deficiency caused a 50% drop of [3H]DA uptake by the hypothalamic tissue in treated fetuses suggesting a stimulating effect of CA's on the early development of the CA system. In pharmacologically treated neonatal rats [3H]DA uptake remained at the control level showing no influence of the CA deficiency on the developing CA system after birth. 6. The usefulness of the proposed pharmacological model for studying of CA influence on differentiating hypothalamic target neurons is discussed.

Animals↗
PubMed1994

Pharmacologic treatment of schizoaffective disorder.

In contrast to the considerable systematic study of the pharmacologic treatment of schizophrenia and mood disorders, the pharmacologic treatment of schizoaffective disorder has been relatively ignored. The authors reviewed the available literature regarding the pharmacologic treatment of schizoaffective disorder. The total number of controlled studies of the acute and prophylactic treatment of schizoaffective disorder was small and few used modern criteria to define the disorder. In studies of schizoaffective disorder, bipolar type (manic), lithium and antipsychotics produced comparable albeit incomplete responses, except in highly agitated patients when antipsychotics exerted superior efficacy. The combination of lithium and antipsychotics appeared to be superior to antipsychotics alone for schizoaffective, bipolar type patients. In the only controlled study of schizoaffective disorder, depressed type, the presumed superiority of combined antidepressant and antipsychotic treatment to antipsychotic alone was not found. Although combined antipsychotic and thymoleptic treatment represents common prophylactic management of schizoaffective disorder in clinical practice, the efficacy of this strategy has not been studied in controlled trials. Advances in the nosology of schizoaffective disorder, emerging epidemiologic data demonstrating large numbers of patients with this disorder in clinical populations, and preliminary evidence that clozapine may have combined antipsychotic and thymoleptic properties as well as efficacy in both the psychotic and affective components of schizoaffective disorder, suggest that renewed interest in the diagnosis and treatment of this disorder may lead to improved delivery of care for this understudied but seriously ill group of patients.

Antipsychotic Agents↗
PubMed1995

Comparative pharmacology of nicotine and ABT-418, a new nicotinic agonist.

ABT-418, a novel cholinergic ligand, was reported to possess potent cognitive-enhancing and anxiolytic properties in animal models with reduced side effects (Decker et al. 1994; Garvey et al. 1994) suggesting selectivity of effects. In this study, the binding properties of ABT-418 to [3H]-nicotine sites were evaluated and its pharmacology investigated in different tests in laboratory animals. ABT-418 binds with high affinity to 3H-nicotine binding sites in the brain with, however, a Ki (6 nM) less than that of nicotine (four-fold). In addition, it acts as a full nicotinic agonist in producing hypomotility, hypothermia and antinociception in mice and engendering nicotine-like responding in rat drug discrimination. The potency of ABT-418 is three to four times less than that of nicotine in all of the animal models, except for hypothermia. In addition, its behavioral effects are completely blocked by mecamylamine, a non-competitive nicotinic antagonist. Although activation of nicotinic receptors by ABT-418 produced several behavioral and pharmacological effects, our results do not suggest high selectivity of different effects as reported by Decker et al. (1994) and Garvey et al. (1994). However, it should be noted that we did not perform some of these tests that produced effects at low doses (Decker et al. 1994) and additional pharmacological studies are needed to establish its selectivity at multiple nicotinic receptors.

Animals↗
PubMed1995

Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats.

While many previous studies have shown that a variety of cannabinoids substitute and cross-substitute for delta 9-tetrahydrocannabinol (THC) in drug discrimination procedures, few have systematically examined potential THC-like effects of non-cannabinoid compounds. The purpose of the present study was to delineate further the pharmacological specificity of THC discrimination. Rats were trained to discriminate THC (3.0 mg/kg) from vehicle. Following determination of a dose-effect curve with THC, substitution tests with selected compounds from a variety of pharmacological classes, including l-phenylisopropyl adenosine, dizocilpine, dextromethorphan, clozapine, buspirone, MDL 72222, muscimol, midazolam and chlordiazepoxide, were performed. Whereas THC produced full dose-dependent substitution, substitution tests with non-cannabinoid drugs resulted in less than chance (50%) levels of responding on the THC-appropriate lever, with the exception of (+)-MDMA (2.5 mg/kg, 50%) and diazepam (3.0 mg/kg, 67%). These results are consistent with those of previous studies and suggest that the discriminative stimulus effects of THC exhibit pharmacological specificity.

Animals↗
PubMed1996

Interaction of expectancy and the pharmacological effects of d-amphetamine: subjective effects and self-administration.

The study examined the effects of expectation on the subjective effects and oral self-administration of 15 mg d-amphetamine (AMP) and placebo in 40 volunteers who reported no prior use of stimulants other than caffeine. A balanced placebo design was used to create four groups: told Placebo/got Placebo (P/P), told Placebo/got Stimulant (P/S), told Stimulant/got Placebo (S/P), told Stimulant/got Stimulant (S/S). There were three sessions. On one session (INFO), participants received a capsule containing AMP or placebo and were given information about the contents of the capsule according to the balanced placebo design. On another session (NO INFO), participants received no information about the capsule's contents and were given placebo. On the final session, participants were allowed to choose either the INFO or NO INFO capsule. Participants came to the laboratory to ingest their capsules, and then returned to their normal environments where they completed subjective effects questionnaires every 2 h for 8 h. Expectancies influenced the subjective effects reported during the INFO session, regardless of whether subjects actually received AMP or placebo: subjects who expected a stimulant had higher ratings of "feel drug" and "like drug". The pharmacological effects of AMP were also evident on the INFO sessions: AMP produced its prototypic subjective effects regardless of subjects' expectancies. Significant interactions between drug and expectancy were obtained on self-report measures of anxiety and arousal: anxiety was higher for groups who received substances that did not match their expectations (P/S and S/P) and arousal increased most in volunteers who expected placebo but received stimulant. Choice of drug was determined primarily by pharmacology: participants who received AMP on the INFO session usually chose that capsule, regardless of information about its identity (P/S: 8/10; S/S: 9/10). In contrast, participants who received placebo on the INFO session chose this capsule at chance levels, regardless of information about its identity (S/P: 3/10; P/P: 6/10). Thus, expectancy influenced some of the subjective effects of AMP and placebo, but the pharmacological effects of the AMP were instrumental in determining whether volunteers would self-administer the drug.

Adult↗
PubMed1990

Pharmacology of airway inflammation in asthma.

Chronic desquamative eosinophilic bronchitis is a characteristic pathologic feature of asthma which may even antedate the onset of symptoms. The pharmacology of asthmatic inflammation has been relatively poorly studied and most of the current data available have been inferred indirectly from studies of bronchial hyperresponsiveness and late-phase responses. Apart from mast cells, the effects of drugs used in the treatment of asthma on other airway inflammatory cells such as eosinophils, alveolar macrophages, etc. have not been extensively studied. The pharmacology of asthmatic inflammation should comprise the study of various aspects of this inflammatory response such as airway microvascular leakage, mediator release, and cell chemotaxis. Ultimately the pharmacologic modulation of the pathologic features of the asthmatic airway by the chronic use of antiasthma drugs, coupled with clinical responses, need to be investigated using bronchial biopsies and broncholveolar lavage in asthmatic patients.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.

Pharmacologic stress testing may be used in the diagnosis of coronary artery disease and risk assessment. The stress agents may be divided into those that produce primary coronary vasodilation (dipyridamole, adenosine, or adenosine triphosphate) and those that produce secondary vasodilation as a result of increase in myocardial oxygen demand (dobutamine and arbutamine). Assessment of myocardial perfusion and function can be made by single-photon imaging, positron emission tomography, two-dimensional echocardiography, magnetic resonance imaging, and contrast angiography. For assessment of myocardial perfusion, either thallium 201-labeled or technetium-labeled perfusion imaging agents may be used. This article will focus on the mechanisms of action, hemodynamic responses, and results of pharmacologic imaging in detecting coronary artery disease. The use of pharmacologic stress testing in risk assessment will be discussed in a separate article.

Adenosine↗
PubMed1984

Pharmacologic treatment of rhinitis.

Major improvements in the quality of recent pharmacologic studies of rhinitis are evident. In many of the studies, the criteria for patient selection are being more carefully described and patients with allergic rhinitis, nonallergic rhinitis with eosinophilia, and vasomotor rhinitis are no longer grouped together. In most studies, efficacy is still being ascertained by subjective symptom scores, although in some of the challenge studies, investigators are making noble attempts to quantitate symptoms objectively, eg, amount of secretions, sneezing, and even itching of the nares. Although nasal congestion is only one symptom of chronic rhinitis, the various methods of measuring nasal resistance by rhinometry are increasingly well described and standardized. General concepts that are emerging from the vast literature on pharmacologic treatment of rhinitis are as follows: 1) The much-maligned H1 receptor antagonists may actually be more useful than previously thought, once further information about how to use them optimally is available. Interesting new antihistamines are being developed. Further investigations of allied drugs such as the tricyclic antidepressants (doxepin) are definitely in order. 2) alpha-adrenergic agonists definitely have short-term usefulness but side effects from this class of drugs have, if anything, been underestimated. Exploration of the use of beta-adrenergic agonists and anti-cholinergics in the treatment of chronic rhinitis has begun. 3) Disodium cromoglycate is not universally effective in chronic rhinitis, perhaps in part because compliance with a prophylactic drug requiring insufflation four or six times daily may not be high. The degree of response and the percentage of patients having an excellent response to the drug is lower than for the new corticosteroids. 4) Topical corticosteroids administered intranasally are clearly the most effective medications for treatment of chronic rhinitis. Further study of the benefit versus the long-term risk of these drugs is mandatory, but their remarkable efficacy and safety in the treatment of chronic rhinitis is undisputed. Some comparisons between the four major groups of drugs are now being made, and further attempts to define the relative roles and the interactions of drugs used in the pharmacologic treatment of rhinitis are definitely needed.

Adrenal Cortex Hormones↗
PubMed2001

Preemptive analgesia I: physiological pathways and pharmacological modalities.

PURPOSE: This two-part review summarizes the current knowledge of physiological mechanisms, pharmacological modalities and controversial issues surrounding preemptive analgesia. SOURCE: Articles from 1966 to present were obtained from the MEDLINE databases. Search terms included: analgesia, preemptive; neurotransmitters; pain, postoperative; hyperalgesia; sensitization, central nervous system; pathways, nociception; anesthetic techniques; analgesics, agents. PRINCIPAL FINDINGS: The physiological basis of preemptive analgesia is complex and involves modification of the pain pathways. The pharmacological modalities available may modify the physiological responses at various levels. Effective preemptive analgesic techniques require multi-modal interception of nociceptive input, increasing threshold for nociception, and blocking or decreasing nociceptor receptor activation. Although the literature is controversial regarding the effectiveness of preemptive analgesia, some general recommendations can be helpful in guiding clinical care. Regional anesthesia induced prior to surgical trauma and continued well into the postoperative period is effective in attenuating peripheral and central sensitization. Pharmacologic agents such as NSAIDs (non-steroidal anti-inflammatory drugs) opioids, and NMDA (N-methyl-D-aspartate) - and alpha-2-receptor antagonists, especially when used in combination, act synergistically to decrease postoperative pain. CONCLUSION: The variable patient characteristics and timing of preemptive analgesia in relation to surgical noxious input requires individualization of the technique(s) chosen. Multi-modal analgesic techniques appear most effective.

Adrenergic alpha-Antagonists↗
PubMed2006

Targeted therapy for cystic fibrosis: cystic fibrosis transmembrane conductance regulator mutation-specific pharmacologic strategies.

Cystic fibrosis (CF) results from the absence or dysfunction of a single protein, the CF transmembrane conductance regulator (CFTR). CFTR plays a critical role in the regulation of ion transport in a number of exocrine epithelia. Improvement or restoration of CFTR function, where it is deficient, should improve the CF phenotype. There are >1000 reported disease-causing mutations of the CFTR gene. Recent investigations have afforded a better understanding of the mechanism of dysfunction of many of these mutant CFTRs, and have allowed them to be classified according to their mechanism of dysfunction. These data, as well as an enhanced understanding of the role of CFTR in regulating epithelial ion transport, have led to the development of therapeutic strategies based on pharmacologic enhancement or repair of mutant CFTR dysfunction. The strategy, termed 'protein repair therapy', is aimed at improving the regulation of epithelial ion transport by mutant CFTRs in a mutation-specific fashion. The grouping of CFTR gene mutations, according to mechanism of dysfunction, yields some guidance as to which pharmacologic repair agents may be useful for specific CFTR mutations. Recent data has suggested that combinations of pharmacologic repair agents may be necessary to obtain clinically meaningful CFTR repair. Nevertheless, such strategies to improve mutant CFTR function hold great promise for the development of novel therapies aimed at correcting the underlying pathophysiology of CF.

Cystic Fibrosis↗
PubMed2003

Pharmacological approaches to correcting the ion transport defect in cystic fibrosis.

Cystic fibrosis (CF) is a lethal genetic disease caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), which mainly (but not exclusively) functions as a chloride channel. The main clinical symptoms are chronic obstructive lung disease, which is responsible for most of the morbidity and mortality associated with CF, and pancreatic insufficiency. About 1000 mutations of the gene coding for CFTR are currently known; the most common of these, present in the great majority of the patients (Delta508) results in the deletion of a phenylalanine at position 508. In this mutation, the aberrant CFTR is not transported to the membrane but degraded in the ubiquitin-proteasome pathway. The aim of this review is to give an overview of the pharmacologic strategies currently used in attempts to overcome the ion transport defect in CF. One strategy to develop pharmacologic treatment for CF is to inhibit the breakdown of DeltaF508-CFTR by interfering with the chaperones involved in the folding of CFTR. At least in in vitro systems, this can be accomplished by sodium phenylbutyrate, or S-nitrosoglutathione (GSNO), and also by genistein or benzo[c]quinolizinium compounds. It is also possible to stimulate CFTR or its mutated forms, when present in the plasma membrane, using xanthines, genistein, and various other compounds, such as benzamidizoles and benzoxazoles, benzo[c]quinolizinium compounds or phenantrolines. Experimental results are not always unambiguous, and adverse effects have been incompletely tested. Some clinical tests have been done on sodium phenyl butyrate, GSNO and genistein, mostly in respect to other diseases, and the results demonstrate that these drugs are reasonably well tolerated. Their efficiency in the treatment of CF has not yet been demonstrated, however. An alternative strategy is to compensate for the defective chloride transport by CFTR by stimulation of other chloride channels. This can be done via purinergic receptors. A phase I study using a stable uridine triphosphate analog has recently been completed. A second alternative strategy is to attempt to maintain hydration of the airway mucus by inhibiting Na(+) uptake by the epithelial Na(+) channel using amiloride or stable analogs of amiloride. Clinical tests so far have been inconclusive. A number of other suggestions are currently being explored. The minority of patients with CF who have a stop mutation may benefit from treatment with gentamicin. The difficulties in finding a pharmacologic treatment for CF may be due to the fact that CFTR has additional functions besides chloride transport, and interfering with CFTR biosynthesis or activation implies interference with central cellular processes, which may have undesirable adverse effects.

Cystic Fibrosis↗
PubMed2004

Cloning, pharmacological characterisation and tissue distribution of a novel 5-HT4 receptor splice variant, 5-HT4(i).

5-HT4 receptor pre-mRNA is alternatively spliced in human (h) tissue to produce several splice variants, called 5-HT4(a) to 5-HT4(h) and 5-HT4(n). Polymerase chain reaction (PCR) with primers designed to amplify both 5-HT4(a) and 5-HT4(b) amplified three additional bands in different tissues, two representing different mRNA species both encoding 5-HT4(g) and one representing mRNA for a novel splice variant named 5-HT4(i), cloned from testis and pancreas respectively. Primary and nested PCR detected both 5-HT4(g) and 5-HT4(i) in multiple tissues. Whereas 5-HT4(i), was found in all cardiovascular tissues analysed, 5-HT4(g) was mainly present in atria. However, quantitative RT-PCR indicated 5-HT4(g) expression also in cardiac ventricle. The pharmacological profiles and ability to activate adenylyl cyclase (AC) were compared between four recombinant h5-HT4 splice variants (a, b, g and i) expressed transiently and stably in HEK293 cells. Displacement of [(3)H]GR113808 with ten ligands revealed identical pharmacological profiles (affinity rank order: GR125487, SB207710, GR113808>SB203186>serotonin, cisapride, tropisetron>renzapride, 5-MeOT>5-CT). In transiently transfected HEK293 cells cisapride was a partial agonist compared to serotonin at 5-HT4(b), 5-HT4(g) and 5-HT4(i) receptors. In membranes from HEK293 cells stably expressing 5-HT4(g) (3,000 fmol/mg protein) or 5-HT4(i) (500 fmol/mg protein), serotonin and 5-MeOT were full agonists while cisapride was full agonist at 5-HT4(g) and partial agonist at 5-HT4(i), probably due to different receptor expression levels. At both 5-HT4(g) and 5-HT4(i), the behaviour of 5-HT4 receptor antagonists was dependent on receptor level. At high receptor levels, tropisetron and SB207710 and to a variable extent SB203186 and GR113808 displayed some partial agonist activity, whereas GR125487 and SB207266 reduced the AC activity below basal, indicating both receptors to be constitutively active. We conclude that the novel 5-HT4(i) receptor splice variant is pharmacologically indistinguishable from other 5-HT4 splice variants and that the 5-HT4(i) C-terminal tail does not influence coupling to AC.

Adenylyl Cyclases↗
PubMed2000

Pharmacological studies on the inhibitory action of melatonin and putative melatonin analogues on porcine vascular smooth muscle.

The effect of high concentrations of melatonin, and related indole-based and naphthalene-based derivatives, has been examined in the porcine coronary artery, pulmonary artery and the marginal artery of the colon. In addition, we have pharmacologically examined the role of cyclic GMP in the relaxatory action of these agents. Cumulative addition of melatonin (3-300 microM) caused a slowly developing relaxation in all three vascular preparations pre-contracted with 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2alpha (U46619), a thromboxane mimetic agent. The estimated pIC50 values were 4.10-3.70 (coronary artery), 3.89 (pulmonary artery) and 3.96 (marginal artery). All melatonin analogues examined also produced concentration-dependent inhibition of U46619-induced contractions of the coronary and marginal arteries in a qualitatively similar manner to melatonin. The rank order of potency (based on the pIC50 values) of these compounds in both vascular tissues was N-[2-(3-ethyl-7-methoxynaphthyl) ethyl]-acetamide (S21634) >2-iodomelatonin = N-[2-(7-methoxynaphth-1-yl)-ethyl]-acetamide (S20098) = N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide (S20928) >melatonin >N-acetyl-5-HT. Finally, the pharmacological characteristics of melatonin and S21634 as phosphodiesterase inhibitors were compared to those of zaprinast, a known cyclic GMP-specific phosphodiesterase inhibitor. Zaprinast also caused concentration-dependent inhibition of U46619-induced tone. All three compounds, zaprinast (10 microM), melatonin (300 microM) and S21634 (30 microM), significantly enhanced sodium nitroprusside-induced relaxations. The inhibitory action of zaprinast per se was greater in the presence of the endothelium and significantly attenuated by 3 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective inhibitor of guanylyl cyclase. In marked contrast, the vasorelaxant action of melatonin and S21634 was not affected by the removal of the endothelium or the addition of ODQ. In summary, we have shown that porcine arterial smooth muscle relaxes in response to high concentrations of melatonin and other related melatonin receptor ligands. However, it appears that the receptive site is pharmacologically different from the melatonin receptors currently known and does not involve inhibition of cyclic GMP-specific phosphodiesterase.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is increasingly used by young people for its euphoric and empathic effects. MDMA presents non-linear pharmacokinetics, probably by inhibition of cytochrome P450 isoform 2D6. Users are known to often take more than one dose per session. This practice could have serious implications for the toxicity of MDMA. OBJECTIVE: To evaluate the pharmacological effects and pharmacokinetics of MDMA following the administration of two repeated doses of MDMA (24 h apart). METHODS: A randomised, double-blind, cross-over, placebo controlled trial was conducted in nine healthy male subjects. Variables included physiological, psychomotor performance, subjective effects, endocrine response and pharmacokinetics. MDMA 100 mg or placebo was administered in two successive doses separated by an interval of 24 h. RESULTS: MDMA produced the prototypical effects of the drug. Following a second dose, plasma concentrations of MDMA increased (AUC 77% and Cmax 29%) in comparison with the first. The increase is greater than those expected by simple accumulation and indicates metabolic inhibition. The pharmacological effects after the second dose were slightly higher than those observed after the first in the majority of variables including blood pressure, heart rate, most subjective effects and cortisol concentrations. The effects were similar in the case of pupil diameter, esophoria and prolactin. CONCLUSIONS: Pharmacological effects after the second administration were higher than those following the first but lower than expected. A disproportionate increase in plasma concentrations in MDMA and MDA was observed most likely due to metabolic inhibition. This inhibition lasts at least 24 h. Further experiments need to be conducted to evaluate its duration.

Adult↗
PubMed2005

Ionotropic and metabotropic glutamate receptor structure and pharmacology.

RATIONALE: L: -Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and mediates its actions via activation of both ionotropic and metabotropic receptor families. The development of selective ligands, including competitive agonists and antagonists and positive and negative allosteric modulators, has enabled investigation of the functional roles of glutamate receptor family members. OBJECTIVE: In this review we describe the subunit structure and composition of the ionotropic and metabotropic glutamate receptors and discuss their pharmacology, particularly with respect to selective tools useful for investigation of their function in the CNS. RESULTS: A large number of ligands are now available that are selective either for glutamate receptor subfamilies or for particular receptor subtypes. Such ligands have enabled considerable advances in the elucidation of the physiological and pathophysiological roles of receptor family members. Furthermore, efficacy in animal models of neurological and psychiatric disorders has supported the progression of several glutamatergic ligands into clinical studies. These include ionotropic glutamate receptor antagonists, which have entered clinical trials for disorders including epilepsy and ischaemic stroke, alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor positive allosteric modulators which are under evaluation as cognitive enhancers, and metabotropic glutamate receptor 2 (mGluR2) agonists which are undergoing clinical evaluation as anxiolytics. Furthermore, preclinical studies have illustrated therapeutic potential for ligands selective for other receptor subtypes in various disorders. These include mGluR1 antagonists in pain, mGluR5 antagonists in anxiety, pain and drug abuse and mGluR5 positive allosteric modulators in schizophrenia. CONCLUSIONS: Selective pharmacological tools have enabled the study of glutamate receptors. However, pharmacological coverage of the family is incomplete and considerable scope remains for the development of novel ligands, particularly those with in vivo utility, and for the their use together with existing tools for the further investigation of the roles of receptor family members in CNS function and as potentially novel therapeutics.

Allosteric Regulation↗
PubMed2007

The pharmacological management of childhood anxiety disorders: a review.

RATIONALE: Pediatric anxiety is a prevalent psychiatric disorder that may have important implications for school, social, and academic function. Psychopharmacological approaches to the treatment of pediatric anxiety have expanded over the past 20 years and increasing empirical evidence helps guide current clinical practice. OBJECTIVE: To review studies which examine the pharmacological treatment of pediatric anxiety disorders, including obsessive-compulsive disorder and to summarize treatment implications. METHODS: All relevant studies were searched using MEDLINE and PsycINFO search engines, supplemented by a manual bibliographical search; studies published between 1985 and 2006 that met inclusion criteria were examined. RESULTS: This article provides a systematic review of the psychopharmacological treatment of pediatric anxiety disorders based on available empirical evidence, with a focus on randomized controlled trials. General treatment principles and pharmacological management of specific pediatric anxiety disorders are also reviewed. CONCLUSION: There is good evidence to support the efficacy of several pharmacological agents including the selective serotonin reuptake inhibitors to treat pediatric anxiety and obsessive-compulsive disorder, although there are still many unanswered questions.

Adolescent↗
PubMed2000

Pharmacological and behavioral characterization of cocaine-kindled seizures in mice.

RATIONALE: Convulsions associated with cocaine toxicity are a serious aspect of cocaine-related emergency room incidents. Seizures can result from a single high dose of cocaine, and evidence is accumulating that correlates repetitive administration of sub-convulsive doses of cocaine with a decreased seizure threshold, a phenomenon known as pharmacological kindling. A murine model of cocaine kindling has not been characterized. OBJECTIVES: To determine the necessary and sufficient conditions for generating increased sensitivity to the convulsive and lethal effects of cocaine and to characterize some of the basic pharmacological and behavioral consequences of this phenomenon in mice. METHODS: Male, Swiss-Webster mice were given repeated injections of cocaine. RESULTS: Daily administration of 60 mg/kg cocaine produced robust kindling; significant leftward shifts in the dose-effect curves for seizures were observed in cocaine-kindled mice. Cocaine kindling was enduring as these left shifts persisted for at least 20 days, indicating possible permanent synaptic changes. Induction of convulsions per se, utilizing 75 mg/kg cocaine, was not sufficient to engender kindling with a non-optimal dose (40 mg/kg). However, administration of a non-kindling dose of cocaine (40 mg/kg) for as few as four occasions produced increased seizure sensitivity to a 60-mg/kg cocaine challenge. The lethal potencies of cocaine and methamphetamine were significantly increased in cocaine-kindled mice. The baseline locomotor activity of kindled mice was not different from that of non-kindled mice. However, challenge doses of cocaine revealed significant differences in the vertically directed activity of kindled versus non-kindled mice. CONCLUSIONS: Overall, this study provides a description of important parameters for a model of cocaine kindling in mice that may be useful for the elucidation of mechanisms responsible for the long-term changes in sensitivity to cocaine and the discovery of novel pharmacological treatments.

Animals↗