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PubMed2000

The pharmacology of headache.

Headache is a common problem which besets most of us at some time or the other. The pharmacology of headache is complex in an overall sense but can be understood in terms of the anatomy and physiology of the pain-producing structures. Migraine can be used as a template to understand the activation of nociceptive systems in the head and thus their neurotransmitter mediation and modulation. In recent years, the role of serotonin (5-HT) in headache pharmacology has been unravelled in the context of both understanding its role in the nociceptive systems related to headache and by exploiting its 5-HT1 receptor subtypes in headache therapeutics. The pharmacology of the head pain systems, as they are known and as they might evolve, are explored in the context of both, the anatomy and physiology of trigeminovascular nociception and in the context of clinical questions, such as those of efficacy, headache recurrence and adverse events.

Brain Chemistry↗
PubMed1999

Subunit- and site-specific pharmacology of the NMDA receptor channel.

N-Methyl-D-aspartate (NMDA) receptor channels play important roles in various physiological functions such as synaptic plasticity and synapse formation underlying memory, learning and formation of neural networks during development. They are also important for a variety of pathological states including acute and chronic neurological disorders, psychiatric disorders, and neuropathic pain syndromes. cDNA cloning has revealed the molecular diversity of NMDA receptor channels. The identification of multiple subunits with distinct distributions, properties and regulation, implies that NMDA receptor channels are heterogeneous in their pharmacological properties, depending on the brain region and the developmental stage. Furthermore, mutation studies have revealed a critical role for specific amino acid residues in certain subunits in determining the pharmacological properties of NMDA receptor channels. The molecular heterogeneity of NMDA receptor channels as well as their dual role in physiological and pathological functions makes it necessary to develop subunit- and site-specific drugs for precise and selective therapeutic intervention. This review summarizes from a molecular perspective the recent advances in our understanding of the pharmacological properties of NMDA receptor channels with specific references to agonists binding sites, channel pore regions, allosteric modulation sites for protons, polyamines, redox agents, Zn2+ and protein kinases, phosphatases.

Animals↗
PubMed1999

Biochemistry and pharmacology of rabbit cardiac growth hormone (GH) receptors.

In this report we present the first in-depth description of the biochemical and pharmacological properties of rabbit cardiac GH receptors. The apparent M(r)'s of the [125I]human (h) GH-receptor complexes were 380, 205, 90, 62, 52 and 38 kDa as demonstrated by an autoradiograph of affinity-labelled cardiac GH receptors separated under non-reducing conditions by SDS PAGE. The [125I]hGH-cardiac GH receptor complexes were disulfide-linked since the M(r)s of the complexes diminished to 170, 116, 97, 71, 45 and 38 kDa under reducing conditions, indicating the presence of multiple receptors, receptor-associated macromolecules or receptor and ligand in various ratios. The pharmacology of cardiac GH receptors is not typical of GH receptors present in other tissues. In radio receptor assays, both bovine GH and ovine prolactin were 50-fold and 100-fold less potent, respectively, than unlabelled hGH, in blocking the binding of [125I]hGH to cardiac binding sites and were, therefore, extremely weak antagonists. Similarly, neither bovine GH nor ovine prolactin blocked the [125I]hGH affinity-labelling of cardiac GH receptors compared to equivalent doses of unlabelled hGH. Parameters which characterize the kinetics for the association, dissociation and equilibrium binding of [125I]hGH to cardiac GH receptors were ascertained. Association kinetics for the binding of [125I]hGH to heart GH receptors exhibited a maximum specific binding at 17 h and 25 degrees C. The association of [125I]hGH to heart GH receptors was reversible with approximately 15 h required for half of the specifically bound [125I]hGH to dissociate. The coupling of [125I]hGH to heart GH receptors was optimum at pH 6 and the strength of the equilibrium binding, as measured by the ED50, was approximately 2 ng/ml. These data indicate that the cardiac GH receptors are pharmacologically distinct and that there is a M(r) heterogeneity in the [125I]hGH receptor complexes.

Animals↗
PubMed2000

Biophysical and pharmacological characterization of voltage-sensitive calcium currents in neonatal rat inferior colliculus neurons.

Calcium conductances have been found in neonatal inferior colliculus neurons, however the biophysical and pharmacological profiles of the underlying calcium currents have not yet been characterized. In this study, we examined which types of voltage-activated calcium currents comprise the whole-cell inward current of neonatal inferior colliculus neurons (10-22microm in diameter). On the basis of their voltage-dependence and pharmacological sensitivities, three major components of barium currents were identified. A low threshold voltage-activated current that activated around -70mV, a mid threshold voltage-activated current that activated near -50mV, and a high threshold voltage-activated current that activated around -40mV. Low and mid threshold voltage-activated currents were present in 33% and 41% of the recordings, respectively, whereas high threshold voltage-activated currents were recorded in all inferior colliculus neurons tested. Nickel chloride (50microM) and U-92032 (1microM), which both block low threshold voltage-activated currents, reduced the amplitude of low threshold voltage-activated peak currents at a test potential of -60mV by 72% and 10%, respectively. In addition, 50microM nickel chloride and 1microM U-92032 reduced the amplitude of mid threshold voltage-activated peak currents measured at -20mV by 55% and 21%, respectively. Further pharmacological analysis indicated the presence of multiple types of high threshold voltage-activated currents in neonatal inferior colliculus neurons. The dihydropyridine nimodipine (1microM), a selective L-type current antagonist, reduced the amplitude of high threshold voltage-activated peak currents by 25%. In addition, FPL 64176 (1microM), a non-dihydropyridine L-type current agonist caused a dramatic 534% increase in the amplitude of the slow sustained component of the tail current measured at -40mV. These data indicate that inferior colliculus neurons express L-type channels. omega-Conotoxin GVIA (1microM), a selective blocker of N-type current, inhibited high threshold voltage-activated peak currents by 28% indicating the presence of N-type channels. omega-Agatoxin IVA (300nM), a potent P/Q-type antagonist, reduced high threshold voltage-activated peak currents by 27%, suggesting that inferior colliculus neurons express P/Q-type channels. Concomitant application of nimodipine (1microM), omega-conotoxin GVIA (1microM) and omega-agatoxin IVA (300nM) onto inferior colliculus neurons decreased the control high threshold voltage-activated peak currents only by 62%.Thus, inferior colliculus neurons may express at least one more type of calcium current in addition to low and mid threshold voltage-activated currents and L-type, N-type and P/Q-type high threshold currents.

Animals↗
PubMed2003

Excitation by dopamine of rat subthalamic nucleus neurones in vitro-a direct action with unconventional pharmacology.

Recent anatomical and physiological studies have pointed to a functional innervation of the subthalamic nucleus by dopamine. This nucleus has a pivotal role in basal ganglia function and voluntary movement control and the possibility that dopamine, and dopaminergic medication used in Parkinson's disease, might directly influence its activity is of considerable interest. We have evaluated electrophysiologically the action and pharmacology of dopamine on single subthalamic neurones in rat brain slices. Dopamine increased firing rate to up to a mean of 60% in 98% of the 261 neurones tested when examined using extracellular single-unit recording. This excitation was unaffected by the GABA antagonist picrotoxin, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted in a low Ca(2+)/raised Mg(2+) solution, indicative of a direct action, independent of synaptic transmission. Of the 33 cells examined using whole patch-clamp recording, only 13 showed measurable increases in firing rate and/or depolarisations in response to dopamine. Dopamine-responsive cells displayed significantly greater access resistance, suggesting that an unidentified cytoplamic constituent, removed by whole-cell dialysis, was required for the response. Using extracellular recording, the D2-like dopamine receptor agonists quinpirole and bromocryptine, but not the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, also consistently caused an excitation. This was mimicked by the catecholamine releaser amphetamine in 60% of cells tested. However, the dopamine excitation was not significantly reduced either by the D1-like receptor antagonist 7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine or the D2-like receptor antagonists (-)-sulpiride, eticlopride and (+)-butaclamol, and the quinpirole excitation was also unaffected by (-)-sulpiride. In contrast, (-)-sulpiride, eticlopride and (+)-butaclamol all abolished the D2-like receptor-mediated inhibition by dopamine of substantia nigra pars compacta neurones. The alpha-adrenoceptor antagonist phentolamine was a weak antagonist of dopamine excitations, but not of those caused by quinpirole. Dopamine excitations also showed weak sensitivity to the 5-HT(2) antagonist ritanserin, but were unaffected by the alpha(1)-adrenoceptor antagonist prazocin and the beta-adrenoceptor antagonist propranolol. The pharmacology of this dopamine excitation is inconsistent with an action on any known catecholamine receptor. However, the effect of amphetamine indicates that an unidentified monamine--possibly dopamine--can be released within the subthalamic nucleus to cause an excitation. The anomalies of its pharmacological characterisation do not strongly support a physiologically relevant direct action of dopamine in the rat subthalamic nucleus.

Amphetamine↗
PubMed1997

Localization and pharmacological characterization of pigeon diazepam-insensitive GABAA receptors.

Transduction mechanisms associated with ligand binding at diazepam-insensitive subtypes of GABAA receptors remain largely unknown, but unique behavioral effects of ligands binding at these sites have been reported in pigeons. The present study further evaluated the pharmacological characteristics of diazepam-insensitive GABAA receptors in pigeon brain, using [3H]Ro 15-4513. Autoradiography detected diazepam-insensitive benzodiazepine sites on GABAA receptors in a number of brain regions, with the highest densities present in the olfactory bulb, hippocampus, thalamic nuclei and cerebellar granule cell layers, with densities of approximately 10-20% of total benzodiazepine receptor binding. Saturation analysis revealed significant densities (approximately 10% of total benzodiazepine receptor binding) of extracerebellar diazepam-insensitive benzodiazepine receptors in optic lobe, hippocampus, and brainstem compared to 27% in cerebellum. As reported for mammalian diazepam-sensitive benzodiazepine receptors, GABA (50 microM) generally increased the affinities of agonists and partial agonists, had little effect on the affinities of antagonists, and decreased the affinity of an inverse agonist for pigeon cerebellar diazepam-sensitive benzodiazepine receptors. GABA modulation of ligand binding to diazepam-insensitive benzodiazepine receptors was less than that observed for diazepam-sensitive sites, and no positive modulation was observed. These results demonstrate the presence of cerebellar and extracerebellar diazepam-insensitive benzodiazepine receptors in pigeon brain, with distribution patterns and pharmacology similar to those reported in mammals. The comparable central localization and pharmacological properties of drugs at diazepam-sensitive and -insensitive benzodiazepine receptors in pigeons and rats attests to the evolutionary conservation of GABAA systems.

Affinity Labels↗
PubMed1998

Pharmacological characterization of ionotropic excitatory amino acid receptors in young and aged rat basal forebrain.

Ionotropic glutamate receptors were characterized in acutely dissociated medial septum/nucleus of diagonal band neurons from one- to four-month- and 24-26-month-old male Fischer 344 rats. Whole-cell patch-clamp recordings were used to study glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, kainate and N-methyl-D-aspartate-induced currents. Pharmacological properties of these ionotropic receptors were studied across different age groups by comparing concentration response curves and EC50 for agonist-induced currents, as well as dissociation constants (Kb) for competitive receptor antagonists. Our results suggest that non-N-methyl-D-aspartate receptors on medial septum/nucleus of diagonal band neurons were predominantly of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type and display biophysical and pharmacological properties similar to other central neurons. However, peak alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-induced currents were enhanced in aged (35.0+/-4.4 pA/pF) compared to young cells (16.2+/-1.7 pA/pF, P<0.005), and the EC50 shifted to the right (4.4+/-0.6 in young compared to 8.8+/-1.3 microM in aged, P<0.05). The Kb for 6,7-dinitroquinoxaline-2,3-dione inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-induced currents likewise shifted to the right (0.16+/-0.02 in young and 0.29+/-0.04 microM in aged, P<0.05) suggesting an age-related decrease in affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors. N-Methyl-D-aspartate-induced currents were generated in standard physiological solutions with the addition of 1 microM glycine and the removal of Mg2+. The N-methyl-D-aspartate responses were predictably modulated by magnesium and glycine, and were antagonized by the competitive antagonist 2-amino-5-phosphonovaleric acid. No age-related change in N-methyl-D-aspartate maximum, EC50, magnesium sensitivity, glycine sensitivity or Kb for 2-amino-5-phosphonovaleric acid was observed. Overall, our results suggest that ionotropic glutamate receptors in the medial septum/nucleus of diagonal band have a similar pharmacological profile compared to glutamate receptors in other brain regions. More importantly, these data suggest that while medial septum/nucleus of diagonal band cells maintain N-methyl-D-aspartate receptors during ageing, a significant increase in current density and decrease in receptor affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, during this same time period, may provide a mechanism for age-related changes in neuronal plasticity and excitotoxicity in the basal forebrain.

Aging↗
PubMed1996

Pharmacologic regulation of Dupuytren's fibroblast contraction in vitro.

Dupuytren's disease is associated with contraction of specialized fibroblasts present in the diseased palmar fascia. Pharmacologic agents were evaluated for their ability to promote or inhibit contraction of Dupuytren's fibroblasts in vitro using a collagen lattice contraction assay. In the first part of the study, lysophosphatidic acid (LPA), serotonin, angiotensin II, and prostaglandin F2 alpha were tested for their ability to promote Dupuytren's fibroblast contraction. Lysophosphatidic acid was found to significantly promote Dupuytren's fibroblast contraction as compared with controls. This response to LPA is dose dependent, with a half-maximal response of 0.07 microM. Angiotensin II, serotonin, and prostaglandin F2 alpha at 1 mM, induced a significant amount of contraction as compared to controls, but the amount of contraction was at least six times less than that observed for LPA. In the second part of the study, prostaglandins E1 and E2 or the calcium blockers nifedipine and verapamil were tested for their ability to inhibit LPA-promoted contraction. It was found that both types of inhibitors partially block LPA-promoted contraction of Dupuytren's fibroblasts. The effect of the various pharmacologic agents on normal palmar fibroblasts was not evaluated. The focus of this study was to examine the regulation of contraction of Dupuytren's fibroblasts. This study demonstrates that LPA is a potent agonist of Dupuytren's fibroblast contraction and that this contraction can be inhibited by specific pharmacologic agents. These findings provide a rational basis for investigating further the clinical use of the calcium channel blockers nifedipine or verapamil and prostaglandins E1 and E2 to control Dupuytren's disease and possibly other fibrotic conditions.

Alprostadil↗
PubMed1982

Determination of diazepam and its pharmacologically active metabolites in blood by bond Elut column extraction and reversed-phase high-performance liquid chromatography.

A rapid and quantitative analytical micro method for the determination of diazepam and its major pharmacologically active metabolites utilizing high-performance liquid chromatography (HPLC) is reported. The drug and its metabolites were extracted from 50-100 microliter samples of whole blood, serum or plasma using Bond Elut C 18 column and quantitated by high-performance liquid chromatography, using Technician Fast-LC-C-8 (RP 5 micrometers) bonded column and a mobile phase consisting of 53% methanol, 1% acetonitrile in KH2PO4 buffer and 10 microliters/l triethylamine. Methyl nitrazepam and medazepam were used as internal and external standards respectively. The extraction and recovery of diazepam and its major pharmacologically active metabolites, i.e., 3-hydroxydiazepam, desmethyldiazepam and oxazepam from blood were higher than 88% for all compounds. The minimum detection range of each compound was approximately 2.5 ng per 100-microliter sample. This micro method of simultaneous quantitation of diazepam and its major pharmacologically active metabolites provides a valuable technique for the study of diazepam pharmacokinetics in a small animal model without disturbance of normal hemodynamics from excess blood loss, as well as in clinical evaluation of pediatric patients.

Chromatography, High Pressure Liquid↗
PubMed2002

Pharmacological effects of lavandulifolioside from Leonurus cardiaca.

Lavandulifolioside was detected for the first time in Leonurus cardiaca var. vulgaris [Moench] Briquet (Lamiaceae). The isolation was performed from the butanolic extract of the aerial parts and the identification by NMR and MS. The pharmacological properties of lavandulifolioside consist of significant negative chronotropism, prolongation of the P-Q, Q-T intervals and QRS complex, and decrease of blood pressure. Contrary to the butanolic extract lavandulifolioside did not reduce the spontaneous locomotor activity. In conclusion, the pharmacological pattern of lavandulifolioside did not explain the pharmacological effects of L. cardiaca L. alone.

Animals↗
PubMed1999

Pharmacologic stress echocardiography. Dobutamine and arbutamine stress testing.

Pharmacologic stress testing is an important noninvasive method for evaluating patients with known or suspected coronary artery disease who are unable to adequately exercise. Pharmacologic stress echocardiography using dobutamine has been developed over the last 10 to 15 years as an alternative to vasodilator stress testing using nuclear perfusion imaging. As experience has grown, digital subtraction echocardiogram has been shown to be a safe, convenient, and reliable method for stress testing in a variety of patient populations. Digital subtraction echocardiogram has comparable sensitivity, specificity, and accuracy when compared to other stress testing methods which employ cardiac imaging and is superior to the exercise echocardiogram. It has certain advantages over nuclear perfusion imaging in terms of cost and convenience. The recent addition of arbutamine echocardiography (which has been shown to be comparable to digital subtraction echocardiogram) provides another alternative method for pharmacologic stress testing. Continued improvement in echocardiographic image quality and the development of new technologies such as tissue harmonic imaging and contrast echocardiography will hopefully improve the echocardiographic evaluation of wall motion therefore increasing the diagnostic accuracy of echocardiographic stress testing.

Adrenergic beta-Agonists↗
PubMed1987

Status of the myocardium and infarct-related coronary artery in 19 necropsy patients with acute recanalization using pharmacologic (streptokinase, r-tissue plasminogen activator), mechanical (percutaneous transluminal coronary angioplasty) or combined types of reperfusion therapy.

In acute myocardial infarction, myocardial salvage is dependent on rapid restoration of blood flow. Pharmacologic (streptokinase, recombinant tissue-type plasminogen activator), mechanical (percutaneous transluminal coronary angioplasty, guide wire perforation) or combined forms of reperfusion therapy can accomplish this goal, but their effects on infarcted myocardium and vessel occlusion site have not been compared at necropsy. The heart of 19 necropsy patients who had received various forms of acute reperfusion therapy was studied: 14 had pharmacologic or combined forms of reperfusion therapy (13 streptokinase and 1 tissue-type plasminogen activator, including 4 with combined balloon angioplasty) and 5 had had purely mechanical (balloon angioplasty) reperfusion therapy. Reperfusion was initially clinically successful in all 19 patients with the average time from onset of symptoms to reperfusion being 3.7 hours. Necropsy observations separated the 19 patients into distinct subgroups based on changes in the myocardium and infarct-related coronary arteries. Of the 19 patients, 14 (74%) had hemorrhagic myocardial infarction and they all received pharmacologic or combined forms of reperfusion therapy. The remaining five patients (26%) had nonhemorrhagic (anemic) infarction and were treated with balloon angioplasty therapy alone. Increased luminal cross-sectional area was present in 8 of 9 patients with acute balloon angioplasty but severe coronary atherosclerotic plaque remained in 9 of 10 patients without acute balloon angioplasty. Severe hemorrhage surrounded angioplasty sites in all four patients who also received streptokinase or tissue-type plasminogen activator. Severe bleeding at the angioplasty site compromised the dilated coronary lumen in one patient. No patient with angioplasty alone had intraplaque bleeding. Thus, acute coronary balloon angioplasty reperfusion therapy alone appears to avoid the potentially adverse effects of myocardial and intraplaque hemorrhage while simultaneously increasing luminal cross-sectional area at the site of acute occlusion.

Adult↗
PubMed1998

Prognostic value of pharmacological stress echocardiography in women with chest pain and unknown coronary artery disease.

OBJECTIVES: In this study we sought to investigate the prognostic value of pharmacological stress echocardiography in women referred for chest pain, having unknown coronary artery disease. BACKGROUND: The noninvasive identification of a high-risk subgroup among women with chest pain and unknown coronary artery disease is an unresolved task to date. METHODS: A total of 456 women (mean [+/-SD] age 63+/-10 years) underwent pharmacological stress echocardiography with either dipyridamole (n = 305) or dobutamine (n = 151) for evaluation of chest pain and were followed-up for 32+/-19 months. None of them had a previous diagnosis of coronary artery disease. RESULTS: No major complication occurred during stress testing. Five tests (1.1%) were prematurely interrupted because of the appearance of side effects. Echocardiographic positivity was identified in 51 patients. During the follow-up, 23 cardiac events occurred: 3 deaths, 10 infarctions and 10 cases of unstable angina; an additional 21 patients underwent coronary revascularization. At Cox analysis, the echocardiographic evidence of ischemia was found as the only independent predictor of hard cardiac events (death, infarction) (odds ratio [OR] = 27.5; 95% confidence interval [CI] = (6.5 to 115.5; p = 0.0000). When spontaneous cardiac events (death, infarction and unstable angina) were considered as endpoints, the positive echocardiographic result (OR = 23.9; 95% CI = 8.6 to 66.8; p = 0.0000) and family history of coronary artery disease (OR = 3.7; 95% CI = 1.5 to 9.1; p = 0.0037) were independently correlated with prognosis. By using an interactive stepwise procedure, the prognostic value of stress echocardiography was found to be incremental to that provided by clinical variables, both considering hard and spontaneous cardiac events as endpoints. The 3-year survival rate for the negative and the positive population was respectively, 99.5% and 69.5% (p = 0.0000) considering hard cardiac events, 99.2% and 50.6% (p = 0.0000) considering spontaneous cardiac events. CONCLUSIONS: Pharmacological stress echocardiography is safe, highly feasible and effective in risk stratification of women with chest pain and unknown coronary artery disease, also when hard endpoints are considered. Its use can have relevant implications in daily clinical practice for selection of patients needing further investigations.

Aged↗
PubMed1999

Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope.

OBJECTIVES: The purpose of the present study was to systematically evaluate the diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in a consecutive series of patients with recurrent unexplained syncope. BACKGROUND: Carotid sinus hypersensitivity (CSH) is an infrequently recognized cause of recurrent unexplained syncope usually diagnosed by carotid sinus massage (CSM) in the supine position. The diagnostic utility of systematic assessment of mechanical, pharmacological and orthostatic stimulation of the carotid sinus has not been clearly established. METHODS: Eighty consecutive patients (63 +/- 12 years) with a history of recurrent unexplained syncope (mean episodes: 6 +/- 3); 30 age-matched controls (65 +/- 14 years) and 16 patients (59 +/- 12 years) with syncope not related to CSH were studied. Pharmacological stimulation of the carotid sinus was achieved by randomly administering bolus injections of nitroprusside and phenylephrine. Mechanical stimulation of the carotid sinus was performed by CSM applied for 5 s in the supine position and after 2 min at 60 degrees. A 60 degree low-dose isoproterenol head-up tilt test (HUTT) was also performed for a total duration of 30 min. RESULTS: Carotid sinus hypersensitivity was elicited by CSM in the supine position in seven (8.7%) patients, two (6.6%) controls and one (6.3%) patient with syncope unrelated to CSH, compared with 48 (60%) patients, two (6.6%) controls and one (6.3%) syncope unrelated to CSH patient after 60 degree HUTT, increasing the diagnostic yield by 51%. Baroreceptor gain was significantly reduced in the CSH group. Head-up tilt test was positive in 12 (25%) patients with CSH, two (6.6%) controls and two (12%) with documented syncope but not positive in any of the patients in which syncope remained unexplained. Diagnostic accuracy was enhanced by 38% (31% supine vs. 69% upright) when CSM was performed at 60 degrees. CONCLUSIONS: CSH was documented in 68% of patients, 8.7% in the supine position and 60% in the upright position. Sensitivity was increased by 51%, and diagnostic accuracy was enhanced by 38% by performing CSM in the upright position. Decreased baroreceptor gain was documented and may play a role in the pathophysiology of CSH.

Aged↗
PubMed1999

Familial polymorphic ventricular arrhythmias: a quarter century of successful medical treatment based on serial exercise-pharmacologic testing.

OBJECTIVES: We sought to determine whether objective tests of antiarrhythmic drug efficacy could produce favorable short- and long-term outcomes in a family with idiopathic malignant ventricular arrhythmias. BACKGROUND: In 1973 a family presented with a history of several generations of syncopal spells and sudden death. Some individuals had nonspecific electrocardiographic (ECG) changes. Their QT intervals were normal at rest and with exercise. Autopsies in two young family members showed no cardiac abnormalities, specifically no evidence of arrhythmogenic right ventricular dysplasia, other cardiomyopathy, myocarditis or gross abnormality of the conduction system. METHODS: Available family members had screening ECGs. Symptomatic members had a battery of tests, including electrophysiologic studies, ambulatory ECGs, audiograms, exercise stress testing, serum catecholamine levels during rest and exercise and isoproterenol infusion. Serial exercise-pharmacologic testing was performed in symptomatic family members until induction of an arrhythmia during exercise required higher work loads or became impossible. RESULTS: Arrhythmias were not induced during electrophysiologic studies. In several family members tested, ventricular premature beats and then rapid polymorphic ventricular arrhythmias occurred whenever the sinus rate exceeded 130 beats/min. Emotional stress, isoproterenol infusion and exercise all elicited similar arrhythmias. Catecholamine levels during exercise were, however, unequivocally normal in two of three family members tested. Beta-blockers appeared to be the most effective pharmacologic agent for prevention of these arrhythmias. The efficacy of treatment has been confirmed during a follow-up of 25 years. CONCLUSIONS: This family appears to have catecholamine hypersensitivity as the basis for their ventricular arrhythmias. Guided therapy using serial exercise-pharmacologic testing provided reliable protection for this familial ventricular arrhythmia during a 25-year follow-up.

Adolescent↗
PubMed1995

[Pharmacologic brain protection: specific agents].

Dysfunctional sodium influx is the first step in the ischaemic cascade. It has been recently demonstrated that reducing ionic flux through voltagegated Na channels shortens the NMDA receptor activity of cultured hippocampal slices in which oxidative phosphorylation and glycolysis have been blocked. The implication of this finding is that blocking initial events in the ischaemic cascade, events which do not directly cause neuronal damage, will reduce the damage done by downstream events. It also seems intuitively reasonable to suppose that truncating initial steps of the ischaemic cascade, as distinct from blocking glutamate receptors and scavening free radicals, will reduce the probability of interfering with endogenous mechanisms of repair. Clinically useful, substantive, prophylactic, pharmacological cerebral protection will come from drugs that work upstream. And for pharmacological protection that can only be initiated subsequent to an ischaemic event, the more we learn about endogenous repair, or genetic pharmacology, the closer we will come to maximizing the benefits and minimizing the costs of downstream intervention.

Apoptosis↗
PubMed1990

[Pharmacology in elderly patients].

The increasing population of elderly patients has special anesthesia care needs. In order to meet those, the pharmacological aspects of aging must be defined. A drug entering the body will generate a blood concentration, then be distributed to the tissues, inducing a pharmacological response. The determinants of blood concentration are absorption when the drug is not administered intravenously, distribution and elimination. Absorption is scarcely affected by ageing. On the contrary, the reduction of the lean mass as well as modifications of the plasma protein concentrations of binding deeply modify distribution. The main organ of drug metabolism is liver. Liver size and hepatic blood flow are reduced in elderly patients. Ageing induces heterogeneous modifications of metabolic pathways. Phase I reactions (oxidation, reduction and hydrolysis) are often slowed down, while phase II reactions (acetylation and conjugation) remain unaffected. Glomerular filtration rate is also reduced in elderly patients. Nevertheless plasma creatinine concentration remains close to the values observed in young healthy patients because of the reduction of the lean mass. The pharmacological response can be affected by the physiological modifications observed with ageing: metabolic rate is reduced, which diminishes the amount of drug necessary to achieve anesthesia. Cardiac index is very often reduced, but the major fact is a very large variability of cardiovascular function and an important reduction of functional reserve. Vascular compliance is diminished, and peroperative arterial pressure can be unstable. Respiratory function is also altered: vital capacity is reduced and hypoxemia frequently observed. Airway protective reflexes are impaired, enhancing the risk of inhalation particularly during recovery.

Aged↗
PubMed1996

[Pharmacological treatment of vasospasm in subarachnoid hemorrhage].

Pharmacological treatment of vasospasm in subarachnoid haemorrhage (SAH) is founded on prevention and treatment of arterial narrowing and delayed ischaemic deficits. Safety and efficacy of different agents have been studied and trials classified according to the level of evidence proposed by the "Stroke Council" of the American Heart Association. Early intracisternal fibrinolysis can prevent vasospasm (level III to V of evidence, grade C). Pharmacological treatment is based on few drugs. Nimodipine reduces poor outcome related to vasospasm, but does not affect angiographic vessel caliber (level of evidence I and II, grade A). Its use is strongly recommended. Nicardipine decreases symptomatic and angiographic vasospasm, but does not affect outcome (level of evidence I to V, grade B). Tirilazad associated with nimodipine prevents delayed ischaemic deficits due to vasospasm and improves outcome in male patients. Intra-arterial infusion of papaverine associated with transluminal angioplasty can improve symptomatic vasospasm, resistant to conventional therapy (level of evidence IV to V, grade C). Pharmacological treatment of vasospasm associated with specific management founded on pathophysiology of SAH has improved patients outcome.

Antioxidants↗