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J A Armijo

Publications and source records attributed to J A Armijo.

At least 19 recordsLinked to original sources
PubMed2006

[Mechanism of action of antiepileptic drugs and new antiepileptic drugs].

INTRODUCTION: Although 10 second generation new antiepileptic drugs are currently available on the market, 30% of patients are resistant to pharmacological treatment. In addition, today's antiepileptic drugs avert or suppress seizures but do not prevent the appearance of epilepsy or its progression. DEVELOPMENT: The foundations of the aetiopathogenesis of epilepsy and the main targets of antiepileptic drugs are described. Describing the important role of gamma-aminobutyric and glutamic acid in the genesis and proliferation of the seizures has allowed for the development of new antiepileptic drugs that increase the inhibitory tone of GABA or inhibit the excitatory tone of glutamate. The discovery that some epilepsies may be due to channelopathies is now making it possible to conduct research into drugs that inhibit calcium channels, activate potassium channels or inhibit abnormal AMPA/KA receptor channels. Recent reports describing a specific attachment of some antiepileptic drugs to the a2d subunits of the calcium channel and to the synaptic vesicles proteins SV2A open up new perspectives. Moreover, research is also being carried out on new drugs that are capable of preventing epileptogenesis, stemming the progression of epilepsy or overcoming the resistance to pharmacological treatment displayed by some epilepsies. CONCLUSIONS: The identification of new pharmacological targets in the aetiopathogenesis of epilepsies has made it possible to develop second generation antiepileptic drugs and it is allowing for the development of third generation antiepileptic drugs.

Anticonvulsants↗
PubMed2005

Ion channels and epilepsy.

The role of voltage-gated and ligand-gated ion channels in epileptogenesis of both genetic and acquired epilepsies, and as targets in the development of new antiepileptic drugs (AEDs) is reviewed. Voltage-gated Na+ channels are essential for action potentials, and their mutations are the substrate for generalised epilepsy with febrile seizures plus and benign familial neonatal infantile seizures; Na+ channel inhibition is the primary mechanism of carbamazepine, phenytoin and lamotrigine, and is a probable mechanism for many other classic and novel AEDs. Voltage-gated K+ channels are essential in the repolarisation and hyperpolarisation that follows paroxysmal depolarisation shifts (PDSs), and their mutations are the substrate for the benign neonatal epilepsy and episodic ataxia type 1; they are new targets for AEDs such as retigabine. Voltage-gated Ca2+ channels are involved in neurotransmitter release, in the sustained depolarisation-phase of PDSs, and in the generation of absence seizures; their mutations are a substrate for juvenile myoclonic epilepsy and the absence-like pattern seen in some mice; the antiabsence effect of ethosuximide is due to the inhibition of thalamic T-type Ca2+ channels. Voltage-gated Cl- channels are implicated in GABA(A) transmission, and mutations in these channels have been described in some families with juvenile myoclonic epilepsies, epilepsy with grand mal seizures on awakening or juvenile absence epilepsy. Hyperpolarisation-activated cation channels have been implicated in spike-wave seizures and in hippocampal epileptiform discharges. The Cl- ionophore of the GABA(A) receptor is responsible for the rapid post-PDS hyperpolarisation, it has been involved in epileptogenesis both in animals and humans, and mutations in these receptors have been found in families with juvenile myoclonic epilepsy or generalised epilepsy with febrile seizures plus; enhancement of GABA(A) inhibitory transmission is the primary mechanism of benzodiazepines and phenobarbital and is a mechanistic approach to the development of novel AEDs such as tiagabine or vigabatrin. Altered GABA(B)-receptor function is implicated in spike-wave seizures. Ionotropic glutamate receptors are implicated in the sustained depolarisation phase of PDS and in epileptogenesis both in animals and humans; felbamate, phenobarbital and topiramate block these receptors, and attenuation of glutamatergic excitatory transmission is another new mechanistic approach. Mutations in the nicotinic acetylcholine receptor are the substrates for the nocturnal frontal lobe epilepsy. The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

Action Potentials↗
PubMed2002

[Evidence based treatment of epilepsy].

OBJECTIVE: Evidence based medicine is becoming popular in all fields of medicine. Through systematic reviews, critical evaluation, and statistical strategies such as meta analysis it aids to take decisions in clinical practice. We revise the information on the treatment of epilepsy found in the main sources of evidence based medicine. DEVELOPMENT: After commenting some basic concepts such as systematic review, meta analysis, odds ratio, relative risk and numbers needed to treat, we describe the main primary, secondary and tertiary drug information sources with emphasis on sources of evidence based medicine. Some representative examples are given about the information on treatment of epilepsy found in the main sources of evidence based medicine such as TRIP, DARE, Cochrane Library, clinical practice guidelines, Clinical Evidence or Bandolier. Most clinical trials analyze the efficacy and tolerability of add on new antiepileptic drugs in partial refractory epilepsy. However, we found few trials on efficacy and tolerability of these drugs in monotherapy, in newly diagnosed partial epilepsy, on other types of epilepsy or in children. There are also few trials comparing the new antiepileptic drugs between them or in relation to the old ones. CONCLUSION: Treatment of epilepsy is yet an art more than a science because clinical practice decisions depends on therapeutic habits and clinical expertise more than on the results emerging from randomized and controlled clinical trials. Large comparative trials are needed but relevant criteria of efficacy and validated procedures to evaluate quality of life, tolerability or cognitive function outcomes should be used in these trials.

Anticonvulsants↗
PubMed2002

[Monitoring serum levels of new antiepileptics].

AIM: Therapeutic monitoring of old antiepileptic drugs has been useful in improving their use in clinical practice. The new antiepileptic drugs have been developed with the idea that monitoring their serum levels was going to be unnecessary. We review the characteristics of the new antiepileptic drugs that can be relevant to their being monitored and their possible uses. DEVELOPMENT: After discussion of the evolution of the therapeutic monitoring of antiepileptic drugs in general, we take a more detailed look at the requirements needed for it to be useful, such as the indications, the procedure and a correct interpretation of the results. We point out the reasons why monitoring the new antiepileptic drugs can be worthwhile and we examine the characteristics of felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide which may be relevant in their monitoring. These include the type of kinetics, the factors that have an influence on the relationship between dosage and serum levels, the concentration/dose ratio, data on the relationship between serum levels and effects, the factors that can influence this relationship, as well as the characteristics of sampling. CONCLUSION: The new antiepileptic drugs present a wide interindividual and intraindividual variability which leads us to believe that some of they may be suitable candidates for therapeutic monitoring, but at present no target ranges have been clearly defined for any of them. Therefore, routine monitoring cannot be recommended, but it may be useful to establish an individual reference level that allows control over compliance and dosage readjustment in the presence of factors that alter their pharmacokinetics. Specific prospective studies are needed to establish target ranges that allow to individualize dosage in the absence of clinical criteria and to resolve doubts about the efficacy and toxicity of these drugs. Quicker and simpler assays that make monitoring easier are also needed.

Anticonvulsants↗
PubMed2000

[Ion channels and epilepsy].

OBJECTIVE: We review the role of ligand-gated ion channels and voltage-gated ion channels as a substrate for the epileptogenesis and as targets in the development of new antiepileptic drugs. DEVELOPMENT: Voltage-gated calcium channels are involved in the release of neurotransmitters, in the sustained depolarization-phase of paroxysmal depolarisation shifts (PDS), and in the generation of absences; they are also the genetic substrate of generalized tonic-clonic convulsions and absence-like pattern seen in some mice. The voltage-gated potassium channel has been implicated in the hyperpolarization-phase of PDS, it is the genetic substrate of the long QT syndrome, benign neonatal epilepsy, and episodic ataxia/myokymia syndrome, and it is the target of some antiepileptic drugs which activate this channel. The voltage-gated sodium channel is the target of most of the classical and newer antiepileptic drugs; it is also the substrate for generalized epilepsy with febrile seizures plus. The sodium channel of the nicotinic acetylcholine receptor is the substrate for nocturnal frontal lobe epilepsy. The sodium channels of the AMPA and KA glutamate receptors have been proposed as substrate for juvenile absence epilepsy and are a target for new antiepileptic drugs which inhibit it. The calcium channel of the NMDA glutamate receptor has been implicated in the sustained depolarization-phase of PDS and in epileptogenesis after kindling and is a main target for new antiglutamate drugs. The chloride channel of the GABAA receptor is responsible for the rapid hyperpolarization of PDS, it has been involved in epileptogenesis after kindling, it may be the substrate of the Angelman syndrome, and it is activated by many classical and new antiepileptic drugs. CONCLUSION: The knowledge of the role of the ion channels in the epilepsies is allowing the design of new and more specific therapeutic strategies.

Angelman Syndrome↗
PubMed2000

[Antiepileptic drugs and the liver].

OBJECTIVES: We review the metabolism of antiepileptic drugs with particular emphasis on the formation of active metabolites and toxic intermediate metabolites, together with the factors altering this and the possibility of interactions between the antiepileptic drugs themselves and with other drugs. DEVELOPMENT: Most antiepileptic drugs undergo complex metabolic processes in the liver which determine the time course of their concentration in the organism and therefore their therapeutic and toxic effects. Also, the processes by which drugs are metabolised may be influenced by many physiological and pathological factors, as well as the presence of other drugs which cause clinically relevant interactions. We analyze the function of the liver in the metabolism of these drugs with special reference to the microsome oxidation mediated by cytochrome P-450 and the glucuronidation catalysed by glucuronosyltransferase and the processes of enzyme induction and inhibition. Subsequently, we describe the metabolism of the antiepileptic drugs, their main routes of elimination, factors affecting this, role of the active and intermediate metabolites and the involvement of the enzyme induction and inhibition underlying the interactions of these drugs. Finally, we describe the metabolism of the most important classical and new antiepileptic drugs, the isoforms of cytochrome P-450 involved, the factors altering this and the most relevant interactions with other antiepileptic and non-antiepileptic drugs. CONCLUSION: Knowledge of the paths by which the antiepileptic drugs are metabolised, particularly the isoforms of cytochrome P-450 involved facilitates understanding of the influence of various factors on the metabolism of drugs, and also of their complex interactions.

Anticonvulsants↗
PubMed1999

Effects of increasing doses of vigabatrin on platelet gamma-aminobutyric acid-transaminase and brain gamma-aminobutyric acid in rats.

We report the relationship of GABA-transaminase inhibition in platelets and brain with the increase in brain gamma-aminobutyric acid (GABA), as percents of the control, at 24 h after single and after 3 and 8 days of treatment with increasing doses (1, 3, 10, 30, 100 and 300 mg kg(-1) day(-1) of vigabatrin in rats. The inhibition of GABA-transaminase in platelets correlated at least as well as that in brain with the increase in brain GABA after 3 days (r = - 0.87 vs. r = -0.78), and 8 days of treatment (r = -0.77 vs. r = -0.74), and when the data of single and multiple doses were pooled (r = -0.77 vs. r = -0.75). The correlation between platelet GABA-transaminase and brain GABA fitted to a power curve, the increase in brain GABA being significant only when platelet GABA-transaminase was inhibited to less than 50% of the control. Our results suggest that platelet GABA-transaminase could be a peripheral marker of the effect of vigabatrin on brain GABA in rats.

4-Aminobutyrate Transaminase↗
PubMed1999

Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications.

Using bivariate and multivariate methods, we retrospectively analyzed the influence of patient age and the use of concomitant antiepileptic drugs (AEDs) on the lamotrigine (LTG) concentration-to-dose (C/D) ratio in samples from 164 patients (68 children, 96 adults) with epilepsy receiving LTG alone (n = 28) or in combination with various antiepileptic drugs (n = 136). The LTG C/D ratio increased with age in children receiving LTG alone (r = 0.60, p < 0.01), but decreased with age in adults receiving LTG and inducers (r = -0.42, p < 0.001). In patients receiving LTG and inducers, the ratio was statistically lower in those younger than 9 years of age (0.23 +/- 0.08) and older than 30 years of age (0.32 +/- 0.15) than it was in those between 9 and 30 years of age (0.44 +/- 0.15). The mean LTG C/D ratio was 0.37 +/- 0.15 in patients receiving LTG and inducers (n = 92), 0.84 +/- 0.41 in patients receiving LTG alone (n = 28), 1.09 +/- 0.44 in those receiving LTG with VPA plus inducers (n = 17), and 3.41 +/- 1.18 in those receiving LTG and VPA (n = 27). Differences in the LTG C/D ratio between treatment groups were similar in children and in adults. We reached the following conclusions: The LTG C/D ratio increased with age in children but may decrease with age in adults receiving concomitant enzyme-inducing AEDs; the LTG C/D ratio was 10 times lower in patients receiving LTG and inducers than in those receiving LTG and VPA (in both children and adults), and this difference was higher than the four-fold difference described for LTG half-life and the two-fold differences currently used in LTG dosage.

Adolescent↗
PubMed1999

Time course of the GABAergic effects of vigabatrin: is the time course of brain GABA related to platelet GABA-transaminase inhibition?

PURPOSE: To analyze the time course of the effects of vigabatrin (VGB) on brain gamma-aminobutyric acid (GABA), and its relation with 4-aminobutyrate-2-ketoglutarate amino-transferase (GABA-T) in brain and platelets. METHODS: Blood and brain samples were collected at 4, 24, 48, and 72 h after a single dose and after 3 and 8 days of treatment with 200 mg/kg of VGB in rats. RESULTS: Time courses of the GABAergic effects of VGB were different after single and multiple doses: with multiple doses, the inhibition of brain GABA-T was quicker and longer, the inhibition of platelet GABA-T was greater and longer, the increase in brain GABA was greater, and recovery began earlier. After pooling the data obtained at 4, 24, 48, and 72 h, we observed a power correlation between the increase in brain GABA in individual rats as percentage of the control and both the inhibition of brain GABA-T after a single dose of VGB (r = -0.40; p < 0.05), and the inhibition of platelet GABA-T after 3 days (r = -0.48; p < 0.01) and 8 days of treatment (r = -0.53; p < 0.01). When all data after single and multiple doses were pooled, the increase in brain GABA correlated better with the inhibition of GABA-T in platelets (r = -0.62; p < 0.001) than in brain (r = -0.38; p < 0.001). Platelet GABA-T correlated with brain GABA at 4 h (r = -0.64; p < 0.001) and 24 h (r = -0.66; p < 0.001) but not at 48 and 72 h. CONCLUSIONS: Platelet GABA-T reflects the time course of the increase in brain GABA better than does brain GABA-T after multiple doses of VGB in rats.

4-Aminobutyrate Transaminase↗
PubMed1998

Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study.

The ability of nimodipine, a dihydropyridine calcium antagonist, to reduce the daily dose of oral morphine in cancer patients who had developed dose escalation, was tested in 54 patients under randomized, double-blind, placebo-controlled conditions. We selected patients that required at least two successive increments of morphine to maintain pain relief. A possible pharmacokinetic interaction between nimodipine and morphine was also studied in 14 patients by assaying steady-state serum levels of morphine and its 3- and 6-glucuronides. A total of 30 patients completed the study, 14 and 16 in the nimodipine and placebo groups, respectively. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313+/-52 to 174+/-33 mg/day (P < 0.001) in the nimodipine group, and from 254+/-26 to 218+/-19 mg/day (not significant) in the placebo group. The percentages of reduction in the daily dose of morphine also showed significant differences between both groups (P=0.02). One week after introducing nimodipine or placebo, while the dose of morphine remained similar to that of the pre-test week, the serum levels of morphine and its glucuronides were not modified significantly. We conclude that the introduction of nimodipine in patients chronically treated with morphine may be a safe alternative to reduce the daily requirements of the opioid. It is suggested that interference with Ca2+-related events may attenuate the development and/or expression of tolerance to morphine in a clinically relevant way.

Aged↗
PubMed1998

Propofol concentrations in whole blood: influence of anticoagulants and storage time.

Blood samples for propofol determination are collected with oxalate, heparin and EDTA, but we have not found any study comparing the influence of those anticoagulants on propofol concentrations. This study was carried out on 50 samples from patients taking propofol for anesthesia or cerebral protection. First, 26 samples were simultaneously collected into tubes containing lithium heparin or sodium fluoride potassium oxalate as anticoagulant. In a second investigation, 24 samples were simultaneously collected into tubes containing heparin or EDTA. Propofol was assayed by HPLC 2 days after sampling and 2 weeks later. In the first assay, propofol concentration in samples collected with heparin were similar to those collected with oxalate (3.65 +/- 3.50 vs. 3.62 +/- 3.49 mg/l, ns) or EDTA (3.89 +/- 2.58 vs. 3.84 +/- 2.67 mg/L, ns). After storing for 2 weeks at 4 degrees C, propofol concentrations were slightly but insignificantly higher than in the first assay in samples collected with heparin (3.58 +/- 3.24 vs. 3.40 +/- 2.92 mg/l, ns), slightly higher in samples with oxalate (3.86 +/- 3.49 vs. 3.62 +/- 3.49 mg/l, p = 0.06), and slightly but significantly lower in samples with EDTA (3.63 +/- 2.67 vs. 3.84 +/- 2.67 mg/l, p < 0.05). It is concluded that the three anticoagulants used in this study seem to be suitable for determination of propofol concentration in whole blood, and that the stability of propofol concentration when samples are stored at 4 degrees C for up 2 weeks is acceptable.

Anticoagulants↗
PubMed1997

Vigabatrin serum concentration to dosage ratio: influence of age and associated antiepileptic drugs.

The relationship between the ratio of vigabatrin concentration to dosage (VGB C/D) and both patient age and the presence of other antiepileptic drugs (AEDs) was analyzed retrospectively by bivariate and multivariate methods in 179 patients with epilepsy (114 children and 65 adults). Of the 179 patients, 33 received VGB alone (30 children and 3 adults) and 146 received VGB with other AEDs (84 children and 62 adults). Vigabatrin trough steady-state serum concentration correlated better with VGB dosage in milligrams per kilogram than the dosage in milligrams in children (r = 0.62 vs. r = 0.17, P < 0.001) but not in adults (r = 0.51 vs. r = 0.49, NS). The correlation between milligrams per kilogram and serum concentration of VGB was greater in children on monotherapy (r = 0.83) than in those on polytherapy (r = 0.46). Vigabatrin C/D ratio increased significantly with age (r = 0.51, P < 0.001), being lower in children than in adults both by Student's t-test (0.087 +/- 0.039 vs. 0.128 +/- 0.057, mean +/- SD, P < 0.001) and by two-way analysis of variance when controlling for other AEDs (P < 0.001). Inducing AEDs seemed to increase VGB C/D ratio in the bivariate tests, but this influence decreased and even disappeared if patient age was considered in the multivariate analysis. However, the increase in VGB C/D ratio with VPA serum concentration (r = 0.46, P < 0.001) was confirmed by multiple regression including age (P < 0.001). Intrapatient variability of VGB C/D ratio was 29 +/- 18%. It was concluded that trough steady state VGB serum concentration may be more predictable in children based on the milligrams per kilogram dosage than on the milligram dosage, and that the influence of patient age should be considered if the VGB C/D ratio is used to estimate patient compliance.

Adolescent↗
PubMed1997

[Which drugs should be chosen for the different types of epilepsy?].

The selection of an antiepileptic drug is based primarily on its efficacy. When the efficacy of several antiepileptic drugs is similar, what is frequently observed, their safety, pharmaco-kinetics, and cost should be also considered. Efficacy, dose-dependent and idiosyncratic toxicity, pharmacokinetics features, and interactions of phenobarbital, phenytoin, carbamazepine, valproate, felbamate, gabapentin, lamotrigine and vigabatrin are comparatively analyzed, and drugs of choice for generalized epilepsies and partial epilepsies are proposed. It is concluded that phenobarbital, primidone and phenytoin are being replaced by carbamazepine and valproate as first choice drugs for most types of epilepsies due to a similar (and even better) efficacy, besides a better safety profile and easier dosing. Features of new antiepileptic drugs make they adequate to be used as add-on drugs in treatment-resistant patients: lamotrigine and felbamate are effective in Lennox-Gastaut syndrome, and vigabatrin in West syndrome, most of the new antiepileptic drugs are well tolerated and show less interactions than the standard ones. However, the efficacy and safety of the new antiepileptic drugs in monotherapy, and their long-term safety have not been yet established, and they will cost more than the standard drugs. Therefore, the new antiepileptic drugs are currently considered as second choice drugs, although vigabatrin has been proposed as a first choice drug in West syndrome.

Anticonvulsants↗