RESUMEN
PURPOSE: Data on the blood pharmacokinetics of vigabatrin, an antiepileptic drug with a unique and novel mechanism of action, in the rat are sparse. Additionally, little is known of the kinetics of vigabatrin in the central cerebrospinal fluid (CSF) compartment. We therefore investigated the rate of penetration into and the inter-relationship between serum and CSF compartments following systemic administration of vigabatrin in the rat. METHODS: Sprague-Dawley rats were implanted with a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively. Vigabatrin was administered by intraperitonial injection at three different doses (250, 500 and 1000mg/kg) and blood and CSF collected at timed intervals up to 8h. Vigabatrin concentrations in sera and CSF were determined by high performance liquid chromatography. RESULTS: Vigabatrin concentrations in blood and CSF rose linearly and dose-dependently and the time to maximum concentration (Tmax) was 0.4 and 1.0h, respectively. Vigabatrin is not protein bound in serum and its elimination from serum (mean t1/2 values, 1.1-1.4 h) is rapid and dose-independent. The efflux of vigabatrin from CSF was significantly slower than that seen for serum (mean t1/2 values, 2.2-3.3h). CONCLUSIONS: The kinetics of vigabatrin are linear with rapid entry into CSF. However, although vigabatrin CSF kinetics parallel that seen in serum, CSF vigabatrin concentrations represent only 2% of concentrations seen in serum and do not reflect free drug concentrations in serum.
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Anticonvulsivantes/farmacocinética , Vigabatrin/farmacocinética , Animales , Anticonvulsivantes/sangre , Anticonvulsivantes/líquido cefalorraquídeo , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Vigabatrin/sangre , Vigabatrin/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To test the hypothesis that cortical excitability changes prior to seizures, using transcranial magnetic brain stimulation (TMS). METHODS: We studied 18 patients with unilateral temporal lobe epilepsy (TLE) twice using TMS: prior to (day 1) and following (day 3) reduction of antiepileptic drugs in a monitored inpatient setting. Short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were measured. Time since most recent seizure prior to day 1, and time until next seizure after day 3, were recorded. RESULTS: On day 1, prior to antiepileptic drug withdrawal, there were no correlations with recent or next seizures. On day 3, patients who had seizures in the subsequent 48 hours had weaker SICI and ICF in the hemisphere ipsilateral to seizure onset, vs patients who did not have seizures in the next 48 hours (p = 0.033). Additionally on day 3, there was a strong correlation between the difference between ICF and SICI in the ipsilateral hemisphere and time to next seizure (p < 0.001). CONCLUSIONS: Change in cortical excitability, measured with transcranial magnetic brain stimulation, may reflect a long-lasting and widespread pre-ictal state.
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Anticonvulsivantes/efectos adversos , Corteza Cerebral/fisiopatología , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia/diagnóstico , Síndrome de Abstinencia a Sustancias/diagnóstico , Estimulación Magnética Transcraneal/métodos , Enfermedad Aguda/terapia , Adulto , Anticonvulsivantes/administración & dosificación , Corteza Cerebral/efectos de los fármacos , Electroencefalografía/normas , Electromiografía , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/fisiopatología , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Valor Predictivo de las Pruebas , Síndrome de Abstinencia a Sustancias/fisiopatología , Estimulación Magnética Transcraneal/normasRESUMEN
This article investigates the relationship between brain extracellular fluid free phenytoin concentration and plasma free phenytoin concentration in adults with acute brain injury. Daily cerebral microdialysate free phenytoin concentration was measured in eight adults with acute brain injury and compared with simultaneous measurement of plasma free phenytoin concentration. The group data revealed no significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.34, p = 0.41). However, in two patients, with a sufficient number of samples for intra-individual analysis, there was a significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.92, p < 0.001 and r = 0.88, p < 0.01). In vitro microdialysis relative recovery for phenytoin was 2.1%. In the context of acute brain injury, measurement of free plasma phenytoin concentration may not provide an accurate reflection of regional brain extracellular fluid free phenytoin concentration and may have limitations with respect to achieving reproducible brain extracellular fluid free phenytoin concentrations. This has implications for dosing regimens relying on plasma phenytoin levels.
Asunto(s)
Anticonvulsivantes/análisis , Líquido Extracelular/química , Fenitoína/análisis , Adolescente , Adulto , Anticonvulsivantes/sangre , Química Encefálica , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/diagnóstico , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Femenino , Humanos , Masculino , Microdiálisis , Persona de Mediana Edad , Monitoreo Fisiológico , Fenitoína/sangre , Proyectos PilotoRESUMEN
OBJECTIVE: To assess the effect of caffeine on motor thresholds, short interval intra-cortical inhibition (SICI), intra-cortical facilitation (ICF) and cortical silent periods in a placebo controlled double-blinded trial. METHODS: In eleven healthy non-smoking subjects the following parameters were measured using transcranial magnetic stimulation (TMS): motor thresholds (rest, RMT and active, AMT), SICI and ICF at different conditioning stimulus intensities (60, 70, 80, 90% AMT), cortical silent periods at 130, 150 and 175% AMT, and size of motor evoked potential at rest at 110, 125 and 150% RMT. Measurements were repeated after one cup of decaffeinated coffee. On another day, measurements were obtained before and after one cup of decaffeinated coffee that contained caffeine (3 mg/kg bodyweight). Caffeine concentrations were measured in serum before and after experiments. Experiments were conducted and data were evaluated blinded to the experimental condition. RESULTS: The results of repeated measurements of all parameters were similar comparing experiments on each day, or when comparing the caffeine arm of the study with the placebo arm. CONCLUSIONS: Caffeine in a concentration similar to that in a strong cup of coffee does not have a major effect on TMS measures of motor cortex excitability. SIGNIFICANCE: In healthy controls, the design of TMS experiments that investigate the parameters assessed in this TMS study does not need to control for caffeine.
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Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Adulto , Umbral Diferencial/efectos de los fármacos , Método Doble Ciego , Estimulación Eléctrica , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Humanos , Magnetismo , Masculino , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/fisiología , Factores de TiempoRESUMEN
BACKGROUND: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.
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Discinesias/tratamiento farmacológico , Mucuna/química , Enfermedad de Parkinson/tratamiento farmacológico , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Administración Oral , Anciano , Antiparkinsonianos/farmacocinética , Estudios Cruzados , Método Doble Ciego , Discinesias/etiología , Femenino , Humanos , Levodopa/farmacocinética , Masculino , Persona de Mediana Edad , Placebos , Preparaciones de Plantas/farmacocinética , Semillas/química , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
We investigated the effect of felbamate, administered singly and in combination with carbamazepine, phenobarbital, phenytoin or clonazepam, on various behavioral and electrographic correlates of seizures in amygdala-kindled rats. Felbamate (5 or 10 mg/kg) significantly increased afterdischarge threshold, shortened seizure and afterdischarge durations but remained without effect on seizure severity. Furthermore, the combination of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg; both drugs at their subeffective doses), was associated with the reduction in seizure severity and afterdischarge duration. In relation to the afterdischarge duration, the antiseizure potency of felbamate and carbamazepine, in combination, was comparable with that of carbamazepine (10 mg/kg) administered alone. Neither carbamazepine (7.5 and 10 mg/kg) nor felbamate (2.5-10 mg/kg) affected seizure severity, whereas the combined administration of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg) led to significant reduction in seizure severity from the fifth to the third stage of Racine's scale. Among the conventional antiepileptic drugs evaluated in this study, only valproate (100 mg/kg) and clonazepam (0.1 mg/kg) exerted similar action on seizure severity. However, the combinations of felbamate (2.5 mg/kg), with subeffective doses of valproate, phenobarbital, phenytoin or clonazepam, were not associated with any protective action. As blood and brain felbamate and carbamazepine concentrations were unaffected, a pharmacokinetic interaction can be excluded and a pharmacodynamic interaction concluded. These data suggest that felbamate and carbamazepine, administered in combination, may be useful in patients with drug-resistant partial epilepsy.
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Amígdala del Cerebelo/efectos de los fármacos , Anticonvulsivantes/farmacología , Excitación Neurológica/efectos de los fármacos , Glicoles de Propileno/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Anticonvulsivantes/metabolismo , Anticonvulsivantes/uso terapéutico , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Felbamato , Excitación Neurológica/fisiología , Masculino , Fenilcarbamatos , Glicoles de Propileno/metabolismo , Glicoles de Propileno/uso terapéutico , Ratas , Ratas Wistar , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismoRESUMEN
Levetiracetam is the latest in a series of nine new antiepileptic drugs (AEDs) to be licensed for clinical use. Its present license is for use as adjunctive therapy for the treatment of patients with partial seizures with or without secondary generalization that are refractory to other established first line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in patients of all ages with epilepsy, and in certain special populations. Results of these studies indicate that levetiracetam has a very favorable pharmacokinetic profile, characterized by excellent oral absorption and bioavailability (> 95%) and a mean elimination half-life in adults, children and the elderly of 7, 6 and 10.5 h, respectively. Levetiracetam is not bound to plasma proteins and is not metabolized in the liver, so it is not expected to be associated with significant pharmacokinetic interactions. Indeed, to the best of the author's knowledge, no clinically relevant pharmacokinetic interactions with levetiracetam have yet been identified. However, pharmacodynamic interactions with carbamazepine and topiramate have been highlighted. As levetiracetam is primarily excreted unchanged in urine, dosage adjustments are necessary for patients with moderate-to-severe renal impairment. Overall, the pharmacokinetic characteristics of levetiracetam can be considered highly desirable.
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Anticonvulsivantes/farmacocinética , Piracetam/análogos & derivados , Piracetam/farmacocinética , Factores de Edad , Anticonvulsivantes/metabolismo , Proteínas Sanguíneas/metabolismo , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Monitoreo de Drogas , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Humanos , Levetiracetam , Piracetam/metabolismo , Unión ProteicaRESUMEN
1. The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non-generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti-epileptic drug in this model. 2. One microl of tetanus toxin solution (containing 12 mLD(50) microl(-1) of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non-generalized seizures. 3. Carbamazepine (4 mg kg(-1) h(-1)) and levetiracetam (8 and 16 mg kg(-1) h(-1)) were administered during a 7 day period via an osmotic minipump which was placed in the peritoneal cavity. Carbamazepine (4 mg kg(-1) h(-1)) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non-generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non-generalized seizures were unaffected. This time-dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady-state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001). 4. Levetiracetam administration (8 and 16 mg kg(-1) h(-1)) was associated with a dose-dependent reduction in the frequency of both generalized (39 v 57%) and non-generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose-dependent reduction in overall generalized seizure duration was observed. 5. These data provide experimental evidence for the clinical efficacy of levetiracetam for the management of patients with complex partial seizures. Furthermore, levetiracetam probably does not act by preventing ictogenesis per se but acts to reduce seizure severity and seizure generalization.
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Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Epilepsia Parcial Compleja/tratamiento farmacológico , Piracetam/análogos & derivados , Piracetam/uso terapéutico , Toxina Tetánica/toxicidad , Animales , Epilepsia Parcial Compleja/inducido químicamente , Epilepsia Parcial Compleja/fisiopatología , Levetiracetam , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
gamma-Aminobutyric acid (GABA) is considered to be the major inhibitory neurotransmitter in the brain and loss of GABA inhibition has been clearly implicated in epileptogenesis. GABA interacts with 3 types of receptor: GABAA, GABAB and GABAC. The GABAA receptor has provided an excellent target for the development of drugs with an anticonvulsant action. Some clinically useful anticonvulsants, such as the benzodiazepines and barbiturates and possibly valproic acid (sodium valproate), act at this receptor. In recent years 4 new anticonvulsants, namely vigabatrin, tiagabine, gabapentin and topiramate, with a mechanism of action considered to be primarily via an effect on GABA, have been licensed. Vigabatrin elevates brain GABA levels by inhibiting the enzyme GABA transaminase which is responsible for intracellular GABA catabolism. In contrast, tiagabine elevates synaptic GABA levels by inhibiting the GABA uptake transporter, GAT1, and preventing the uptake of GABA into neurons and glia. Gabapentin, a cyclic analogue of GABA, acts by enhancing GABA synthesis and also by decreasing neuronal calcium influx via a specific subunit of voltage-dependent calcium channels. Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with intractable epilepsy. Despite this, additional GABA enhancing anticonvulsants are presently under development. Ganaxolone, retigabine and pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally, CGP 36742, a GABAB receptor antagonist, may prove to be particularly useful in the management of primary generalised absence seizures. The exact impact of these new GABA-enhancing drugs in the treatment of epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other anticonvulsants.
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Anticonvulsivantes/clasificación , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Ácido gamma-Aminobutírico/biosíntesis , Animales , Anticonvulsivantes/farmacología , Epilepsia/metabolismo , Humanos , Receptores de GABA/biosíntesis , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
Using a rat model which allows serial blood sampling and concurrent brain microdialysis sampling, we have investigated the temporal kinetic inter-relationship of levetiracetam in serum and brain extracellular fluid (frontal cortex and hippocampus) following systemic administration of levetiracetam, a new antiepileptic drug. Concurrent extracellular amino acid concentrations were also determined. After administration (40 or 80 mg kg(-1)), levetiracetam rapidly appeared in both serum (T(max), 0.4 - 0.7 h) and extracellular fluid (T(max), 2.0 - 2.5 h) and concentrations rose linearly and dose-dependently, suggesting that transport across the blood-brain barrier is rapid and not rate-limiting. The serum free fraction (free/total serum concentration ratio; mean+/-s.e.mean range 0.93 - 1.05) was independent of concentration and confirms that levetiracetam is not bound to blood proteins. The kinetic profiles for the hippocampus and frontal cortex were indistinguishable suggesting that levetiracetam distribution in the brain is not brain region specific. However, t(1/2) values were significantly larger than those for serum (mean range, 3.0 - 3.3 h vs 2.1 - 2.3 h) and concentrations did not attain equilibrium with respect to serum. Levetiracetam (80 mg kg(-1)) was associated with a significant reduction in taurine in the hippocampus and frontal cortex. Other amino acids were unaffected by levetiracetam. Levetiracetam readily and rapidly enters the brain without regional specificity. Its prolonged efflux from and slow equilibration within the brain may explain, in part, its long duration of action. The concurrent changes in taurine may contribute to its mechanism of action.
Asunto(s)
Anticonvulsivantes/farmacocinética , Piracetam/farmacocinética , Aminoácidos/efectos de los fármacos , Aminoácidos/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Espacio Extracelular/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Levetiracetam , Masculino , Microdiálisis , Piracetam/análogos & derivados , Piracetam/sangre , Ratas , Ratas Sprague-Dawley , Taurina/efectos de los fármacos , Taurina/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with gamma-aminobutyric acid (GABA)-related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye. METHODS: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. RESULTS: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain. CONCLUSIONS: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.
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Anticonvulsivantes/efectos adversos , Ácidos Nipecóticos/efectos adversos , Retina/efectos de los fármacos , Vigabatrin/efectos adversos , Trastornos de la Visión/inducido químicamente , Campos Visuales/efectos de los fármacos , Animales , Masculino , Ratas , Ratas Sprague-Dawley , TiagabinaRESUMEN
Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.
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Apomorfina/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Apomorfina/efectos adversos , Apomorfina/sangre , Apomorfina/farmacocinética , Catéteres de Permanencia/efectos adversos , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Infecciones/etiología , Bombas de Infusión , Infusiones Intravenosas/efectos adversos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Trombosis/inducido químicamente , Trombosis/cirugía , Resultado del TratamientoRESUMEN
Compliance is a problem in all areas of therapeutic medicine. Methods for its assessment are classified as either indirect or direct. Indirect assessment is based on criteria such as pill counts, questionnaires, and self-reporting; direct methods involve the analytic measurement of the drugs in biologic fluids such as plasma or urine. Drugs taken either therapeutically or recreationally become incorporated into hair. This prospective study investigated the relation between the daily intake of the antiepileptic drug carbamazepine and both its trough plasma and hair concentrations in a highly supervised inpatient population of patients with epilepsy during a period of 6 months. Results showed that although there was a significant variation between patients resulting from the substantial range in the daily intake of carbamazepine (800-2400 mg/day), the intrapatient variation in both trough plasma and hair concentrations during the 6-month period were not significantly different. The mean intrapatient percentage coefficient of variation in total plasma and hair concentrations of carbamazepine was 11.5 +/- 4.7 and 15.0 +/- 5.2, respectively, both of which were independent of the daily dosage. This relatively small intrapatient variation in hair concentration over time and its close relation to the plasma concentration suggests that hair analysis may be a complementary and useful technique in monitoring drug-taking behavior.
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Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Epilepsia/metabolismo , Cabello/química , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Carbamazepina/administración & dosificación , Carbamazepina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Estudios RetrospectivosRESUMEN
PURPOSE: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches. METHODS: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. RESULTS: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point. CONCLUSIONS: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.
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Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Agonistas de los Canales de Calcio/farmacología , Bases de Datos como Asunto/estadística & datos numéricos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Agonistas del GABA/farmacología , Ácido Glutámico/efectos de los fármacos , Humanos , MEDLINE/estadística & datos numéricos , Ratones , Conejos , Ratas , Bloqueadores de los Canales de Sodio , Resultado del TratamientoRESUMEN
Topiramate has been recently licensed as an antiepileptic drug. A fluorescence polarization immunoassay (FPIA), the Innofluor, has been developed to determine topiramate in heparinized plasma. Since therapeutic drug monitoring laboratories may not have control over collection of the samples submitted to them, it is important for analytical methods to be robust and able to cope with any specimen. The effect of different anticoagulants on the topiramate FPIA assay was investigated by collecting blood from 50 patients with epilepsy being maintained on a range of topiramate doses as part of their therapy. After venesection the blood was divided among four tubes: plain, heparinized, EDTA, and fluoride/oxalate. Erythrocytes were separated by centrifugation and supernatant fluid frozen to await duplicate assay by FPIA. Results were compared by means of Altman and Bland difference plots which indicated that there was no significant difference between values obtained with heparinized plasma and the other fluids. It was concluded that the Innofluor assay is robust and gives similar results when blood samples are collected into any of the specified anticoagulants.
Asunto(s)
Anticonvulsivantes/sangre , Fructosa/análogos & derivados , Adulto , Femenino , Inmunoensayo de Polarización Fluorescente , Fructosa/sangre , Humanos , Masculino , Persona de Mediana Edad , TopiramatoRESUMEN
We investigated the rate of penetration into and the intra-relationship between the serum, cerebrospinal fluid (CSF) and regional brain extracellular fluid (bECF) compartments following systemic administration of lamotrigine in rat. The serum pharmacokinetics were biphasic with an initial distribution phase, (half-life approximately 3 h), and then a prolonged elimination phase of over 30 h. The serum pharmacokinetics were linear over the range 10 - 40 mg kg(-1). Using direct sampling of CSF with concomitant serum sampling, the calculated penetration half-time into CSF was 0.42+/-0.15 h. At equilibrium, the CSF to total serum concentration ratio (0.61+/-0.02) was greater than the free to total serum concentration (0.39+/-0.01). Using in vivo recovery corrected microdialysis sampling in frontal cortex and hippocampus with concomitant serum sampling, the calculated penetration half-time of lamotrigine into bECF, 0.51+/-0.11 h, was similar to that for CSF and was not area or dose dependent. At equilibrium, the bECF to total serum concentration ratio (0.40+/-0.04) was similar to the free to total serum concentration (0.39+/-0.01), and did not differ between hippocampus and frontal cortex. The species specific serum kinetics can explain the prolonged action of lamotrigine in rat seizure models. Lamotrigine has a relatively slow penetration into both CSF and bECF compartments compared with antiepileptic drugs used in acute seizures. Furthermore, the free serum drug concentration is not the sole contributor to the CSF compartment, and the CSF concentration is an overestimate of the bECF concentration of lamotrigine.
Asunto(s)
Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Triazinas/farmacocinética , Animales , Anticonvulsivantes/sangre , Anticonvulsivantes/líquido cefalorraquídeo , Lamotrigina , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Triazinas/sangre , Triazinas/líquido cefalorraquídeoRESUMEN
Levetiracetam is a novel orally active antiepileptic drug with a unique preclinical profile. It has a high therapeutic index and potential antiepileptogenic effects. Results of clinical trials indicate activity in partial-onset and generalized seizures. The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug, with good bioavailability, rapid achievement of steady-state concentrations, linear and time-invariant kinetics, minimal protein binding, and minimal metabolism. The major metabolic pathway of levetiracetam is not dependent on the hepatic cytochrome P450 system, and levetiracetam does not inhibit or induce hepatic enzymes to produce clinically relevant interactions. Sixty-six percent of an administered levetiracetam dose is eliminated unchanged in urine; 24% is metabolized to an inactive metabolite that is detectable in blood and is also excreted in urine. Total body clearance of levetiracetam is decreased in patients with renal impairment, and doses should be modified according to creatinine clearance values. Levetiracetam is not appreciably protein-bound, nor does it affect the protein binding of other drugs. Thus, because of its minimal protein binding and lack of hepatic metabolism, the risk of drug interactions is very low. Levetiracetam has a wide margin of safety and patient-friendly pharmacokinetics that distinguish it from other currently available antiepileptic drugs. This profile may facilitate the clinical management of patients with epilepsy by providing a safer and less-complicated therapeutic strategy.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Piracetam/análogos & derivados , Absorción , Adolescente , Adulto , Anciano , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Niño , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Interacciones Farmacológicas , Humanos , Enfermedades Renales/complicaciones , Levetiracetam , Hepatopatías/complicaciones , Persona de Mediana Edad , Piracetam/efectos adversos , Piracetam/farmacocinética , Piracetam/uso terapéutico , Equivalencia TerapéuticaRESUMEN
Until recently, the drug treatment of epilepsy has been empirical. However, in recent years as a result of improved understanding of seizure neurochemistry and mechanisms of action of antiepileptic drugs (AEDs), drug treatment has become somewhat more rational. Nevertheless, it is currently impossible to predict which patient will respond to a particular AED, and which patient will experience adverse drug effects. The only practical way to determine whether a patient will find a drug useful is to try it. The discovery of genetic polymorphism in drug metabolism has contributed significantly to understanding of the variability in dose-concentration relationships, susceptibility to adverse effects, and susceptibility to seizure intractability. The discovery that predisposition to seizure intractability and expression of brain neuromolecules consequent to seizures is under genetic control may allow a more rational approach to AED choice. In the future, treatment may be guided by a series of pharmacogenetic tests, which would serve not only to choose the most appropriate AED (in terms of efficacy and adverse effects) but also to monitor the antiepileptogenic and the evolution status of the disease.
Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/metabolismo , Farmacogenética , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Resistencia a Medicamentos , Epilepsia/tratamiento farmacológico , Humanos , Factores de Transcripción/metabolismoRESUMEN
Approximately 1% of the world population (50 million people) suffers from epilepsy. Although the long-established anti-epileptic drugs allow 80% of newly diagnosed patients to remain seizure-free, many patients experience intolerable side effects the remaining 20% of patients do not respond to these drugs. There has therefore been a need for new anti-epileptic drugs, and the past decade has seen the licensing of eight new drugs worldwide, although these drugs have made little impact on the prognosis of refractory epilepsy. Furthermore, the side effect profiles of these new drugs do not differ significantly from the established antiepileptic drugs, so new anti-epileptic drugs with novel therapeutic targets, enhanced efficacy and minimal side effects are needed.