1,721,412 research outputs found
Age-Related Changes in Pharmacokinetics: Predictability and Assessment Methods
No full textAlthough there have been relatively few studies of the pharmacokinetics of antiepileptic drugs (AEDs) in old age, available evidence indicates that the clearance of most old and new generation AEDs is reduced on average by about 20-40% in elderly patients compared with nonelderly adults. Depending on the pharmacokinetic characteristics of the drug, the reduction in clearance can be ascribed to a physiological reduction in rate of drug metabolism, to a decrease in renal excretion rate, or to both. Studies have consistently demonstrated that interindividual pharmacokinetic variability in old age is particularly prominent, due not only to the influence of aging-related physiological changes, but also to the impact of comorbidities and drug-drug interactions. For extensively metabolized drugs, there are no reliable tools to predict with a high degree of accuracy the pharmacokinetic behavior of an AED in an individual patient. With renally eliminated drugs, determination of creatinine clearance may provide a useful clue in predicting individual changes in drug clearance and the consequent need for dosage adjustment. In the therapeutic setting, measurement of serum AED concentrations can be valuable in individualizing dosage in an elderly person, even though it should be remembered that in the case of drugs that are highly bound to plasma proteins the total serum concentration may underestimate the level of unbound, pharmacologically active drug. Because aging is also associated with important pharmacodynamic changes that may alter the relationship between serum drug concentration and pharmacological effects, pharmacokinetic measurements alone are not a substitute for the need to monitor clinical response carefully and to adjust dosage accordingly. © 2006 Elsevier Inc. All rights reserved
A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Commentary.
No full text1 The antipyrine clearance and the urinary excretion of D-glucaric acid (D-GA) were determined in 122 patients receiving chronic anticonvulsant drug treatment and ill 21 drug-free control subjects.
2 Patients treated with carbamazepine (CBZ), phenytoin (DPH), primidone (PMD) and phenobarbitone (PB), either alone or in combination, showed higher values of antipyrine, clearance and excreted larger amounts of D-GA as compared to controls, While antipyrine clearance values did not differ significantly from one drug group to another, D-GA excretion was significantly higher in patients treated with CBZ than in those treated with DPH.
3 In patients treated with sodium valproate antipyrine clearance did not differ from control values. There was a trend for D-GA excretion to be higher in these patients but the difference was not statistically significant.
4 Significant positive correlations were found between the dosage of CBZ, DPH, PMD and PB and both indices of enzyme induction. These data demonstrate a dose-dependent degree of enzyme induction in patients receiving therapeutic doses of these anticonvulsants. The relative potency at average dose levels for antipyrine clearance was PB (1), DPH (0.92), CBZ (0.84), PMD (0.82) and for log D-GA excretion was PB (1), CBZ (0.96), PMD (0.95), DPH (0.90)
Active control trials: Endpoints beyond conventional efficacy and tolerability measures
No full textClinical trial endpoints often extend beyond conventional efficacy and tolerability measures. While it is generally assumed that seizure control without major adverse drug effects is by far the most important determinant of quality of life, other factors also are important. Pharmacokinetic endpoints could also provide relevant information for optimal drug use. Outcome measures could reveal drug effects on mood, headache, and sleep disorders, as well as overall quality of life and seizure severity
An introduction to antiepileptic drugs.
No full textIn recent years, the number of commercially available antiepileptic drugs (AEDs) has increased steadily. Although this may complicate management choices, it also offers welcome new options to individualize treatment more effectively. Because each of the available AEDs differs from others in many clinically relevant properties, opportunities to tailor drug treatment to the characteristics of the individual patient have never been greater. Properties that are especially important in drug selection in patients with epilepsy include spectrum of efficacy in different seizure types, adverse effects profile, pharmacokinetic properties, susceptibility to cause or be a target of clinically important drug-drug interactions, ease of use, and cost. Other factors that need to be considered in tailoring drug choice include availability of user-friendly pediatric formulations, and potentially favorable effects on co-morbid conditions. In fact, a number of AEDs are efficacious and widely prescribed in additional indications, particularly psychiatric disorders, migraine prophylaxis, and neuropathic pain. Recently, advances have been made in understanding the mechanisms of actions of AEDs at the molecular level. While a fully mechanistic approach to the clinical use of these agents is not yet feasible, knowledge of mechanisms of action offers useful clues in predicting their efficacy profile and spectrum of potential adverse effects
Pharmacological principles as a basis for polytherapy.
No full textMost patients with newly diagnosed epilepsy can be optimally controlled by prescribing a single anti-epilepsy drug, selected on the basis of its efficacy and safety profile. In about one-third of patients, however, seizures persist during monotherapy, despite the intake of the maximally tolerated drug dose. In such cases, substantial therapeutic benefit may be achieved by prescribing appropriate drug combinations. Safe use of multiple drug therapy requires a good knowledge of clinical pharmacology, particularly an awareness of potentially adverse drug interactions. As many older anti-epilepsy drugs have similar modes of action, their interaction may not always be of clinical benefit, because drug side-effects may also be additive. There is, however, evidence that specific combinations may be particularly advantageous; for example, valproate and ethosuximide in the management of refractory absence seizures. Compared with older drugs, some of the recently developed agents possess different and more selective mechanisms of action, which may result in enhanced therapeutic benefit when specific combinations are used. Preliminary observations do suggest that, in some cases, the efficacy exhibited by certain new drugs could be explained in terms of their pharmacological effect being 'complementary' to that of concurrently used agents
Topiramate: from a drug of last resort to a first-line treatment option. 9th Iranian Congress of Neurology and Clinical Neurophysiology
No full textBirth defects after prenatal exposure to antiepileptic drugs.
No full textBACKGROUND: Exposure to antiepileptic drugs (AEDs) in the first trimester of pregnancy has been associated with an increased risk of major congenital anomalies (MCAs) in offspring. Most of the studies, however, have been fraught with methodological shortcomings, and differences in ascertainment methods and classifications prevent meaningful data pooling. Individual studies lacked the statistical power to assess comparative risks associated with specific AEDs. RECENT DEVELOPMENTS: Several larger-scale studies, including collaborative multinational registries, have been set up to compare MCA risks associated with different treatments, including newer generation AEDs. Results have largely been consistent with the notion that monotherapy with the most commonly used AEDs is associated with an increase in risk of MCAs by two to three times, and that the magnitude of risk increases in offspring exposed to polytherapy. Available evidence does not suggest that epilepsy per se is associated with a major increase in the risk of MCAs. Almost all studies have suggested that exposure to valproic acid is associated with a greater incidence of MCAs than other AEDs. Valproic acid is also the only AED for which a dose-dependency has been confirmed in several studies: the increase in risk of MCAs, compared with other AEDs, is especially evident at doses above 800-1000 mg/day. Data from the North American registry have suggested that phenobarbital may also have a higher teratogenic risk compared with AEDs other than valproic acid, but evidence remains inconclusive. Information about effects on fetuses of newer generation AEDs other than lamotrigine and oxcarbazepine is scant. Although teratogenic effects of lamotrigine and oxcarbazepine have not been established with certainty, none of the investigations to date identified any statistically significant difference in rates of MCAs between infants exposed to lamotrigine or oxcarbazepine and infants exposed to carbamazepine. In the case of lamotrigine, moreover, a positive correlation between maternal dose and rates of MCAs has been identified. WHERE NEXT?: Collaborative pregnancy registries worldwide are at work to fill remaining gaps in knowledge. Issues to be addressed include the comparative risks associated with phenobarbital, with low-dose valproic acid, with newer generation AEDs, and with specific AED combinations; the influence of potential confounders; and the interaction of AED-associated risks with other risk factors, such as genetic profiles. Large scale studies may also clarify whether individual AEDs differ in their ability to cause specific anomalies. Finally, studies are urgently needed to investigate other potential adverse effects of AED exposure, with special reference to effects on postnatal intellectual development
Established antiepileptic drugs.
No full textThe major established drugs used in the management of epilepsy are carbamazepine, valproic acid, phenytoin, phenobarbital, primidone, ethosuximide and benzodiazepine drugs. Carbamazepine and phenytoin are used mainly in the treatment of partial seizures and primarily or secondarily generalized tonic-clonic seizures. Valproic acid is effective against all types of seizures, but it is used most extensively in the management of generalized epilepsies. Ethosuximide is effective against absence seizures. Phenobarbital and primidone are effective against all types of seizures (except for absences) although they are less commonly used because of their sedative properties and adverse effects on cognition. Benzodiazepines are most valuable in the treatment of status epilepticus, but their long-term use is often associated with undesirable sedation and development of tolerance to their antiepileptic effect. Irrespective of the drug used, optimal clinical management requires individualization of dosage and dosing schedules based on careful evaluation of clinical response and sound knowledge of the pharmacokinetics and interaction potential of the individual compounds. Monitoring serum drug concentrations may provide a useful guide to dosage adjustments, particularly in the case of phenytoin, which shows dose-dependent kinetics within the therapeutic dosage range
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