Subtherapeutic free phenytoin levels following fosphenytoin therapy in status epilepticus.
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Anticonvulsants↗
Biomedical subjects
Dirk Deleu
Publications and source records attributed to Dirk Deleu.
Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease.
Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.
Animals↗
An evidence-based review of dopamine receptor agonists in the treatment of Parkinson's disease.
Apomorphine and certain ergot alkaloids (bromocriptine, lisuride and pergolide) have been available for several decades; for the last few years, they were joined by newer dopamine agonists (cabergoline, pramipexole and ropinirole) most of them are non-ergolines. Each of these dopamine agonists has its own pharmacological characteristics and occupies a place in the pharmacotherapy of Parkinsons disease. In this evidence-based review, emphasis is put on the clinical efficacy of dopamine agonists in early and advanced Parkinsons disease, and where possible comparative evidence regarding their efficacy and safety is provided. In addition, their clinical pharmacokinetics, adverse effect profiles and most relevant interactions will be summarized.
Dopamine Agonists↗
Estimation of population pharmacokinetic parameters of free-phenytoin in adult epileptic patients.
BACKGROUND: Serum concentrations of free-phenytoin (F-PHT) obtained in adult epileptic patients receiving PHT in monotherapy were analyzed to estimate the Michaelis-Menten pharmacokinetic parameters. METHODS: Steady-state F-PHT serum concentrations, PHT dosing history, and associated information were collected prospectively. The maximum metabolic rate (Vm) and Michaelis-Menten constant (Km) of F-PHT and their interindividual variability data were estimated using nonlinear mixed effects modeling (NONMEM). RESULTS: Twenty-nine patients with two or more available steady-state F-PHT serum concentrations (total of 63 dose/serum concentration pairs) met the inclusion criteria. Patients were taking PHT (100-500 mg/day) in monotherapy. The population estimates of F-PHT for Vm and Km were 9.1 mg/kg/day and 7.3 mg/L, respectively. The model was prospectively evaluated in a small group (seven) of additional patients. CONCLUSIONS: The recommended daily dose in this population to achieve a F-PHT concentration of 1.5 mg/L is 6.1 mg/kg.
Adolescent↗
Prevalence and clinical characteristics of headache in a rural community in Oman.
OBJECTIVES: To perform a prospective epidemiological study of headache in a rural community in Oman, assessing prevalence, symptom profile, and health care utilization pattern. METHODS: Using a door-to-door survey prevalence estimates were based on a detailed structured headache assessment questionnaire performed in 1158 subjects. Migraine and tension-type headache were diagnosed according to the International Headache Society criteria. RESULTS: The crude lifetime and last-year prevalence of headache were 83.6% and 78.8%, respectively, with a female preponderance. The last-year prevalence of migraine and tension headache was 10.1% and 11.2%, respectively. There was no significant gender difference in migraine prevalence (4.5% in male and 5.6% in female), but tension-type headache was 2.6 times more common in females (3.1% in male and 8.1% in female). Last-year prevalence of frequent headaches was 5.4%. Forty eight percent of respondents sought medical assistance for their headaches and 79% were using medication, 40% of them used self-medication. CONCLUSIONS: This prospective study shows that headache is also highly prevalent in this community. Migraine and tension-type headache have the same prevalence, but the sex distribution for migraine is different from that observed in the Western world. Tension-type headache prevalence was substantially lower than that observed in other parts of the world. Frequent headaches were as common as in other population-based studies worldwide. Analgesic use/overuse probably also coexisted with headache, because self-medication was quite common.
Adolescent↗