The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic-dynamic modeling for both effects was carried out according to the "link" effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (H&Y II, III, and IV). Median effective concentrations (EC 50 ) were increased at the more advanced clinical stage (p < 0.001), from a median 0.2 microg/mL in patients at H&Y stage I to 0.9 microg/mL in patients at H&Y stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new antiepileptic drug (AED) topiramate and the potential relation between topiramate plasma levels and side effects in a cohort of 116 patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two subgroups, otherwise comparable for age and weight-adjusted daily dose of topiramate. Group A (n = 73) received topiramate plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin. Group B (n = 43) received topiramate plus AEDs without inducing properties of CYP metabolism (namely valproic acid and lamotrigine). Weight-normalized topiramate clearance values, calculated as dosing rate/steady-state plasma drug concentration, were about 1.5-fold in patients receiving AED inducers compared with patients receiving AED noninducers. Topiramate plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 25 to 800 mg/d, although, at a given daily dose, a large interpatient variability was observed in matched plasma drug concentrations within each group of patients. Thirty-nine patients (34%) reported side effects associated with topiramate, mostly central nervous system effects. No consistent relation was observed between topiramate plasma concentrations and adverse effects, either in the cohort of patients as a whole or within each subgroup. From a clinical point of view, patients receiving concurrent treatment with enzyme-inducing AEDs can show twofold lower topiramate plasma concentrations compared with patients receiving valproic acid or lamotrigine, and appropriate topiramate dosage adjustments may be required when concomitant AED inducers are either added or withdrawn. Due to the observed variability in topiramate metabolic variables and the complex spectrum of possible pharmacokinetic and pharmacodynamic interactions with the most commonly coprescribed AEDs, monitoring of plasma topiramate concentrations may help the physician in the pharmacokinetic optimization of the drug dosage schedule in individual patients.

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SYNOPSIS Nine patients with migraine (5 with migraineous stroke) were investigated for defects of mitochondrial energy metabolism. During effort, blood lactate rose significantly higher in migraineurs. Muscle biopsy showed ragged‐red fibres deficient in cytochrome‐c‐oxidase activity in one case. On muscle biochemistry, depression of some respiratory chain enzymes was found for the whole group of patients, and especially in 2 for cytochrome‐c‐oxidase, succinate‐cytochrome‐c‐reductase and NADH‐cytochrome‐c‐reductase. Our findings are still preliminary, but they suggest impaired mitochondrial energy metabolism in migraine.

The current symptomatic treatment of Parkinson's disease mainly relies on agents which are able to restore dopaminergic transmission in the nigrostriatal pathway, such as the dopamine precursor levodopa or direct agonists of dopamine receptors. Ancillary strategies include the use of anticholinergic and antiglutamatergic agents or inhibitors of cerebral dopamine catabolism, such as monoamine oxidase type B inhibitors. Levodopa is the most widely used and effective drug. Its peculiar pharmacokinetics are characterised by an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme aromatic-amino acid decarboxylase and rapid adsorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both drug intestinal absorption and delivery to the brain and clinical effect include standardisation of levodopa administration with respect to meal times and a controlled dietary protein intake. The levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, with swings in the therapeutic response ('wearing-off' phenomena). 'Wearing-off' phenomena can be also associated, at the more advanced disease stages with a 'negative', both parkinsonism-exacerbating and dyskinetic effect of levodopa at subtherapeutic plasma concentrations. Dyskinesias may be also related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone, and simultaneous monitoring of levodopa concentration-effect relationships may prove useful to disclose the underlying mechanism and in planning the correct pharmacokinetic management. Controlled-release levodopa formulations have been developed in an attempt to smooth out fluctuations in plasma profiles and matched therapeutic responses. The delayed levodopa absorption and lower plasma concentrations which characterise controlled-release formulations compared with standard forms must be taken into account when prescribing dosage regimens and can be complicating factors in the management of the advanced disease stages. The pharmacokinetic and pharmacodynamic characterisation of the other antiparkinsonian agents is hampered by the lack of sensitive and specific analytical methods to measure their very low plasma drug concentrations and by the difficulty in quantitatively assessing overall moderate drug clinical effects. In clinical practice an optimal dosage schedule is still generally found for each patient on an empirical basis. Future strategies should focus on the search for pharmacological agents with a better kinetic profile, particularly a higher and reproducible bioavailability and a predictable relationship between plasma drug concentration and clinical response. ...

To investigate energy metabolism in migraine, we determined platelet mitochondrial enzyme activities in 40 patients with migraine with aura and in 40 patients with migraine without aura during attack-free intervals and in 24 healthy control subjects. NADH-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities in both patient groups were significantly lower than in controls (p < 0.01), while NADH-cytochrome-c-reductase activity was reduced only in migraine with aura (p < 0.01). No alteration in succinate-dehydrogenase was observed. Monoamine-oxidase activity differed between sexes (p < 0.05) but within each sex group no difference was observed between patients and controls. We hypothesize that the defect in mitochondrial enzymes observed indicates a systemic impairment of mitochondrial function in migraine patients.

We prospectively evaluated over 4 years the intrasubject relationship between levodopa plasma concentration and the tapping effect after a standard oral levodopa test in 28 patients with mild-to-moderate idiopathic Parkinson's disease. The onset and duration of the tapping effect significantly shortened over years; response amplitude did not vary. Levodopa plasma kinetics remained unchanged. Pharmacodynamic modeling indicated a progressive decrease in the equilibration half-life between plasma drug concentration and effect, which correlated with the shorter motor response. No clear-cut change in maximum response (Emax) emerged, but levodopa concentration needed to yield 50% of maximum effect (EC50) significantly increased. These data indicate that the duration of motor response becomes a major determinant of drug efficacy over years. The modifications in levodopa effect-compartment equilibration half-life and EC50 further support the suggestion that alterations in cerebral levodopa kinetics have an important role in the development of response fluctuations.