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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.

We present a simple and fast method for the determination of the novel antiepileptic drug topiramate in human plasma by high-performance liquid chromatography coupled with turbo ion spray mass spectrometry. Plasma sample pre-treatment was based on simple deproteinization by acetonitrile. Liquid chromatographic analysis was carried out on a reversed-phase column (C18, 125x4 mm I.D., 5 microm) using acetonitrile-ammonium acetate buffer, pH 6.3 as the mobile phase, at a flow-rate of 0.8 ml/min. Retention time for topiramate was 2.1 min. The detector was a single quadrupole mass spectrometer coupled to a turbo ion spray ion source and a heated nebulizer probe, operating in the positive ion mode. Ion source temperature was off; voltage was +5800 V; nebulizer and curtain gas flow-rates were 6 and 10 ml/min, respectively. Calibration curves for topiramate were linear over the range 1 to 20 microg/ml. Absolute recovery ranged between 92 and 95%. Intra- and inter-assay precision was <4%. The present procedure, omitting extraction and drying steps, is faster and simpler than the previously reported analytical methods for topiramate and was demonstrated to possess adequate sensitivity for routine therapeutic drug monitoring in plasma from patients with epilepsy.

Metoclopramide (MCP), a central and peripheral dopaminergic blocker with cholinergic activity, has been proposed to treat orthostatic hypotension (OH) on the basis that it could antagonize the vasodilator and natriuretic effects of dopamine. The authors evaluated cardiovascular responses to MCP in 11 subjects with OH: 6 with multiple system atrophy (MSA) and 5 with pure autonomic failure (PAF), along with 6 healthy control subjects. Supine blood pressure (BP), heart rate (HR), and breathing were continuously monitored before, during, and after MCP infusion. The pre-MCP head-up tilt test was tolerated at 65 degrees for 10 minutes in all subjects except in one with PAF, who tolerated 30 degrees for only 5 minutes. Tilting confirmed the OH in patients with MSA (change in mean arterial pressure [deltaMAP] = -31 +/- 13 mm Hg) and PAF (AMAP = -34 +/- 8 mm Hg). Infusion of MCP was given in four 5-mg doses every 5 minutes, with the subject in a supine position. Infusion of MCP induced the following effects: (1) A transient hypotensive effect occurred after each infusion in both patients and control subjects, the fall in MAP being counteracted by an increase in HR in control subjects but not in patients; this acute MAP fall was mo resevere in patients. (2) A progressive reduction of MAP occurred during the test,which never returned to preinfusion levels in patients; this effect was so pronounced in two PAF patients as to prevent them from receiving the last dose. Post-MCP tilting was tolerated in control subjects but in only in 5 MSA patients and 4 PAF patients. In those patients who tolerated the test, the MAP fall was similar to, or worse than, that before MCP (MSA: deltaMAP = -28 +/- 16 mm Hg; PAF: deltaMAP = -38 +/- 16 mm Hg). The cardiovascular effect of MCP in normal subjects was a transient hypotension counterbalanced by reflex tachycardia. The lack of an HR increase and the progressive fall in supine BP in MSA and PAF patients, together with worsening orthostatic tolerance after MCP infusion, are effects that should strongly discourage the use of this drug in the treatment of OH.

Objective: To evaluate whether the circadian rhythm of body core temperature (CRT degrees ) can differentiate Multiple-System Atrophy (MSA) from Idiopathic Parkinson's disease (IPD)., Methods: We evaluated 14 patients with probable MSA, seven with IPD, and eight controls. After a preliminary evaluation of cardiovascular autonomic function, rectal temperature and sleep-wake cycle were monitored continuously for 48 hours in a temperature-controlled room, at constant bed rest with controlled food intake and fixed light-dark schedule., Results: MSA patients showed cardiovascular autonomic sympathetic and parasympathetic failure. IPD had normal cardiovascular autonomic function. A 24-hour rhythm of body core temperature (BcT degrees ) was present in all subjects. IPD had CRT degrees comparable to controls. In MSA the mesor was higher and mean BcT degrees of each hour was significantly higher from 11 p.m. to 7 a.m. The analysis of mean BcT degrees during the different sleep phases showed significantly higher values during both NREM (1--2, 3--4) and REM sleep stages in MSA., Conclusions: The physiological nocturnal fall of BcT degrees is blunted in MSA patients mainly because BcT degrees did not decrease during sleep. This CRT degrees pattern is not justified by differences in sleep structure and may reflect an impairment of central sympathetic nervous system function., (Copyright 2001 Movement Disorder Society.)

The authors report preliminary findings on the effect of the new generation antiepileptic drug (AED) felbamate (FBM) on steady state plasma concentrations of clobazam (CLB), a benzodiazepine (frequently used as add-on therapy in patients with refractory epilepsy) and its active metabolite n-desmethyl-clobazam (N-CLB). The authors prospectively collected plasma samples from 66 children and adults with epilepsy receiving chronic CLB therapy. On the basis of concomitant AEDs, patients were divided into three subgroups otherwise comparable for age and weight-adjusted daily dose of CLB: group A (n = 22), receiving CLB monotherapy or CLB plus AEDs without inducing properties of cytochrome P450 (CYP) metabolism, namely valproic acid (VPA) or lamotrigine (LTG); group B (n = 28), receiving CLB plus AED inducer polytherapy (carbamazepine, phenobarbital, phenytoin), even associated with VPA (n = 9) or LTG (n = 12); group C (n = 16), receiving CLB plus FBM, associated with AED inducers, VPA or LTG. Level to weight-adjusted dose ratio (L/D) of CLB in groups B and C was twofold lower compared to group A (p < 0.001). L/D of N-CLB was twofold higher in group B and fivefold in group C compared to group A (p < 0.00 1). The metabolite-to-parent drug ratio shifted from a median value of 2.8 in group A to 13 in group B, and up to 29 in patients receiving polytherapy with FBM (p < 0.001). These data confirm previous reports of a significant increase in CLB clearance in patients receiving AED inducers, leading to an accumulation of its main metabolite. They also provide novel evidence of a further marked increase in N-CLB plasma concentrations in patients receiving FBM cotherapy. From a clinical point of view, this finding should be kept in mind in explaining possible toxicity in patients on complex AED polytherapy. Furthermore, knowledge of the in vivo interaction between CLB and FBM could help in identifying the CYP isoforms involved in the metabolism of both CLB and N-CLB.

We compared the kinetic-dynamic profile of a postprandial dose of levodopa-benserazide dispersible formulation to that of the standard form in eight patients with parkinsonism presenting delayed or irregular patterns of after-meal levodopa dose effects. Patients were studied on two occasions, one week apart, according to an intra-subject randomized cross-over design. Thirty minutes after the consumption of a standard meal, patients received their usual levodopa-benserazide postprandial dose, on one occasion in the standard formulation and on the other one in the dispersible form. Blood venous samples for analysis of plasma levodopa concentrations were drawn at 15-minute intervals for the first 2 hours, then half-hourly until 5 hours after dosing. Motor response to the levodopa test dose was assessed by the finger tapping test at the same times as blood was sampled. The only statistically significant finding was a shorter time to peak plasma levodopa concentration with the levodopa-benserazide dispersible formulation compared with the standard form, whereas comparisons of levodopa pharmacodynamics showed little advantage of either formulation. Considering that liquid formulations of levodopa are less practical, we suggest reserving dispersible levodopa-benserazide tablets for selected patients and carefully monitoring drug dose motor response.

Tubulin carboxypeptidase is the enzyme that releases the C-terminal tyrosine from alpha-tubulin, converting tyrosine-terminated (Tyr) to detyrosinated (Glu) tubulin. The present study demonstrates that this enzyme is associated with microtubules in living cells. We extracted cultured cells (COS-7) with Triton X-100 under microtubule-stabilizing conditions and found tubulin carboxypeptidase activity in the cytoskeleton fraction. We ruled out, by using several control experiments, the possibility that this result was due to contamination of the isolated cytoskeletons by non-associated proteins contained in the detergent fraction or to an artifact in vitro during the extraction procedure. The associated carboxypeptidase activity showed characteristics similar to those of brain tubulin carboxypeptidase and different from those of pancreatic carboxypeptidase A. In comparison with cultures at confluence, those at low cell density contained small (if any) amounts of carboxypeptidase activity associated with microtubules. In addition, the enzyme was shown to be associated only with cold-labile microtubules. The tubulin carboxypeptidase/microtubule association was also demonstrated in Chinese hamster ovary, NIH 3T3 and PC12 cells. Interestingly, this association was not observed in cultured embryonic brain cells. Our results demonstrate that tubulin carboxypeptidase is indeed associated with microtubules in living cells. Furthermore, the findings that this association occurs with a subset of microtubules and that its magnitude depends on the degree of confluence of the cell culture indicate that it could be part of the mechanism that regulates the tyrosination state of microtubules.

Objectives: We describe two patients with hypothalamic hamartoma and gelastic seizures., Methods: We performed ictal neurophysiological studies with polygraphic recordings of autonomic parameters and hormonal ictal plasma concentration measurements., Results: Ictal recordings showed a stereotyped modification of autonomic parameters: increase in blood pressure and heart rate, peripheral vasoconstriction and modification of respiratory activity. At seizure onset, the norepinephrine plasma level was high and epinephrine unchanged, whereas prolactin and adrenocorticotropic hormone were increased in both cases. Growth hormone and cortisol plasma concentrations in each patient showed a different response to seizures., Conclusions: These data provide evidence that gelastic seizures are accompanied by an abrupt sympathetic system activation, probably due to the direct paroxysmal activation of limbic and paralimbic structures or other autonomic centres of the hypothalamus and medulla.

Objective: The aims of the study were to follow prospectively the intrasubject progression of idiopathic PD in a cohort of patients using levodopa kinetic-dynamic modeling and to assess the relation between the rate of progression of the disease and patients' different clinical characteristics., Methods: Thirty-four patients (Hoehn and Yahr stages 1 to 3) enrolled in the longitudinal follow-up. Each patient was examined at 1-year intervals over a median 4 years by a standardized oral levodopa test. The primary measure outcome was the computed half-life of levodopa in the "effect compartment" (t1/2eq), a proposed indicator of nigrostriatal dopaminergic functionality and integrity., Results: Values of levodopa t1/2eq correlated negatively with severity of symptoms (r = -0.652, p < 0.0001) and decreased over the years together with a worsening of patients' clinical stage (p < 0.001). The rate of reduction in drug t1/2eq was more rapid in patients at the earlier stages of the disease compared with the more advanced ones, falling from a median annual reduction of 37 minutes in patients at initial Hoehn and Yahr stage 1 to 6.5 minutes in stage 3 patients (p < 0.001). Patients without tremor at onset, otherwise comparable to patients with tremor for baseline values of levodopa t1/2eq, disease severity, duration, and daily dose of levodopa, tended to show a higher rate of reduction in levodopa t1/2eq than patients with tremor. Overall, patients' annual reduction in levodopa t1/2eq over baseline values averaged 17+/-9%., Conclusions: These results are in keeping with PET findings on the objective assessment of idiopathic parkinsonism evolution, and they support the suggestion that levodopa pharmacodynamic modeling may offer a practical clinical tool to assess indirectly the functional integrity of the nigrostriatal dopaminergic system over time in parkinsonian patients.

Objective: The aim of the study was to assess the effect of the time of ingestion of a meal on the pharmacokinetics and pharmacodynamics of a levodopa/carbidopa controlled-release formulation in parkinsonian patients on chronic levodopa therapy., Methods: The kinetic-dynamic profile of one tablet of controlled-release levodopa/carbidopa 200/50 mg was monitored in eight patients, according to an intrasubject randomized cross-over design in two different sessions. A standard meal was consumed by the patients after they had fasted for 15-17 h, on one occasion 30 min before the ingestion of the test dose, and on the other occasion 2 h after the ingestion of the same drug dose. Blood venous samples for analysis of plasma levodopa and its metabolite 3-O-methyldopa were drawn at 20-min intervals up to 6 h after dosing. Motor response to the levodopa test dose was assessed by the finger tapping and walking speed tests at the same times as blood was drawn., Results: Controlled release [corrected] levodopa intake after meals resulted in a significant delay in drug absorption, with an almost twofold increase in time of initial appearance of levodopa in plasma and time to peak plasma concentration. Peak plasma drug concentrations were not significantly different in the two experimental conditions; the area under the 6-h plasma concentration-time curve showed an average reduction of 24% in the fed condition, partly reflecting the incomplete assessment of levodopa absorption, within the 6 h of examination, due to 5-h delayed peak plasma levodopa concentration in two patients. With reference to levodopa pharmacodynamics, time to onset of motor response was significantly delayed and duration of motor response significantly curtailed in the fed condition, while the magnitude and overall extent of motor effect were unchanged., Conclusions: In keeping with previous findings on levodopa standard-release preparations, these data show that time of meal ingestion is an important determinant of levodopa disposition, even from controlled-release preparations in parkinsonian patients. From a clinical point of view, these results help to explain some of the delayed, curtailed and even lacking responses that often complicate afternoon motor performances in patients at the more advanced stages of the disease.

Ten patients with primary autonomic failure, followed up in a prospective clinical and laboratory study, were finally diagnosed as pure autonomic failure or multiple system atrophy with autonomic failure. Polysomnographic studies were performed in all patients. Whereas all four patients with multiple system atrophy complained of sleep related episodes suggesting REM sleep behaviour disorder (RBD) confirmed by polysomnography, RBD remained absent in the remaining six patients with pure autonomic failure. The data indicate that RBD is an important clinical feature, often heralding multiple system atrophy, but which is absent throughout the course of pure autonomic failure; its recognition can thus be useful in the prognostic evaluation of early primary autonomic failure syndromes.

Prolonged Q-T interval predicts severe arrhythmias and sudden death, and has been shown to occur in alcoholic liver disease and cirrhotic patients who are candidates for liver transplantation. This study first evaluated the prevalence of prolonged Q-T interval in a large population of unselected patients with cirrhosis, and assessed the relationship between abnormal Q-T, etiology, and severity of liver disease and mortality of patients. Possible causes of Q-T abnormality were also explored. Ninety-four patients with cirrhosis without overt heart disease and 37 control subjects with mild chronic active hepatitis were enrolled. Rate-corrected Q-T interval (Q-Tc) was assessed along with routine liver tests, Child-Pugh score, serum bile salts, electrolytes and creatinine, plasma renin activity, aldosterone, norepinephrine, atrial natriuretic factor and, gonadal hormones. Q-Tc was longer in patients with cirrhosis than in controls (440.3 +/- 3.2 vs. 393.6 +/- 3.7 ms; P < .001) and prolonged (> 440 ms) in 44 patients (46.8%) and 2 controls (5.4%; P < .001). Q-Tc length was not influenced by the etiology of cirrhosis and correlated with Child-Pugh score (r = .53; P < .001), liver tests such as prothrombin activity, and serum concentrations of albumin and bilirubin, plasma bile salts, and plasma norepinephrine. Multivariate analysis showed that only Child-Pugh score and plasma norepinephrine were independently correlated with Q-Tc duration. Over a median follow-up period of 19 months (range, 2-33 months), patients with Q-Tc longer than 440 ms had a significantly lower survival rate than those with normal Q-Tc. Q-T interval is frequently prolonged in patients with cirrhosis, regardless the etiology of the disease, worsens in parallel with the severity of the disease, and may have an important prognostic meaning. In addition to other undefined factors related to the severity of cirrhosis, sympathoadrenergic hyperactivity may play a pathogenetic role.

We conducted a 3-year prospective assessment of the relationship between levodopa (L-DOPA) plasma concentration and both dyskinesias and tapping motor response after a standard oral L-DOPA dose in 11 parkinsonian patients, Hoehn & Yahr (H & Y) stages 2-3, with L-DOPA therapeutic response complicated by involuntary movements. Over the 3-year period, duration of the tapping effect significantly decreased, while that of dyskinesias showed minor changes. Initially, the L-DOPA therapeutic response significantly outlasted the dyskinesia effect and progressively shortened to parallel the dyskinesia profile at the more advanced clinical stage. According to kinetic-dynamic modeling, L-DOPA concentrations producing 50% of maximum therapeutic and toxic effects (EC50) also changed independently. EC50 for dyskinesias did not vary over time. EC50 for the tapping effect was, at the first observation, significantly lower than that of the matched value for dyskinesias and progressively rose to values similar to the EC50 for dyskinesias by the third year of follow-up. These data suggest a dissociation of the kinetic-dynamic relationship of L-DOPA motor and dyskinesia effects, possibly reflecting different cerebral handling of exogenous levodopa-derived dopamine with 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 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. Treatments aimed not only at controlling the symptoms, but also at slowing the neurodegenerative process, are currently under intensive investigation.

We assessed the nature of foot strike and the potential effect of acute levodopa dosing in Parkinsonian patients with mild to severe fluctuations of motor performances in comparison with healthy volunteers. Forty-eight patients were enrolled in the study and compared with 33 age and gender matched controls. Each patient was assessed by a computerized electropodographic system before levodopa dosing and 1 and 2-h after intake of a standard fasting morning dose of levodopa plus benserazide. Twelve foot strikes (six right, six left) were analysed per patient. The controls underwent three repeated examinations at 1-h intervals. Patients' motor response to acute levodopa dosing was evaluated at fixed times by a battery of motor tests. Foot strike dynamics differed between patients and controls: in particular, first ground contact of the foot was significantly shifted from heel to forefoot in patients compared to controls. The forward shift in footprint during walking was more marked on the more affected body side but was unrelated to the severity and duration of Parkinsonism and unresponsive to levodopa dosing. Tapping and walking tests were overall responsive to acute levodopa intake. The system seemed suitable to detect irregular patterns of foot strike even at the early stages of Parkinsonism, when lower limb disorder was not clinically overt, and might be useful in the search for clinical markers of Parkinsonian gait., (1996 Lippincott Williams & Wilkins.)

We investigated the relationship between the rate of motor response after a standard levodopa oral dose and drug dynamic variables and disease-related factors in 66 patients with Parkinson's disease. Time to maximum finger tapping effect was positively correlated with matched duration of levodopa dose response and fell from a median 120 minutes in patients at Hoehn and Yahr stage I and II to 60 minutes in stage IV patients (p < 0.001). The accelerated response to levodopa dose with the advancement of disease was also apparent as an increased steepness of the tapping effect versus time curve, with a shift from a hyperbolic to a sigmoid profile. The rate of motor response to oral levodopa may reflect the rate of dopamine interaction with the postsynaptic receptors, providing an indirect objective index of presynaptic dopaminergic homeostasis.

Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, non-linear mixed effect modelling with the program NON-MEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid EMax representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient., Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets., Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

We systematically assessed the potential effects of disease severity and acute levodopa dosing on body balance by a stable force measuring platform in 56 patients with Parkinson's disease, and compared them to 34 healthy volunteers. Postural sway variables were significantly higher in both patient groups without (Hoehn and Yahr 1-2) and with (Hoehn and Yahr 3-4) a clinically evident deficit of postural stability compared to controls. Levodopa dosing significantly increased postural sway 1 and 2 hours post-dose. The standardization of static posturography with respect to the clinical characteristics and drug schedule of patients may improve the sensitivity of the test, disclosing abnormalities of postural stance even at the early stages of the disease and revealing possible acute drug effects.

To investigate the relationship between nocturnal changes in blood pressure (BP) and diurnal cardiovascular reflexes we examined a group of 19 male normotensive obstructive sleep apnea syndrome (OSAS) patients. All patients underwent a full polysomnographic examination including BP monitoring by a finger arterial pressure device (Finapres) and a battery of cardiovascular reflex tests; plasma catecholamine levels at rest were also measured. During sleep, BP increased with an average difference of 15.4 +/- 7.5 mmHg for systolic and 8.3 +/- 4.6 mmHg for diastolic pressure. Compared with control subjects, OSAS patients had lower values of Valsalva ratio (VR) (1.75 +/- 0.4 vs 1.34 +/- 0.2, p = 0.0004), E/I ratio (1.35 +/- 0.2 vs 1.13 +/- 0.9, p = 0.0004) and baroreflex sensitivity index (BRSI) (5.4 +/- 2.1 vs 2.7 +/- 1.9 mms/mmg, p = 0.0006) and a higher systolic (p = 0.02) and diastolic (p = 0.002) pressure response to tilting-up test. Noradrenaline plasma levels were also significantly higher (345 +/- 125 vs 224 +/- 92 pg/ml, p = 0.001). No significant correlations were found between the nocturnal rise in BP and the pressure responses during sympathetic manoeuvres or rest levels of noradrenaline. The nocturnal changes in systolic blood pressure during the night were negatively dependent on the diurnal BRSI (r = -0.91, p = 0.0007) and VR (r = -0.70, p = 0.006). We conclude that the high levels of noradrenaline at rest and the altered sympathetic cardiovascular reflexes alone do not account for the nocturnal variation in blood pressure in OSAS.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Fatal familial insomnia is a prion disease in which a selective thalamic degeneration leads to total sleep deprivation, hypertension, dysautonomia, adrenal overactivity, and impaired motor functions. With patients under continuous recumbency and polysomnographic control, we assessed the changes in the 24-hour patterns of blood pressure, heart rate, plasma catecholamines, corticotropin, and serum cortisol in three patients at different stages of the disease. Six healthy volunteers were used as control subjects. A dominant 24-hour component was detected at rhythm analysis of all variables, both in patients and control subjects. In the patients, the amplitudes gradually decreased as the disease progressed, leading to the obliteration of any significant dirunal variation only in the preterminal stage. A shift in phase corresponded to the loss of the nocturnal fall in blood pressure in an early stage of the disease, when nocturnal bradycardia was still preserved. Plasma cortisol was high and became increasingly elevated, whereas corticotropin remained within normal levels; abnormal nocturnal peaks appeared in their circadian patterns. The disrupted patterns of cortisol and blood pressure preceded the development of hypertension and severe dysautonomia, which in turn were paralleled by increasing catecholamine and heart rate levels. Our data demonstrate that in patients with fatal familial insomnia the changes detectable in the rhythmic component of diurnal blood pressure variability result in a pattern of secondary hypertension. Disturbances in thalamic, pituitary-adrenal, and autonomic functions seem to be involved in mediating these changes.

Cardiovascular autonomic function in normotensive awake patients with obstructive sleep apnoea syndrome was studied in 21 normotensive (mean age 48 +/- 14 years), drug-free men with obstructive sleep apnoea syndrome. Cardiovascular reflex tests with continuous blood pressure monitoring and biochemical indices were performed the morning after a standard polygraphic sleep recording. A group of 20 age-matched (mean age 49 +/- 19 years) normal subjects was used as controls. The obstructive sleep apnoea syndrome patients showed higher heart rate and noradrenaline plasma levels (p < 0.05) at rest and a higher blood pressure response to head-up tilt (p < 0.01), suggesting sympathetic overactivity. Respiratory arrhythmia, baroreflex sensitivity index and Valsalva ratio were significantly lower in the obstructive sleep apnoea syndrome group (p < 0.01) whereas the decrease in heart rate induced by the cold face test was significantly higher (p < 0.05) showing a blunting of reflexes dependent on baroreceptor or pulmonary afferents with normal or increased cardiac vagal efferent activity. These abnormalities in autonomic regulation may predispose obstructive sleep apnoea syndrome patients to cardiovascular complications like hypertension and cardiac arrhythmias.

We investigated the relationship between levodopa plasma concentration and the tapping effect, after a standard oral levodopa test, by kinetic-dynamic modeling in 40 parkinsonian patients with stable or fluctuating response to levodopa, and found no difference in levodopa plasma pharmacokinetics between stable and fluctuating patients. Conversely, levodopa equilibration half-life between plasma and effect-site concentration was five-fold shorter on average in fluctuating patients. Overall, levodopa equilibration half-life highly correlated with the duration of tapping response and provided a reliable quantitative index of central mechanisms that affect the length of clinical effect. Individual fitting of tapping measures to modeled drug effect-site concentrations by sigmoid Emax model revealed that fluctuating patients required almost two-fold higher levodopa concentrations (EC50) to elicit almost the same motor response (Emax). These findings suggest that shortening of levodopa clinical effect may be accompanied by a reduced drug affinity for the nigrostriatal dopaminergic system (EC50), with no change in its intrinsic activity (Emax).

We studied the effect of chronic bromocriptine cotherapy on levodopa kinetics in seven patients with Parkinson's disease who were receiving levodopa therapy. Plasma levodopa concentrations were measured after a standard oral levodopa fasting dose over a 5-hour period, on two different sessions, without and with bromocriptine at a fixed daily dose of 15 mg. We found no statistically significant difference in the rate and extent of levodopa absorption between the two treatments, with minimal intrasubject variability. Our observations suggest that chronic bromocriptine cotherapy is unlikely to affect the plasma levodopa pharmacokinetics under standardized intake conditions or to contribute to a less predictable pattern of drug plasma concentrations.

The effect of aging on carbamazepine (CBZ) plasma level/dose ratio was evaluated retrospectively in 15 children who were receiving CBZ monotherapy and who were followed up for at least 3 years. Subjects of the study were selected from a population of roughly 4,500 patients attending our therapeutic drug monitoring service during a 12-year period. Results showed that the CBZ plasma level/dose ratio increases within subject during childhood, in agreement with data obtained in between-patient studies. However, the increase is not linear with age, the greatest modifications being observed between 9 and 13 years of age. Weight gain alone does not seem to explain this finding, implicating the involvement of complex physiological changes occurring during puberty.

Symptoms suggestive of dysautonomia are often reported in Myotonic Dystrophy (MD) patients. 12 patients with MD underwent cardiovascular function testing with assay of plasma noradrenaline (NA) and adrenaline (A) in supine rest condition and after orthostatic and cold stimulus. Statistical analysis showed no differences between MD patients and an age and sex matched control group.

We describe a 37-year-old man with a long-standing history of impotence and urgency of defaecation. The latter invariably followed the ingestion of food. Studies of cardiovascular autonomic function disclosed asymptomatic orthostatic hypotension due to isolated sympathetic noradrenergic failure with intact cardiac vagal control. There were no other neurological abnormalities. Levels of plasma noradrenaline and urinary vanillylmandelic acid were very low but plasma dopamine and urinary homovanillic acid were normal. A low level of dopamine-beta-hydroxylase activity was detected in plasma. The patient's parents were first cousins. The parents, the brother and the sister were investigated and clinical and biochemical studies showed no abnormalities. We conclude that this is a further observation of orthostatic hypotension due to isolated adrenergic failure with clinical and biochemical features different from cases previously described.

The potential difference in the concentration-effect relationship of oral sequential doses of levodopa was explored in six Parkinsonian patients with complex fluctuating response. These patients showed "wearing-off phenomena" characterized by a transient worsening of motor function at the end of the first morning dose response to below baseline values and complained of a progressive reduction of levodopa effect during the day. A first standard levodopa dose was given in the morning, after an overnight fast and levodopa withdrawal. A second equal levodopa dose was administered immediately at the end of the first dose deterioration phase. Postimprovement worsening of motor response was also observed after the second levodopa dose in all patients. No significant difference in the pharmacokinetics of levodopa or in duration or magnitude of motor response could be appreciated between the two doses. These results further support the suggestion that, under controlled dietary conditions, plasma levodopa levels and effects relationship is reproducible between doses. Moreover, even when transient deterioration of motor function occurs between levodopa doses, the central dopaminergic system appears to remain responsive to the drug.

We used a chronobiological inferential statistical method to investigate circadian rhythms of hypophyseal hormones, cortisol, melatonin and catecholamines in two females of the same family affected by fatal familial insomnia. Case 1 (confirmed at autopsy) presented an absent or progressive loss of circadian rhythms of all hormones. In case 2 there was a loss of GH circadian rhythm and a less significant rhythm for melatonin, catecholamines and gonadotropins. These results confirm the role of the thalamus in regulating hormonal circadian rhythm.

Autonomic nervous system functions were studied in 13 females with migraine without aura during headache-free intervals, using physiological, pharmacological and biochemical methods. Heart-rate in the resting condition and blood pressure rises in the cold-face and isometric handgrip tests were higher than in controls. Normal cardiovascular responses to the Valsalva manoeuvre and to noradrenaline infusion suggest that the baroreflex arc is intact. Normal heart rate responses to the Valsalva manoeuvre, to the cold-face test and to deep breathing confirmed a normal cardiac parasympathetic function. Clonidine infusion showed a sedative and depressor effect and an inhibition of plasma NA similar to those occurring in controls, suggesting a normal central sympathetic tone. As a whole, the physiological, pharmacological and biochemical tests were consistent with a non-specific sympathetic hyperactivity, but do not confirm any impairment of the autonomic control of the cardiovascular system in migraine patients in headache-free intervals.

The effect of chronic intake of the anticholinergic drug orphenadrine on the bioavailability of levodopa was studied in six patients with Parkinson's disease. Plasma levodopa profiles and corresponding motor response to a standard dose of levodopa plus an inhibitor of peripheral L-aromatic aminoacid decarboxylase (benserazide) were followed, over a 5-h period, on two different sessions, with and without anticholinergic cotherapy. Six control patients were also included in the study for assessment of intrasubject variability in levodopa absorption under identical conditions. A considerable delay in levodopa absorption was found in one patient, and decreased absorption in an additional two patients while on anticholinergic. Patients' clinical performance corresponded well to plasma levodopa profiles. A significant impairment of basal clinical state was observed in two cases on anticholinergic withdrawal, probably as a result of pharmacodynamic interactions. Our observations suggest that chronic anticholinergic intake may contribute to a less predictable pattern of levodopa absorption and related therapeutic response in some subjects.

Autonomic control of the cardiovascular system was assessed in two patients with Fatal Familial Insomnia. The diagnosis was confirmed at autopsy in patient 1. In the resting state blood pressure and heart rate were higher than controls in patient 1; plasma noradrenaline levels were elevated in both patients. Evaluation of cardiovascular reflexes indicated intact baroreflex pathways but with exaggerated blood pressure and biochemical responses to certain stimuli (postural change, Valsalva manoeuvre, isometric handgrip). There was no pressor response to intravenously infused noradrenaline, an increased response to atropine and diminished depressor and sedative effects to clonidine. Overall these results are indicative of an unbalanced autonomic control with preserved parasympathetic and higher background and stimulated sympathetic activity. These physiological, biochemical and pharmacological data, together with known neuro-pathological findings in this disorder, emphasize the possible role played by the thalamus in regulating autonomic control of cardiovascular function in man.

The influence of age on the kinetics of a standard oral dose of levodopa administered with an inhibitor of peripheral dopa decarboxylase enzymes (benserazide) has been evaluated in 40 patients with Parkinson's disease (age 34-78 y) on chronic therapy. They were divided into 2 groups, on the basis of age below (21 patients, Group A) or above (19 patients, Group B) 65 y. The area under the plasma concentration-time curve (AUC) of levodopa was significantly greater in the older group (547 versus 428 mumol.l-1.min in Group B), coupled with a reduced apparent oral clearance (8.1 versus 10.7 ml.min-1.kg-1) and a longer plasma elimination half-life (67.6 versus 54.6 min). The age of the patients was positively correlated with the AUC of levodopa (r = 0.474) and its plasma elimination half-life (r = 0.391), and was negatively correlated with clearance (r = -0.489). The findings confirm previous data on volunteers that showed a reduction in the systemic clearance of levodopa due to age, which would probably account for the finding of a greater AUC of levodopa in older patients. The observed, age-mediated differences in levodopa pharmacokinetics, albeit statistically significant, were moderate and were likely to be of only minor importance for the dosing schedule.

A 39 year old man with acute panautonomic and mild somatic neuropathy had severe postural hypotension 1 week after onset. Porphyric neuropathy was excluded. The final diagnosis was Guillain-Barré syndrome (GBS). After 2 months he began to recover progressively and after 9 months he presented asymptomatic postural hypotension. We consider the hypothesis of a spectrum of clinico-pathological entities at one end of which lies GBS with autonomic signs and at the other acute pure dysautonomia. The site of the autonomic lesion, might have been in post-ganglionic sympathetic fibers and vagus nerve.

The acute dose-response profile of a standard oral levodopa dose was followed, over a maximum 8-h period, in 13 patients with and 10 patients without motor fluctuations using a battery of motor quantitative tests (tapping and walking speed, and multiple choice reaction and movement times). Thirteen age-matched normal controls performed tapping and psychomotor tests, at the same time intervals, over a 4-h period. Tapping test and movement times proved significantly impaired in all patients and were the best indicator of levodopa effect, while walking speed and reaction times were apparently of less value, except in severely affected patients. The duration of the levodopa antiparkinsonian effect differed markedly between the two groups, since fluctuating patients returned to prelevodopa dose values within 4 h (mean +/- SEM: 203 +/- 16 min), while in the stable group motor scores remained significantly higher than baseline values up to at least 7 h postdose. The magnitude of the effect was similar in the two groups, but response was complicated by mild to severe dyskinesias in 9 of 13 fluctuating subjects. The pharmacokinetic parameters of levodopa were almost identical in the two groups. Our data add further weight to the hypothesis that cerebral pharmacokinetic or pharmacodynamic factors are responsible for motor fluctuations. Oral levodopa doses coupled with objective tests of motor performance may prove a practical clinical tool to assess and optimize the relationship between drug dose and therapeutic effect.

The binding of propranolol enantiomers to human albumin (ALB), alpha 1-acid glycoprotein (alpha 1-AGP) and plasma was studied. (-) propranolol is more bound than (+)propranolol to alpha 1-AGP (P less than 0.001) and to plasma (P less than 0.05). In solutions containing ALB at a constant concentration (580 mumol/l) and alpha 1-AGP at increasing concentrations, the binding of both isomers increases but the stereo selectivity is evident throughout the alpha 1-AGP concentration range examined (25-100 mumol/l).

A case of Chiari malformation type I with orthostatic hypotension and sleep apnea leading to convulsive attacks is presented.

Metoclopramide extracted from plasma and urine has been analysed using reversed phase HPLC with acetic acid/acetonitrile/triethylamine as eluent and fluorescence detection. This method exploits the natural fluorescence of metoclopramide for its detection in patients on multiple drug therapies.

The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in nine epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a three-times-daily or four-times-daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in five patients and showed an intermittent pattern in four. Side effects were never found at total carbamazepine levels less than 34 mumol/L but invariably appeared at levels greater than 38 mumol/L. At levels between 34 and 38 mumol/L adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels greater than 7.2 mumol/L. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.

The binding of valproic acid (VPA) to human serum albumin (HSA) and to pooled human plasma has been investigated by using equilibrium dialysis with three different dialysis solutions: phosphate buffer (solution I), Krebs solution (solution II), and Krebs solution without calcium (solution III). The effect of pH variation from 6.4 to 8.2 has been also investigated. VPA free fraction increased by increasing pH with all the dialysis solutions (from 4.1% at pH 6.4 to 9.4% at pH 8.2 with solution I, from 8.1% to 11.3% with solution II, and from 10.6% to 14.3% with solution III, in plasma). At each pH value, free fraction obtained with solution III was the highest and that obtained with solution I was the lowest. Data in plasma and HSA solution were similar. In a separate experiment we compared (at pH 7.4, with plasma) the three more frequently used dialysis solutions: phosphate buffer, phosphate buffer with NaCl, and Krebs solution. They gave, respectively, a mean VPA free fraction of 7.8, 10.3, and 12.7%. These findings can explain the wide range of VPA free fraction values reported in the literature. Researchers intending to determine VPA free concentration by equilibrium dialysis should take into account these methodological aspects.

Plasma protein binding of propranolol (PROP) was determined in 18 migraine patients chronically treated with different doses (from 60 to 240 mg/day) of the drug. In 9 patients serum lipids and PROP binding were determined before and during the therapy. Free fractions of PROP ranged from 4.7 to 13.3% and they were similar to those found in vitro in healthy volunteers. Total and free concentrations were highly correlated (r = 0.929; p less than 0.001); correlations between daily doses (in mg/kg) and free and total concentrations were very similar: r = 0.76 and r = 0.73 respectively. Changes in binding and serum lipids during the therapy were insignificant and unrelated.

The performance of the enzyme multiplied immunoassay technique (EMIT) in the measurement of total and free plasma carbamazepine (CBZ) levels was assessed in 140 clinical specimens and compared with a reference high pressure liquid chromatography (HPLC) technique. Free drug was measured in plasma filtrates obtained by the Free Level system. Both total and free CBZ levels as determined by EMIT correlated strongly with corresponding HPLC values (r = 0.88 and 0.92, respectively). Plasma CBZ concentrations, however, were higher by EMIT than by HPLC. The degree of CBZ overestimation by EMIT was relatively small (about 14%) in whole plasma but quite considerable (35% on average) in the filtrates. As a result, estimated values of free CBZ fraction were also higher for EMIT than for HPLC. Separate experiments in vitro suggested that the discrepancies between the two methods were due to cross-reaction of the EMIT reagent with the 10,11-epoxide metabolite of CBZ. The greater degree of overestimation for the free drug can be explained by the higher proportion of less protein-bound metabolite in the filtrates. These results need to be taken into account in the interpretation of free CBZ level data from laboratories using different techniques.

Total and free serum concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) at steady state were determined in 10 infants (ages 4-13 months), 10 preschool children (ages 3-5 years), and 11 school children (ages 7-11 years) receiving equivalent doses of CBZ alone. Free and total CBZ levels tended to increase with increasing age, while CBZ-E levels did not show any significant age dependency. As a result, CBZ-E/CBZ ratios were higher in infants and preschool children than in the older age group. The degree of plasma protein binding of CBZ and CBZ-E did not show any important differences among the various groups. These data provide evidence that, within a pediatric population, CBZ shows age-related dispositional changes which may be clinically important.

The relationship between the serum protein binding of carbamazepine (CBZ) and carbamazepine-10,11 epoxide (CBZ-E) and the concentration of alpha 1-acid glycoprotein (AAG) and albumin (HSA) was examined in 39 CBZ-treated epileptic children aged 4 months to 12 years. A significant inverse correlation was found between the free fraction of both compounds and serum AAG, even though changes in AAG concentration explained only part of the variation in binding. No correlation was found between the free fraction of CBZ and CBZ-E and HSA, probably due to the small intersubject variation in HSA concentration. In vitro experiments showed that both CBZ and CBZ-E were bound to HSA and to a lesser extent to AAG. At equivalent HSA concentrations, the binding of CBZ and its metabolite increased proportionately with increasing AAG concentration within the range occurring clinically.

The incidence of lateral gaze nystagmus and its correlation with free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine-10, 11-epoxide (CBZ-E) were examined in 97 epileptic patients receiving chronic treatment with CBZ alone (n = 54) or in combination with phenobarbital (PB) (n = 43). All patients had plasma CBZ concentrations within the clinically optimal range (less than 50 mumol/L). Nystagmus was seen in 26% of patients receiving monotherapy and in 33% receiving combination therapy. Within each group, however, nystagmus was much more frequent among patients with higher CBZ concentrations. For patients receiving PB in combination the CBZ levels above which nystagmus was particularly frequent appeared to be lower than in the monotherapy patients--a finding that could not be attributed to differences in plasma PB concentrations. The correlation of CBZ-E levels (or the sum of CBZ + CBZ-E) with the occurrence of nystagmus was no better than that observed with CBZ levels alone. Free drug levels did not appear to be superior to total levels in discriminating between patients with or without nystagmus. These results indicate that the occurrence of nystagmus is concentration-dependent within the therapeutic plasma CBZ concentration range and suggest that the threshold at which this neurological sign appears is reduced in the presence of PB, possibly as a result of a pharmacodynamic interaction.