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R Riva

Publications and source records attributed to R Riva.

At least 55 records · Page 3Linked to original sources
PubMed1994

Oxcarbazepine: pharmacokinetic interactions and their clinical relevance.

Antiepileptic drug (AED) interactions are a common problem during epilepsy treatment. Oxcarbazepine (OCBZ) is a keto homologue of carbamazepine (CBZ) with a completely different metabolic profile. In humans, the keto group is rapidly and quantitatively reduced to form a monohydroxy derivative (MHD), which is the main active agent during OCBZ therapy. MHD is eliminated by renal excretion, glucuronidation and, marginally, by hydroxylation to a diol derivative. This metabolic profile, and in particular the limited involvement of oxidative microsomal enzymes, suggests that OCBZ may have fewer drug interactions compared with traditional AEDs. This possibility has been investigated in experimental studies and, retrospectively, in data obtained from clinical trials. The capacity of OCBZ to induce microsomal enzymes of the P-450 family has mostly been examined by use of antipyrine and CBZ kinetics as markers. The results suggest that OCBZ has little enzyme inducing capacity. In clinical trials in which OCBZ was substituted for CBZ, plasma concentrations of concomitant AEDs were increased, possibly as a consequence of total or partial de-induction. OCBZ interference with other drugs has been evaluated for warfarin, felodipine, and oral contraceptives, three medications strongly influenced by enzyme-inducing AEDs. OCBZ does not modify the anticoagulant effect of warfarin, whereas some reduction in felodipine concentration and a clinically significant reduction of contraceptive drug levels and efficacy were observed. Polytherapy with established AEDs does not significantly modify OCBZ disposition (MHD kinetics); however, available information is not extensive. Finally, the action on OCBZ kinetics of a group of drugs (verapamil, cimetidine, erythromycin, dextropropoxyphene, and viloxazine) known to inhibit the metabolism of some AEDs has been studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsants↗
PubMed1994

Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson's disease.

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.

Adult↗
PubMed1993

Pharmacodynamic modeling of oral levodopa: clinical application in Parkinson's disease.

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).

Administration, Oral↗
PubMed1992

Kinetic-dynamic relationship of oral levodopa: possible biphasic response after sequential doses in Parkinson's disease.

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.

Adult↗
PubMed1992

No effect of chronic bromocriptine therapy on levodopa pharmacokinetics in patients with Parkinson's disease.

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.

Aged↗
PubMed1992

A within-subject analysis of carbamazepine disposition related to development in children with epilepsy.

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.

Adolescent↗
PubMed1992

Therapeutic monitoring of antiepileptic drugs. I--Clinical aspects.

The management of epilepsy has been markedly improved during the last twenty years, although no new drug has been developed. These therapeutic advantages have been made possible by applying the concept of "therapeutic range" of antiepileptic drugs. This range was the result of some pioneer studies showing a good relationship between clinical effects and drug concentrations. Today, the approach to the drug therapy of epilepsy is heavily dependent on the application of this concept. Infact, important factors as patient compliance, variability in drug bioavailability and drug metabolism, drug interactions, disease interactions, etc, that may influence the clinical effect of a given dose, may be controlled by regular monitoring of antiepileptic drugs. However, the concept of "therapeutic range" should not be applied mechanically to patient treatment. The best results are obtained when the analytical results, the therapeutic situation and the clinical status of the patient are considered together. In this case, an important improvement of the quality of life of the epileptic patients can be reached.

Anticonvulsants↗
PubMed1992

Therapeutic monitoring of antiepileptic drugs. II--Analytical techniques.

Recent development of analytical techniques for therapeutic drug monitoring of antiepileptic drugs are reviewed. The most commonly used procedures are high performance liquid chromatography (HPLC) and immunochemical techniques. Innovations in HPLC include commercialization of instrumentations for automatic extraction and injection of biological samples and development of restricted access media columns for direct injection of plasma without prior extraction. For immunochemical techniques, principles of "classical" major procedures are described together with the new immunoenzymatic and immunochromatographic methods in solid phase, specifically developed with the aim of making drug monitoring possible outside the traditional laboratory.

Anticonvulsants↗
PubMed1991

Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson's disease.

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.

Administration, Oral↗
PubMed1991

Effects of acute valproic acid administration on carnitine plasma concentrations in epileptic patients.

Serial plasma samples collected after an acute administration of valproic acid, (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P less than 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total carnitine was unchanged but free carnitine was decreased (P less than 0.05) and carnitine esters were increased (P less than 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.

Adult↗
PubMed1991

Atrial natriuretic peptide and catecholamines in obstructive sleep apnea syndrome.

Nocturnal polyuria with repeated micturitions during the night is a clinically evident feature of obstructive sleep apnea syndrome (OSAS). These effects are reversed by continuous positive airway pressure (CPAP). There is some evidence that atrial natriuretic peptide (ANP) and catecholaminergic activity may be implicated in the pathogenesis of these symptoms. We studied these biochemical parameters in six patients with severe OSAS during two nights: the first (basal) in their normal conditions and the second during CPAP treatment. CPAP treatment reversed apnea episodes in all our patients. A significant (p less than 0.035) reduction of nocturnal urine volume (from 902 +/- 297 to 447 +/- 130 ml; mean +/- SD), sodium excretion (from 150 +/- 33 to 89 +/- 35 mEq/12 h), noradrenaline excretion (from 95 +/- 101 to 52 +/- 16 micrograms/g creatinine), noradrenaline plasma concentrations (from 325 +/- 96 to 259 +/- 75 pg/ml), ANP plasma concentrations (from 35 +/- 20 to 19 +/- 5 pg/ml) was observed during the night under CPAP application. These data suggest that in OSAS patients the high ANP plasma concentration is responsible for the observed elevated diuresis and sodium excretion. These effects are rapidly reversible, as they are reversed during the first CPAP treated night.

Adult↗
PubMed1991

Combined levodopa-anticholinergic therapy in the treatment of Parkinson's disease. Effect on levodopa bioavailability.

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.

Adult↗
PubMed1990

Response to a standard oral levodopa test in parkinsonian patients with and without motor fluctuations.

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.

Adult↗
PubMed1990

Flunarizine plasma concentrations and side effects in migraine patients.

Flunarizine plasma concentrations and side effects were evaluated in migraine patients during a 3 month course of prophylactic treatment. Plasma concentrations did not correlate with daily dose (in mg/kg). Mean flunarizine levels were higher in patients showing sleepiness or sedation. Weight gain was independent of plasma concentrations. Future clinical trials of flunarizine should be supported by drug monitoring in order to clarify the relationship between plasma levels and drug effects.

Adolescent↗
PubMed1990

[Amiodarone-induced pigmentation. A histological, ultrastructural study and review of the literature].

Amiodarone is an iodinated cardiac antiarrhythmic drug that causes a slate- gray discoloration of sun-exposed skin. Histopathologically, biopsy specimens of two patients affected by amiodarone pigmentations reveal yellow-brown granules in the reticular dermis, both in the cytoplasm of macrophages and between the collagen bundles. The histochemical stainings of the granules suggest that a lipofuscin pigment rather than melanin is present in the granules. Electron microscopy displays distinctive intracytoplasmic inclusions in many dermal cell types. Six morphologic types can be seen: 1) electron-lucent, membrane bound granules, 2) granules with electron dense nucleus, 3) lamellar "myelin-like" granules, 4) granules with a combination of electron-dense and electron-lucent areas, 5) electron-dense membrane-bound granules, 6) electron-dense no-membrane granules. The different dimensions, structure and shape are related to the structural and aggregational phases of the granules. In particular their pathogenesis may be related to the action of the drug on cell membranes with thesaurismosis, local metabolic damage, accumulation of the drug in the lysosomes and acceleration of the physiological ageing cell process.

Aged↗
PubMed1989

Computer analysis of saccadic eye movements: assessment of two different carbamazepine formulations.

The central effects of two different formulations of Carbamazepine (CBZ) have been examined by analysis of saccadic eye movements (SEM) in 6 healthy volunteers, who took part in a double-blind, latin-square, placebo controlled study. Both a conventional- and a controlled-release formulation of CBZ produced a significant effect on peak saccadic velocity and saccade accuracy, but only the former affected saccade latency. Computer analysis of SEM confirmed it to be a highly sensitive method for detection of subclinical drug effects on the CNS.

Adult↗
PubMed1989

Increased dosage of carbidopa in parkinsonian patients on low carbidopa-levodopa regimen. Effect on levodopa bioavailability.

The effect of a 2.5-fold increase in daily carbidopa intake on the bioavailability of levodopa was studied in six patients with Parkinson's disease on a low chronic regimen of carbidopa-levodopa (Sinemet) at the fixed ratio of 1:10. The extent of levodopa absorption, expressed as the area under the 11-h plasma levodopa concentration-time curve (AUC0-11 h), was not enhanced by the higher carbidopa dose. A significant increase in the AUC was found for the levodopa metabolite 3-O-methyldopa at the higher carbidopa intake. Clinical performances of individual patients were identical with both carbidopa-levodopa ratios. From these data, an adequate inhibition of peripheral decarboxylation and hence a good bioavailability of levodopa may be expected in patients taking low doses of carbidopa-levodopa, using currently available commercial preparations.

Aged↗