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Biomedical subjects

F Albani

Publications and source records attributed to F Albani.

At least 37 records · Page 2Linked to original sources
PubMed1998

A genetic polymorphism in the human HOXB1 homeobox gene implying a 9bp tandem repeat in the amino-terminal coding region. Mutations in brief no. 200. Online.

In man there are 39 homeobox genes of the HOX family in four loci, HOXA, HOXB, HOXC and HOXD on chromosomes 7, 17, 12, and 2. We discovered the existence of two major alleles, termed a and b, of gene HOXB1. They differ at a specific position in the 5' portion of the coding region. Sequencing the two alleles revealed that the allele HOXB1A, contains two copies of the 9bp sequence 5'ACAGCGCCC3', starting at position 65 of the coding region, whereas the allele HOXB1b contains three copies of this sequence (Fig. 1). As a consequence, the allele HOXB1b encodes a homeoprotein containing two copies of the tripeptide HisSerAla, starting at amino acid residue 25, which is present in only one copy in allele HOXB1a. We analyzed 250 individuals and found that the allelic frequencies of HOXB1a and HOXB1b were 78.8% and 21.2%. The murine homologue contains only one copy of the 9bp repeat (Fig. 1). 7 mouse strains, namely 129, BALB/c, C57BL/6, C57BL/10, CAST/Ei, C3H and SPRET/Ei, are homozygous for this allele. The allele present in gibbon and rhesus monkey appears to be identical to the human HOXB1b (Fig. 1).

Animals↗
PubMed1997

Relationship between levodopa concentration, dyskinesias, and motor effect in parkinsonian patients: a 3-year follow-up study.

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.

Adult↗
PubMed1996

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients.

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).

Administration, Oral↗
PubMed1996

Rate of motor response to oral levodopa and the clinical progression of Parkinson's disease.

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.

Administration, Oral↗
PubMed1996

Pharmacokinetic optimisation in the treatment of Parkinson's disease.

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.

Antiparkinson Agents↗
PubMed1996

Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations.

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.

Anticonvulsants↗
PubMed1995

Carbamazepine clinical pharmacology: a review.

The tricyclic anticonvulsant carbamazepine is being increasingly used to treat a variety of neuropsychiatric disorders. We review the literature on the drug in neurology, psychiatry, and pharmacology, in order to provide the clinical psychiatrist with a comprehensive reference on carbamazepine pharmacokinetics, toxicity, and drug interactions. We also present an overview of the psychiatric disorders in which carbamazepine has been found, or suggested, to be efficacious.

Anticonvulsants↗
PubMed1994

Central action of cinnarizine and flunarizine: a saccadic eye movement study.

The mechanism of action of flunarizine (FZ) and cinnarizine (CZ) on the CNS is not fully understood. Computer analysis of saccadic eye movements (SEM) provides a sensitive and objective method for evaluating drug effect on the function of specific brain structures. This study aimed to assess the effect of a single oral dose of FZ (20 mg) and CZ (150 mg) on CNS function by means of computer analysis of SEM. Ten healthy volunteers were studied according to a double-blind, cross-over, placebo-controlled design. Peak saccadic velocity (PSV), which is related to the function of a specific group of burst neurons located in the brain stem, was significantly reduced by FZ. No significant effect of FZ on saccade accuracy (SA) and saccade latency (SL) was found. CZ did not produce significant effects on SEM, but a trend to decrease PSV. The possibility that a FZ central effect may be related to a stabilizing action on burst activity of neurons is discussed.

Administration, Oral↗
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

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

Kinetics of intravenous metoclopramide in patients with hepatic cirrhosis.

The pharmacokinetics of metoclopramide has been studied after acute IV administration to 12 patients with hepatic cirrhosis (6 with and 6 without ascites) and 6 control subjects. The elimination half-life was significantly longer in patients (11.4 h and 9.9 h in those with and without ascites, respectively, vs 6.4 h in controls). Total plasma clearance was significantly lower in patients (0.29 and 0.36 l.kg-1.h-1 vs 0.52 l.kg-1.h-1 in controls). The differences between patients with and without ascites did not reach statistical significance. Reduction of functional hepatic blood flow in cirrhotic patients is the probable cause of the observed alteration in metoclopramide kinetics.

Adult↗