PubMed Health⌕ Search

Biomedical subjects

M Contin

Publications and source records attributed to M Contin.

At least 19 recordsLinked to original sources
PubMed2007

Ultrastructural characterization of calcification onset and progression in subdermally implanted aortic valves. Histochemical and spectrometric data.

Detailed characterization of the subdermal model is a significant tool for better understanding of calcification mechanisms occurring in heart valves. In previous ultrastructural investigation on six-week-implantated aortic valve leaflets, modified pre-embedding glutaraldehyde-cuprolinic-blue reactions (GA-CB) enabled sample decalcification with concurrent retention/staining of lipid-containing polyanionic material, which lined cells and cell-derived matrix-vesicle-like bodies (phthalocyanin-positive layers: PPLs) co-localizing with the earliest apatite nucleation sites. Additional post-embedding silver staining (GA-CB-S) revealed PPLs to contain calcium-binding sites. This investigation concerns valve leaflets subjected to shorter implantation times to shed light on the modifications associated with PPLs generation and calcification onset/progression. Spectrometric estimations revealed time-dependent calcium increase, for unreacted samples, and copper modifications indicating an increase in acidic, non-glycanic material, for GA-CB-reacted samples. Two-day-implant thin sections showed emission and subsequent reabsorption of lamellipodium-like protrusions by cells, originating ECM-containing vacuoles, and/or degeneration stages characterized by the appearance of GA-CB-S-reactive, organule-derived dense bodies and progressive dissolution of all cell membranes. In one-week-implants, the first PPL-lined cells were found to co-exist with cells where GA-CB-S-reactive material accumulated, or exudated towards their edges, or outcropped at the ECM milieu, so acquiring PPL features. PPL-derived material was observed increasingly to affect the ECM on thin sections of one-week- to six-week-implants. These results show an endogenous source for PPLs and reveal that a peculiar cascade of cell degenerative steps is associated with valve mineralization in the subdermal model, providing new useful parameters for more reliable comparison of this experimental calcification process versus the physiological and pathological processes.

Animals↗
PubMed2003

Levodopa pharmacokinetics and dyskinesias: are there sex-related differences?

We examined the potential sex-related differences in levodopa pharmacokinetics and their relation with the presence of dyskinesias in a group of 115 patients (67 men, 49 women) with Parkinson's disease. The patients were given a standard oral dose of levodopa plus benserazide (100/25 mg). The area under the levodopa plasma concentration time curve, corrected for the levodopa test dose (in mg/kg body weight), (AUC(w)) was significantly higher in women than in men, with a reduced oral clearance. No difference in the proportion of men and women experiencing dyskinesias was observed.

Aged↗
PubMed2001

Simple and rapid liquid chromatographic-turbo ion spray mass spectrometric determination of topiramate in human plasma.

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.

Anticonvulsants↗
PubMed2001

Nocturnal body core temperature falls in Parkinson's disease but not in Multiple-System Atrophy.

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.

Adult↗
PubMed2001

The cardiovascular effects of metoclopramide in multiple system atrophy and pure autonomic failure.

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.

Aged↗
PubMed2001

Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach.

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.

Adult↗
PubMed1999

Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy.

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.

Adolescent↗
PubMed1998

Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors.

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.

Electrocardiography↗
PubMed1998

Effect of meal timing on the kinetic-dynamic profile of levodopa/carbidopa controlled release [corrected] 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.

Aged↗
PubMed1998

Autonomic and hormonal ictal changes in gelastic seizures from hypothalamic hamartomas.

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.

Adult↗
PubMed1998

REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure.

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.

Adult↗
PubMed1998

A levodopa kinetic-dynamic study of the rate of progression in Parkinson's disease.

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.

Adult↗
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↗