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Biomedical subjects

M Baraldo

Publications and source records attributed to M Baraldo.

At least 19 recordsLinked to original sources
PubMed2000

High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures.

The aim of this study was to evaluate retrospectively the importance of a Bayesian pharmacokinetic approach for predicting vancomycin concentrations to individualize its dosing regimen in 18 critically ill patients admitted to intensive care units following cardiothoracic surgery. The possible influence of some coadministered drugs with important haemodynamic effects (dopamine, dobutamine, frusemide) on vancomycin pharmacokinetics was assessed. Vancomycin serum concentrations were measured by fluorescence polarization immunoassay. Vancomycin dosage regimens predicted by the Bayesian method (D(a)) were compared retrospectively with Moellering's nomogram-based dosages (D(M)) to assess possible major differences in vancomycin dosing. D(a) values were similar to D(M) in 10 patients (D(a) approximately D(M) group) (20.52 +/- 8.40 mg/kg/day versus 18.81 +/- 7.24 mg/kg; P = 0.15), whereas much higher dosages were required in the other eight patients (D(a) >> D(M) group) (26.78 +/- 3.01 mg/kg/day versus 18.95 +/- 3.41 mg/kg/day; P < 0.0001) despite no major difference in attained vancomycin steady-state trough concentration (C(min ss)) (9.22 +/- 1. 33 mg/L versus 8.99 +/- 1.26 mg/L; = 0.75) or estimated creatinine clearance (1.23 +/- 0.49 mL/min/kg versus 1.21 +/- 0.24 mL/min/kg; P = 0.95) being found between the two groups. The ratio between D(a) and D(M) was significantly higher in the D(a) >> D(M) group than in the D(a) approximately D(M) group (1.44 +/- 0.18 versus 1.10 +/- 0. 21; P < 0.01). In four D(a) >> D(M) patients the withdrawal of cotreatment with haemodynamically active drugs was followed by a sudden substantial increase in the vancomycin C(min ss) (13.30 +/- 1. 13 mg/L versus 8.79 +/- 0.87 mg/L; P < 0.01), despite no major change in bodyweight or estimated creatinine clearance being observed. We postulate that these drugs with important haemodynamic effects may enhance vancomycin clearance by inducing an improvement in cardiac output and/or renal blood flow, and/or by interacting with the renal anion transport system, and thus by causing an increased glomerular filtration rate and renal tubular secretion. Given the wide simultaneous use of vancomycin and dopamine and/or dobutamine and/or frusemide in patients admitted to intensive care units, clinicians must be aware of possible subtherapeutic serum vancomycin concentrations when these drugs are coadministered. Therefore, therapeutic drug monitoring (TDM) for the pharmacokinetic optimization of vancomycin therapy is strongly recommended in these situations.

Anti-Bacterial Agents↗
PubMed1999

Cyclosporine A pharmacokinetics in rheumatoid arthritis patients after 6 months of methotrexate therapy.

To evaluate the effects of a 6-month methotrexate (MTX) treatment period on cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA was administered to 30 subjects with RA (group A) treated with MTX (10 mg week-1 i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment. The mean doses +/- SD of CsA used in groups A and B were 3.2 +/- 0.5 and 3.3 +/- 0.4 mg kg-1, respectively. CsA levels were determined in whole blood by means of a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal antibody. The following pharmacokinetics parameters were calculated: area under the curve from 0 to 24 h (AUC0-24), half-life of the elimination phase (T1/2 beta), total body clearance CL.F-1; V.F-1 and apparent volume of distribution (Vd beta). The mean blood concentrations and the pharmacokinetic parameters calculated in group A did not present significant statistical differences in comparison to group B. In conclusion, a 6-month MTX therapy does not produce liver function modifications to such an extent as to modify the pharmacokinetics of CsA subsequently added. Therefore, from a clinical pharmacological point of view, an MTX-CsA cotreatment appears feasible.

Adult↗
PubMed1999

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

OBJECTIVE: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. METHODS: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. RESULTS: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); P < 0.01] and IDAOL [2896.60 (736.38) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l x h(-1) x m(-2) vs 139.65 (69.45) l x h(-1) x m(-2); NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) microg x h x l(-1) vs 2896.60 (736.38) microg x h x l(-1); P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. CONCLUSION: The results show that CyA alone at a dose of 10 mg x kg(-1) daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Cyclosporine↗
PubMed1999

Inter-patient and intra-patient variations in the baseline tapping test in patients with Parkinson's disease.

Inter-patient and intra-patient variations in the baseline values of the tapping test were studied in 22 patients with Parkinson's disease using the unequal sample sizes model II one-way analysis of variance (ANOVA). The results show that intra-patient variation accounts for about 15.8% of the total variation, inter-patient variation accounts for about 84.2% of the total variation, and the coefficient of variation (CV) in intra-patient variation is 15.8%. The results suggest that at least two or three baseline tapping tests are needed to determine the baseline value of the tapping test.

Aged↗
PubMed1998

Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia.

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.

Adult↗
PubMed1997

Levodopa and 3-O-methyldopa in cerebrospinal fluid after levodopa-carbidopa association.

Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12 h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level.

Adolescent↗
PubMed1997

Oral gabapentin disposition in patients with epilepsy after a high-protein meal.

PURPOSE: To study the interaction between gabapentin (GBP) and high-protein meals, 12 patients with epilepsy were administered this drug both while in a fasting state and after a high-protein meal. METHODS: After having acquired their informed consent, the patients (suffering from partial complex seizures resistant to other anticonvulsants) were randomly assigned to 2 groups of 6 subjects. Each subject was treated in a fasting state with a single 400 (group A) or 800 (group B) mg GBP oral dose. After 24 h, the GBP dose regimen was repeated, but was given after a high-protein meal. Serum GBP concentrations were measured by LC-Mass at baseline and 0.5, 1, 2, 3, 5, 7, 9, 12, and 24 h. Saliva GBP concentrations were determined at baseline and 2, 4.8, and 12 h. GBP urinary excretion was determined at 0-4, 4-8, and 8-12 h intervals. The following kinetic parameters were calculated: area under the concentration time curve from zero time to 24 h after the dose, AUC 0-24 h; maximal serum concentration, Cmax; time to the maximal serum concentration, Tmax; absorption rate constant, ka; elimination rate constant, beta; elimination half-time, t1/2beta. Student's t test for paired data, with significance assigned at P < 0.05, was used. RESULTS: No statistically significant differences were seen in GBP serum or saliva concentrations or in its urinary excretion (both in A or B group) between fasting and after the high-protein meal. CONCLUSIONS: High-protein meals do not seem to interfere with oral disposition of GBP.

Acetates↗
PubMed1996

Cyclosporin nephrotoxicity in relation to its metabolism in psoriasis.

Cyclosporine (CsA) and some of its metabolites (M9, M17, M18, M21) have been determined by means of an LC-MASS method in eight psoriatic patients developing nephrotoxicity. In comparison with a control group (15 psoriatics who after the same period of time, with the same daily dose, did not develop nephrotoxicity) they showed an increase of CsA metabolites, especially M17. Because M17 blood concentrations in the nephrotoxic group tended to be higher than in the control group from the first week of treatment we suggest that M17 might be considered a marker of ongoing nephrotoxicity.

Area Under Curve↗
PubMed1996

Blood concentrations and clinical effect of cyclosporin in psoriasis.

After approval by the Local Ethical Committee, 60 psoriatic patients, who participated in a previous pharmacokinetic study on cyclosporin A (CsA), gave their informed consent to continue to be studied during the maintenance treatment and at withdrawal. Peak concentration (Cmax), area under the concentration-time curve (AUC), bioavailability, elimination half-life, distribution volume, and body clearance were determined at monthly check-ups, along with blood pressure, psoriasis area, severity index (PASI), and creatinine serum levels. No modifications over time of treatment were observed on kinetic parameters. At the dose of 5 mg/kg in two daily administrations, a complete remission of the disease was observed after 1 month's treatment. At withdrawal, a worsening of PASI appeared when CsA daily dose reached 2 mg/kg b.w., the mean trough levels or AUC values being, respectively, 100 and 2,200 ng/ml.hr. There was a trend for patients with hypertension and nephrotoxicity at the end of the maintenance treatment to have higher trough, Cmax, and AUC values. Furthermore, blood pressure and serum creatinine tended to correlate better with AUC and Cmax, than with trough levels.

Adult↗
PubMed1995

Calculating percentage prediction error: a user's note.

The equations of calculation of percentage prediction error (percentage prediction error = [equation: see text] x 100 or percentage prediction error = [equation: see text] x 100) and similar equations have been widely used. However, not much is known about the property of this type of equation and the caution which should be taken into account when using this type of equation. Moreover, little is known about the power of percentage prediction error as statistical inference. In the present study we address these points in the use of this type of equation.

Bias↗
PubMed1995

Effects of different sampling strategies on predictions of blood cyclosporine concentrations in haematological patients with multidrug resistance by Bayesian and non-linear least squares methods.

The Bayesian method (BM) can use previous information for the optimization of dosage regimen. However, Bayes' law remains true when the parameters are obtained from the infinite population. Therefore a bias might exist in the previous information and affect BM predictive performance. To overcome this shortcoming, the blood drug concentration of a patient can be used to individualize his pharmacokinetic parameters. Until now, at least two sampling strategies, i.e. steady-state and non-steady-state sampling strategies, have been developed to individualize and predict blood drug concentration. In the present study we used five sampling strategies: (1) all samples; (2) post-infusion samples; (3) during-infusion samples; (4) samples within 95% confidence interval/interquartile range of a steady-state concentration; (5) the sample of the mean/median at the mid-time-point of a steady-state to individualize and predict blood cyclosporine concentrations in haematological patients with multidrug resistance. We investigated the effects of different sampling strategies on BM and the nonlinear least squared method (NLLSM) predictive performances. The results showed that BM predictive performance was better than NLLSM. But the results did not prove that the steady-state sampling strategies were superior to the non-steady-state ones.

Adult↗
PubMed1995

Oral and intravenous disposition of cyclosporine in psoriatic patients.

After informed consent was obtained and with the approval of the Local Ethical Committee, cyclosporine A (CsA) kinetics was studied in 63 psoriatic patients by giving them 2.5 mg/kg CsA orally. In order to calculate oral bioavailability, F, 22 patients were given the same dose i.v. Values of the calculated kinetic parameters were oral F = 22-63%; half-life, t1/2 beta, = 11.05-13.70 h; volume of distribution, Vd, = 4.00-5.02/L/kg; total body clearance, Cl, = 4.25-4.14 ml/min/kg. The area under the blood concentration time curve was more closely related to the dose (r = 0.66) than were trough levels (r = 0.52). No significant relationship was observed between the kinetic parameters studied and the age of the patient.

Administration, Oral↗
PubMed1994

Somatomedin C (insulin-like growth factor 1) levels decrease during acute changes of stress related hormones. Relevance for fibromyalgia.

OBJECTIVE: To determine the effects of stress hormones on insulin-like growth factor 1 (IGF-1). METHODS: Insulin induced hypoglycemia (< 3 mmol/l) and clonidine induced depression of noradrenergic tone were used to assess the acute effects of cortisol, human growth hormone (hGH), and norepinephrine (NE). RESULTS: Despite the increase of hGH during hypoglycemia, a statistically significant decrease of IGF-1 was observed along with the expected rise of cortisol and NE. To eliminate the role played by NE, NE tone was depressed by administering clonidine. A statistically significant decrease of IGF-1 was also observed. CONCLUSION: Acute cortisol release or a NE decrease induce low IGF-1 levels.

Clonidine↗
PubMed1993

Plasma levels of levodopa and its main metabolites in parkinsonian patients after conventional and controlled-release levodopa-carbidopa associations.

The paper reports plasma levels of levodopa (LD), its main metabolites [dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-O-methyldopa (3-O-MD)] and carbidopa in 14 parkinsonian patients first treated with Sinemet and thereafter with Sinemet-CR4. A good relationship was observed between LD plasma levels and pharmacological effects. While the LD area under the curve increased after Sinemet-CR4, the same was not observed with metabolites, except with 3-O-MD. The experiments in volunteer subjects confirmed the increase in 3-O-MD in plasma after Sinemet-CR4. Higher levels were observed also in the CSF with a reduction of LD concentrations. This seems to corroborate the hypothesis of an interference with LD passage through the blood-brain barrier in humans.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Chlorpromazine disposition in relation to age in children.

The pharmacokinetics of chlorpromazine after intravenous infusion were studied in 25 children. The pharmacokinetic parameters studied are markedly different from those reported for adults. A clear relationship was demonstrated between age, serum terminal half-life (r = 0.75) and systemic clearance (r = -0.43). It appears that the pharmacokinetics of chlorpromazine are more rapid in children than in adults.

Adolescent↗