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Biomedical subjects

M Furlanut

Publications and source records attributed to M Furlanut.

At least 19 recordsLinked to original sources
PubMed2005

Therapeutic mycophenolic acid monitoring by means of limited sampling strategy in orthotopic heart transplant patients.

Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM of mycophenolate mofetil requires area under the curve AUC determinations but appears laborious, costly, and clinically impractical. To overcome these problems, limited sampling strategies (LSS) have been proposed in adult and pediatric renal transplant patients. The purpose of this study was to develop an LSS in heart transplant patients. Forty-four mycophenolic acid (MPA) full AUC(0-12h) profiles were generated by high-performance liquid chromatography in nine heart transplant patients during the first 12 weeks posttransplant. Each patient received concomitant cyclosporine and prednisone therapy. Multiple stepwise regression analysis was used to define the time points of MPA levels to explain the MPA AUC(0-12h). Agreement between abbreviated AUC and the full AUC(0-12h) was tested by means of a Bland and Altman analysis. The highest coefficient of determination r(2) among MPA AUC and single concentrations (r(2) = .610) was observed with C(2), while C(12) provided the lowest one (r(2) = .003). Stepwise linear regression showed that the minimal model with the best estimation of MPA AUC(0-12h) was obtained at timed values of 1.25, 2, and 6 hours. The corresponding estimated model was AUC = 5.568 + 0.902 * C(1.25) + 2.022 * C(2) + 4.594 * C(6) (r(2) = .926). Bland and Altman analysis revealed good agreement between predicted AUC and full AUC. A further interesting model equation obtained by four samples was AUC = 3.800 + 1.015 * C(1.25) + 1.819 * C(2) + 1.566 * C(4) + 3.479 * C(6) (r(2) = .948).

Adult↗
PubMed2003

Circadian variations in cyclosporine C2 concentrations during the first 2 weeks after liver transplantation.

The strategies currently used to monitor concentrations of cyclosporine (CsA) in transplanted patients include whole blood trough (C0), total or abbreviated area under the curve (AUC) concentration and population pharmacokinetic approaches. Recently, a single blood concentration measurement at 2 hours (C2) after CsA administration has been shown to be helpful to predict clinical effects during the first weeks after transplantation of liver and kidney grafts. However, this approach has raised multiple questions about pharmacokinetic variability, analytical methods, and organizational requirements. From a pharmacokinetic point of view, the variability of CsA blood concentrations may relate to circadian variations. The present study sought to characterize the circadian variation in C0 and C2 CsA levels among 20 liver transplant recipients during the first 2 weeks posttransplant. All patients received two equal oral doses of CsA microemulsion formulation every 12 hours. Blood samples were collected before and 2 hours after CsA administration in the morning (AM) and in the evening (PM). Whole blood concentrations of CsA were assayed using the monoclonal fluorescence polarization immunoassay system. During the first 2 weeks posttransplant, C2 AM mean levels were significantly higher than C2 PM levels (542 +/- 241 vs 383 +/- 182 ng/mL, P =.005), while the C0 AM mean level was not statistically different from the C0 PM (285 +/- 174 vs 223 +/- 124 ng/mL, P =.367). Our results suggest that morning CsA blood samples may afford a better approach to optimize the CsA dosage, especially based on C2 values.

Area Under Curve↗
PubMed2003

Pharmacology of ifosfamide.

Ifosfamide is a bifunctional alkylating agent, used as a racemic mixture by intravenous route in the treatment of various tumors. It is an oxazaphosphorine derivative with a structural formula similar to that of cyclophosphamide. As a prodrug it requires activation in the liver by a cytochrome mixed-function oxidase system. Among various metabolites, ifosforamide mustard probably represents the most important cytotoxic compound able to produce irreparable cross-links between DNA strands. Resistance is due to the ability of neoplastic cells to repair DNA damages. Acrolein may induce hemorrhagic cystitis, whereas chloroacetaldehyde may be responsible both for nephro- and neurotoxicity. A thiol donor (mesna) can prevent urotoxic effects but not nephro- and neurotoxicity. Pharmacokinetics is markedly influenced by route of administration and duration of treatment, age, co-medication, liver and renal function.

Animals↗
PubMed2003

Urinary pharmacokinetics and theoretical pharmacodynamics of intravenous levofloxacin in intensive care unit patients treated with 500 mg b.i.d. for ventilator-associated pneumonia.

This study assessed the urinary pharmacokinetics and theoretical pharmacodynamics of levofloxacin in ICU patients treated with 500 mg b.i.d. i.v. for ventilator associated pneumonia to evaluate if this high dosage regimen might ensure appropriate exposure in the treatment of severe UTIs in ICU patients. Nineteen patients (11M, 8F; age, 52 +/- 21 years; weight, 75 +/- 16 kg) presenting with normal renal function (estimated creatinine clearance, 1.83 +/- 0.61 ml/min/kg; diuresis, 1709 +/- 643ml / 24h) were assessed. In steady-state conditions, urine samples were collected at 0-2h, 2-4h, 4-8h and 8-12h during a dosing interval, and urinary concentrations of levofloxacin were assayed by HPLC. Mean (+/- SD) levofloxacin urinary concentrations were 329.1 +/- 159.9, 388.6 +/- 143.5, 266.0 +/- 102.8 and 168.1 +/- 93.3mg/L at 0-2h, 2-4h, 4-8h and 8-12h, respectively, with urinary AUC0-tau of 3171.4 +/- 1192.1mg/L x h. Mean (+/- SD) levofloxacin excretion rates were 44.1 +/- 20.7, 42.8 +/- 8.2, 31.7 +/- 5.8 and 19.8 +/- 4.2 mg/h during the 0-2h, 2-4, 4-8h and 8-12h interval, respectively. Our findings suggest that, consistently with levofloxacin showing high renal excretion as unmodified drug, 500mg b.i.d. i.v. of levofloxacin ensure and maintain urinary concentrations at least 50-fold higher than the MIC90 of most sensitive uropathogens during the overall dosing interval in ICU patients with normal renal function. Considering the major pharmacodynamic determinants for the concentration-dependent bactericidal activity of levofloxacin as applicable at the urinary level (CU/MIC of >12.2 and/or AUC24h U /MIC of >125h), this high dosage regimen may ensure optimal exposure for the treatment of catheter-related and severe lower UTIs not only against sensitive microorganisms, but probably also whenever microorganisms usually considered as intermediate susceptible or resistant to levofloxacin may be involved.

Adult↗
PubMed2001

Monitoring of L-dopa concentrations in Parkinson's disease.

Although it is the treatment of choice in the management of idiopathic Parkinson's disease, l-DOPA (LD) shows a decline in its efficacy after years of prolonged use, with the appearance of severe motor disturbances. These complications have been interpreted on pharmacokinetic and pharmacodynamic grounds. The main pharmacokinetic reason is considered to be the decreased capacity in LD activation to dopamine along with reduction of its storage ability in the nigrostriatal terminals, as a result of disease progression. At this stage the LD action in the extrapyramidal system is thought to be closely dependent on its synaptic cleft concentrations, being directly related to those in the systemic circulation and to the events possibly perturbing them. Therapeutic drug monitoring might be useful to explain these modifications in relation to the clinical effect and even to possible problems in transport competition and so to define the LD dosage regimen. Recently LD threshold concentrations have been suggested by means of sophisticated pharmacokinetic-pharmacodynamic approaches. Unfortunately they do not correspond to real therapeutic ranges but to levels in a hypothetical effect compartment in no steady-state conditions, due to remarkable LD fluctuations. However they are considered helpful to the functional state interpretation of the nigrostriatal system.

Antiparkinson Agents↗
PubMed2001

Pharmacokinetics of two oral cyclosporin a formulations in clinically stable heart-transplant patients.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 +/- 0.4 mgkg(-1)body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in C(max)(ss)( 732 +/- 178 vs 935 +/- 250 ng ml(-1), P< 0.001) and t(max)( 2.63 +/- 1.21 vs 1.36 +/- 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 +/- 19 vs 66 +/- 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations.

Administration, Oral↗
PubMed2001

Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions.

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.

Anti-Infective Agents↗
PubMed2000

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia.

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2alpha 4.54 +/- 0.87 h; VdSS 2.88 +/- 0.93 l/m2; Cl 0.47 +/- 0.26 l/h/m2) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0-infinity 456.27 +/- 182.64 microg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200-to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 +/- 7.13 microg/ml x h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues. thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.

Acute Disease↗
PubMed2000

Determination of tamoxifen and its metabolites in the endometrial tissue of long-term treated women.

Concentrations of tamoxifen and its metabolites were analysed in the endometrium of 23 post-menopausal asymptomatic breast cancer patients who were on chronic tamoxifen therapy. Small endometrial samples were collected during diagnostic hysteroscopy. Analysis of both serum and tissue for these compounds was performed by mass spectrometry. Tamoxifen and its metabolites were far more concentrated in the endometrium than in serum; tamoxifen was also significantly more concentrated in endometrium with hyperplastic changes than in atrophic endometrium. Endometrial polyps of an additional 9 women showed a trend to a lesser concentration of compounds. Increased concentration of tamoxifen compounds could possibly be explained by the avidity of these compounds for oestrogen receptors (ER).

Antineoplastic Agents, Hormonal↗
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↗
PubMed2000

Ciprofloxacin disposition in elderly patients with LRTI being treated with sequential therapy (200 mg intravenously twice daily followed by 500 mg per os twice daily): comparative pharmacokinetics and the role of therapeutic drug monitoring.

Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI). The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch i.v./os regimen of ciprofloxacin (200 mg i.v. bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI. The pharmacokinetic study was performed on a cohort of 17 elderly inpatients. Blood samples were collected in steady state conditions at appropriate intervals. Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package. The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower Cmax after i.v. administration and higher CL both after i.v. and oral administration). Cmax after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 +/- 0.9 mg/L vs 2.6 +/- 1.0 mg/L; p = 0.054). The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid i.v. administration (AUC(0-tau) 11.4 +/- 4.3 mg/L x h vs 5.5 +/- 1.8 mg/L x h). The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microorganisms (MIC < 0.1 mg/L). In fact, because the peak serum level to MIC ratio (Cmax/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC24h/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg i.v. bid regimen and a cost-effective treatment of LRTI. However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h i.v. and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-tau) or at least of Cmax should be performed to individualize therapy in this subpopulation.

Aged↗
PubMed1999

Fidelity of polymerase chain reaction-direct sequencing analysis of damaged forensic samples.

Polymerase chain reaction (PCR) direct sequence analysis was performed on aged forensic samples, six or thirteen years old. This method allowed unambiguous genetic typing, but PCR products from such samples showed several artifacts. Control samples generated sequence ambiguities at a frequency of 1 in 567 bases, but the aged samples had an error frequency about 30-fold higher. In order to study the molecular composition of these aged DNA samples, reversed-phase high performance liquid chromatography (HPLC) was performed. Reduced amounts of the four DNA bases were observed and anomalous peaks were found. These peaks were analyzed by ionization mass spectrometry and identified as molecular products of DNA oxidation. The frequency of sequencing artifacts was found to be proportional to the decay of the PCR templates. Although PCR fidelity is a relevant concern in the forensic analysis of damaged samples, our data indicate that the risk of mistyping is circumventable by sequencing both strands and by performing replicate amplifications from the same PCR template.

Base Sequence↗