Search PubMed⌕ Search

Biomedical subjects

Rocco Orlando

Publications and source records attributed to Rocco Orlando.

15 recordsLinked to original sources
PubMed2006

Liver dysfunction markedly decreases the inhibition of cytochrome P450 1A2-mediated theophylline metabolism by fluvoxamine.

BACKGROUND AND OBJECTIVES: In vivo inhibition of cytochrome P450 (CYP) 1A2 by fluvoxamine causes a reduction in the clearance of the high-extraction drug lidocaine, which decreases in proportion to the degree of liver dysfunction. The objectives of this study were (1) to evaluate the effect of liver cirrhosis on the inhibition by fluvoxamine of the metabolic disposition of theophylline, a CYP1A2 substrate with a low-extraction ratio, to assess whether decreased sensitivity to CYP1A2 inhibition in liver disease is a general characteristic of CYP1A2 substrates, regardless of their pharmacokinetic properties, and (2) to investigate the mechanism(s) underlying the effect of liver dysfunction on CYP1A2 inhibition. METHODS: The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild liver dysfunction (Child class A) and 10 with severe liver dysfunction (Child class C), according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 7 days; in the other phase they received one 50-mg fluvoxamine dose for 2 days and two 50-mg fluvoxamine doses, 12 hours apart, in the next 5 days. On day 6, 4 mg/kg of theophylline was administered orally 1 hour after the morning fluvoxamine dose. Concentrations of theophylline and its metabolites, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, were then measured in plasma and urine up to 48 hours. RESULTS: Fluvoxamine-induced inhibition of theophylline clearance decreased from 62% in healthy subjects to 52% and 12% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CYP1A2-mediated formations of 3-methylxanthine and 1-methyluric acid were almost totally inhibited in control subjects, whereas they were only reduced by one third in patients with Child class C cirrhosis. Inhibition of 1,3-dimethyluric acid formation, which is catalyzed by CYP1A2 and CYP2E1, progressively decreased from 58% in healthy subjects to 43% and 7% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CONCLUSIONS: The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elimination is a general phenomenon, independent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less and less important as liver function worsens. Two mechanisms, as follows in order of importance, are responsible for the effect of liver dysfunction: (1) decreased sensitivity to fluvoxamine of CYP1A2-mediated biotransformations in the cirrhotic liver, probably resulting from reduced uptake of the inhibitory drug, and (2) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.

Adult↗
PubMed2006

Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis.

BACKGROUND AND OBJECTIVES: The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (1) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (2) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro. METHODS: In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CL(cr)] >80 mL/min x 1.73 m(-2)), 10 subjects with moderate renal insufficiency (CL(cr) between 30 and 60 mL/min x 1.73 m(-2)), 10 subjects with severe renal insufficiency (CL(cr) <30 mL/min x 1.73 m(-2)), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes. RESULTS: In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean +/- SD, 6.01 +/- 2.54 mL/min x kg versus 11.87 +/- 2.97 mL/min x kg; P < .001), and half-life was approximately doubled (4.55 +/- 1.71 hours versus 2.24 +/- 0.55 hours, P < .001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P < .05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 +/- 6 micromol/L) was 2 orders of magnitude higher than its concentrations in vivo. CONCLUSIONS: Our in vivo findings have both clinical and methodologic implications: (1) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (2) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed.

Area Under Curve↗
PubMed2004

Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function.

OBJECTIVES: This study was designed (1) to evaluate the effect of a cytochrome P450 (CYP) 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of intravenous lidocaine and its 2 pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), to confirm recent in vitro results indicating that CYP1A2 is the main isoform responsible for lidocaine biotransformation and (2) to assess whether liver function has any influence on the fluvoxamine-lidocaine interaction. METHODS: The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 6 days; in the other phase they received 50 mg fluvoxamine for 2 days and 100 mg fluvoxamine for the next 4 days. On day 6, a 1-mg/kg lidocaine dose was administered intravenously 2 hours after the last dose of fluvoxamine or placebo. Plasma concentrations of lidocaine, MEGX, GX, and fluvoxamine were measured up to 12 hours after lidocaine injection. RESULTS: The effects of fluvoxamine coadministration were dependent on liver function. Lidocaine clearance was decreased on average by 60% (from 12.1 mL/min.kg to 4.85 mL/min.kg, P <.001) in healthy subjects and by 44% (from 9.83 mL/min.kg to 5.06 mL/min.kg, P <.001) in patients with mild liver dysfunction, with proportional increases in terminal half-lives, whereas virtually no effect was produced in patients with severe liver dysfunction (4.21 mL/min.kg versus 3.65 mL/min.kg, P >.05). Analogous effects were observed on MEGX and GX formation kinetics, which were drastically impaired in healthy subjects and patients with mild liver cirrhosis but virtually unaffected in patients with severe cirrhosis. CONCLUSION: CYP1A2 is the enzyme principally responsible for the metabolic disposition of lidocaine in subjects with normal liver function. The extent of fluvoxamine-lidocaine interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of CYP1A2. These observations indicate that results obtained in healthy subjects cannot be extended a priori to patients with liver dysfunction, but the clinical consequences of inhibition of drug metabolism must also be assessed in such patients.

Anti-Arrhythmia Agents↗
PubMed2003

Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function.

AIMS: The objectives of this study were: (i) to evaluate the effect of a cytochrome P450 (CYP) 3A4 inhibitor, erythromycin, on the pharmacokinetics of intravenous lignocaine and its two pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX); (ii) to assess whether the effects of the erythromycin inhibitory action on lignocaine clearance and the results of the MEGX liver function test depend on liver functional status; and (iii) to determine the effects of both moderate and severe liver dysfunction on the disposition kinetics of lignocaine. METHODS: The study was carried out on 10 healthy volunteers, and 10 Child's class A and 10 class C cirrhotic patients, according to a double-blind, randomized, two-way crossover design. On day 1 of the investigation, all subjects received three oral doses of erythromycin (600 mg of the ethylsuccinate ester) or placebo, and two further doses on day 2. One hour after the fourth dose, subjects were given 1 mg kg-1 lignocaine intravenously. Timed plasma samples were then obtained until 12 h for determination of the concentrations of lignocaine, MEGX and GX. RESULTS: Erythromycin caused statistically significant, although limited, modifications of lignocaine and MEGX pharmacokinetic parameters. In healthy volunteers, lignocaine clearance was decreased from 9.93 to 8.15 ml kg-1 min-1[mean percentage ratio (95% CI), 82 (65-98)] and the half-life was prolonged from 2.23 to 02.80 h [mean percentage ratio (95% CI), 130 (109-151)]; MEGX area under the concentration-time curve from 0 h to 12 h was increased from 665 to 886 ng ml-1 h [mean percentage ratio (95% CI), 129 (102-156)]. Quantitatively similar modifications were observed in the two cirrhotic groups. GX concentrations were lowered in all study groups, although not to statistically significant extents. Erythromycin coadministration caused no appreciable interference with the results of the MEGX test. Only in patients with Child's grade C liver cirrhosis were lignocaine kinetic parameters significantly altered with respect to healthy volunteers. Thus, clearance was approximately halved, steady-state volume of distribution was increased, and terminal half-life was more than doubled. CONCLUSIONS: Although erythromycin only modestly decreases lignocaine clearance, it causes a concomitant elevation of the concentrations of its pharmacologically active metabolite MEGX. A pharmacodynamic study following lignocaine infusion to steady state appears necessary to assess the actual clinical relevance of these combined effects. The degree of liver dysfunction has no influence on the extent of the erythromycin-lignocaine interaction, whereas it markedly influences the extent of the changes in lignocaine pharmacokinetics. These findings indicate that no dose adjustment is needed in patients with moderate liver cirrhosis, whereas the lignocaine dose should be halved in patients with severe cirrhosis.

Adult↗
PubMed2003

Needle and trocar injuries in diagnostic laparoscopy under local anesthesia: what is the true incidence of these complications?

Laparoscopy is a relatively safe invasive procedure, but complications can occur, mainly related to Veress needle and trocar insertion. The rate of these complications is generally reported to be low, but the true incidence may be higher because of underreporting. We retrospectively studied the records of 2650 consecutive diagnostic laparoscopies performed by the same operator with the aim of assessing the true incidence and nature of these complications. Major complications occurred in 0.41% of cases and included bladder injury, bowel perforation, hemoperitoneum, and abdominal wall hematoma. Minor complications, including omental and subcutaneous emphysema, occurred in 1.58% of cases. Some of these resolved spontaneously, whereas others required surgical or medical treatment. We believe that all laparoscopic complications should be reported to a registry so that their potential risk can be quantified. Simply reporting complications as major or minor on the basis of the follow-up does not allow laparoscopists to understand their true incidence completely.

Adolescent↗
PubMed2003

Macro-aspartate aminotransferase (macro-AST). A 12-year follow-up study in a young female.

We describe a case of chronic elevation of serum aspartate aminotransferase (AST) activity due to the presence of a macro-enzyme form of AST (macro-AST) in a young female followed up for 12 years. This biochemical abnormality, although generally detected in acute and chronic hepatitis, malignancies and autoimmune disease, was not associated with any particular illness and did not seem to be congenital, as normal AST concentrations were reported in the patient's family members. Moreover, the normal or quasi-normal values of AST associated with peak levels observed in our case suggest that this phenomenon has a fluctuating behaviour rather than persisting for many months or years. In conclusion, we believe that it is important: 1) to reassure the patient with macro-AST, as this condition has a benign evolution and does not require any specific treatment; 2) to keep in mind this biochemical abnormality in all cases of unexplained AST elevation in order to avoid unnecessary invasive diagnostic procedures.

Adult↗
PubMed2002

Hand-assisted laparoscopic liver surgery.

HYPOTHESIS: The hand-assisted laparoscopic technique may be applied to the treatment of liver tumors. DESIGN: A case series with mean follow-up of 13 months. SETTING: University-affiliated tertiary care center. PATIENTS: A total of 15 patients with hepatic neoplasms underwent screening tests, including appropriate tumor marker analyses, abdominal sonography, and computed tomographic scan and, in most cases, magnetic resonance imaging to determine operability. Contraindications included extrahepatic disease, more than 5 liver lesions, coagulopathy, and ascites. INTERVENTION: Between March 1, 1998, and April 30, 2001, 15 patients underwent 16 hand-assisted diagnostic laparoscopic operations to rule out extrahepatic disease. Four patients had extrahepatic disease. In the 11 patients without evidence of extrahepatic disease, intraoperative ultrasound was used to establish the number and location of liver lesions. Operative strategies included resection, cryoablation, or both. MAIN OUTCOME MEASURES: Operative time, conversion to open procedure, length of stay, complications, and recurrence of disease. RESULTS: Of the 15 patients with liver tumors, 6 patients had more extensive disease than was detected by either preoperative imaging or laparoscopic exploration They included extrahepatic disease (3), additional liver lesion (2), or both (1). Hand-assisted management included resection only (3), cryoablation only (5), and a combination of the 2 (3). A total of 9 lesions were resected and 10 lesions were cryoablated. The mean operative time was 197 minutes with a mean length of stay of 4.5 days. There were no conversions to open procedures. One patient experienced minor postoperative bleeding but required no treatment. All treated patients are alive, and 5 have had recurrence of disease. CONCLUSIONS: Hand-assisted technique can be applied safely and effectively to laparoscopic liver surgery and may identify presence of otherwise undetectable disease.

Adult↗
PubMed2002

Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis.

BACKGROUND: Plasma creatinine concentration and calculated creatinine clearance are of limited value as glomerular filtration rate (GFR) markers in patients with decompensated liver cirrhosis. We assessed plasma cystatin C as an indicator of GFR in such patients. METHODS: We studied 36 patients with decompensated liver cirrhosis and 56 noncirrhotic controls, both groups including individuals with normal and impaired renal function. GFR was measured in all individuals by inulin clearance, with values <72 mL x min(-1) x 1.73 m(-2) considered decreased. We measured cystatin C and creatinine in plasma and calculated (from plasma concentrations) and measured creatinine clearances, using for them decision points of 1.25 mg/L, 115 micromol/L, and 72 and 72 mL x min(-1) x 1.73 m(-2), respectively. RESULTS: Plasma cystatin C concentrations were similar in controls and cirrhotics and, at the usual cutpoint, could detect decreased GFR with similar sensitivities in the two groups (73% and 88%, respectively). Serum creatinine was markedly lower in cirrhotics and remained mostly within the reference interval at all GFR values; the diagnostic sensitivity of creatinine was much lower in cirrhotics than in controls (23% vs 64%). Lower diagnostic sensitivity was also observed for calculated creatinine clearance (53% vs 100% in controls), whereas similar sensitivities were found for measured creatinine clearance (86% and 81%) in controls and cirrhotics, respectively. ROC analysis showed that all four variables had similar diagnostic accuracies in cirrhotic patients. However, it also revealed that good diagnostic accuracies for plasma creatinine and calculated creatinine clearance can be obtained only if reference intervals different from those used for the general population are adopted. CONCLUSIONS: Plasma cystatin C concentration is an accurate GFR marker in cirrhotic patients. Plasma creatinine concentration and calculated creatinine clearance are of no practical value, as their reference values vary with the severity of the liver disease.

Adult↗
PubMedDate not supplied

Adrenocortical carcinoma: a 15-year survival after complete resection and repeated resection. A retrospective study in a patient with an expected poor prognosis.

Adrenocortical carcinoma is a rare but aggressive malignancy with metastases being present in 30-40% of cases at the time of diagnosis. A number of prognostic factors have been identified in patients with adrenocortical carcinoma, but criteria predicting survival are not uniform. We report the case of a 58-year-old man with a large, non-functioning and poorly-differentiated adrenocortical carcinoma who, according to current knowledge, was expected to have a short survival. On the contrary, the prompt diagnosis and curative resection of the primary tumour, together with two reoperations for local recurrences, allowed a 15-year survival and a good quality of life. A revision of both clinical and histological prognostic factors is therefore needed in patients with this type of malignancy.

Adrenal Cortex Neoplasms↗
PubMedDate not supplied

Recurrent dermatofibrosarcoma protuberans sixteen years after radical excition. A case report.

We report the case of a young patient with an apparently benign slowly growing lesion which was excised 15 years after its occurrence. However, the histopathological examination revealed a DFSP which necessitated two more surgical procedures for inadequate surgical margins and a skin graft. Notwithstanding these radical operations, the patient presented a local recurrence 16 years later, suggesting that the insidious behavior of the tumour must be taken into account and that patients with DFSP need a life-long follow-up.

Adult↗