Infective endocarditis in patients with hepatic diseases.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD- patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD- patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD- and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian Study on Endocarditis.

BACKGROUND: The characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients. METHODS: We conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE. RESULTS: A total of 1,082 patients with definite IE were included. Of these, 753 (69.6%) patients had infection on a native valve, 277 (25.6%) on a prosthetic valve, and 52 (4.8%) on an implantable electronic device. Overall, community-acquired (69.2%) was more common than nosocomial (6.2%) or non-nosocomial (24.6%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0%). In-hospital mortality was 15.1%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality. CONCLUSIONS: The current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke.

Sternal osteomyelitis due to Aspergillus fumigatus after cardiac surgery.

Sternal osteomyelitis due to Aspergillus fumigatus after cardiac surgery occurred in two nonimmunosuppressed patients. The clinical features of the infection were markedly different in the two cases. In the first patient, sepsis showed a late and insidious onset followed by slow progression. In the second case, fungi were isolated from wound swabs within a few days of surgery and the clinical picture showed acute onset and rapid progression. Only a few cases of sternal osteomyelitis due to Aspergillus have been described previously after cardiac surgery. Aspergillus infection should be considered in the differential diagnosis of mediastinitis after cardiac surgery, especially in a clinical setting of otherwise unexplained sepsis or nonhealing wound despite apparently adequate treatment.

Impaired bioavailability of famotidine given concurrently with a potent antacid.

The effect of a high potency antacid on the oral bioavailability of a single dose of famotidine (40 mg) was evaluated in normal volunteers according to a randomized cross-over design. Ingestion of the antacid concurrently with famotidine resulted in a significant reduction of peak plasma famotidine concentration (from 156 +/- 22 to 104 +/- 7, P less than 0.05) and area under the famotidine plasma concentration curve (from 956 +/- 125 to 607 +/- 56, P less than 0.02). No significant interaction was observed when the antacid was ingested 2 hours after famotidine administration.

Lack of effect of cholestyramine on phenytoin bioavailability.

The effect of cholestyramine (4 g qid for 5 days) on the kinetics of phenytoin (400 mg orally) was investigated in normal subjects. Apart from a trend toward faster phenytoin absorption, the serum level profile of the drug during concurrent cholestyramine coadministration was similar to that observed in a control session. Areas under the serum phenytoin concentration curves were virtually identical in the two occasions. It is concluded that cholestyramine does not significantly affect the bioavailability of a single dose of phenytoin.

ECMO and inhaled nitric oxide for cardiopulmonary failure after heart retransplantation.

Cardiopulmonary failure occurred in a 62-year-old patient a few hours after emergency cardiac retransplantation. Venoarterial extracorporeal membrane oxygenation was required to support biventricular dysfunction; thereafter, inhaled nitric oxide was given for residual hypoxemia and pulmonary hypertension. We report survival after venoarterial extracorporeal membrane oxygenation and inhaled nitric oxide treatment for both heart and lung failure in a heart recipient.

Salicylic acid disposition in children with rheumatoid arthritis.

The plasma level profile of SA and SUA after a single oral dose of ASA was studied in 8 children with juvenile rheumatoid arthritis, aged 3.5-15.0 years. Pharmacokinetic parameters were on average similar to those reported in the literature for adult subjects, although a somewhat larger intersubject variability was found.

Pharmacokinetics of dextromoramide in surgical patients.

The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC-MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 micrograms/L usually achieved within 0.5-4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half-lives of 0.4-1.6 h for the first phase and 6.3-21.8 h for the terminal phase. In the remaining patients, no clear-cut biphasic pattern was seen and half-lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 1.h-1.kg-1 and from 0.6 to 2.4 l.kg-1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 micrograms/L) in all subjects.

Aortic arch surgery: retrospective analysis of outcome and neuroprotective strategies.

OBJECTIVE: To review intra- and postoperative data regarding surgical reconstruction of the aortic arch performed at our cardiosurgical centre during the past four years, and thus to deepen understanding of neurologic morbidity and of what constitutes the most effective neuroprotection. EXPERIMENTAL DESIGN: Retrospective study. SETTING: Regional University Hospital. PATIENTS: 29 patients who underwent reconstruction of aneurysm or dissection of the aortic arch. Intervention. Surgical replacement of the diseased aorta during deep hypothermia, alone or with selective cerebral perfusion (antegrade or retrograde). MEASURES: Overall mortality rate, neurologic morbidity rate, duration of extracorporeal circulation, of hypothermic circulatory arrest or of selective cerebral perfusion. Evaluation of the importance to neurological outcome of age, modality of operation (emergency or routine), biochemical parameters (glycemia, hematocrit) and perfusion technique. Recording of postoperative time of arousal, and possible correlation with length of selective cerebral perfusion. RESULTS: We observed a mortality rate of 39% (11 deaths) and a neurologic morbidity rate of 34%. Hypothermic circulatory arrest alone did not assure valid neuroprotection (5 cases, all with severe neurologic impairment), while better results were obtained with selective cerebral perfusion, especially antegrade (14 cases, with only 7% of neurologic morbidity rate). Hyperglycemia (>250 mg%) proved to be significantly associated (p=0.002) with increased incidence of adverse neurologic outcome, and the same association was observed between emergency status and adverse neurologic outcome (p=0.002). Moreover, we found an unexpected linear correlation between time of selective cerebral perfusion and postoperative time of arousal (r=0.728, p=0.000). CONCLUSIONS: Deep hypothermic circulatory arrest with selective cerebral perfusion currently represent a valid therapeutic option for brain preservation during reconstruction of the aortic arch in adults. It is mandatory to carry out a tight control of perfusion parameters (flow, pressures and temperature gradients) and biochemical variables (avoidance of hyperglycemia and modified ultrafiltration for fluid balance).

Enantioselective effects of levodropropizine and dropropizine on psychomotor functions in normal volunteers: a placebo-controlled, double-blind comparative study.

Levodropropizine is the l-isomer of dropropizine, a racemic drug widely used as a cough suppressant. Compared with the racemate, levodropropizine retains equal antitussive activity but exhibits considerably lower central nervous system (CNS) depressant effects in animal models. In order to assess whether the same differential pharmacodynamic profile also applies to man, a double-blind placebo-controlled study was carried out to investigate the effects of single oral doses (60 and 120 mg) of levodropropizine and dropropizine on subjective alertness (scored on visual analogue scales), general tolerability and psychomotor function tests (cancellation, tapping, choice reaction times and critical flicker fusion frequency) in ten normal volunteers. Treatments were administered in random sequence at intervals of at least one week, evaluation procedures being carried out at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. Following intake of a 60 mg levodropizine dose, subjective effects and objective estimates of psychomotor function were superimposable to those recorded after placebo. There was a trend for 60 mg dropropizine and 120 mg levodropropizine to produce detrimental effects at occasional evaluations, although the changes associated with these treatments could not be differentiated from placebo on the basis of most subjective scores and psychomotor function tests. Conversely, administration of 120 mg dropropizine was consistently associated with subjective CNS impairment and with reduced performance (compared to baseline) in recognition time, critical flicker fusion thresholds and possibly tapping rate, for up to three hours after dosing. These data are consistent with evidence that racemic dropropizine adversely affects central nervous system function to a greater extent compared with the levo-isomer.

The disposition of theophylline in patients with lung and breast cancer.

The influence of extrahepatic neoplastic disease on the biotransformation of theophylline was assessed by comparing the pharmacokinetic and metabolic profile of the drug in six patients with advanced breast or bronchial carcinoma, without detectable liver metastases, and in six appropriately matched control subjects. Each subject was given a single dose of theophylline (5 mg/kg) in oral solution; blood and urinary samples were collected for up to 24 h after dosing. Theophylline was absorbed rapidly in all subjects and within 2 h reached comparable peak concentrations in both groups (cancer patients: 57.8 +/- 14.4 mumol/l; controls; 65.0 +/- 10.6 mumol/l; N.S., means +/- s.d.). No significant differences were observed between cancer patients and controls for theophylline apparent volume of distribution (0.44 +/- 0.07 vs 0.40 +/- 0.06 l/kg), total body clearance (40.8 +/- 12.8 vs 34.8 +/- 13.0 ml kg-1 h-1) and elimination half-life (8.0 +/- 1.6 vs 8.5 +/- 1.8 h). The excretion of the major metabolites 3-methyl-xanthine and 1,3-dimethyl-uric acid was also very similar in the two groups. These data do not provide any evidence for an altered rate or pattern of theophylline biotransformation in patients with advanced extrahepatic neoplastic disease.

Pharmacokinetics of salicylic acid following administration of aspirin tablets and three different forms of soluble aspirin in normal subjects.

The pharmacokinetic profile of an innovative formulation of soluble aspirin (l-ornithine acetylsalicylate, ldB 1003) was compared with that of conventional tablets and two other soluble dosage forms (d, l-lysine acetylsalicylate and a buffered effervescent formulation of acetylsalicylic acid) after administration of single oral doses in six normal volunteers. All soluble forms showed a rapid absorption profile, peak plasma salicylic acid levels being attained after about 30 min on average and without statistically significant differences among the solutions tested. As compared to the soluble formulations, acetylsalicylic acid given as tablets resulted in slower absorption, with peak plasma salicylic acid levels being reached more than 1 h after dosing. Despite these differences in time course of plasma level profiles, the extent of absorption was similar for all formulations. Apart from the potential advantages in terms of improved gastric tolerability, the increased rate of absorption of aspirin solutions is therapeutically useful whenever a rapid onset of action is required. In this respect, the kinetic pattern of the innovative formulation compares favourably with that of other available soluble dosage forms.

Effect of flurithromycin, a new macrolide antibiotic, on carbamazepine disposition in normal subjects.

The effects of flurithromycin, a new macrolide antibiotic, on the disposition of a single oral dose of carbamazepine (CBZ) (400 mg) were investigated in seven normal subjects. Flurithromycin (2 x 250 mg thrice daily for 10 days) caused a slight increase in the CBZ area under the serum concentration curve and a moderate reduction in carbamazepine-10, 11-epoxide (CBZ-E) levels. These results suggest that flurithromycin can inhibit the conversion of CBZ to CBZ-E, although, at the dosage tested, the magnitude of this effect was significantly smaller than that observed after administration of erythromycin in the same subjects.

Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects.

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.

Pharmacokinetics of flutoprazepam, a novel benzodiazepine drug, in normal subjects.

The single dose pharmacokinetics of flutoprazepam and its active N-desalkyl metabolite were determined in 8 normal subjects by using newly developed, highly sensitive, GC-MS and HPLC techniques. Following a 2 mg dose of the drug, the concentrations of unchanged flutoprazepam in serum were extremely low (below 5 ng/ml at 2 h) and declined rapidly to undetectable levels within 6-9 h after dosing. At all sampling times, the serum concentration of the N-dealkylated metabolite (N-desalkylflurazepam) was much greater than that of the parent compound. This metabolite appeared in serum rapidly (within 2 h), reached a peak between 2 and 12 h and declined slowly, with an elimination half-life of about 90 h on average. The serum concentration of two additional putative metabolites (3-hydroxy-flutoprazepam and N-desalkyl-3-hydroxy-flutoprazepam) was below the limit of detection (2 ng/ml) in all samples. Mild CNS effects (documented by prolonged choice reaction time) were present at 2 and 4 h but were no longer detectable at 9 h. It is suggested that unchanged flutoprazepam is unlikely to contribute significantly to clinical effects and that the drug exerts its therapeutic activity through conversion to the slowly eliminated N-desalkyl metabolite.

Comparative pharmacokinetics and pharmacodynamics of eterobarbital and phenobarbital in normal volunteers.

The comparative pharmacokinetics and pharmacodynamics of single oral doses of eterobarbital (N,N'-dimethoxymethylphenobarbital, DMMP, 400 mg) and phenobarbital (200 mg) were evaluated in a double-blind study in 8 normal volunteers. Following administration of DMMP, no unchanged drug could be detected in serum. The active monomethoxymethyl metabolite (MMP) appeared rapidly in the circulation but its concentration remained generally low and declined below the limit of detection (0.5 micrograms/ml) usually before 9.5 h. Serum levels of DMMP-derived PB increased slowly and reached a peak between 24 and 48 h in most cases. One subject showed an atypical pharmacokinetic profile, characterized by relatively high levels of MMP and a delayed appearance of low levels of PB. After administration of PB, serum drug levels peaked within 1.5 h and remained, at all sampling times, higher than those observed after intake of DMMP. Compared with DMMP, PB induced greater sedative effects as assessed by visual analogue rating scale, critical flicker fusion frequency and multiple sleep latency tests.

Protective effect of cyanidin (IdB 1027) against aspirin-induced fall in gastric transmucosal potential difference in normal subjects.

The effect of the natural flavonoid cyanidin (IdB 1027), 1200mg daily for 8 days, on the fall in gastric transmucosal potential difference induced by a single dose of aspirin (1000mg by nasogastric tube) was evaluated in 7 normal male volunteers. As compared to pretreatment values, IdB 1027 caused a significant reduction in both the percentage fall in transmucosal potential difference at the time of peak aspirin effect (from 37 +/- 18% to 18 +/- 5%, p less than 0.05) and the area under potential difference baseline (from 811 +/- 624 mvolt. min to 338 +/- 150 mvolt. min, p less than 0.05). These results provide evidence for a protecting effect of IdB 1027 against aspirin-induced gastric mucosal damage in man.

Effects on cimetidine bioavailability of metoclopramide and antacids given two hours apart.

Plasma cimetidine levels were determined in 9 normal subjects after a single oral dose of cimetidine 400 mg under control conditions, 2 h before metoclopramide 20 mg and 2 h after a potent antacid. The bioavailability of cimetidine was not significantly affected by metoclopramide and it was marginally reduced by the antacid.

A comparative study of free plasma choline levels following intramuscular administration of L-alpha-glycerylphosphorylcholine and citicoline in normal volunteers.

L-alpha-glycerylphosphorylcholine (alpha-GPC) is a recently developed cognitive enhancer whose mode of action is considered to involve the release of free choline, which is then utilized for acetylcholine and phosphatidylcholine biosynthesis in the brain. The purpose of this study was to evaluate the profile of free plasma choline levels following a single i.m. dose of alpha-GPC in 12 normal volunteers. Citicoline (CTC), which also acts as a choline precursor, was included for comparison purposes. Each subject was studied on three randomized occasions, (i) in a control day in the absence of drug administration (to evaluate the plasma level profile of endogenous choline), (ii) after i.m. alpha-GPC (1,000 mg) and (iii) after i.m. CTC (1,000 mg) respectively, with a wash-out period of at least 1-week between sessions. Blood samples for plasma choline HPLC determinations were collected at regular intervals over a 6 h period. In the control session, plasma choline levels remained stable during the sampling period. The administration of alpha-GPC was associated with a rapid rise in plasma choline, peak levels being usually observed at the first (0.25 h) or second (0.5 h) sampling time after the injection. Thereafter, the concentration of choline declined gradually and returned to near baseline values at the end of the observation period. After the administration of CTC, plasma choline levels showed a similar time course but were considerably lower than those observed after the administration of alpha-GPC.(ABSTRACT TRUNCATED AT 250 WORDS)