[Biological monitoring of the PAH exposure in the hardening of metals]. / Monitoraggio biologico dell'esposizione ad IPA nella tempra dei metalli.

The hardening of metals involves the immersion of hot components in mineral oil with production of aerosols containing PAHs, to wich workers can be exposed. The determination of airborne PAHs and urinary 1-hydroxypyrene (1-OHPy) was performed for a group of workers and the latter resulted within the reference values. However, the average 1-OHPy concentration on metal workers (0.07 microg/g creatinine) was statistically different from the average value obtained for a group of employees (0.03 microg/g creatinine), highlighting the risk of exposure to PAHs. Therefore, being these potentially carcinogenic compounds, interventions were prescribed in order to reduce the risk of occupational exposure.

Propafenone for refractory ventricular arrhythmias: correlation with drug plasma levels during long-term treatment.

The efficacy of propafenone, a new antiarrhythmic drug, was studied in 21 patients with ventricular arrhythmias refractory to previous antiarrhythmic medications. Group A included 10 patients with chronic ventricular premature complexes (VPCs), 6 of whom had nonsustained ventricular tachycardia (VT) and 4 of whom had recurrent, sustained VT; all received propafenone, 900 mg/day. Group B included 11 patients, all with chronic VPCs, 9 of whom had nonsustained VT and 5 of whom had sustained VT; all received propafenone, 450 mg/day. Drug efficacy was evaluated as a 70% or greater reduction in VPC frequency with complex VPC abolition in ambulatory monitoring and suppression of nonsustained VT and sustained VT during a follow-up period up to 154 +/- 58 days in group A and 96 +/- 42 days in group B. Drug plasma levels were measured during chronic therapy in pharmacologic steady state. In group A, propafenone reduced the frequency of chronic VPCs in 9 patients and abolished nonsustained VT in 4 of 6 and sustained VT in 3 of 4; in group B, propafenone reduced the frequency of chronic VPCs in 6 patients and abolished nonsustained VT in 6 of 9 and sustained VT in 3 of 5. Two patients with recurrences of sustained VT in this group were later successfully treated with propafenone, 900 mg/day; overall, 8 of 9 patients with recurrences of sustained VT were successfully treated with 900 mg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Tocainide and metoprolol: an efficacious therapeutic combination in the treatment of premature ventricular beats.

A double-blind crossover study was performed in 20 patients to verify the efficacy of tocainide plus metoprolol in patients with premature ventricular contractions (PVCs) class Lown greater than or equal to 2 (mean frequency greater than or equal to 30/h) judged as being "stable" by at least three basal 24-h Holter ECGs with PVC variation of less than +/- 25%. All 20 patients were submitted to a placebo period; and all were subsequently randomized to therapy with tocainide 1800 mg/day or metoprolol 200 mg/day for 15 days and then to tocainide 1800 mg + metoprolol 200 mg/day or tocainide 1200 mg + metoprolol 200 mg/day for 15 days, followed by a crossover of the two combination treatments. At steady state in every stage we controlled for plasma levels of the drugs, a 24-h Holter recording, and a 12-lead ECG. A modified Lown score was evaluated together with the Lown class. Tocainide (mean plasma level 3.3 +/- 0.7 micrograms/ml) was efficacious in 3 of 8 patients, the modified Lown score decreased from 63 +/- 32 (placebo period) to 42 +/- 27 (p less than 0.01) and Lown 4B arrhythmias were abolished in 3 of 4 patients. Metoprolol (mean plasma level 97.4 +/- 89.6 ng/ml) was efficacious in 2 of 10 patients; the modified Lown score and Lown classes did not change significantly. Administration of tocainide 1200 mg + metoprolol 200 mg obtained a positive response in 9 of 12 patients, the modified Lown score decreased significantly compared with placebo (from 53 +/- 31 to 32 +/- 30, p less than 0.01) and Lown 4B arrhythmias were abolished in 2 of 5 cases. Tocainide 1800 mg plus metoprolol 200 mg was scarcely tolerated owing to neurologic and gastroenteric side effects, and only three patients completed this stage with no better antiarrhythmic results compared to the lower dose. In conclusion, the combination of tocainide at 1200 mg and metoprolol 200 mg is well tolerated, efficacious in a high percentage of patients, and superior to single drug therapy in patients with stable PVCs.

[Clinical pharmacology of propafenone]. / Farmacologia clinica del propafenone.

Aim of our study is to examine some aspects of the relationship between pharmacokinetics and pharmacodynamics of Propafenon that are important as far as its current use is concerned. Orally administered Propafenon is largely absorbed and easily metabolized by the liver. Bioavailability is on the average 50%. Ninety per cent of the administered dose is eliminated in the feces and in the urine in about 60 hours. Because of the lack of a good correlation between chronically administered doses and plasmatic concentration, we tried to see whether the peak concentration after administration of a single dose could predict in some way the response of the patients arrhythmia. So far we do not have a clear cut answer to this question, which probably requires a different, more complex approach to the relations between pharmacokinetics, plasmatic levels and therapeutic range of an antiarrhythmic drug.

Indoor climate and air quality in new offices: effects of a reduced air-exchange rate.

In response to a request from the personnel of a credit bank that had been moved into a new building, an evaluation was made of employee health complaints. The prevalence of symptoms was determined using a self-administered questionnaire. Ventilation effectiveness, contaminant concentrations (which included chemicals and bioaerosols) and microclimate were studied to establish their relationship to environmental discomfort and to the health problems mentioned by the employees. Indoor air quality--which was assessed in different seasons--revealed relatively high levels of carbon dioxide and bioaerosols in areas occupied by employees as compared with other places. Temperature and humidity were considered to be satisfactory. Although a causative agent was not isolated, the authors conclude that an ineffective rate of room air exchange, possibly in interaction with chemical contaminants, may be responsible for the discomfort and, perhaps, for the health symptoms experienced by workers in fully enclosed rooms.

Antiarrhythmic efficacy of propafenone: evaluation of effective plasma levels following single and multiple doses.

In 11 patients with stable premature ventricular beats, the kinetics of single (150 and 300 mg) and multiple (150 mg t.i.d. and 300 mg t.i.d.) oral doses of propafenone were studied with reference to arrhythmia suppression. During the acute phase detectable plasma levels of the drug were achieved only with the higher dose. In 8 out of 10 patients the antiarrhythmic effect was obtained with the 300 mg dose, which was found to predict responsiveness at steady-state. During the chronic phase, antiarrhythmic efficacy was obtained with the lower dose regimen (150 mg t.i.d.) in half of those patients. A wide range of effective plasma levels was observed. The previously suggested therapeutic range (0.5-2.0 micrograms/ml) was not adequate in predicting either antiarrhythmic activity or adverse effects. The results show the role of propafenone metabolites in determining total antiarrhythmic action.

Microbiological events during commercial meat fermentations.

Microbiological developments during industrial meat fermentations (salami), made with and without commercial starter cultures, were followed at two factories in Germany and Italy. In the German product microbial growth was evident only for the first 48 h, followed by a gradual decline in numbers of most micro-organisms. The pH fell from 5.8 to 4.8 in the 28 d required for production. In Italy a similar situation was seen, except that a second period of bacterial growth began around 15 d, coincident with the appearance of intentional surface mould growth which reversed the pH fall, the final pH being 6.2. The German starter culture was a mixture of Lactobacillus plantarum and Staphylococcus carnosus, whereas in Italy only Staph. carnosus was used. The strain of Lact. plantarum used did not grow in the German product whereas the Staph. carnosus grew well in both products to form a substantial proportion of the final microflora.

[Significance of the degree of oxidative hepatic metabolism in conditioning the pharmacokinetics and the pharmacodynamics of propafenone]. / Importanza del grado di metabolizzazione epatica ossidativa nel condizionare la farmacocinetica e la farmacodinamica del propafenone.

The aim of this study was to evaluate plasma concentrations of propafenone (P) and 5-hydroxy-propafenone (5-OH-P) at steady state in 36 patients with ventricular premature beats, Lown class greater than or equal to 2, submitted to antiarrhythmic treatment with propafenone either in acute administration (AA) (300-450 mg) or in chronic administration (CA) (150-300 mg t.i.d. for 14-21 days followed by a wash out), and to define the relationship existing between metabolic oxidative capacity and P and 5-OH-P pharmacokinetics and pharmacodynamics. Antiarrhythmic treatment resulted efficacious in 31/36 cases (86%) during AA and in 28/36 cases (78%) during CA. At steady state a wide interindividual variability was observed in plasma concentrations of P (mean = 835 +/- 619 ng/ml, coefficient of variation = 74%), in plasma concentrations of 5-OH-P (mean = 142 +/- 93 ng/ml, coefficient of variation = 65%) and of their ratio (mean = 6.51 +/- 8.53, coefficient of variation = 131%), without significant differences between responders and nonresponders. In a subgroup of 14 subjects, characterized as extensive oxidizers of dbrisoquine, a significant correlation (r = 0.97, p less than 0.001) was observed between the ratio of P and 5-OH-P plasma concentrations at steady state and oxidative metabolic capacity (expressed as debrisoquine/4-hydroxy-debrisoquine ratio). Oxidative metabolic capacity was also correlated with P half life (r = 0.82, p less than 0.002 in AA and in CA) and with the ratio of P and 5-OH-P area under curve (r = 0.91, p less than 0.001 in AA and r = 0.90) changes at the electrocardiogram (mean values = + 20% for QRS, +26% for PR). In conclusion, oxidative metabolic pathway is a crucial point in propafenone metabolization; indeed the extent of metabolic oxidative capacity, evaluable by analysis of debrisoquine oxidation, is responsible for a wide interindividual variability of P and 5-OH-P plasma concentrations, present even in a population of debrisoquine extensive oxidizers and, moreover, influences the extent of electrocardiographic changes of PR and QRS intervals, which are related to 5-OH-P plasma levels, but not to P plasma levels.

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy.

We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs) greater than or equal to 300/hr and Lown class greater than or equal to 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200 +/- 189 ng/ml vs. 492 +/- 530 ng/ml; p less than 0.05) and for 5-hydroxy-propafenone (82 +/- 40 ng/ml vs. 149 +/- 80 ng/ml; p less than 0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r = 0.91) or after chronic administration (r = 0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Plasma levels of anti-arrhythmic drugs and clinical effectiveness in the treatment of ventricular arrhythmias]. / Livelli plasmatici dei farmaci antiaritmici ed efficacia clinica nel trattamento delle aritmie ventricolari.

In spite of the ratio between plasmatic concentration and antiarrhythmic effects of a drug many factors can be influenced by many factors, the plasma level monitoring plays an important clinical role. The efficacy of the antiarrhythmic therapy should be evaluated not only by means of ECG-Holter monitoring and/or electrophysiological study but also by the means of determination of plasmatic and tissular concentration of a drug and metabolites. This latter is indispensable in the evaluation of new antiarrhythmic drugs and of a dose/effect relationship during acute and chronic therapy.