Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

PURPOSE: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C. METHODS: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. RESULTS: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8%) ARM A and 3 (10%) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0%, and thrombocytopenia, diarrhea and fatigue in 0/3% of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. CONCLUSIONS: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting.

Target organ damage and ambulatory blood pressure in stage I hypertension. The Hypertension and Ambulatory Recording Venetia Study.

According to recent international guidelines the decision on whether to treat young subjects during the early phase of hypertension should be based not only on their office blood pressure but also on their ambulatory blood pressure and whether target organ damage has occurred. Few data on the prevalence of hypertensive complications in young subjects with mild hypertension are available. In the Hypertension and Ambulatory Recording Venetia Study (HARVEST), a multicenter trial conducted in northeast Italy, the percentage of young borderline-to-mild hypertensive subjects with echocardiographic left ventricular hypertrophy was 4.5% and the percentage with concentric remodeling was 4%. Clear differences in cardiac size and geometric adjustment to ambulatory systolic pressure between the two sexes were found. The impact of blood pressure on the walls of the left ventricle and on the left ventricular mass was remarkable in women but weak in men. The assessment of left ventricular systolic function confirmed that many young mild hypertensive subjects have an increased ejective performance. The left ventricular contractility evaluated by midwall measurement was, however, found to be depressed in 9.2% of the HARVEST participants. Their left ventricular diastolic function was similar to that of 50 normotensive controls. The prevalence of microalbuminuria [albumin excretion rate (AER) > 30 mg/24 h) was 6.1%, only slightly higher than that found by other authors among normotensive subjects and much lower than that observed among patients with more severe hypertension. For our stage I hypertensives, however, the AER was correlated to the 24 h blood pressure with high statistical significance, whereas we found no relationship between the AER and left ventricular mass index either for all of the subjects taken together or for the men and women considered separately. The results suggest that renal and cardiac involvement do not occur in parallel during the initial phase of hypertension.

[Alcohol consumption and coronary disease in men]. / Consumo di alcol e malattia coronarica nell'uomo.

It has been recently suggested by many epidemiological studies, and emphasized by a nonspecialistic press, that a moderate alcohol intake may exert a protective role in coronary heart diseases. In our study, by means of a questionnaire, the consumption of alcohol in 100 male patients, less than 70 years old, affected by myocardial infarction and/ or angina pectoris, has been evaluated during a period before and after the admission to our Coronary Care Unit. On the basis of their alcohol intake, patients were divided into five categories: abstainers (8%), daily intake lower than one drink (7%), between one and two drinks (8%) between three and four drinks (46%) and equal or higher than five drinks (31%). In the light of these results, we suggested that, in our region (a country area in the north-east of Italy), there are higher levels of ethanol intake compared to those reported by other authors, that these parameters are only slightly modified by the occurrence of coronary heart diseases and that alcohol consumption, although low and moderate, must be therefore emphasized with extreme caution.

[Colchicine in the treatment of idiopathic recurrent pericarditis. Report of a case]. / La colchicina nel trattamento della pericardite idiopatica recidivante. Descrizione di un caso clinico.

Treatment of recurrence, which is one of the major complications of pericarditis, is often difficult. After three recurrences of idiopathic acute pericarditis, over a period of four months, despite therapy with acetylsalicylic acid, indomethacin and methilprednisolone, a patient, 37 years old, responded favorably to colchine treatment. No recurrences, no side effects were observed, after a prolonged low dose treatment. Our report suggests, therefore, that colchinine may be beneficial in acute attacks of idiopathic pericarditis and may be useful in avoiding recurrent episodes of pericarditis.

Effect of phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values +/- SD = 220.2 +/- 63.5 versus 112.5 +/- 46.0 ml/h/kg, p less than 0.007) and a significantly shorter plasma half-life (mean values +/- SD = 4.3 +/- 1.0 versus 6.7 +/- 0.8 h, p less than 0.0015). These results suggest that PB induces CBZ-E metabolism.

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers. The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation. Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers. The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.

The disposition of primidone in elderly patients.

1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2. Primidone half-lives and clearance values (mean +/- s.d.) were similar in the elderly and in the young (12.1 +/- 4.6 vs 14.7 +/- 3.5 h and 34.8 +/- 9.0 vs 33.2 +/- 7.2 ml h-1 kg-1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.

[Pharmacodynamics and pharmacokinetics of flecainide in cardiac pre-excitation of the bundle of Kent]. / Farmacodinamica e farmacocinetica della flecainide nella pre-eccitazione cardiaca da fasci di Kent.

In order to identify the flecainide plasma concentrations capable to inhibit the abnormal Kent's pathways, 9 patients affected by a Wolff-Parkinson-White syndrome were studied. One of them (a female 21 years old) previously received 200 mg oral flecainide "una tantum", 8 received 100 mg bid for at least 2 weeks. They had a short PR interval and an evident delta wave on the surface ECG, diagnostic for pre-excitation syndrome. The flecainide plasma half-life calculated in 6 patients chronically treated correlated directly and strictly with age. In all patients the flecainide treatment blocked the conduction through the bundle of Kent (normal PR, no delta wave), then the treatment was stopped and the elimination kinetics of flecainide were studied while a Holter 24h ECG monitoring was performed; thus we could extrapolate the flecainide plasma concentrations at which, during the elimination phase, the PR interval became short and the delta wave reappeared. Since short PR and delta wave are the expression of pre-excitation, we were able to determine the minimum concentrations capable to inhibit conduction through the abnormal bundles (290.0 ng ml-1 in the acutely treated patient and average 275.0 ng ml-1 in the chronically treated patients). These plasma levels are near to the lower therapeutic range accepted for ventricular ectopic arrhythmias (200 divided by 800 ng ml-1). Only larger studies will indicate if a relationship exists between the blockade of abnormal pathways and the preventive effect of flecainide on arrhythmias of Wolff-Parkinson-White syndrome. Another open question is whether a simple, non-invasive pharmacodynamic and pharmacokinetic procedure like that one described in the present paper can be used to predict the efficacy of treatment in patients with cardiac pre-excitation.