Efficacy, tolerability, and effects on quality of life of inhaled salmeterol and oral theophylline in patients with mild-to-moderate chronic obstructive pulmonary disease. SLMT02 Italian Study Group.

The aims of management in mild-to-moderate stable chronic obstructive pulmonary disease (COPD) are to improve symptoms and quality of life (QOL), reduce decline in lung function, prevent and treat complications, increase survival while maintaining QOL, and minimize the adverse effects of treatment. Bronchodilator therapy is the keystone of improving COPD symptoms and functional capacity. The primary objective of this open-label study was to compare the efficacy and tolerability of salmeterol 50 microg BID administered by metered-dose inhaler versus oral, titrated, sustained-release theophylline BID, both given for 3 months to patients with a clinical history of chronic bronchitis. The secondary objectives of the study were to evaluate the safety profile of the two drugs for an additional 9-month period and to assess changes in QOL both within and between treatment groups, using the 36-Item Short Form (SF-36) Health Survey. One hundred seventy-eight outpatients (122 men, 56 women; mean age, 56 +/- 12.9 years; mean body weight, 76.1 +/- 11.8 kg) were randomized to the two treatment groups. Patients receiving salmeterol showed significant improvement in mean morning peak expiratory flow rate (16.56 L/min) over the 3-month period compared with patients receiving theophylline (P = 0.02). Salmeterol also significantly increased the percentage of symptom-free days and nights with no additional salbutamol requirement (P < 0.01). A significant difference was found between increases in forced expiratory volume in 1 second compared with baseline for salmeterol compared with theophylline throughout the initial 3-month period (0.13, 0.16, and 0.16 L at months 1, 2, and 3, respectively) and during the additional 9 months. The incidence of adverse events was similar in the two groups (salmeterol, 49.5%; theophylline, 49.4%), with a lower percentage of pharmacologically predictable adverse events in patients receiving salmeterol (4%) compared with those receiving theophylline (14.8%). Both drugs improved QOL, as measured by effects on the eight aspects of life experience analyzed by the SF-36 questionnaire. Salmeterol therapy was effective in more aspects, and the improvements seen in each were numerically greater than those seen with theophylline therapy. Statistically different changes between the two treatment groups were reported for physical functioning, changes in health perception, and social functioning (P = 0.02, P = 0.03, and P = 0.004, respectively). These data suggest that inhaled salmeterol 50 microg BID was more effective and better tolerated than oral, titrated theophylline and allowed better long-term control of airways obstruction and symptoms with improved lung function in patients with COPD.

From hydrofluoroalkane pressurized metered dose inhalers (pMDIs) and comparability with chlorofluorocarbon pMDIs.

Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.

Different dosage regimens of ranitidine in the short-term therapy of duodenal ulcer: a multicentre trial.

A multicentre clinical trial was conducted in 114 Italian endoscopy centres in order to evaluate the comparative efficacy of four different ranitidine dosage regimens in the short-term treatment of active duodenal ulcer. Results were analysed in a total of 1745 patients randomly allocated to treatment with ranitidine 150 mg twice daily - morning and 19h30 (440 patients), ranitidine 150 mg twice daily - morning and 22h30 (438 patients), ranitidine 300 mg once daily at 19h30 (434 patients) or ranitidine 300 mg once daily at 22h30 (433 patients). The four groups were well matched for patient characteristics at entry. Initial treatment was for three weeks, with continuation to six weeks in cases with endoscopically unhealed ulcers at three weeks. Efficacy was evaluated in terms of endoscopic ulcer healing and control of pain symptoms in 24 h (daytime, nocturnal, daytime plus nocturnal). No statistically significant differences were found between any of the groups either as regards control of pain symptoms or ulcer healing rates (mean healing rates at three and six weeks were 77% and 98%, respectively). The results in this very large patient sample confirm equivalent efficacy of twice daily and single bedtime dose regimens and provide no evidence for superior efficacy of early evening compared with bedtime administration. In the population as a whole, concomitance of the three main risk factors (more than 20 cigarettes/day, ulcer size greater than 1 cm, deformation of the duodenal cap) was associated with a distinctly lower three-week healing rate (40.9% versus 87.4% in patients presenting none of these factors), though this difference tended to disappear at six weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of antihypertensive therapy with lacidipine on ambulatory blood pressure in the elderly.

Recent multicenter trials have demonstrated that, in hypertensive elderly people, blood pressure control can significantly decrease the rate of cardiovascular and cerebrovascular events. Twenty-four-hour ambulatory blood pressure monitoring has proved to be superior to isolated sphygmomanometer blood pressure readings in the diagnostic evaluation of hypertension and in assessing the blood pressure response to treatment. We used 24-h ambulatory monitoring in a small, double-blind, randomly-allocated, placebo-controlled, parallel-group study of antihypertensive treatment with lacidipine given once a day at 2 or 4 mg. In our elderly subjects, the lacidipine treatment provided adequate blood pressure control both by day and by night with no effect on the heart rate profile. Furthermore, after drug therapy, we found a significant reduction in systolic blood pressure variability (standard deviation). This study shows that lacidipine can provide adequate control of arterial hypertension in the elderly.

Simple graphical methods of displaying multiple clinical results.

A common challenge in clinical research trials is for applied statistics to manage, analyse, summarize and report an enormous amount of data. Nowadays, due to advances in medical technology, situations frequently arise where it is difficult to display and interpret results. Consequently, a creative approach is required to summarize the main outcomes of the statistical analyses in a form which is easy to grasp, to interpret and possibly to remember. In this paper a number of clinical case studies are provided. Firstly, a topographical map of the brain summarizing P-values obtained from comparisons across different EEG sites; secondly, a bulls eye plot, showing the agreement between observers in different regions of the heart; thirdly, a pictorial table reporting inter- and intra-rater reliability scores of a speech assessment; fourthly a star-plot to deal with numerous questionnaire results and finally a correlogram to illustrate significant correlation values between two diagnostic tools. The intention of this paper is to encourage the effort of visual representations of multiple statistical outcomes. Such representations do not only embellish the report, but aid interpretation by conveying a specific statistical meaning.

Evaluation of personality as a component of the healthy condition of volunteers participating in phase I studies.

OBJECTIVE: The present study was conceived in order to recommend use of the Minnesota Multiphasic Personality Inventory for the evaluation of the personality of volunteers participating in Phase I clinical trials. The study was intended to describe personality profiles as objectively as possible, attempting to identify any common traits or tendencies, and to evaluate whether age or cultural background can be associated with significant differences in volunteer personality profiles. SUBJECTS: 358 subjects were evaluated (290 males and 68 females; mean age 30 y, range 18-78 y). Mean values of scales and indices were compared and analysed, both for the sample as a whole and on the basis of its breakdown according to sex, age and education. RESULTS: No psychopathological values were found in terms of sex and education. The mean profile showed common traits of a substantially balanced, self-assured, reliable person, motivated by extremely realistic objectives. CONCLUSION: The Minnesota Multiphasic Personality Inventory seems to be a useful tool for screening healthy volunteers.

A study of plasma disposition kinetics of lacidipine after single oral ascending doses.

This study was designed to assess the plasma disposition kinetics of single oral 4-, 6-, and 8-mg doses of lacidipine, a new once-daily calcium-entry blocker. Seventeen healthy volunteers attended the study. In almost all cases, detectable levels were found up to 24 h after the drug administration, using a new HPLC-RIA assay. The usual pharmacokinetic parameters were calculated: Cmax, tmax, AUCinf, lambda z and t1/2. The half-life was similar after all doses, around 7 h, whereas Cmax and AUCinf did not show a linear correlation with the doses.

The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects.

AIMS: Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. METHODS: The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). RESULTS: Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. CONCLUSIONS: The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.

Population pharmacokinetic-pharmacodynamic model of craving in an enforced smoking cessation population: indirect response and probabilistic modeling.

PURPOSE: A population pharmacokinetic-pharmacodynamic model accounting for placebo effect was used to relate nicotine concentration and enforced smoking cessation craving score measured by the Tiffany rating scale short form. METHODS: Twenty-four smokers were enrolled in a placebo-controlled, randomized, double-blind, three periods, crossover trial. The study objective was to describe the nicotine-induced changes on craving scores. Two modeling strategies based on a mechanistic (indirect response models with drug-related inhibition on the k(in) synthesis rate and with a drug-related stimulation of the k(out) removal rate were evaluated) and a probabilistic (logistic regression) approach were used. RESULTS: Placebo response model properly fitted the circadian changes on craving scores. The analysis revealed that the indirect response model with inhibition on k(in) was the preferred model for the smoking data whereas the preferred model for the Nicotine Replacement Therapy data was the one with stimulation on k(out). The logistic analysis showed that the nicotine concentration was a significant predictor of reduction in craving during the free-smoking period. CONCLUSIONS: Nicotine dosage regimen can influence the nicotine mechanism of action: an instantaneous delivery at an individually selected time seems to inhibit the onset of craving while constant delivery at a pre-defined time seems to attenuate the craving.

Hepatocellular carcinoma in liver cirrhosis. A prospective study.

From January 1984 to December 1991 we carried out a prospective surveillance of the development of hepatocellular carcinoma (HCC) in 200 cirrhotic patients, monitored from the first histologic diagnosis of cirrhosis. Real-time ultrasonography (US) and serum alpha-fetoprotein (AFP) assays were performed every 3-6 months. During this period we detected HCC in 38 patients. The overall cumulative incidence of HCC in the 8 years was 41%, with a yearly incidence of 5.1%. Eighteen of 38 patients (48%) had a tumor < 5 cm in diameter. AFP reached diagnostic levels (> 500 ng/ml) in eight cases only (21%). Patients with initial AFP values > 20 ng/ml developed HCC more frequently than patients with values < or = 20 ng/ml; the percentage of HCC was statistically higher (p < 0.01) in patients in Child's B and C than in Child's A class. A periodic follow-up, using US and AFP, is suggested for the early diagnosis of HCC in cirrhotic patients.

Effects of therapeutic doses of salbutamol alone and combined with beclomethasone dipropionate on airway responsiveness and cyclic AMP plasma levels in asthmatic patients.

Twelve asthmatic patients received by inhalation for 2 weeks, in a double-blind, cross-over design, beclomethasone dipropionate (BDP; 600 micrograms/day) plus salbutamol (S; 900 micrograms/day), or S (900 micrograms/day) alone. Before and after each treatment course the subjects received intravenous cumulative doses of S up to 200 micrograms. In basal conditions and immediately before the next dose forced expiratory volume in 1 s (FEV1) and plasma cyclic AMP (cAMP) were measured. BDP+S treatment increased FEV1 basal values (p < 0.05) whereas inhaled S resulted in unsignificant improvement of ventilatory parameters. The slopes of the dose-response curves of FEV1 and plasma cAMP to intravenous S were unaffected by the two treatment courses. Our results suggest that DBP+S, differently from S alone, improves ventilatory function in asthmatic patients and that neither S nor S+BDP seem to affect adrenergic function.

Salmeterol and fluticasone propionate given as a combination. Lack of systemic pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.

Clinical presentation, diagnostic work-up and therapeutic choices in two consecutive series of patients with hepatocellular carcinoma.

In two consecutive series of patients with hepatocellular carcinoma (HCC), we compared clinico-laboratory and ultrasonographic characteristics, diagnostic work-up, survival of untreated patients and, finally, therapeutic choices. In addition of the clinical examination, we tested for blood serum alpha-fetoprotein levels, HBsAg and anti-HCV antibodies. Ultrasonography was performed in all the patients. In most cases, a pathologic diagnosis was obtained by ultrasound-guided fine-needle biopsy. As curative treatment we considered open surgery, percutaneous alcohol injection and radio frequency thermal ablation. In the second series, we observed an increased number of patients with compensated cirrhosis and with small HCCs, therefore the number of patients undergoing a potentially curative treatment was higher. The percentage of multiple tumours was comparable in two series implying the presence of two kinds of HCC, different ¿ab initio'. The survival rate of untreated patients was better in the second series.

Troglitazone has no effect on red cell mass or other erythropoietic parameters.

OBJECTIVE: Troglitazone is a new anti-diabetic agent for the treatment of type 2 diabetes. In placebo-controlled trials troglitazone improves glycaemic control, reduces hyperinsulinaemia and has beneficial effects on blood lipids. However, minor, reversible reductions in erythrocyte count, haemoglobin and haematocrit with no associated clinical symptoms have been observed in some troglitazone-treated patients. The primary objective of the present study was to determine if these changes could be explained by a decrease in red cell mass or change in plasma volume. METHODS: Twenty-four healthy males were randomized in a double-blind manner to troglitazone (200 or 600 mg per day) or placebo for 6 weeks. Blood samples for the measurement of red cell mass and plasma volume were obtained in the 2 weeks prior to treatment and after 6 weeks of treatment. Reticulocyte and erythrocyte counts, haemoglobin and haematocrit were also measured. RESULTS: At the end of the treatment period there were no statistically significant changes in red cell mass. Similarly there were no changes in reticulocyte count, erythropoietin or soluble transferrin receptors. These data indicate that troglitazone does not affect erythropoiesis. In addition, troglitazone was not associated with increased red blood cell destruction or haemolysis. There was a trend towards increased plasma volume in the troglitazone groups: increases of 2.5 ml x kg(-1) (5.7% increase) in the troglitazone 200 mg group and 3.4 ml x kg(-1) (7.8% increase) in the troglitazone 600 mg group were observed compared with placebo. CONCLUSION: These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.

Incidence of gallstones in a population of patients with cirrhosis.

One hundred and sixty-five patients with cirrhosis were prospectively investigated, by regular ultrasonographic follow up, to assess the incidence of gallstones. The mean length of follow up was 33 months (range 12 to 108). Cholelithiasis was diagnosed in 31 patients (18.8%), with a cumulative incidence over 84 months of 38.3% (4.7% yearly incidence). The risk of gallstones was similar in males (38%) and females (38.3%), although the final cumulative incidence was reached at 72 months in males. The percentage of patients with new stones was higher in alcoholic cirrhosis (28.9%) (with a cumulative incidence of 48.8% at 84 months) and lower in hepatitis-related cirrhosis (1.9%) (only one new case at 96 months of follow up) (p < 0.001). The cumulative incidence of gallstones in the Child's C group reached 49.3% at 48 months versus 24% in Child's B and 6.4% in Child's A (p < 0.0001). At multivariate analysis, Child's C and alcoholic cirrhosis were shown to be the independent variables significantly associated with a high risk of development of cholelithiasis. This study confirms that cirrhosis represents a high risk factor for gallstones. The risk is greater for alcoholic cirrhosis and increases with the severity of the disease.

Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer.

OBJECTIVE: The aim of this study was to evaluate the usefulness of RF interstitial thermal ablation for treating hepatic cancer. SUBJECTS AND METHODS: Fifty patients, 39 who had 41 hepatocellular carcinoma nodules and 11 who had 13 hepatic metastatic nodules, underwent RF interstitial thermal ablation. In all but one, a thermal necrosis volume greater than the tumoral nodule volume was created to obtain total tumor destruction. One large tumor was treated for debulking purposes. RESULTS: Hepatocellular carcinoma nodule destruction was achieved in a mean of 3.3 sessions of RF interstitial thermal ablation. During a mean follow-up of 22.6 months (range, 3-66 months), 16 (41%) of 39 patients had recurrences; two (5%) of these patients showed local recurrences and the remaining 14 (36%) had new lesions. Nine of these 16 patients underwent further RF interstitial thermal ablation that proved effective. RF interstitial thermal ablation was also successfully repeated in four patients who had a second recurrence. With RF interstitial thermal ablation, we treated 54 hepatocellular carcinoma nodules in 39 patients. Eleven (28%) of the 39 patients died: five from hepatic failure due to advanced cancer and six from causes other than cancer. Autopsy was performed on three patients who died from causes other than cancer, one had had two new courses of RF interstitial thermal ablation for two new lesions. Gross examination failed to detect two treated tumor nodules; histologic examination of three other treated tumor nodules showed total necrosis in two nodules and a 3-mm focus of viable cancer cells in the other nodule. Cumulative survival curves showed the median survival time to be 44 months. The survival rate for the first year was 0.94, 0.86 for the second year, 0.68 for the third year, and 0.40 for the fourth and fifth years. In the patients treated for metastatic nodules, posttreatment imaging studies showed necrosis that varied from 80% to 100% in all cases. Pathologic studies performed on two patients who underwent surgery after RF interstitial thermal ablation showed 100% necrosis in one case and 80% necrosis in the other. CONCLUSION: RF interstitial thermal ablation is a useful percutaneous treatment for hepatic cancer.