Skip pattern approach toward the early access of innovative anticancer drugs.

BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.

Low-antigen-content diet in the treatment of patients with mixed cryoglobulinemia.

PURPOSE: The effects of a low-antigen-content diet (LAC diet) versus a standard normocaloric diet on the signs and symptoms of mixed cryoglobulinemia (MC) were compared in a crossover randomized study. PATIENTS AND METHODS: The study consisted of 24 outpatients with MC, and was carried out in a 48-week period. After 18 weeks of either the LAC or the placebo diet, patients returned to a totally unrestricted diet for 12 weeks (washout period) and crossed over to the second half of the study for the other 18 weeks. RESULTS: After three weeks of the restricted LAC diet, the cryocrit decreased from 3.5 +/- 3.4% (mean +/- SD) to 2.3 +/- 2.0% (p less than 0.01), and the circulating immune complex levels decreased from 48 +/- 30% to 39 +/- 34% (p less than 0.01). At the same time, the purpura score (p less than 0.05), glutamic pyruvic transaminase level (p less than 0.01), and gamma glutamyl transferase level (p less than 0.001) significantly improved. Splenic reticuloendothelial function, measured as the half-life of heat-damaged autologous red cells, decreased from 41 +/- 21 minutes to 21 +/- 10 minutes (p less than 0.005). In contrast, no significant parallel clinical, biochemical, and immunologic changes occurred in the same patients during the placebo (standard normocaloric) diet. CONCLUSION: These data show that an LAC diet decreases the amount of circulating immune complexes in MC and can modify certain signs and symptoms of the disease. These effects of the LAC diet may be explained by postulating a functional restoration of the mononuclear phagocytic system.

Effects of chronic antihypertensive treatment with ketanserin versus metoprolol on blood pressure and large arteries' compliance in humans: a cross-over double-blind study.

The antihypertensive efficacy of a serotonin-receptor antagonist, ketanserin, was compared with that of a well-established antihypertensive drug, metoprolol, and their cardiac and forearm hemodynamic effects were investigated using echocardiography and bidimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive subjects completed a double-blind, cross-over, randomized study using ketanserin and metoprolol. Two 5-week courses with ketanserin or metoprolol were preceded by a placebo period; the total duration of the study was 15 weeks. Despite a comparable efficacy in reducing systolic and diastolic blood pressure (about 10% of the basal value), the two drugs showed quite different effects on forearm hemodynamics. Ketanserin increased forearm blood flow and induced a significant decrease in forearm vascular resistance (from 141 +/- 16 to 75 +/- 11 mm Hg/mL/sec, P less than .01). Furthermore, this treatment was able to improve brachial artery compliance (from 1.89 +/- .3 to 3.2 +/- .3 cm4/dyne 10(-7), P less than .01). On the contrary, metoprolol did not modify forearm hemodynamics. Both drugs did not significantly modify cardiac performance, as evaluated by left ventricle circumferential fiber shortening. Cardiac output was increased by ketanserin (from 5.9 +/- .3 to 6.6 +/- .5 L/min, P less than .05) and fell during treatment with metoprolol (from 5.9 +/- .4 to 4.9 +/- .3 L/min P less than .01). Thus, the two drugs reduce blood pressure through different hemodynamic mechanisms and the effects of ketanserin on systemic and peripheral circulation seem more favorable.

Prophylaxis of fatal pulmonary embolism in general surgery using low-molecular weight heparin Cy 216: a multicentre, double-blind, randomized, controlled, clinical trial versus placebo (STEP). STEP-Study Group.

The effectiveness of low-molecular weight heparin CY 216 in the prophylaxis of fatal pulmonary embolism in patients undergoing general surgery was assessed in a multicentre, double-blind, randomized, clinical trial against placebo. A total of 4,498 patients aged over 40 undergoing general surgery were enrolled in the 18 centres which took part in the trial. Patients received a single daily subcutaneous injection of 7,500 anti-Xa units I.C. of CY 216 or placebo two hours before surgery, 12 hours after the initial injection and then daily for at least seven days. A post-mortem examination had to be carried out in every patient who died. The two groups of patients were well-matched for age, sex, type of disease, site and duration of operation as well as for incidence of risk factors which could predispose to the development of thromboembolism. Twenty-six deaths were recorded and validated: eight (0.36%) in the CY 216 group and 18 (0.80%) in the placebo group (p less than 0.05). At the post-mortem examination, carried out in 23 patients (88.5%), two deaths were found to be directly due to pulmonary embolism (0.09%) in the CY 216 group and four (0.18%) in the placebo group. Pulmonary embolism contributed to death in four other placebo-treated patients. Pulmonary or extrapulmonary thromboembolism was a significantly less frequent direct cause of death (p less than 0.05) in the CY 216 group (two pulmonary embolisms) than in the placebo group (four pulmonary embolisms, one acute myocardial infarction, one disseminated intravascular coagulation, two ischemic cerebral strokes).(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension.

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.

Canrenone and androgen receptor-active materials in plasma of cirrhotic patients during long-term K-canrenoate or spironolactone therapy.

Plasma levels of canrenone and androgen receptor-active materials (ARM) were determined during long-term oral K-canrenoate or spironolactone therapy in cirrhotics with chronic recurrent ascites. Mean plasma canrenone level was approximately 3 times higher under K-canrenoate than under spironolactone treatment; moreover, the levels were not dose related. Either type of treatment did not affect plasma aldosterone and testosterone concentrations. Plasma ARM during K-canrenoate treatment did not change, whereas in the spironolactone group a 3-fold increase of ARM occurred (p less than 0.05). No dose-related effect was evident with the latter treatment. The lower incidence of gynecomastia in the K-canrenoate group was not correlated with values of plasma canrenone or ARM (p greater than 0.05). Our study questions the traditional view that the mode of action of spironolactone is via its metabolite canrenone. The two antialdosterone drugs, although equally effective in clearing ascites from cirrhotics, appear to act through partially different metabolites. The lower incidence of antiandrogenic or estrogen-like side effects during K-canrenoate seems to be related to metabolites other than canrenone itself.

Plasma glucose and insulin responses to carbohydrate food (rice) with different thermal processing.

The effects of thermal processing on plasma glucose and insulin responses in healthy subjects were examined. Fourteen volunteers, after being tested with a glucose load, were randomly administered a test meal, consisting of an amount of rice, calculated to yield the same quantity of glucose, used for the glucose tolerance test (70 g). Rice (90 g, raw) was cooked in two different manners: (a) boiled in salted water and (b) baked for 10 min at 160 degrees C after boiling as in the first test. A clear difference in viscosity and in in vitro hydrolytic rates between the two rice items could be established, whereas the plasma glucose and insulin responses in the volunteers differed to a smaller extent. In particular the 60-min incremental area for glucose was significantly lower in the case of baked rice, compared to boiled rice. These findings suggest that thermal processing of complex carbohydrates may differently affect glycemic responses in man.

Increased cardiac output and lowered peripheral resistance during metoprolol treatment.

Echocardiography was performed at every six months in hypertensives well controlled on metoprolol, 100 mg twice a day. After six months' treatment blood pressure was reduced from 177/110 mm Hg to 147/88 (p less than 0.02). LV wall thickness (septum + posterior wall) was unchanged 2.10 cm (2.14), and a significant drop in cardiac output (CO) to 5.0 l/min (6.1, p less than 0.02) was recorded (pretreatment values in brackets). After 24 months' treatment LV wall thickness was reduced to 1.94 cm (p less than 0.02), total peripheral resistance (TPR) to 17.3 mm Hg/l/min (23.4, p less than 0.02) and CO increased to 6.7 l/min (6.1, n.s.). After six months' treatment, there was thus a drop in BP with a significant drop in CO and unchanged TPR. After 24 months' treatment, however, CO was back to the pretreatment level and the drop in BP was entirely caused by a drop in TPR which was probably secondary to a reduction in the wall thickness of the arterial resistance vessels as judged by the relationship between the reduction in wall thickness in the LV and the reduction in TPR during the treatment.