Vincenzo Coto

Effects of Picotamide, an Antithromboxane Agent, on Carotid Atherosclerotic Evolution A Two-Year, Double-Blind, Placebo-Controlled Study in Diabetic Patients

BACKGROUND AND PURPOSE We assessed the effects of long-term treatment with picotamide, an antiplatelet agent with dual antithromboxane activity, on the evolution of early asymptomatic carotid atherosclerotic lesions in diabetic patients. METHODS In a double-blind, placebo-controlled, 2-year study, 50 type II normotensive diabetic patients (35 men; mean age, 66 +/- 5 years) with asymptomatic mild or moderate nonstenotic (< 50%) carotid atherosclerotic lesions and negative history of cerebrovascular ischemic events were enrolled and randomly given picotamide (300 mg TID) or the corresponding placebo. A high-resolution, real-time B-scan echographic assessment of carotid arteries was performed at baseline and after 1, 3, 6, 12, 18, and 24 months of double-blind treatment. Prevalence and evolutionary trends of carotid atherosclerotic lesions (number per patient and mean stenosis expressed as percent) were considered as efficacy primary end points. RESULTS At baseline, mean +/- SD numbers of carotid atherosclerotic lesions per patient were 2.7 +/- 1.8 and 2.2 +/- 1.2 in the picotamide and placebo groups, respectively. Mean +/- SD percent stenosis was 25.3 +/- 7% in the picotamide group and 27.3 +/- 6% in the placebo group. Forty-nine patients completed the study. At month 24, the placebo group (n = 24) showed a significant progression in number of carotid atherosclerotic lesions (3.04 +/- 1.8; P < .02 versus baseline) and in mean percent stenosis (35 +/- 17%; 95% confidence interval, 33% to 37%; P < .01 versus baseline). In the picotamide group (n = 25), mean number of carotid atherosclerotic lesions (2.7 +/- 1.6) and percent stenosis (26 +/- 9%; 95% confidence interval, 24.8% to 27.2%) remained unchanged. At month 24, compared with randomized placebo, lesion numbers (P < .03) and percent stenosis (P < .01) in the picotamide group were significantly lower. During the study, 12 patients experienced major or minor ischemic vascular events (9 in the placebo group and 3 in the picotamide group; P = .07). CONCLUSIONS In diabetic patients compared with patients receiving placebo, long-term treatment with picotamide can slow the evolution of early carotid atherosclerotic lesions, inhibiting progression of plaque number and growth.

Clinical Efficacy of Picotamide in Long-Term Treatment of Intermittent Claudication

The clinical efficacy of picotamide was investigated in a randomized, double- blind, placebo-controlled study in patients with peripheral occlusive arterial disease of the lower limbs at functional stage II of the Fontaine classification. Forty patients with a history of claudication for at least six months were admit ted to the study and were given either 3 x 300 mg tablets of picotamide (20 subjects) or three identical placebo tablets (20 subjects) for six months. The two groups of patients were similar in regard to clinical features and potential risk factors. At the end of treatment painfree walking distance and systolic ankle-arm pressure ratio improved more in the picotamide than in the placebo group (p=0.05). Systolic ankle pressure curves, determined before and after the six- month treatment, showed a positive trend to a higher postexercise ankle pres sure and a faster return to the preexercise levels in the picotamide group; however, the difference was not statistically significant. Laboratory monitoring revealed a slight prolongation of bleeding time, a significant decrease in arachi donic acid-induced platelet aggregation, and an enhanced fibrinolysis with ab sence of interference with hemostasis in the picotamide group. One patient in the placebo group developed a major cardiovascular event (angina pectoris) during the study. These results indicate that picotamide is an effective drug that may modify the natural course of intermittent claudication and associated vascular prob lems.

Long-Term Safety and Efficacy of Picotamide, a Dual-Action Antithromboxane Agent, in Diabetic Patients with Carotid Atherosclerosis: A 6-Year Follow-Up Study

In a controlled, randomized, 6-year trial the safety and efficacy of picotamide, a dual-action antithromboxane agent, were assessed in 50 patients with type 2 diabetes mellitus at increased risk of thrombotic vascular events. The patients were randomized to two groups of equal size and received 900 mg picotamide daily or placebo. After phase I (double-blind; years 1–2), patients receiving placebo were treated, if necessary, with antiplatelet drugs (aspirin, ticlopidine) while members of the other group continued to receive 600 mg picotamide daily. In the course of the study 21 vascular events occurred: 16 in the group receiving placebo (fatal myocardial infarction, n = 7; non-fatal stroke, n = 3) and five in the group receiving drug (fatal myocardial infarction, n = 2) (P < 0.005; Fishers exact test). One patient (placebo group) died of malignant disease. During the initial double-blind phase a total of nine vascular events was observed (six and three in the groups receiving placebo and drug, respectively). Picotamide treatment was well tolerated and no major side-effects were observed during the study periods.

Prevalence of Carotid Kinking and Coiling in a Population at Risk

The prevalence of carotid kinking and coiling in patients with hypertension or diabetes was investigated. The authors studied three groups: 130 subjects with hypertension, 105 with diabetes, and 50 normal subjects who were comparable for age, sex distribution, and the presence of other risk factors. Color flow ultrasonography of the extracranial carotid arteries was performed by standard technique. Hard-copy photographs were obtained in three long-axis and three short-axis projections. The prevalence of carotid kinking and coiling was significantly higher in the group of hypertensive patients than in diabetics and normal subjects (14.6% vs 2% and 14.6% vs 4%, respectively; P < 0.01 for both compar isons). The prevalence of carotid kinking was associated with the duration of hyperten sion, whereas it did not show any association with cigarette smoking and serum choles terol levels. A long-term observation of these patients is necessary for determining the natural history of carotid kinking and the potential for modification by adequate antihy pertensive therapy. The results of this study show that a significantly higher prevalence of carotid kinking is present in hypertensive patients in comparison with normal subjects and diabetics and this is correlated with the time of onset of hypertension.

Antiaggregatory Effects of Picotamide in Long-Term Treatment: A 2-Year, Double-Blind Placebo-Controlled Trial

The ex vivo antiaggregatory activity of picotamide, a dual antithromboxane agent, was assessed to find whether it was maintained in long-term treatment. In a double-blind, placebo-controlled 2-year study, 50 type 2 diabetic patients (35 men and 15 women; mean age 66 ± 5 years) were enrolled and randomly given picotamide, 300 mg t.i.d. or the corresponding placebo. Platelet aggregation studies were performed at baseline and after 1, 3, 6, 12, 18 and 24 months. Compliance to the treatment was assessed by pill count at each visit. Forty-nine patients concluded the study. Starting from month 1, compared with placebo, picotamide-treated patients showed a significant inhibition of agonist-induced (ADP, arachidonic acid and collagen) platelet aggregation (–41%). The antiaggregatory effect was maintained throughout the study. At month 24, in the picotamide group, platelet aggregation was significantly lower compared with placebo (–30%). After 24 months of treatment, 20 out of 23 (86%) picotamide-treated patients showed a significant inhibition of platelet aggregation, whereas the remaining three patients had a normal platelet response. During the study, 12 patients suffered from thrombotic events of death: nine in the placebo group and three in the picotamide group, respectively. It was concluded that picotamide maintains its antiaggregatory effect, in long-term treatment, in more than 85% of patients.

Regression of left ventricular hypertrophy and systolic function in hypertensive patients during long-term treatment with ketanserin

SummaryIt is now generally accepted that antihypertensive therapy can induce regression of left ventricular hypertrophy (LVH) in hypertensive subjects. However, the influence of LVH reversal on both the systolic and diastolic functions, and particularly the ability of the heart to meet sudden overloads caused by exercise and/or recurrence of hypertension, remain unanswered questions. The long-term effects of ketanserin, a selective serotonin S2-receptor antagonist with additional alpha1-adrenergic blocking properties, on LVH and systolic function were studied in 13 untreated subjects (age range 35–55 years) with mild-to-moderate essential hypertension, echocardiographic evidence of LVH, and normal ejection fraction. Blood pressure values and echocardiographic measurements of dimensions, wall thicknesses, and indices of LV mass were determined before and after 3, 6, and 12 months treatment; ejection fractions at rest and during exercise were evaluated by equilibrium multigated radionucleide angiocardiography at baseline and after 12 months of therapy. Mean arterial pressure was significantly reduced from the first month of treatment (p<0.001) and remained well controlled up to the end of the trial. Both posterior and septum wall thicknesses decreased after 3 months of therapy and remained stable throughout the whole study period. LV mass index decreased from a mean ± SD of 187.7±47.6 g/m2 to a mean of 157.81±31.63 g/m2 (p<0.01) at the third month, reaching greater decreases after 6 months (156.05±31.00 g/m2) and after 12 months (153.21±28.80 g/m2) of treatment. A significant correlation was found between LV mass and posterior wall thickness at the different observation times in the study. Finally, the regression of LVH at the end of therapy was not associated with impairment of systolic function, as assessed by measurements of ejection fraction at rest and during exercise.

SOCIOECONOMIC STATUS AND HYPERTENSION IN CHILDREN OF TWO STATE SCHOOLS IN NAPLES, ITALY: PRELIMINARY FINDINGS

Most epidemiologic studies have shown a relationship between high blood pressure and socioeconomic status in childhood. Systolic and diastolic pressure were measured in 296 schoolboys and 338 schoolgirls aged 10 to 13 years. The presence of known and suspected risk factors for hypertension was evaluated by a standardized questionnaire consisting of two sections: one completed by the subjects and another by their parents. Descriptive analysis showed a lack of association between socioeconomic background, parental educational levels and childhood hypertension, a relatively strong association between a sedentary style of life and hypertension (p<0.001) and a statistically significant influence of maternal or paternal history of hypertension or diabetes in the sample studied (p<0.05). However, when all the variables were assessed, by multiple correspondence analysis, two nuclei of schoolchildren were delimited. One was composed of hypertensive children with family histories of hypertension and/or diabetes mellitus who lead sedentary lives, live in large dwellings with a low crowding index and whose parents are better educated. The second nucleus was composed of normotensive subjects with opposite characteristics. The data obtained indicate that there may be a relationship between blood pressure in children and the socioeconomic status and educational level of their parents and suggest` that -these factors may have an impact on the childs blood pressure at a relatively young age.

Steady-state pharmacokinetics of idebenone in patients with moderate renal impairment

Idebenone (45 mg twice daily) was administered to 7 patients with moderate renal impairment (creatinine clearance 21-40 ml/min) for 10 days. Standard pharmacokinetic parameters were computed on day 1 (single administration) and on day 10. On day 1 the mean of the maximum plasma concentration values (C(max)) was 364 ng/ml (standard deviation (S.D.) 100); time to C(max) (t(max)) was in the range of 1-2 h for 6 patients and 12 h for the remaining patient: the mean was 3 h (S.D. 3.99); the mean area under the plasma concentration vs. time curve (AUC) was 3005 ng h/ml (S.D. 1152). On day 10 the mean C(max) was 531 ng/ml (S.D. 355.3), the mean t(max) was 0.07 h (S.D. 0.19), the mean AUC was 3167 ng/ml (S.D. 2944) and the mean elimination half-life (t(1/2)) was 4.9 h (S.D. 1.1). Idebenone metabolites (QS-4, QS-6 and QS-10) showed a kinetic profile similar to the parent compound, with pharmacokinetic parameters comparable to idebenone for QS-4 and lower than idebenone for QS-6 and QS-10. Idebenone was metabolized and easily excreted and no accumulation was observed for the compound and its metabolites. No significant modification of the biohumoral indexes and vital signs and no adverse reactions were observed.