[The dobutamine-dopamine combination versus amrinone in congestive heart failure with a marked edematogenic sign complicated by functional kidney failure. A comparison between 2 different models of inotropic stimulation and diuresis potentiation]. / Associazione dobutamina-dopamina versus amrinone nello scompenso cardiaco congestizio a marcata impronta edemigena complicato da insufficienza renale funzionale. Confronto tra due diversi modelli di stimolazione inotropa e di potenziamento della diuresi.

BACKGROUND: We evaluated the diuretic output in patients with decompensated chronic heart failure (CHF), previously treated by i.v. infusion with dobutamine and dopamine (dob-dop) or with amrinone (amr). Our target was to identify the possible discrepancies in urinary output perhaps linked to the different type of inotropic stimulation in the two subsets. METHODS: Adjunctive therapy with dob-dop or amr was chosen because the administration of diuretics only, without cardiac support, as tested in previous hospitalizations, had been demonstrated to produce unfavourable results, mainly expressed by finding of a low output syndrome in 50% of cases or more. The administration of i.v. infusion was maintained during 17 hours (1000 min approximatively), and included infusion in separate pumps of the two amines, dobutamine at dose of 5 micrograms/kg/min and dopamine at dose of 2.8 micrograms/kg/min or, alternatively, i.v. infusion of amr, administered at dose of 7 micrograms/kg/min. Infusion volumes were similar in the two subsets. The two subsets were homogeneous relatively to renal impairment, i.e. to the parameters (urinary Na, U/P creatinine, U/P urea, urinary osmolality) we fixed as markers idoneous to demonstrate the occurrence of organic renal damage (acute tubular necrosis). RESULTS: The diuresis was recovered in all 24 patients, and the urine volume resulted more pronounced in the subset attributed to the dob-dop at both the 8th and the 17th hour readings. We found no harmful alterations in HR and AP, whereas renal function parameters have been shown to enhance in both the dob-dop and amr arms. The diuretic effectiveness of the SIEV obtained by catecholamine implementation exercised a synergistic, favourable effect on diuresis, renal flow, glomerular filtration rate, and sodium post-proximal delivery. Amr resulted less effective then dob-dop simultaneous administration relatively to the diuretic effect. No remarkable differences were found in the two subsets as regards the heart rate, whereas a decrease in arterial pressure was found after amr. A persistent shift towards a condition of chronic renal failure, was identified in 4/24 patients, the two groups despite of the prolonged treatment at optimized doses: no remarkable side effects were reported. CONCLUSIONS: Thus, the selective effect upon renal hemodynamics, as exercised by dob-dop infusion low doses of dop, together with the enhanced renal output due to dob, has been shown to be more effective than amr influence: thus, the catecholamine therapeutical approach has been demonstrated to possess the best effectiveness in excitation of diuresis, among the CHF oliguric patients.

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; Fisher's 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.

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.

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.

Platelet aggregability in patients with a VVI pacemaker.

Several studies have suggested an increased incidence of thromboembolic events in patients with VVI pacemaker (VVI patients); furthermore, other authors have demonstrated that a treatment with anticoagulants or antiplatelet drugs may be effective in reducing thromboembolic events, thus suggesting an increased formation of platelet thrombi in these patients. In this respect, platelet aggregability was investigated in ten VVI patients and ten age- and sex-matched subjects. beta-thromboglobulin (beta-Tg) and platelet factor 4 (PF4) plasma levels were determined as well as platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid. Plasma beta-Tg levels were increased in the patient group (86 +/- 24 vs 24 +/- 13 ng/mL; P < 0.001) in presence of normal PF4 values (14 +/- 11 vs 13 +/- 6 ng/mL; NS). Aggregation curves showed abnormal values of maximal amplitude, slope, and lag time. In particular, maximal amplitude was significantly higher in VVI patients as compared with controls (ADP P < 0.01, collagen P < 0.001, adrenaline P < 0.01, arachidonic acid P < 0.05). These findings strongly suggest an increase of platelet activity in VVI patients.

Steady state pharmacokinetics of idebenone in patients with moderate hepatic impairment.

The kinetics of idebenone (45 mg twice daily p.o.) in 6 Caucasian chronic hepatopathic patients without portal hypertension were studied. The pharmacokinetic parameters were evaluated both for single (day 1) and multiple (day 10) administrations. These 6 patients showed a first order bi-compartimental kinetic curve for idebenone and for its metabolites, superimposable on the curves obtained from healthy volunteers. The C(max) parameters, tmax and bioavailability confirm the absence of accumulation. On day 12, 48 h after the last administration (performed on day 10), there was no evidence of residual drug. One of these patients was being treated with diuretics (chlorthalidone) and with perfusion fluids, including 5% glucose, and no interference was shown between the two drugs. There is no evidence of any particular side effect or alteration of the haematochemical parameters that could be thought to be drug related. This study confirms that idebenone at the dose of 90 mg/day p.o. administered to hepatopathic patients does not cause accumulation or toxicity.

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.

Evaluation of the clinical efficacy of idebenone in patients affected by chronic cerebrovascular disorders.

This study evaluated the efficacy and tolerability of idebenone, a new neuroactive drug, in 33 patients aged from 50 to 80 years. They were affected by chronic cerebrovascular disease (CCVD) and their last cerebrovascular accident had taken place at least 3 months prior to enrollment. All these subjects presented a score within the range of the following psychometric scales: Hamilton Scale for Depression <24; Hachinski Dementia Score >/=18 and < 25; Mini Mental State >/=16 and

[Diabetes and atherosclerosis: a follow-up echographic study of atherosclerotic carotid lesions]. / Diabete ed aterosclerosi: studio ecografico evolutivo delle lesioni aterosclerotiche carotidee.

A two years follow up on 105 diabetic patients and 50 normal subjects was carried out by high resolution real time echotomography, aiming to evaluate the prevalence and the evolutionary trends of carotid atherosclerotic plaques. The prevalence of atherosclerotic lesions was higher in diabetic patients than in normal subjects, and the most part of them showed an "intermediate" echographic pattern, minimal stenosis and regular surface. The results of the two years follow up indicate that the "soft" and the "hard" plaque types were those showing a more significant progression toward to the "mixed" type. "Hard" and "mixed" plaques, particularly those showing irregular surface, resulted most associated with higher degree of vessel stenosis. Four diabetic patients experienced three minor and one major ischemic events during the follow up; however all the patients had shown plaques with "intermediate" pattern, regular surface, and no signs of vessel stenosis progression. Further studies, performed for longer period of time with a higher number of patients are needed to evaluate the evolutionary trends of carotid plaques in diabetic patients and their relationship with clinical ischemic events.

POEMS syndrome: an Italian case with diagnostic and therapeutic implications.

A young Italian patient with a multisystem disorder and a solitary osteosclerotic bone lesion is described. His clinicopathological situation involved sensory-motor polyneuropathy, organomegaly, endocrine dysfunction, skin alterations, edema of the lower limbs and generalized lymphadenopathy. These features were consistent with the diagnosis of POEMS syndrome, reported primarily in Japanese patients. M components were not found in this patient's serum or urine. Bone marrow biopsy showed only a slight plasma cell infiltrate; histological study of the sural nerve evidenced a mixture of both axonal degeneration and segmental demyelinization. Lymph node biopsy revealed peculiar pathological changes resembling those of type II Castleman-like disease. A wide bone defect with osteosclerotic margins and trabeculation was evidenced in the right ilium. The relationship of these findings to plasma cell dyscrasias is discussed. After prednisone and local radiotherapy failed, the patient was treated with human recombinant interferon for 18 months. After three months of therapy he has experienced remarkable improvement of his neurological symptoms and almost complete recovery of organomegaly and lymphadenopathy. These improvements have continued to the present.

The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study.

An investigation on the therapeutic effect of L-carnitine was performed at three different centres and included two hundred patients, 40 to 65 years of age, with exercise-induced stable angina. In one hundred randomly selected patients the drug was administered orally in daily doses of 2 g in addition to the already instituted therapy, and the effect studied over a 6-month period. Compared with the control group, these patients showed a significant reduction in the number of premature ventricular contractions (PVC) at rest, as well as an increased tolerance during ergometric cycle exercise as demonstrated by an increased maximal cardiac frequency, increased maximal systolic arterial blood pressure and therefore also increased double cardiac product and reduced ST-segment depression during maximal effort. This was accompanied by improvement in cardiac function and resultant performance, as shown by an increase in the number of patients belonging to class I of the NYHA classification and a reduction in the consumption of cardioactive drugs. Laboratory analysis showed an improvement in plasma lipid levels. The authors conclude, after having discussed the particular metabolic mechanisms, that L-carnitine undoubtedly represents an interesting therapeutic drug for patients with exercise-induced stable angina.

[Restrictive cardiomyopathy in eosinophilic leukemia: echocardiographic and nuclear magnetic resonance aspects]. / Miocardiopatia restrittiva in corso di leucemia eosinofila: aspetti ecocardiografici e di risonanza magnetica nucleare.

This paper reports a case of endomyocardial disease due to hypereosinophilic syndrome. Two-dimensional echocardiography showed prevalent right ventricular involvement, with obliteration of the apex due to an echogenic mass progressively filling the whole ventricular cavity. RMN accurately defined the presence and the characteristics of the infiltrative mass in the right ventricular chamber. A different intensity of spin-echo imaging sequence was used to differentiate between thrombotic and infiltrative leukemic images. It is concluded that prevalent right ventricular involvement during eosinophilic endomyocardiopathy is a relatively rare disease which can be detected and evaluated by the use of echocardiography and RMN studies.

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

It 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 alpha 1-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 radionuclide angiocardiography at baseline and after 12 months of therapy. Mean arterial pressure was significantly reduced from the first month of treatment (p less than 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 less than 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.

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 admitted 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 pressure 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 arachidonic acid-induced platelet aggregation, and an enhanced fibrinolysis with absence 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 problems.

Clinical investigation of the effect of ketanserin: a new antihypertensive drug.

The antihypertensive effect of a recently introduced antiserotoninic drug, ketanserin, was examined in a single-blind, placebo-controlled parallel group study in 28 patients with mild to moderate hypertension. Supine and standing blood pressure, electrocardiogram, heart rate and laboratory parameters of liver, kidney and bone marrow functions were checked before and after 3 months of treatment. After 12 weeks' treatment with ketanserin (20-40 mg twice a day), there was a highly significant reduction of both systolic and diastolic blood pressure, as compared to placebo in the supine position (p less than 0.0001/p less than 0.001). In the standing position, the reduction of systolic pressure was more significant than the diastolic pressure (p less than 0.0001/p less than 0.01). Eleven out of 28 hypertensive patients showed electrocardiographic evidence of left ventricular hypertrophy (LVH) according to the ECG criteria of Romhilt and Estes. Although a reduction of the mean point score for LVH as compared to placebo was observed in the ketanserin group, that difference was not statistically significant. These preliminary observations suggest a possible role of ketanserin in the regression of LVH due to essential hypertension.

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 less than 0.001) and a statistically significant influence of maternal or paternal history of hypertension or diabetes in the sample studied (p less than 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 child's blood pressure at a relatively young age.