Indenolol in hypertension.

After a complete washout 14 hypertensive inpatients were given placebo for 3 days. Undistinguishable 30- or 60-mg indenolol tablets were then given twice daily for 14 days in a double-blind, randomized manner. Supine and standing arterial pressure and heart rate were measured at rest three times a day. Indenolol decreased systolic and diastolic arterial pressure as well as heart rate in subjects in supine and standing positions. Placebo had no effect. The effect of indenolol on systolic arterial pressure was dose and time related, but independent of the intensity of hypertension. No dose-effect relationship was found on diastolic arterial pressure. Decrease of heart rate was dose and time related, although bradycardia was never noted. Indenolol was well tolerated.

Serum lipids and apolipoproteins in patients with essential hypertension.

Fifty hypertensive untreated outpatients (34 women, 16 men), with stage I and II essential hypertension, were studied in comparison to 50 age- and sex-matched controls with similar life-styles. Total cholesterol triglycerides, LDL-cholesterol, VLDL-cholesterol, and HDL-cholesterol were measured by enzymatic methods, and apolipoproteins AI, AII, B, CII, CIII and E by RID. The results showed significant differences between hypertensives and controls respectively in triglycerides (135.2 +/- 73.9 versus 90.2 +/- 33.8, P less than 0.01) and VLDL cholesterol (26.7 +/- 14.8 versus 17.7 +/- 6.6, P less than 0.01) while no significant differences were observed in total, LDL and HDL cholesterol. Significant differences between the two groups were also observed in apolipoproteins, particularly in apo AI (130.0 +/- 28.2 versus 144.9 +/- 27.9, P less than 0.05), apo AII (32.9 +/- 10.2 versus 39.6 +/- 11.4, P less than 0.01), apo CII (4.0 +/- 2.6 versus 5.4 +/- 2.9, P less than 0.05) and apo E (5.0 +/- 1.8 versus 4.3 +/- 1.8, P less than 0.05), while no significant differences were observed in apo B and CIII values. The results suggest that in untreated hypertensive patients alterations in the apolipoproteins profile are present which, in part, may be responsible for the elevated incidence of cardiovascular disease, independently from the blood pressure values.

The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue.

The reduced fibrinolytic response after aspirin intake may be due to prevention of prostacyclin production. The effect of iloprost (a stable prostacyclin analogue) was tested on the fibrinolytic activity (euglobulin lysis area on fibrin plate [E.L.A.], t-PA antigen, PAI activity and PAI-1 antigen) of plasma drawn after venous stasis test from six healthy male volunteers, who each received all the following treatments according to a single-blind randomized cross-over design: placebo, iloprost, aspirin + placebo, aspirin + iloprost. The mean E.L.A. value after venous occlusion was significantly higher than the basal level after every treatment but aspirin. Within each treatment group the t-PA antigen levels in response to venous stasis were significantly higher than the basal ones. PAI-1 antigen levels did not change significantly before and after venous stasis either within or among the treatment groups. These data are consistent with the hypothesis that the mechanism related to aspirin's effect on fibrinolysis is mediated by suppression of vessel wall prostacyclin production. Aspirin's inhibitory effect on fibrinolysis was in fact prevented by replacing endogenous prostacyclin with iloprost. Iloprost enhances fibrinolytic activity reduced by aspirin, but not by promoting t-PA release or by inhibiting release of the specific inhibitor, PAI-1.

Defective fibrinolytic response in atherosclerotic patients--effect of iloprost and its possible mechanism of action.

Plasma fibrinolytic activity and tissue-type plasminogen activator (t-PA) were defective in response to venous stasis in five out of ten patients with peripheral occlusive artery disease. Discontinuous infusions of iloprost, a stable synthetic analogue of prostacyclin, restored a normal fibrinolytic response in all five patients but did not induce a parallel increase of plasma t-PA. These findings suggest that in addition to the possible benefits due to its vasodilatory and antiplatelet activity, iloprost may improve the fibrinolytic activity in patients with atherosclerotic disease, providing them with further antithrombotic protection. The profibrinolytic effect of iloprost seems not to depend on its ability to induce vascular t-PA release. Rather, it might be related to its inhibitory effect on PAI release from platelets, endothelial cells and/or hepatocytes. Venous occlusion test represents an easy diagnostic approach to fibrinolytic defects, even if related to arterial disease, and may help select patients who need therapeutic intervention.

Beta-TG and plasma catecholamines levels after sympathetic stimuli in hypertensives and patients with peripheral vascular disease.

The influence of the sympathetic nervous system on platelet functions in vivo is still controversial. The aims of our study were to compare the response to various sympathetic stimuli in normal subjects and in patients with essential hypertension (HT) or peripheral vascular disease (PVD) and to evaluate any correlations among plasma levels of catecholamines, beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4). In basal conditions beta-TG and PF4 values in the HT patients were higher than those observed in the controls of the same age but lower than those of the PVD patients. Although the different sympathetic stimuli (90 degrees tilting, handgrip, treadmill test, bicycle test) caused a significant increase of the plasma epinephrine (E) and norepinephrine (NE) levels, they did not modify the beta-TG and PF4 levels in any of the groups studied. The platelet activation indices, therefore, regardless of the basal values, do not seem to be influenced by sympathetic stimulation.

Lipid profile during antihypertensive treatment. The SLIP Study Group. Study on Lipids with Isoptin Press.

Some antihypertensive drugs adversely affect the plasma lipid profile, and this has to be taken into account when choosing treatment for hypertension because it may offset the beneficial blood pressure-lowering effect of these agents. In this study, the long term effects of verapamil sustained release (SR) 240mg daily and enalapril 20mg daily on plasma lipid levels were investigated in 931 patients with mild to moderate hypertension. Patients whose blood pressure was not effectively lowered after at least 1 month of monotherapy had either enalapril 20mg once daily added to their verapamil treatment or hydrochlorothiazide 12.5mg once daily added to their enalapril treatment. Blood pressure and lipid profile were assessed before and after 6 months of treatment. Of 864 evaluable patients, 563 patients (65.1%) were successfully treated with monotherapy and 220 patients (25.5%) required combination therapy. A total of 81 patients withdrew from the trial. Systolic and diastolic blood pressure were significantly reduced by treatment with either verapamil or enalapril, and heart rate was reduced slightly, but significantly, by both treatments. Total cholesterol, triglycerides and low density lipoprotein were significantly reduced by both treatments. High density lipoprotein levels were significantly increased in verapamil recipients, but not in enalapril recipients. Adverse effects occurred in 37 (3.9%) patients receiving verapamil SR and 25 (2.7%) patients receiving enalapril. In conclusion, long term treatment with the antihypertensive agents verapamil and enalapril, alone or in combination regimens, significantly improved the plasma lipid profile. Verapamil SR had the most beneficial effect on plasma lipid levels.

Effects of treatment with verapamil SR and captopril on the lipid profile of hypertensive patients.

The potential beneficial effects of antihypertensive drugs on cardiovascular morbidity and mortality may be compromised by their adverse effects on serum lipid levels. In our study we compared verapamil and captopril and evaluated their effects on blood pressure and on serum lipid and lipoprotein levels, with particular attention to lipoprotein(a) [Lp(a)]. 20 hypertensive patients were treated with sustained release verapamil 240mg once daily or captopril 25mg twice daily for 3 months in a double-blind randomised study. Diastolic blood pressure was reduced from 100 +/- 3mm Hg to 87 +/- 6mm Hg (p < 0.01) and from 100 +/- 5mm Hg to 92 +/- 7mm Hg (p < 0.05) in the verapamil and captopril groups, respectively. Small but significant changes in serum lipid levels were noted: total cholesterol was reduced from 6 to 5.8 mmol/L (verapamil) and from 6.1 to 5.9 mmol/L (captopril); low density lipoprotein (LDL) cholesterol was reduced from 4 to 3.8 mmol/L (verapamil) and from 4.2 to 3.9 mmol/L (captopril); apolipoprotein C-III was reduced from 0.3 +/- 0.07 to 0.2 +/- 0.06 mmol/L (9.7 +/- 2.5 to 9.2 +/- 2.3 mg/dl) [verapamil] and from 0.2 +/- 0.1 to 0.2 +/- 0.09 mmol/L (9.1 +/- 3.7 to 8.3 +/- 3.4 mg/dl) [captopril]; apolipoprotein A-II increased only with verapamil (p < 0.02). Lp(a) levels showed only minor changes in individual patients. In conclusion, in our study verapamil and captopril were effective antihypertensive agents and did not adversely effect the lipid profile.

Indenolol pharmacokinetics and pharmacodynamics after single and repeated daily doses.

The relationship between indenolol (an investigational agent) plasma levels and the drug's effect on blood pressure and heart rate was investigated after single and repeated once daily administration at two dosage levels (60 mg and 120 mg) in two different groups of patients with first or second stage hypertension, according to the World Health Organization classification. The pharmacokinetic data were indicative of a first order absorption-elimination curve; time of maximum plasma levels was 1.5 to two hours, and elimination half-life was four hours. The drug did not accumulate in the central compartment after repeated administrations. A long-lasting decrease of both resting and isometric exercise systolic pressure values was recorded after acute indenolol administration. Diastolic pressure was affected only by repeated administrations. The lower dose (60 mg daily) of indenolol did not affect heart rate, whereas the higher dose (120 mg daily) decreased this parameter. A steady state of pressure values and heart rate was reached after 14 days of once daily treatment.

Platelet activation indices and apolipoproteins in hypertensive patients.

We have studied the platelet activation indices beta-thromboglobulin (beta-TG and platelet factor 4(PF4), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and apolipoprotein (A1, A2, B, C2, C3, E) profiles of 22 untreated essential hypertensive subjects (WHO stages 1 and 2) and 22 controls, to see if there might be some causal relationship between lipoprotein abnormalities and greater platelet activation. The results showed the patients had both greater platelet activation than the controls, as demonstrated by higher plasma beta-TG levels (P less than 0.01) and lower apolipoprotein A2 levels (P less than 0.05). However there were no significant correlations between the platelet activation indices and the plasma levels of apolipoproteins, lipoproteins or lipids in either group.

Diurnal blood pressure variability in essential hypertension and vascular reactivity to isometric stress.

The present study was designed to assess the hemodynamic conditions, by means of impedance cardiography methods, and the relation existing between vascular reactivity to isometric stress (isometric handgrip test) and the day/night blood pressure variations, estimated by ABPM. Fifty unselected untreated non-obese EEH adult subjects (WHO class I) with a duration of disease not exceeding 3 years were classified as dippers or non-dippers according to commonly accepted criteria. Twenty three normotensive volunteers acted as controls. SBP, DBP, HR, CI and SVRI were assessed at rest and after IHG test. At rest dippers, non-dippers and controls showed comparable CI. SVRI were more enhanced in EEH than in controls and, although not significantly, in non-dippers than in dippers. During IHG all subjects showed a significant rise of SBP, DBP and HR; CI variations were of comparable size in all groups while SVRI increases were not. Non-dippers showed a significant SVRI rise after IHG in comparison with resting values. In dippers and in controls SVRI increment was insignificantly different in comparison with resting values. Non-dippers showed a closest correlation between BP and SVRI rise during IHG while dippers showed a less consistent association. In conclusion, our data suggest that in adults with short duration EEH the existence of non-dipper condition may be unrelated to myocardial hypertrophy. Blunted nocturnal BP fall is associated with vascular hyper-reactivity revealed by a bigger elevation of SVRI during IHG.(ABSTRACT TRUNCATED AT 250 WORDS)

Placebo effect and adaptation to noninvasive monitoring of BP.

Three 24 h ambulatory monitorings of BP were performed at two-week intervals in 21 untreated hypertensives (mean age 38 +/- 10 yrs, 13 males and 9 females). After the first baseline monitoring, the patients were randomised, according to a cross-over design, to one of the following sequences: no therapy to placebo or placebo to no therapy. At the end of each period, noninvasive ambulatory monitoring was performed. Mean +/- SE 24 h systolic (SBP) and diastolic (DBP) pressures recorded at the first monitoring were 129.2 +/- 3.5 mmHg and 81.7 +/- 2.3 mmHg respectively. At the second and third monitorings, mean 24 h BP differences versus baseline levels were -2.9 +/- 1.8 and -4.7 +/- 1.7 mmHg for SBP, and -2.0 +/- 1.1 and -2.7 +/- 1.5 mmHg for DBP. Both SBP and DBP differences at repeated monitorings were significant by analysis of variance (P less than 0.05). No significant effects on BP of treatment sequence or of placebo administration were found. Analysis of covariance showed a significant relationship between initial 24 h BP and subsequent mean 24 h BP differences (SBP: beta = -0.260, DBP: beta = -0.124). ANOVA performed on waking and sleeping BP separately showed the observed differences to be significant only during waking hours. Regression analysis showed that the decrease in 24 h BP at repeated monitorings was significantly related to the extent of 'white coat'-induced BP increase only for DBP (P = 0.022). For both 24 h SBP and DBP, however, a negative correlation between the alarm reaction to the presence of the physician and 24 h BP decrease at repeated monitorings was observed. It is concluded that noninvasive ambulatory monitoring is subject to adaptative phenomena but not to placebo effect. Factors influencing the defence reactions to manual measurements and to ambulatory monitoring might be partly different.

Cardiovascular responses to physical exercise and tyramine infusion in hypertensive and normotensive subjects.

The aim of our investigation was to assess blood pressure and heart rate variations in 20 essential hypertensive male in-patients (WHO class I and II) and in 20 normotensive healthy volunteers submitted to three provocation tests: isometric handgrip (IHG), bicycle ergometric exercise (BEE) and tyramine infusion (TI) given as i.v. boluses alternating with saline in a single-blind fashion. According to our data IHG induced a comparable rise of systolic BP, diastolic BP and heart rate both in hypertensive and normotensive subjects. BEE, compared with IHG, caused a more significant (P less than 0.01) rise in SBP and heart rate in both groups. By contrast, DBP during BEE was significantly increased in hypertensive (P less than 0.01), but slightly decreased in normotensive subjects (P = NS). TI caused a dose dependent SBP rise in both groups studied, while DBP and HR were unaffected. BP elevation was, however, more marked in hypertensive subjects. Confirming this finding significantly lower tyramine doses were required to produce the same SBP increase in hypertensives than in the normotensive volunteers. In short, SBP rise during TI and DBP rise during BEE may be the markers of an enhanced cardiovascular reactivity of hypertensive subjects. Our study suggests that BP reactivity to stress may be different according to the laboratory stress employed and also that BEE and TI are more useful than IHG for the assessment of an enhanced cardiovascular response to stress in hypertensive subjects.

Balanced 24-hour blood pressure control by angiotensin-converting enzyme inhibitors administered once daily.

Traditional sphygmomanometric measurements may inaccurately reflect the actual blood pressure level over a 24-h period. This is due to several factors which are known to affect cuff blood pressure readings, including the limited number of readings obtainable throughout the 24 h and the alerting reaction and pressor response induced in patients by the presence of the physician. Twenty-four-hour ambulatory blood pressure monitoring has been reported to be superior to isolated cuff blood pressure readings in the diagnostic evaluation of hypertension and in assessing the blood pressure response to treatment. It does not trigger any emotionally induced pressor reaction and is able to provide a dynamic evaluation of blood pressure profiles over 24 h. The latter feature is particularly important in assessing the ability of once-daily antihypertensive treatment to reduce and maintain blood pressure at an appropriate level throughout the 24-h period. Studies to date using ambulatory blood pressure monitoring techniques suggest that once-daily administration of certain ACE inhibitors is capable of providing this long-term control of blood pressure. The 24-h antihypertensive action exerted by once-daily administration of ACE inhibitors is characterized by balanced blood pressure control throughout the day and night, and treatment does not appear to alter the neural mechanisms responsible for cardiovascular homeostasis, as suggested by the fact that these drugs have been shown not to affect 24-h blood pressure and heart rate variability. Furthermore, during administration of ACE inhibitors the sensitivity of arterial baroreceptor control of circulation is unaltered or even enhanced. These observations emphasise the potential importance of long-acting ACE inhibitors in the control of arterial hypertension.

Isolated office hypertension: are there any markers of future blood pressure status?

BACKGROUND: The introduction of ambulatory blood pressure monitoring into clinical practice has defined a clinical condition called 'isolated office hypertension'. OBJECTIVE: The aim of this study was to evaluate the long-term systolic and diastolic blood pressure changes in patients with isolated office hypertension and to identify the presence of markers capable of identifying which patients will develop sustained hypertension. METHODS: All the 407 patients enrolled had a random office systolic or/and diastolic blood pressure of over 140/90mmHg and a mean daytime ambulatory blood pressure of 130/84mmHg or less. At enrollment, each patient underwent a 'baseline examination' made up of a physical evaluation, a 24h ambulatory blood pressure monitoring, and a mental arithmetic test performed at the end of the 24h ambulatory monitoring. RESULTS: Of the 173 patients finally studied, 102 (58.9%) developed sustained hypertension with an increase in both ambulatory systolic and diastolic blood pressure. At the time of the baseline examination, the patients were divided into two groups. Group A included patients with mean ambulatory systolic and diastolic blood pressures in the first hour of 130/84mmHg or less; group B included patients with mean ambulatory systolic and diastolic pressures in the first hour of greater than 130/84mmHg. During the mental arithmetic test, the systolic and heart rate values increased significantly only in group B patients. Of the 102 patients who had become hypertensive by the time of the follow-up examination, 84 (82%) belonged to group B. CONCLUSION: These data suggest that isolated office hypertension may indeed be a transitional state towards the development of sustained hypertension. Moreover, the mean ambulatory blood pressure value during the first hour can be considered to be a marker of a higher risk of developing sustained hypertension.

Treatment of claudication with dipyridamole and aspirin.

The effects of dipyridamole in association with acetylsalicylic acid were compared with the effects of acetylsalicylic acid alone in patients with peripheral vascular disease. The following parameters were studied in each patient: symptoms-free interval on the treadmill, ankle-arm arterial pressure gradient, oscillographic index, venous occlusion plethysmography and any untoward reactions. Changes were observed in the pain-free interval (p less than 0.005), and in the venous occlusion plethysmography (p less than 0.001) in the patients treated with the two drugs in association.

Pharmacokinetic study of intravenous and oral idarubicin in cancer patients.

Idarubicin (4-demethoxydaunorubicin) is a new anthracycline analogue which lacks the methoxyl group at the C-4 position of the aglycone moiety. The present study was undertaken to investigate the pharmacokinetics and bioavailability of idarubicin in man. The drug was administered at 3-week intervals to six patients by both intravenous and oral routes. Doses used were 13-15 mg/m2 intravenous and 45 mg/m2 p.o. Plasma levels of unchanged idarubicin and of its metabolite idarubicinal were assayed by high performance liquid chromatography (HPLC). After intravenous administration the plasma levels of the unchanged drug declined very rapidly reaching the sensitivity limits of the analytical method (1-2 ng/ml) 24 h after dosing. Plasma levels of idarubicinal reached a peak of about 10 ng/ml within two hours then decreased very slowly with a plasma t1/2 of about 2.5 days. After the oral dose of 45 mg/m2, the plasma level patterns of both parent compound and the idarubicinal were roughly similar to those after 15 mg/m2 intravenous except for the obvious difference linked to the absorption of idarubicin. The absorption of oral idarubicin was rapid and, in terms of area under curve of the metabolite, the availability after oral administration can be estimated as about 30% of the dose. The urine findings reflected the plasma situation. The metabolite levels were much higher and longer lasting than those of the parent compound. Urinary recovery after intravenous (16% of the dose in four days) and oral administration (approximately 5% of the dose) confirmed the 30% absorption estimated on the basis of plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral tramadol and buprenorphine in tumour pain. An Italian multicentre trial.

In this multicentre trial tramadol and buprenorphine were compared for the treatment of neoplastic pain no longer responsive to non-steroidal antiinflammatory drugs. A total of 131 adults (86 M, 45F) were treated with tramadol (one 100-mg slow-release tablet every 8-12 h), or buprenorphine (one sublingual 0.2-mg tablet every 6-8 h). The trial was to continue for up to six months. Most patients started treatment with 2-3 tablets/day in both groups, and the mean treatment period was 58 days for tramadol and 51 for buprenorphine. Almost all dose changes needed were made in the first fortnight in both treatment groups, and the largest number of patients dropped out because of inadequate pain relief or progression of the underlying disease. The results achieved in the first two weeks persisted throughout the rest of the trial, and the investigator's assessments on each patient's clinical chart corresponded closely with those that patients made in their own daily diaries. In the four hours after the first dose both drugs virtually halved the severity of pain (measured using a visual analogue scale), and this relief lasted throughout treatment. By the end of the first week the proportion of patients with strong/unbearable pain in the tramadol group had fallen significantly (from 98.4% to 48.1%, p < 0.05), as compared to a drop from 92% to 66.7% for buprenorphine. The quality of sleep also tended to improve in the tramadol group, with the proportion of patients enjoying good or deep sleep rising from 37% to 50%, as compared to 33% to 40-44% with buprenorphine. Karnofsky's and Spitzer's indices reflecting the quality of life did not change in the tramadol group; in the buprenorphine group the Karnofsky index dropped slightly after a fortnight (p < 0.05 between treatments). In the first two months of the trial the number of patients with no/moderate pain rose continuously in the tramadol group (71% and 80% after one and two months); the rise was less marked in the buprenorphine group (number of patients with mild/moderate pain, 45% and 65%). In both the short term and in the longer term, it was found that the levels of efficacy and acceptability were always significantly better in the tramadol group than in the buprenorphine group. General and biological safety in both drugs was good. The most typical side-effects were those characteristic of opioids (nausea and/or vomiting, drowsiness). Adverse reactions were reported in 17 patients taking tramadol (25%) and in 16 taking buprenorphine (26%). There were six drop-outs in the first group (9%) and seven in the second (11%). Serious symptoms arose more frequently in the buprenorphine group (19% cf. 10%). No signs of dependence or tolerance were noted.

Bone metastases from breast cancer treated with calcitonin. Case report.

A case of bone metastases from breast cancer is reported. After 6 months of therapy with calcitonin, the skeletal radiological examination showed an evident change in the roentgenographic pattern of a large metastasis of the left femur. A possible relationship between the calcitonin treatment and the radiological change is discussed.

Plasma and tissue distribution of adriamycin in patients with pelvic cancer.

The levels of adriamycin in plasma, ascitic fluid and normal and neoplastic tissues sampled during surgery of 3 patients with advanced pelvic cancer were measured by fluorimetry. The highest content of fluorescent compounds was found in tumoral masses in necrotic or scarcely viable tissue; viable and invasive tumor areas scored fluorescence levels comparable with normal adnexa. Ascitic fluid contained levels of fluorescence comparable to the last observed phase of plasma levels. Adipose and cutaneous tissue scored the lowest concentrations.

Enzymuria in carboplatin nephrotoxicity.

Urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is an early marker of nephrotoxicity. NAG activity was assayed by the fluorimetric method of Leaback and Walker in 17 patients treated (22 courses) with carboplatin (CBDCA, 220-550 mg/m2) before infusion and 24, 48, 72 and 96 h after. Increased excretion of NAG, a sensitive index of renal tubular damage, was observed following 10 of the 22 courses. A transient increase in plasma creatinine and/or abnormal proteinuria was observed in 6 cases. Impaired renal function prior to therapy seems to be a predisposing factor to the nephrotoxicity.