Combination treatment in antihypertensive drug trials.
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Antihypertensive Agents↗
Biomedical subjects
G Grassi
Publications and source records attributed to G Grassi.
Comparison between reproducibility and sensitivity of muscle sympathetic nerve traffic and plasma noradrenaline in man.
1. Although plasma noradrenaline and muscle sympathetic nerve traffic have been shown to be suitable markers of sympathetic activity in man, no study has systematically compared the reproducibility and sensitivity of these two indices of adrenergic tone. 2. Reproducibility data were collected in 10 subjects, in whom plasma noradrenaline was assessed by HPLC on blood samples withdrawn from an antecubital vein and efferent postganglionic muscle sympathetic nerve activity was measured by microneurography from a peroneal nerve, together with arterial blood pressure (Finapres technique). Measurements were obtained in a first session (session 1), 60 min later (session 2) and after 14 days (session 3). While muscle sympathetic nerve activity values recorded in the three different experimental sessions were closely and significantly correlated with each other (r always > 0.90, P < 0.001), noradrenaline showed a less significant correlation between sessions 1 and 2 (r = 0.71, P < 0.05) or no correlation between sessions 1 and 3 (r = 0.45, P not significant). 3. Sensitivity data were collected by evaluating muscle sympathetic nerve activity and noradrenaline values in three different age groups (young, middle-age and old subjects, n = 18), in three groups with different blood pressures (normotensive, mild and severe hypertensive subjects, n = 30) and in a group of eight subjects before and after a physical training programme, i.e. conditions known to increase or reduce sympathetic cardiovascular drive. Muscle sympathetic nerve activity was significantly increased by aging and hypertension, and reduced by physical training. The noradrenaline changes were much less marked and consistent. 4. These data suggest that muscle sympathetic nerve activity has a greater short- and medium-term reproducibility than noradrenaline. In several conditions known to modify sympathetic cardiovascular drive muscle sympathetic nerve activity also appears to change more clearly than noradrenaline.
Adolescent↗
Antihypertensive effects of combined lisinopril and hydrochlorothiazide in elderly patients with systodiastolic or systolic hypertension: results of a multicenter trial.
This study was aimed at evaluating the antihypertensive effect of lisinopril and hydrochlorothiazide administered in the fixed combination of 20 and 12.5 mg, respectively, on clinic and 24-h blood pressure in elderly patients (age, 68.8 +/- 5.8 years, mean +/- SD) with mild-to-moderate essential systodiastolic or isolated systolic hypertension. After a washout period of 4 weeks, patients received once daily lisinopril combined with hydrochlorothiazide for a 6-week period. At the end of the washout and treatment periods, clinic blood pressure was assessed 24 h after dosing, and 24-h ambulatory blood pressure was monitored, taking blood pressure readings every 15 min. Pretreatment clinic blood pressure was 171.3 +/- 14.0/103.7 +/- 5.1 mm Hg (systolic/diastolic) in the group with systodiastolic hypertension (n = 405) and 179.6 +/- 9.4/83.6 +/- 5.4 mm Hg in the group with isolated systolic hypertension (n = 165). The corresponding 24-h average blood pressures were 144.1 +/- 13.9/88.7 +/- 8.4 mm Hg (n = 114) and 150.7 +/- 15.5/80.8 +/- 9.4 mm Hg (n = 40). Clinic blood pressure was significantly reduced by treatment in both groups. This was the case also for ambulatory blood pressure, which was reduced by 9.6 +/- 0.9%/9.9 +/- 0.9% in systodiastolic and by 11.8 +/- 1.3%/8.5 +/- 1.5% in isolated patients with systolic hypertension (p < 0.05 at least for all differences). The antihypertensive effect was similar in patients older and younger than 70 years. In all groups, it was manifest both during the day and the nighttime and was still significant after 24 h. Thus single daily administration of combined lisinopril-hydrochlorothiazide effectively reduces blood pressure in elderly patients with hypertension.
Aged↗
Primary prevention of cardiovascular disease.
Antihypertensive drug treatment has been shown to significantly decrease cardiovascular morbidity and mortality rates in hypertensive subjects and to reduce the occurrence of major hypertension-related complications, such as stroke, coronary artery disease, congestive heart failure and renal insufficiency. Despite these favorable effects, several issues related to antihypertensive treatment remain to be clarified. This paper will discuss some of these issues, with particular reference to the effects of blood pressure lowering on renal diseases and coronary heart disease. It will also discuss the ongoing clinical trials aimed at clarifying some unsolved issues of antihypertensive treatment. The objective of the International Nifedipine GITS Study Intervention as a Goal in Hypertensive Treatment was to provide information on the effects of calcium antagonist treatment on high blood pressure values and on hypertension-related cardiovascular complications in a high-risk hypertensive population.
Antihypertensive Agents↗
Baroreflex impairment by low sodium diet in mild or moderate essential hypertension.
Low sodium intake is the most widely used nonpharmacological approach to the treatment of hypertension. Although nonpharmacological treatment is by definition regarded as safe, the suggestion has been made that low sodium intake is not totally devoid of inconveniences, and animal data have shown it to be accompanied by an impairment of reflex blood pressure control and homeostasis. However, no data exist on this issue in humans. In mild essential hypertensive patients (age, 34.1+/-3.3 years [mean+/-SEM]), we measured beat-to-beat arterial blood pressure (finger photoplethysmographic device), heart rate (electrocardiogram), and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during baroreceptor stimulation and deactivation, induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at the end of three dietary periods, ie, after 8 days of regular sodium intake (210 mmol NaCl/d), low sodium intake (20 mmol NaCl/d) with unchanged potassium intake, and again regular sodium intake. Compared with the initial regular sodium diet, low sodium intake reduced urinary sodium excretion, whereas urinary potassium excretion was unchanged. Systolic blood pressure was significantly (P<.05), although slightly, reduced, whereas diastolic blood pressure was unaffected. Muscle sympathetic nerve activity was increased by 23.1+/-5.2% (P<.05). The increase was accompanied by a clear-cut impairment of the baroreceptor ability to modulate muscle sympathetic nerve activity, ie, by a 43.9+/-5.7% (P<.01) reduction in the sensitivity of the baroreceptor-muscle sympathetic nerve activity reflex compared with the control condition. Baroreceptor modulation of heart rate was also impaired, although to a smaller and less consistent extent. When regular sodium intake was restored, all the above-mentioned parameters and baroreflex responses returned to the values observed at the initial regular sodium diet. These data raise evidence that in humans sodium restriction may impair the arterial baroreflex. This may be responsible for the sympathetic activation occurring in this condition and for the impairment of blood pressure homeostasis.
Adult↗
Ambulatory and home blood pressure normality in the elderly: data from the PAMELA population.
To determine ambulatory blood pressure (BP) means and distributions in an elderly population, we studied a random sample of 800 subjects stratified by sex and representative of residents aged 65 to 74 years of the city of Monza. Participation was 50%. Measurements consisted of clinic BP (average of three measurements with mercury sphygmomanometry), home BP (average of morning and evening measurements with a semiautomatic device), and ambulatory BP (SpaceLabs 90207). Clinic BP was obtained before and after home and ambulatory BP measurements. In normotensive and untreated hypertensive subjects (n=248), clinic, home, and ambulatory BPs were significantly related (P<.001). The means of the clinic BPs obtained on consecutive days were very similar and markedly higher than 24-hour average BP (+25 mm Hg systolic and + 10 mm Hg diastolic, P<.001). Nighttime BP was markedly less than daytime BP (-14 and -13 mm Hg, P<.001), whereas home BP values occurred approximately midway between clinic and 24-hour average BP values. Only minor differences existed between data in men and women, and the differences in clinic, home, and ambulatory BP values occurred in both normotensive and untreated hypertensive subjects. All BPs were similar in the untreated and treated hypertensive groups. Thus, as previously reported in subjects younger than 65 years, in the elderly fraction of the population, 24-hour average BP is much lower than clinic BP. The upper limit of normality for 24-hour average BP (calculated as the value corresponding to 140/90 mm Hg clinic BP) is about 120 mm Hg systolic and 76 mm Hg diastolic. At variance with data from younger subjects, home BP in the elderly is higher than 24-hour average BP. However, similar to data from younger subjects, clinic, home, and ambulatory BPs are higher in treated hypertensive than normotensive elderly subjects, indicating that in hypertensive elderly subjects, antihypertensive treatment does not commonly achieve full BP control both inside and outside the clinic environment.
Age Factors↗
Sympathetic activity, blood pressure variability and end organ damage in hypertension.
Animal studies have provided clearcut evidence that sympathetic factors are involved in the development and maintenance of high blood pressure (BP). This also appears to be the case in humans, in which sympathetic activation, detected through plasma noradrenaline measurement, noradrenaline spillover technique and direct recording of muscle sympathetic nerve activity, has been shown to characterize the early phases of the hypertensive state and parallel its severity. Sympathetic factors also play in a variety of pathophysiological states frequently associated with hypertension, such as obesity, insulin resistance and atherosclerosis. In addition evidence has been collected that adrenergic factors represent one of the mechanisms involved in determining BP variability, which is strictly associated with end organ damage. Taken together these findings underline the importance that the therapeutical approach to hypertension is aimed not only at lowering BP but also at reducing sympathetic activity.
Animals↗
[Secondary prevention of stroke through arterial blood pressure reduction].
Large scale observational studies have conclusively demonstrated that systolic and diastolic blood pressure values are linearly related to the incidence of cerebrovascular diseases and that high blood pressure is an important risk factor for both primary and secondary development of stroke. Interventional studies have shown that blood pressure lowering by antihypertensive treatment reduces the incidence of stroke in hypertensive patients without a history of previous stroke. Whether this is the case also for the secondary prevention of cerebral ischemic attacks has not been unequivocally shown, however. The PROGRESS ("Perindopril Protection Against Recurrent Stroke Study") study has been designed and is under way to collect information on this important issue of the antihypertensive treatment, its purpose being to evaluate the blood pressure lowering effects with an ACE-inhibitor on recurrent stroke in an overall population of 6000 patients with a positive history of previous cerebral ischemic attacks or stroke.
Cerebrovascular Disorders↗
The sympathetic nervous system in human hypertension.
While animal models of hypertension have clearly shown an increase in sympathetic activity, a similar demonstration in humans has been more difficult to obtain for methodological reasons. There is now clear evidence, however, of an increase sympathetic activity in essential hypertension by the finding of either an increase in plasma norepinephrine and an increase in muscle sympathetic nerve traffic. Among the mechanisms responsible for this sympathetic activation the arterial baroreflex may play a role although probably a non specific and late one. Central neural influences associated with an excessive hypothalamic response to stress may also be involved, but conclusive evidence is still lacking due to the difficulty of assessing cardiovascular reactivity to stress in man. A deeper insight into the features of human sympathetic cardiovascular control may be offered now by new techniques which allow neural cardiovascular regulation to be assessed in daily life through computer analysis of noninvasive ambulatory beat-by-beat blood pressure and heart rate recordings.
Animals↗
[Improvement of short-term prognosis in patients with refractory heart failure].
BACKGROUND: Prognosis of patients with severe heart failure is poor, despite improved results in medical therapy. Heart transplantation is the only treatment possible in end-stage heart failure. The aim of this study was to evaluate the variation in prognosis over the past six years in the patients admitted to Intensive Care Unit for heart failure in spite of optimal oral therapy. STUDY POPULATION AND METHOD: Between January 1990 and December 1995, 133 patients with heart failure were admitted to the Intensive Care Unit, despite the fact that they were on optimal oral therapy. All patients were in New York Heart Association (NYHA) functional class III to IV and required intravenous administration of sympathomimetic amines, in addition to standard heart failure treatment procedures. Cumulative survival at six months of patients observed between 1990-1992 (group A) was compared with the survival rate of patients observed from 1993 to 1995 (group B). RESULTS: Clinical and haemodynamic parameters were similar in groups A and B, but ACE-inhibitors were used more frequently in group B (75 vs 31% respectively, p < 0.05). During the follow-up period, heart transplantation was indicated in a similar percentage of patients (A 53% vs B 58%). However, mortality on the waiting list (58% group A vs 21% group B; p < 0.05) and the percentage of patients who underwent heart transplantation (41% group A vs 78% group B; p < 0.05) differed. Moreover, all patients in group A and 50% of group B were operated on as "status one" patients. The total six-month mortality rate decreased from 69% before 1992 to 48% thereafter (p < 0.05). CONCLUSION: The short-term prognosis of patients with refractory heart failure improved over time. In the latter period, ACE-inhibitors were used more frequently and the number of heart transplantations was greater. Nevertheless, our results do not allow us to identify the causes of the improved survival rate.
Adult↗
[Antihypertensive therapy: why and how?].
Many clinical trials have shown that lowering increased blood pressure by an antihypertensive agent reduces the risk of morbidity and mortality due to hypertension. Despite these beneficial effects, several questions remain largely unanswered, particularly with respect to the degree of cardiovascular protection conferred by the antihypertensive complications. This article addresses some of these questions by reviewing the recommended means of lowering the blood pressure in hypertensive patients. The clinical value of effective blood pressure control throughout the 24 hour period is discussed together with the therapeutic strategies available to obtain this objective.
Antihypertensive Agents↗
Pilot study on the safety and efficacy of intravenous natural beta-interferon therapy in patients with chronic hepatitis C unresponsive to alpha-interferon.
BACKGROUND: Since a large fraction of patients affected by chronic hepatitis C do not respond to alpha-interferon therapy, we planned a pilot study of intravenous beta-interferon therapy in Italian patients non responsive to several courses of alpha-interferon. METHODS: Ten Italian patients with chronic hepatitis C were treated intravenously with beta-interferon to assess the biochemical and virological responses. Each patient received intravenously 6 MU of beta-interferon daily for 7 days a week for a period of 2 months; in responders, this treatment was followed by intramuscular beta-interferon administration 6 MU three times a week for an additional 8 weeks. RESULTS: All the patients were infected by the genotype 1b of hepatitis C virus and had a high serum concentration of HCV-RNA (4.1 +/- 3.3 x 10(7) copies/ml). During intravenous therapy, 4 patients (40%) showed a complete return to normal of alanino-aminotransferase and 3 cases became HCV-RNA negative. During intramuscular beta-interferon administration, two patients breakthrough. At the end of the follow-up (six months after the end of the treatment) two patients only showed return to normal of alanino-aminotransferase, but one of them remained HCV-RNA positive. CONCLUSIONS: These results indicate that even genotype 1b of hepatitis C virus can be suppressed by intravenous beta-interferon therapy, as previously described in similar cases in Japan. The rate of sustained biochemical and virologic response was, however, low, suggesting that further studies are needed to define the best regimen to achieve eradication of hepatitis C virus infection.
Adult↗
[Surgical treatment of Basedow's disease: total thyroidectomy].
The Authors report their experience in the treatment of Graves disease. After a short review of the literature, the Authors stress the medical trait of such disease with possible spontaneous resolution. Therefore the number of cases surgically treated is necessarily low. Thirty patients, all with specific antibodies, were treated with total thyroidectomy. The therapy chosen and the results obtained are herein shown. No definitive hypoparathyroidism and inferior laryngeal nerve injuries were registered.
Graves Disease↗
Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia.
Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 +/- 16.9 mg/dl, mean +/- S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAC) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 +/- 0.9 vs 1.6 +/- 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, p < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant both after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration.
Anticholesteremic Agents↗
Functional reconstitution of oxidase activity in X-linked chronic granulomatous disease by retrovirus-mediated gene transfer.
The feasibility of correction of the disease phenotype by gene gene transfer was investigated in cells of four patients with X-linked chronic granulomatous disease. These patients carry point mutations of the gp91-phox gene, encoding for the large subunit of the catalytic core of the phagocytic cell NADPH oxidase. A retroviral vector expressing the gp91-phox protein was constructed and used to transduce lymphoblastoid cell lines established from the patients. Several transduced lymphoblastoid cell clones were investigated for mRNA and protein expression, and for functional reconstitution of oxidase activity. Although extensive quantitative variability was detected among different clones, functional reconstitution of O2- production was obtained in most cases, with oxidase function within the same range as in B cell lines derived from normal individuals. The same vector was also used for transduction of hematopoietic precursors from bone marrow or peripheral blood either with or without enrichment for CD34+ cells. A comprehensive analysis was performed on differentiated myeloid colonies, to evaluate the efficiency of transduction, the levels of gp91-phox expression, and the extent of functional reconstitution of oxidase activity. A high efficiency of transduction was obtained in most experiments, with 60-100% of colonies containing proviral DNA. Among the transduced colonies, an extensive variability in the levels of expression of the transduced gene and of functional restoration of NADPH oxidase activity was observed. These results represent a step toward the development of a gene therapy protocol for these patients.
3T3 Cells↗
Benefit versus risk of calcium antagonists in hypertensive patients with concomitant risk factors.
BLOOD PRESSURE REDUCTION AND CARDIOVASCULAR MORBIDITY AND MORTALITY: Several hypertension trials have shown that antihypertensive treatment can reduce the cardiovascular morbidity and mortality accompanying this condition. They have also shown, however, that the reduction does not entirely normalize the risk of hypertensive patients. STRATEGIES TO IMPROVE THE BENEFIT OF ANTIHYPERTENSIVE TREATMENT: Although some of the risk of the hypertensive patient may prove to be irreversible, pathophysiological and clinical evidence obtained in recent years suggests that some modifications to antihypertensive treatment strategies might increase the benefit. For example, greater use of drugs such as calcium antagonists and angiotensin converting enzyme (ACE) inhibitors as first-line agents might bring greater benefits, because some properties of these drugs which are additive to their blood pressure lowering effects, such as regression of cardiovascular structural changes, nephroprotection and delay of atherogenesis, may provide a degree of protection against target-organ damage. ONGOING CLINICAL TRIALS AND THE INTERNATIONAL NIFEDIPINE (GITS) GASTROINTESTINAL SYSTEM STUDY OF INTERVENTION AS A GOAL IN HYPERTENSIVE TREATMENT (INSIGHT): Several ongoing clinical trials are aimed at comparing the effects of calcium antagonists and ACE inhibitors versus beta-blockers and diuretics on cardiovascular morbidity and mortality. INSIGHT is particularly interesting because the effects of nifedipine GITS and a combined thiazide and potassium-sparing diuretic on cardiovascular morbidity and fatal events are being compared in patients with hypertension plus one or more additional risk factors, such as hypercholesterolemia, smoking, diabetes, left ventricular hypertrophy, etc. INSIGHT is therefore the first trial to address, in a prospective fashion, the prognostic influence of antihypertensive treatment in hypertensives with concomitant risk factors.
Calcium Channel Blockers↗
Evaluating sympathetic and haemodynamic responses to mental stressors: hankering or achievement?
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Behavior↗
Bombesin enhances monocyte and macrophage activities: possible role in the modulation of local pulmonary defenses in chronic bronchitis.
Increased lung levels of bombesin-related peptides (BRPs) have been described in smokers and in patients with chronic obstructive pulmonary diseases (COPDs). Moreover, previous studies have shown that BRPs are endowed with immunoregulatory activities. The aim of the present study was to assess the in vitro influence of synthetic bombesin on the activity of mononuclear phagocytes obtained from healthy donors and from COPD patients. Bombesin significantly enhanced in vitro phagocytosis of monocytes and alveolar macrophages in both groups of subjects, restoring deficient phagocytosis in a group of COPD patients. Moreover, bombesin stimulated superoxide anion production and interleukin-8 release by peripheral monocytes.
Aged↗