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Biomedical subjects

N Ferrara

Publications and source records attributed to N Ferrara.

At least 235 records · Page 13Linked to original sources
PubMed1978

[Efficacy and tolerability of a cardioselective beta-blocking drug (atenolol) in the treatment of essential hypertension. A double blind study (author's transl)].

The antihypertensive effect of atenolol, a new beta 1 receptor blocking agent, was studied in a double blind non cross-over trial in 40 patients (pts) affected by mild to moderately severe essential hypertension with normal plasma renin activity. After a run-in period (15 days) of placebo treatment pts were assigned to two groups. The first (group A) continued placebo treatment for 30 days, the second (Group B) were given atenolol (ICI 66082) 100 mg daily for 30 days also. Atenolol significantly reduced systolic and diastolic blood pressure in recumbent and standing position and heart rate at rest. No significantly changes of the same parameters were observed in group A. Body weight and plasma renin activity was unchanged in both groups. Atenolol treatment never was discharged in order to side effects. These results seem to suggest that atenolol can be an useful drug in the treatment of systemic blood hypertension.

Adult↗
PubMedDate not supplied

Efficacy and pharmacokinetics of gallopamil in patients with coronary artery disease.

We prospectively studied 10 patients with stable exertional ischaemia, selected from a larger group of patients referred for suspected coronary artery disease or to detect residual ischaemia after myocardial infarction, to evaluate pharmacokinetic changes during chronic treatment with gallopamil and its correlation with clinical efficacy in patients with coronary artery disease. Our study consisted of a 1-week run-in single-blind placebo treatment and a 4-week single-blind gallopamil treatment. At the end of the run-in period patients underwent two different exercise tests, the first 2 hours and the second 7 hours after placebo administration. During active treatment all patients underwent two different exercise tests, the first 2 hours and the second 7 hours after gallopamil (50 mg) administration on the 1st and 28th days of gallopamil therapy. On the same days in eight of the patients we evaluated gallopamil pharmacokinetic changes. Our data revealed a rapid increase of unchanged gallopamil and its metabolite (norgallopamil) in the plasma, and a peak concentration of these substances about 2 hour after oral administration on both the 1st and 28th day of observation. Moreover, our results demonstrated an increase between the first and 28th day of treatment in peak concentration of unchanged gallopamil in the plasma, and of AUC 0-infinity and AUC o-c values during chronic treatment with gallopamil. Our clinical data showed an improvement in exercise results during gallopamil therapy related to increased concentration of the drug.

Aged↗
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Orthostatic hypotension due to autonomic dysfunction--different therapeutic effects of propranolol.

In two patients with orthostatic hypotension, due to autonomic dysfunction, hemodynamic changes induced by the assumption of erect position have been evaluated before and during chronic propranolol treatment. Under control conditions, the change in posture induced in Patient 1 a fall in systolic and diastolic blood pressure by 51.4 and 30.7%, respectively. Cardiac output was reduced by 26.8% and systemic vascular resistance by 23.3%. During propranolol treatment, systolic pressure decreased only by 28% and diastolic pressure by 7.7%. The decline in systemic vascular resistance on standing was abolished, while the reduction in cardiac output remained unmodified. In Patient 2, symptoms of orthostatic hypotension were related to marked decrease in systolic blood pressure, the diastolic pressure remaining unchanged. Moreover, systemic vascular resistance increased and, thus, orthostatic hypotension was exclusively dependent upon the severe fall in cardiac output on standing. As a consequence, propranolol failed to control orthostatic hypotension in this patient. These data suggest that when orthostatic hypotension is secondary to failure in peripheral vasoconstriction, propranolol may act beneficially. When it is secondary to a fall in cardiac output, beta-blockade is ineffective.

Aged↗
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Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.

Aging↗
PubMedDate not supplied

Congestive heart failure in the elderly.

Several aspects of congestive heart failure are discussed in the light of international literature and of recent findings of our group. The annual incidence of heart failure in elderly subjects, aged >or=75y, is 13 to 50/1000, while it is 1.6/1000 in people aged 45-54 y. The prevalence of heart failure is about 3% in subjects aged 45-64% in subjects aged more than 65 y and 10% in subjects aged more than 75 y. These data are confirmed by our population based study in elderly subjects. The etiology of congestive heart failure is similar in elderly and middle-aged patients. However, several anatomo-functional, hormonal and autonomic nervous system changes, typical of congestive heart failure, occur during physiologic ageing processes also. These findings may explain the dramatic evolution of congestive heart failure in elderly patients. Moreover, some features of the elderly - e.g. comorbidity, atypical clinical presentations, loss of autonomy, increased iatrogen risk should be considered. No specific drugs exist for the pharmacologic treatment of heart failure in the elderly, so that the geriatric specificity in the treatment of heart failure can be recognized in the art of drug choice and dosage, to obtain the best results with the least side effects. The multiple etiology of congestive heart failure, the comorbidity, the loss of autonomy and the deterioration of cognitive functions suggest the need for multidimensional approach and continuative intervention in elderly patients with heart disease, and in particular with congestive heart failure. Further studies on disease- and age-related changes are necessary to develop new and more potent strategies to secure 'successful ageing'.

Journal Article↗
PubMedDate not supplied

Evaluation of the efficacy of slow-release nifedipine in systemic hypertension by ambulatory intraarterial blood pressure monitoring.

We assessed the effect on blood pressure of administration of slow-release nifedipine tablets (20 mg) by continuous intraarterial blood pressure monitoring (Oxford system) in 10 patients with untreated essential hypertension. Blood pressure was recorded under control conditions and during nifedipine therapy. During each monitoring period patients were instructed to perform various types of exercise. The initial dose of nifedipine was 20 mg twice a day (8:00 a.m. and 8:00 p.m.). For patients in whom arterial pressure control was not achieved, the dose of the drug was increased at weekly intervals, first to 40 mg in the morning and 20 mg at night and then to 40 mg twice a day. The average daily dose was 52 mg. Nifedipine twice a day significantly reduced systolic and diastolic blood pressures both during the day and during the night. The rise in blood pressure due to dynamic or isometric exercise or to mental testing was blunted. Heart rate did not change. Orthostatic hypotension was not observed, and there were only minor side effects, which did not require withdrawal of the patient from the trial. Bioavailability of nifedipine from this preparation was satisfactory, as shown by plasma concentrations which remained constantly in the therapeutic range. Thus, slow-release nifedipine given twice a day represents an effective treatment in patients with essential arterial hypertension. The reduced frequency of administration required may improve patient compliance with this treatment.

Adult↗
PubMedDate not supplied

Direct coronary vasodilator effects of intracoronary histamine administration in humans.

Histamine is widely present in human tissues and can be released by immunologic and nonimmunologic reactions. Although several direct cardiovascular effects of histamine have been demonstrated in humans, little is known about the direct effects of histamine on the human coronary circulation in vivo. Therefore, we investigated the changes in coronary hemodynamics induced by bolus intracoronary administration of 4 micrograms of histamine to 11 patients with angiographically normal coronary arteries under continuous monitoring of R-R interval from the electrocardiogram, arterial pressure (AP), and coronary sinus blood flow (CBF), measured by thermodilution. Immediately after the end of the intracoronary histamine bolus, with R-R interval and AP unchanged, CBF increased from 144 +/- 20 to 238 +/- 27 ml/min (p less than 0.01) and coronary vascular resistance decreased from 0.7 +/- 0.16 to 0.42 +/- 0.1 mm Hg/ml/min (p less than 0.01). No change in coronary hemodynamics was observed after bolus intracoronary administration of physiologic saline. The effects of histamine on systemic hemodynamics consisted of a transient fall in AP and R-R interval, starting after the onset of changes in coronary hemodynamics. These data show that histamine possesses a direct coronary vasodilator effect in humans, independent of the determinants of myocardial oxygen consumption.

Adult↗
PubMedDate not supplied

Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans.

The development of a neovascular supply (angiogenesis) is a major aspect of tumorigenesis. Recent work has indicated that vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis. In vitro and in vivo studies have demonstrated that an anti-VEGF antibody is capable of suppressing the growth of human tumor cell lines. The following study was conducted in tumor-bearing nude mice to evaluate the concentration-response relationship of murine anti-VEGF monoclonal antibody (muMAb VEGF) so that an efficacious plasma concentration of the recombinant humanized form (rhuMAb VEGF) in cancer patients could be estimated. (This study was included in our Investigational New Drug application to support the clinical dosing regimen and projected human safety factors for the toxicology program.) Additionally, the growth dynamics of the tumors were evaluated as a function of dose to explore whether a mechanismic interpretation of tumor growth inhibition by muMAb VEGF is possible. On day 1, A673 human rhabdomyosarcoma cells (2 x 10(6) cells/mouse) were injected subcutaneously in 188 beige nude mice (16-24 g). Treatment with muMAb VEGF (0.05-5.0 mg/kg; n = 24/group), phosphate-buffered saline (n = 10), or anti-gp120 isotype-matched control antibody (5.0 mg/kg; n = 10) began 24 hr later. Each animal received intraperitoneal injections of test material twice weekly for 4 wk. Immediately prior to each dose, 2 mice from each muMAb VEGF group were selected randomly, and plasma was collected for pharmacokinetic evaluation; at the end of the study, samples were collected from all animals for pharmacokinetic evaluation. Tumor dimensions were recorded weekly, and at the end of the study, tumor weight and dimensions were recorded. Satisfactory tumor suppression in nude mice was achieved at muMAb VEGF doses of > or =2.5 mg/kg, where the average trough muMAb VEGF plasma concentration was 30 microg/ml (concentrations in individual animals >10 microg/ml). Assuming the pharmacokinetics of rhuMAb VEGF in patients will resemble the pharmacokinetics of a similar humanized anticancer monoclonal antibodies, a clinical dosing regimen was designed to maintain the rhuMAb VEGF plasma concentration in this efficacious range. This study shows an approach that can be used to estimate a human dosing regimen from preclinical pharmacokinetic/pharmacodynamic data. Because we have just initiated clinical trials with rhuMAb VEGF we cannot judge clinical outcome in relation to these preclinical predictions; nonetheless, it is hoped that by sharing our approach and thought processes with other investigators we can assist the discovery and development of anticancer therapeutics.

Animals↗
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Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration.

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.

Animals↗
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Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin.

In the present study, we evaluated the effects of a neutralizing anti-Vascular Endothelial Growth Factor (VEGF) mAb, A4.6.1(200 micrograms twice weekly, i.p.), on angiogenesis and growth of tumor spheroids of human breast cancer cell lines (MCF-7, ZR-75 and, SK-BR-3) in nude mice. Furthermore, we investigated if in the presence of effective VEGF blockade, a conventional chemotherapeutic drug (doxorubicin, (5 mg/kg, weekly) could be effective, and if so would there be an additive effect of the combination regimen. Tumor Spheroids were implanted in dorsal skinfold chambers in nude mice. Tumor cells were pre-labeled with a fluorescent vital dye (CMTMR), which allowed the estimation of growth of implanted tumor spheroids. FITC (fluorescein isothiocyanate)-Dextran was used to evaluate formation of neo-vasculature at the tumor site. In control animals all three cell-lines produced extensive neovasculature and there was significant tumor growth throughout the observation period. Treatment with the anti-VEGF mAb caused significant suppression of angiogenic activity for all cell lines, stressing the critical role VEGF plays in breast tumor angiogenesis. Doxorubicin alone reduced the growth rate of MCF-7 cells, but did not significantly affect angiogenesis. Doxorubicin in combination with A4.6.1 resulted in significant tumors regression. Histology indicated that some chambers lacked viable tumor cells at the end of the two week observation period, lending strong support that neutralization of VEGF in combination with conventional cytotoxic agents could be a new innovative treatment regimen for metastatic breast cancer.

Animals↗
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Atypical fibroxanthoma with osteoclast-like multinucleated giant cells.

Atypical fibroxanthoma (AF) is generally considered as a low grade superficial variant of fibrohistiocytic neoplasm. In this report we present an unusual variant of this neoplasm arising from actinic damaged skin of an elderly individual. The case was characterized by numerous multinucleated osteoclast-like giant cells uniformly scattered through a pleomorfic cellular proliferation. The osteoclasts giant cell observed represent multinucleated histiocytes rather than true osteoclasts.

Actins↗
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Neuroendocrine differentiation in non-small cell lung carcinomas.

The immunohistochemical expression of ten neuroendocrine and neural differentiation-related antigens in 200 specimens from patients with surgically resected non-small cell lung carcinomas were evaluated. Poorly differentiated adenocarcinomas and undifferentiated large cell carcinomas showed the highest percentage of positive samples (30%-60%) for the markers evaluated with diffuse and intense immunostaining. Poorly differentiated squamous carcinomas bronchioalveolar adenocarcinomas, and giant cell carcinomas showed a lower percentage of positive samples (20%) with moderate immunostaining. Well differentiated tumors were very rarely positive for the neuroendocrine markers. It is concluded that neoplasms positive for the neuroendocrine markers can be considered as non-small cell carcinoma with neuroendocrine features, even if they do not have the histological appearance of neuroendocrine lung neoplasms.

Adrenocorticotropic Hormone↗