M. Guerrini

Placebo Controlled Double Blind Study with Pentoxifylline of Walking Performance in Patients with Intermittent Claudication

A double blind placebo-controlled randomised crossover study was performed with Pentoxifylline (Trental 400 tablets with 400 mg active ingredient) in 24 patients (19 males, 5 females, aged between 40 and 71 years) suffering from peripheral occlusive arteriopathy of stage II severity (Fontaines classification). In 12 patients (group I) the treatment was started with placebo, and in another 12 subjects with Pentoxifylline (group II). The dosage was 3 tablets of either formulation t.d.s., the treatment periods were 8 weeks each with a two week washout between. The standardised walking test (120 steps/min under metronome control) was used for the assessment of the walking capacity. There was a significant 60% increase in pain-free walking distance in either Pentoxifylline treatment periods, whereas there were no clinically relevant changes in the placebo periods. When comparing the two starting periods only, there was an increase in the Pentoxifylline group from 223 to 359 m on average and in the placebo group from 208 to 215 m, patients in both groups being comparable at basal level as to the distribution of sex, age, location of occlusion, duration of disease as well as in respect to the walking capacity. No adverse reactions were recorded during the trial.

Studies of the Clinical Pharmacology and Therapeutic Efficacy of Pentoxifylline in Peripheral Obstructive Arterial Disease

Studies were carried out to investigate the effects of pentoxifylline on various hemorheological (whole blood, plasma and serum viscosity, erythrocyte filtrability, hematocrit), hemostasiological (blood coagulation and fibrinolysis: euglobulin lysis time, fibrinogen, plasminogen, alpha-2-macroglobulin, alpha-1-antitrypsin, antiplasmin; platelet function: β-thromboglobulin), and hemodynamic factors (limb perfusion: rest and peak flow, time to peak flow; systemic blood pressure, heart rate). In addition, clinical efficacy was monitored in claudicants by assessing walking capacity under placebo controlled double blind cross over conditions. The investigations disclosed the positive influence of acute and chronic pentoxifylline administration on hemorheological, hemostasiological and perfusion parameters, most of the changes recorded being statistically significant. The clinical benefit of pentoxifylline (Trental 400) treatment was demonstrated by the significantly superior increase in walking capacity in comparison to placebo in the controlled study.

Pulmonary embolism in the elderly: clinical, instrumental and laboratory aspects.

Objective: To focus on diagnostic and therapeutic problems of pulmonary embolism in the elderly. Methods: Retrospective analysis of 5 years of clinical, instrumental, and laboratory data (collected at the time of hospital admission) for patients 65 years and older with pulmonary embolism proven by a high-probability scintigraphic lung scan or necropsy. Sixty-eight patients, 46 females and 22 males, 78.61 ± (SD) 7.71 years old, were enrolled in the study. Results: Dyspnea, chest pain, tachycardia, and tachypnea were the most common symptoms and signs; they were present alone or in combination in all patients. Bed rest over 4 days was found in 65% of the patients and deep vein thrombosis in the leg in 35%. Only 7 patients were on anticoagulant therapy which was likely to reduce the incidence of pulmonary embolism. The mortality was 29.5%. Major bleeding due to anticoagulant therapy was observed in 4.4% of the patients; 1 case was fatal. Sinus tachycardia, ST segment and T wave abnormalities in anterior leads, and incomplete bundle branch block were the most frequent electrocardiographic findings. Chest X-ray was normal in 19.5% of the patients and compatible with pulmonary embolism in 10%. A transthoracic two-dimensional echocardiogram was abnormal in 74% of the cases, with involvement of the right ventricle in the majority of them. Many patients had laboratory parameters within the normal range. The value of the latex agglutination D-dimer assay was less than the cutoff value of 500 µg/l in 16% of the patients. Hypoxemia and a high alveolar-arterial oxygen gradient were the most frequent aspects of the arterial blood gas analysis. Respiratory alkalosis was observed in only one third of the patients. Conclusions: Pulmonary embolism is often underdiagnosed in the elderly. Clinical, instrumental, and laboratory findings are nonspecific. Only acute suspicion can increase the number of diagnoses, reduce the time to diagnosis, and improve the prognosis.

Strain Gauge Plethysmography in the Study of Circulation of the Limbs

Plethysmography means registration of spontaneous or provoked volume changes in a segment of the body, with which it is possible to obtain information on the circulation of blood in that segment. This method has been known for a long time and has been applied by physiologists to several circulatory problems. However, the first plethysmographic instruments, water plethysmographs, presented such difficult technical problems that their use was restricted to sophisticated research in animals and only rarely in man. The water-filled plethysmograph was then replaced by the air-filled types, but these instruments also had grave technical problems. The principle of the so-called impedance plethysmography or rheography is based on electric impedance changes when a high-frequency and low-power alternating electric current passes through the body segment under investigation. This method, developed in the 1950s and designed to detect pulse waves in the limb, does not really reflect volume changes, but changes in the electrolyte content of the segment; so it cannot be compared with methods developed to measure blood flow.

Primary and Secondary Blood Hyperviscosity Syndromes, and Syndromes Associated with Blood Hyperviscosity

SummaryDespite the methodological difficulties of evaluating the role of a single rheological component, some clinical situations characterised by an increase of blood viscosity can be identified. These are classified as ‘blood hyperviscosity syndromes’ and can be divided into 2 groups. The first includes pathophysiological conditions in which a primary blood abnormality causes a decrease of blood flow, as occurs in polycythaemic, sclerocythaemic and seric hyperviscosity syndromes, and may be referred to as ‘primary blood hyperviscosity syndromes’.The second group includes pathological conditions in which a primary reduction of blood supply to tissue provokes tissue ischaemia, and an impairment of rheological properties of blood can be observed at microcirculatory level. Thus, these situations have been described as ‘secondary blood hyperviscosity syndromes’. Patients with peripheral obliterative arterial disease, ischaemic cardiopathies and cerebrovascular insufficiencies show a diminution in blood fluidity during spontaneous or provoked ischaemic conditions which disappears after reperfusion of the tissue. The pathogenesis of this rheological damage is unclear, but may arise from the complex relationship among blood cells (red cells, leucocytes, platelets), endothelium and plasma components.In addition to these 2 groups of blood hyperviscosity syndromes, several pathological states such as diabetes, shock, surgery, and rheumatic disease have been described in which an increase of blood viscosity can be observed. For these situations, which require much further investigation, the term ‘syndromes associated with blood hyperviscosity’ could be proposed.RésuméIl existe des difficultés méthodologiques lors de l’évaluation du rôle d’un composant rhéologique isolé, mais on peut cependant identifier certaines situations cliniques caractérisées par une augmentation de la viscosité sanguine. Ces manifestations sont classées parmi les «syndromes d’hyperviscosité sanguine» et peuvent être séparées en deux groupes. Le premier comprend les atteintes physiopathologiques où une anomalie sanguine primitive est responsable d’une réduction du débit sanguin, comme dans le cas de la polycythémie, la sclérocythémie et les syndromes d’hyperviscosité sérique. Ces troubles peuvent être désignés sous l’expression «syndromes primitifs d’hyperviscosité sanguine». Le second groupe d’affections comprend les situations pathologiques où une diminution primitive de l’irrigation tissulaire provoque une ischémie et une altération des propriétés rhéologiques sanguines peut être observée au niveau de la microcirculation. On a donc qualifié ces états de «syndromes secondaires d’hyperviscosité sanguine». Les malades atteints d’artériopathies oblitérantes périphériques, de cardiopathies ischémiques et d’insuffisance vasculaire cérébrale présentent une diminution de la fluidité sanguine au cours de situations ischémiques spontanées ou provoquées. Le trouble disparaît avec la reperfusion des tissus. La pathogénèse de ces altérations rhéologiques est mal connue, mais peut être liée aux relations complexes qui s’établissent entre les cellules sanguines (érythrocytes, leucocytes, plaquettes), l’endothélium et les composants plasmatiques.Outre ces deux groupes de syndromes d’hyperviscosité sanguine, on a décrit plusieurs états pathologiques où une augmentation de la viscosité sanguine peut être observée (diabète, choc, intervention chirurgicale et affection rhumatologique). On pourrait proposer le terme de «syndromes associés à une hyperviscosité sanguine» pour qualifier ces états, qui nécessitent de nombreuses études complémentaires.RiassuntoMalgrado le difficoltà metodologiche di valutazione del ruolo di un singolo componente reologico, si possono identificare alcune situazioni cliniche caratterizzate da un incremento délia viscosità del sangue. Queste, classificate corne «sindromi da iperviscosità ematica» possono essere divise in due gruppi. Il primo comprende condizioni fisiopatologiche nelle quali una anormalità primaria ematica causa una diminuzione del flusso sanguigno quale si verifica nella policitemia, nella sclerocitanemia e iperviscosità serica e può essere definito «delle sindromi di iperviscosità ematica primaria». Il secondo gruppo comprende condizioni patologiche nelle quali una riduzione primaria deïïafflusso di sangue al tessuto provoca ischemia tissutale e deterioramento délie proprietà reologiche del sangue che può essere rilevato a livello circolatorio. Quindi queste situazioni sono state descritte come «sindromi di iperviscosità ematica secondaria». Pazienti con occlusióne arteriosa periferica, con cardiopatia ischemica e insufficienza cardiovascolare mostrano una diminuzione nella fluidità sanguigna durante condizioni di ischemia spontanea o provocata che scompaiono alla riperfusione del tessuto. La patogenesi di questo danno reologico è oscura, ma può derivare da una complessa relazione tra le cellule del sangue (globuli rossi, leucociti, piastrine), endotelio e componenti del plasma sanguigno.Oltre a questi due gruppi di sindromi di iperviscosità ematica, sono stati descritti stati patologici come diabete, shock, interventi chirurgici, malattie reumatiche nei quali è possibile osservare un incremento délia viscosità ematica. Per queste situazioni patologiche, che richiedono ulteriori studi, si propone il termine di «sindromi associate con iperviscosità ematica’.SamenvattingOndanks de methodologische moeilijkheden die bij de beoordeling van de roi van een geïsoleerde reologische component optreden, kan men bepaalde klinische aandoeningen identificeren die door een toename van de bloedviscositeit gekenmerkt worden. Die “hyperviscositeitssyndromen” kunnen in twee groepen onderverdeeld worden. De eerste groep omvat de pathofysiologische aandoeningen, waarbij een primaire bloedabnormaliteit een vermindering van de bloedtoevoer veroorzaakt, wat bijvoorbeeld het geval is bij polycythemische, sclerocythemische en sereuze hyperviscositeitssyndromen. Aan deze groep kunnen we met de benaming ‘primaire bloedhyperviscositeitssyndromen’ refereren.In de tweede groep brengen we die pathologische aandoeningen onder die gekenmerkt worden door weefselischemie als gevolg van de primaire vermindering van de bloedtoevoer naar de weefsels. Daarnaast is ook een verslechtering van de reologische eigenschappen van het bloed op microcirculatieniveau waarneembaar. Naar deze verschijnselen wordt verwezen met de term ‘secundaire bloedhyperviscositeitssyndromen’. Typisch voor patiënten met een perifere arteriële aandoening van oblitererende aard, ischemische hartziekten of cerebrovasculaire insufficiënties is dat de vloeibaarheid van het bloed onder spontaan optredende of uitgelokte ischemische condities afneemt. Na reperfusie van het weefsel verdwijnt die toestand. De pathogenese van deze reologische beschadiging is onduidelijk, maar zou kunnen voortvloeien uit de complexe wisselwerking tussen de bloedcellen (rode bloedlichaampjes, leukocyten en bloedplaatjes), het endotheel en de plasmacomponenten.Naast deze twee groepen van bloedhyperviscositeitssyndromen zijn er ook verscheidene andere pathologische toestanden beschreven, waarbij een toename van de bloedviscositeit optreedt: diabetes, shock, heelkundige ingrepen, reumatiek... Voor deze Varianten, die nog veel studie vergen, zou de benaming ‘met bloedhyperviscositeit gepaard gaande syndromen’ kunnen worden voorgesteld.

Action of Cinnarizine on the Hyperviscosity of Blood in Patients with Peripheral Obliterative Arterial Disease

Cinnarizine, a drug capable of improving blood flow, was studied for its action on blood viscosity and its main components in patients affected by peripheral obliterative arterial diseases (POAD). Both acute and chronic ad ministration of the drug diminished the increased whole-blood viscosity in patients, without affecting plasma and serum viscosity, hematocrit, plasma fibrinogen concentration, and plasma osmolality. Since cinnarizine also led to a significant increase of peripheral muscular blood flow, it was hypothesized that this action may be due to an increased deformability of the red cells, and may play a considerable role in the therapeutic approach to POAD.

Length of hospitalization in elderly patients with community-acquired pneumonia

Community-acquired pneumonia (CAP) is a serious social and medical problem in the elderly. Mortality, hospitalization and length of stay increase with age. The aim of this study was to determine the risk factors associated with prolonged hospital stay in elderly patients with CAP. Clinical and laboratory data were collected for 115 community-living patients, 65 years old and over, admitted to the geriatric ward of a University Hospital from 1995 to 1998 because of symptoms and signs of pneumonia confirmed by a pulmonary infiltrate on chest x-ray. We divided the patients into two groups, with length of stay more than 13 days (70 patients, cases), and length of stay less than 13 days (45 patients, controls) according to Diagnosis Related Groups criteria for complicated and uncomplicated pneumonia, respectively. A prolonged hospital stay was associated with a higher fever peak and a higher number of days with fever (p<0.005), greater comorbidity (p<0.001), urinary catheterization and secondary urinary infections (p<0.001), higher erythrocyte sedimentation rate (p<0.001), dehydration (p<0.005), and caloric-proteic malnutrition (p=0.01). In conclusion, knowledge of the risk factors for prolonged hospital stay in elderly patients with CAP may be used to identify high-risk patients, prevent the risks with prophylactic measures, and contain the costs of hospitalization.

Effect on rheological and some peripheral haemodynamic parameters of defibrotide in POAD patients

Received 1.12.1986; Accepted 19.1.1987 by Editor T. DiPerri) In ten POAD patients, 800 mg. of Defibrotide (polideoxynucleotide extracted from mammalian lung, with antitrombotic and fibrinolytic activity) were infused i.v. Blood and plasma viscosity, haematocrit, blood filterability and fibrinogen concentration were controlled, in basal conditions and after one hour from the end of infusion. Haemodynamic parameters: rest flow, peak flow, time to peak flow, half time and total time of reactive hyperemia by means of strain gauge pletismography, were controlled at lower limbs before infusion and after 1 h., 2 h., 6 h., from the end of infusion. The present investigation showed an improvement of rheological parameters and a decrease of total time and half time of reactive hyperemia. These data demonstrate a rheological activity of Defibrotide as well as the fibrinolytic one.

Influence of Non-Selective and Selective Beta Adrenoceptor Blockade on Isoxsuprine-Dependent Hemodynamic and Rheologic Changes

The infusion of isoxsuprine was followed by an increase of heart rate and calf blood flow and by a decrease of arterial diastolic pressure and blood viscosity both in normal controls and patients with peripheral obstructive arterial disease. The pre-treatment with a non-selective beta adrenoceptor blocker (propranolol) canceled all the isoxsuprine-dependent changes, while the pre-treatment with a selective beta adrenoceptor blocker (metoprolol) abolished only tachycardia and did not influence the increase of calf blood flow and the decrease of blood viscosity. These findings indicate the different role of vascular beta receptors in the regulation of muscular blood flow and suggest the pharmacologic possibility to unmask the beta2-dependent vaso dilation.

Action of pentoxifylline on cytosolic calcium and on the erythrocytic morphology during ageing

Cytosolic calcium is an important parameter of cell functionality and its concentration is determined by homeostatic mechanisms which are ATP dependent. When an energetic depletion occurs, as in the case of ischaemia, uncontrolled accumulation of ion in the cytosol, with a reduction of membrane deformability, and the modification of the physiologic shape of erythrocyte can be noted. Pentoxifylline has a rheological effect acting on energetic metabolism of red cells. Our objective was to verifY the action of pentoxifylline on calcium concentration and on the erythrocytic morphology of cell ageing. We used as ageing model the conservation of blood in vitro: 3 blood samples (from 6 taken by 8 normal subjects), have been incubated with pentoxifylline (1.4XIO-4M). We dosed cytosolic calcium and evaluated cell morphology in 2 samples (with and without pentoxifylline) in basal conditions, after 4 and after 8 hours of conservation at 37°C. Dosage of intraerythrocytic calcium was made with FURA2-AM (Calbiochem) according to the David-Dufilho method. Erythrocytic morphology was evaluated with an optical microscope following the Zipursky method. Results showed a reduction of the increase of cytosolic calcium and a major conservation of the erythrocytic physiologic morphology in samples incubated with pentoxifylline after 4 and 8 hours in comparison with control samples. These observations confirm that pentoxifylline delays uncontrolled accumulation of calcium which, in ageing, causes cell suffering and keeps its morphologic physiology for a longer time.