Calcium Entry Blockers and Tissue Protection

Buflomedil hydrochloride is a vasoactive drug with a variety of pharmacodynamic properties. Importantly, it seems to improve nutritional blood flow in ischaemic tissue of patients with peripheral and/or cerebral vascular disease by a combination of pharmacological effects: inhibition of alpha-adrenoceptors, inhibition of platelet aggregation, improved erythrocyte deformability, nonspecific and weak calcium antagonistic effects, and oxygen sparing activity. Therapeutic trials with buflomedil in patients with peripheral vascular diseases have shown that it increases walking distances in those with intermittent claudication and heals trophic lesions and reduces rest pain in many patients with more severe vasculopathies. In open clinical trials a good to very good clinical response was achieved in 57 to 87% of those treated. In comparative studies buflomedil 600 mg/day orally was shown to be significantly superior to placebo and comparable in efficacy to pentoxifylline (oxpentifylline) and naftidrofuryl. In patients with symptoms presumed to be due to cerebrovascular insufficiencies and elderly patients with senile dementia, buflomedil 450 to 600 mg/day alleviated symptoms associated with impairment of cognitive and psychometric function and was significantly superior to placebo and slightly more effective than drugs such as cinnarizine, flunarizine and co-dergocrine mesylate. Overall, buflomedil at dosages of up to 600 mg/day has been very well tolerated and discontinuation of therapy has rarely been necessary. Thus, buflomedil would seem to be a useful adjunct to conservative treatment in patients with mild-to-moderate peripheral vascular disease and/or cerebrovascular insufficiency, and well worth a try in patients with more severe peripheral disease unable to undergo surgery. However, a few well-designed long term studies are needed to fully define its overall place in therapy.

Buflomedil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in peripheral and cerebral vascular diseases.

Assessment of intermittent claudication by quantitation of exercise-induced microalbuminuria.

The hypothesis that intermittent claudication initiates a systemic inflammatory response was investigated by studying the effect of exercise on markers of neutrophil activation and vascular permeability in 25 claudicants and 10 controls. Urinary albumin excretion, previously demonstrated to reflect vascular permeability, increased significantly after exercise in claudicants and was associated with decreased neutrophil filterability and increased serum lysozyme activity. No similar exercise-induced changes were seen in controls or in claudicants after successful arterial bypass surgery. These results suggest that intermittent claudication is associated with potentially deleterious systemic manifestations that are surgically reversible.

Effect of surgery on the systemic inflammatory response to intermittent claudication.

Thromboxane and neutrophil changes following intermittent claudication suggest ischaemia-reperfusion injury.

Introduction Increases in blood viscosity may be present in several clinical conditions characterized by regional circulatory insufficiency which develop acutely or chronically (Chien 1972, Dintenfass 1971, Di Perri 1979, Dormandy 1970), such as myocardial infarction or peripheral occlusive arterial disorders (Di Perri et al 1977, Di Perri et al 1978, Forconi et al 1979). Patients with vascular disorders sometimes present a haemorrheological picture' entirely normal when at rest; however, alterations of the rheological parameters may appear in these cases under physical stress, for example during an exercise test in patients with angina pectoris, or while walking in patients with peripheral circulatory insufficiency (Di Perri et aI1977, Forconi et aI1977a, Forconi et al 1977b, Lake & Dintenfass 1975). In all of these situations, a cause-andeffect relationship appears to exist between the increase in blood viscosity and the onset of tissue ischaemia. Thus, definition of a syndrome with secondary blood hyperviscosity, quite different from similar clinical conditions, designated as primary hyperviscosity syndromes can be justified. Primary hyperviscosity syndromes may be induced by a primary increase in the total number of red blood cells (polycythaemic hyperviscosity), by a primary alteration in the internal RBC viscosity (sclerocythaemic hyperviscosity) or by an increase in plasma proteins (plasmatic hyperviscosity) (Wells 1970). Secondary hyperviscosity which develops under ischaemic conditions does not appear to be related to significant changes in the number of erythrocytes or to changes in the other nonerythrocyte rheological parameters, but rather seems attributable to changes in the internal viscosity of the RBC attendant with alterations in RBC deformability and aggregability. The haemodynamic effects of reduced erythrocyte deform ability affect the entire circulatory system, but the most important effects, from a physiopathological viewpoint, are exerted at the microcirculatory level, since the conditions of flow through the capillaries are closely related to the capacity of the RBC to change or deform their shape. A reduced number of perfused capillaries and a slowing of blood flow are consequences of diminished RBC deformability (Chien 1972, SchmidtSchonbein 1976). The ultimate effect of these phenomena is tissue ischaemia, followed by metabolic acidosis with an alteration in vascular regulation and a further deterioration of the rheological picture. Clinical situations of ischaemic vasculopathy exist in which blood hyperviscosity is not always present or, if present, is not pathological. Under these conditions, if the metabolic demands of a vascular region are

Protective effects of buflomedil against exercise-induced reductions in regional erythrocyte deformability of patients with peripheral arterial disease.

Effect of controlled physical activity on haemorheological and metabolic changes in poad patients

Drugs such as dipyridamole (200 μg/kg/min), an adenosine uptake in hibitor, and theophylline (300 μg/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hypere mia in normal subjects, as well as in POAD patients. Moreover, dipyrida mole pretreatment was able to antag onize the reduction of peak flow in duced by nifedipine, and the potenti ating effect of flunarizine on postis chemic hyperemia was affected sig nificantly by theophylline, thus sug gesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes — PMN) the inhibitory ef fect of calcium entry blockers on stimulated functions (degranulation and free radical production) was highly antagonized by theophylline. Finally, a1H-NMR spectroscopy study showed a binding interaction between adenosine and flunarizine on the cell membrane. An adenosine-re ceptor coupling to the calcium entry blocker channels is suggested.

In vivo and in vitro evidence of an adenosine-mediated mechanism of calcium entry blocker activities.

Blood hyperviscosity and peripheral ischemia; The secondary hyperviscosity syndrome of ischemizing vascular diseases

Action of cigarette smoking on microcirculation. Effects on some haemorheological, haemodynamic and metabolic parameters

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