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Buflomedil

A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Peripheral and Cerebral Vascular Diseases

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Summary

Synopsis

Buflomedil hydrochloride 1 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 α-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.

Pharmacodynamic Properties

Results from in vitro experiments with isolated canine blood vessels suggest that the major pharmacological action of buflomedil on vascular smooth muscle is non-selective competitive inhibition of α-adrenoceptors. Haemodynamic studies in man have shown that buflomedil increases peripheral arterial blood flow, producing better perfusion of impaired vascular beds, with a minimum of effect on central haemodynamics. Generally, the greatest improvements have been documented in the most severely affected limbs of patients with peripheral vascular occlusive disease. Compared with placebo, buflomedil 450 mg/day significantly improved the microcirculation in ischaemic tissue (p < 0.05) in 22 patients with acral gangrene. Transcutaneous oxygen tension measurement has been used to assess discrete changes in the microcirculation, and in single-dose studies showed that buflomedil probably increases collateral blood flow by reducing collateral resistance. Animal studies have also demonstrated the microcirculatory effects of buflomedil and shown that it decreases vascular resistance by dilating both skin and skeletal muscle vessels.

However, the clinical effects of buflomedil may be partially the result of several other actions. A number of studies have demonstrated that buflomedil increases erythrocyte deformability, associated with increases in erythrocyte adenosine triphosphate (ATP) and cyclic adenosine monophosphate (cAMP), and a decrease in erythrocyte 2,3-diphosphoglycerate. Other studies measuring haemorheological parameters have shown that buflomedil inhibits platelet aggregation induced by a variety of stimuli, decreases blood viscosity and increases erythrocyte flow in a dose-dependent manner; these changes were usually noted in single-dose studies but seemed to be maintained during longer term treatment. Buflomedil did not affect plasma viscosity, haematocrit, blood fibrinogen levels or erythrocyte sedimentation rate.

Using radiotracer techniques, single-doses of buflomedil (50 to 200mg administered intravenously or intra-arterially), and longer term administration (600mg orally for up to 14 days), generally increased regional, hemispherical and global cerebral blood flow in patients with cerebrovascular disease. Interestingly, blood flow was most increased in those regions which were poorly perfused at baseline.

In a placebo-controlled study, buflomedil 200mg intravenously increased mean tissue oxygen tension 30 minutes after infusion (+ 23%; p < 0.05) in 15 patients with peripheral arterial obstructive disease. Tissue oxygen tension was still elevated 2 hours after infusion. Animal studies have shown that buflomedil possesses oxygen-sparing activity without affecting oxidative metabolism and this suggests that the effects of buflomedil on tissue oxygen are potentially protective in nature.

Pharmacokinetic Properties

Buflomedil is readily absorbed from the gastrointestinal tract attaining mean maximal plasma concentrations between 1.5 and 4 hours after oral administration. Based on values for area under the plasma concentration-time curve (AUC) and mean maximum plasma concentration, the absorption pharmacokinetics of buflomedil appear to be linearly related to the dose administered. Single-dose studies demonstrated the bioequivalency of various formulations of buflomedil while comparison of AUCs following oral and intravenous administration indicated that between 50 and 80% of an oral dose is available to the systemic circulation.

The apparent volume of distribution of buflomedil has ranged between 82 and 109L, and that of the central compartment between 25 and 38L following intravenous administration of 50, 100 or 200mg doses. These values are indicative of extensive distribution throughout the fluid compartments and/or tissues. At therapeutic plasma concentrations in humans buflomedil is 60 to 80% bound to plasma proteins.

Values for total body (16 to 38 L/h), renal (2 to 7 L/h) and metabolic (12 to 19 L/h) clearances highlight the importance of metabolism in the elimination of buflomedil and it has been estimated that about 20% of an absorbed dose undergoes first-pass metabolism. Following oral administration, almost 90% of the dose is excreted in the urine after 4 days, approximately 20% as unchanged buflomedil. The elimination half-life of buflomedil appears to be independent of dose and is usually within the range of 2 to 3 hours.

Preliminary data suggest that the elimination of buflomedil may be impaired in patients with renal and liver disease, but further studies are needed to determine the exact extent of such reductions in the elimination of the drug.

Therapeutic Trials

In short to medium term open studies buflomedil (usually administered parenterally for 1 to 3 weeks and then orally) increased walking distances in patients with intermittent claudication and healed trophic lesions and reduced rest pain in many of those with more severe vasculopathies. A good to very good clinical response was reported for between 57 and 87% of patients treated. Various assessment techniques have shown that buflomedil generally improved perfusion in the lower limbs. Similar clinical improvements have been reported in longer term therapeutic trials (> 3 months) and, in one study, a dosage of 300mg twice daily was found to be optimal in terms of increasing walking distances without producing serious side effects. In comparative clinical trials in patients with peripheral vascular disease, buflomedil 600 mg/day (but not 450 mg/day) orally produced significantly greater improvements than placebo, and it was found to be comparable in efficacy with pentoxifylline and naftidrofuryl.

Several studies evaluated the efficacy of buflomedil for treating skin necroses resulting from severe vascular insufficiencies. Dosages of up to 600 mg/day reduced ischaemic pain in almost all patients and overall clinical improvement (usually marked or complete regression of skin lesions) was documented in 50 to 90% of those treated, many of whom had proven refractory to previous treatment. In one study, 72% of patients treated with buflomedil (versus 23% treated with placebo) developed significant improvement in microcirculatory blood flow in the skin of ischaemic tissue.

Preliminary investigation of the use of buflomedil in the treatment of other peripheral vascular disorders such as Raynaud’s phenomenon, diabetic retinopathy, frostbite and algodystrophies have been promising and would seem to warrant further research.

Clinical trials assessing the efficacy of buflomedil in patients with symptoms presumed to be due to cerebrovascular insufficiency and elderly patients with senile dementia have clearly shown that dosages of 450 to 600 mg/day alleviate symptoms associated with impairment of cognitive and psychosomatic function. In comparative studies, buflomedil was significantly superior to placebo and slightly more effective than drugs such as cinnarizine, flunarizine, nicergoline, vincamine and co-dergocrine mesylate. Studies in patients with cochlear-vestibular disturbances with symptoms of vertigo, tinnitus, dizziness or sudden deafness demonstrated significant improvements during treatment with buflomedil 450 mg/day. There was some evidence that the best results were achieved in patients with circulatory disorders, which suggests that the drug improves blood flow in the microcirculation of both the cochlea and the brain stem.

Side Effects

Buflomedil 300 to 600 mg/day in divided doses has been very well tolerated and discontinuation of therapy has rarely been necessary (in approximately 1% of those treated). Adverse effects most frequently reported during treatment include flushing, headache, vertigo, gastrointestinal discomfort and dizziness. However, many such ‘side effects’ were reported with about equal frequency in patients receiving placebo in placebo-controlled studies. In comparative studies, buflomedil was at least as well tolerated as other drugs used to treat patients with peripheral and/or cerebral vascular disease.

Dosage and Administration

The recommended oral dosage of buflomedil hydrochloride (tablets or drops) is 450 to 600 mg/day — usually in 2 or 3 divided doses, although a 600mg sustained release tablet is available in some countries for once daily administration. The usual intravenous dosage of buflomedil is 50 to 200 mg/day, either in divided doses or as a slow infusion. Buflomedil 50mg can also be administered intramuscularly up to 3 times daily for a maximum of 14 days.

Buflomedil is contraindicated immediately post partum and in patients with severe arterial bleeding, and there is preliminary evidence that dosage adjustments may be necessary in patients with liver disease.

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Authors and Affiliations

  1. ADIS Drug Information Services, Centorian Drive, Private Bag, Mairangi Bay, Auckland 10, New Zealand

    Stephen P. Clissold, Sharon Lynch & Eugene M. Sorkin

  2. Atlanta VA Medical Center, Atlanta, USA

    Stephen P. Clissold, Sharon Lynch & Eugene M. Sorkin

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  1. Stephen P. Clissold
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  2. Sharon Lynch
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Various sections of the manuscript reviewed by: T. Di Perri, Instituto di Patologia Speciale Medica, Università di Siena, Siena, Italy; J.A. Dormandy, St. James’ Hospital, London, England; B. Fagrell, Department of Medicine, Karolinska Institutet, Danderyd Hospital, Sweden; C. Le Devehat, Centre de Diabetologie et des maladies de la nutriton, C.H. de Nevers, Pougues les Eaux, France; K. Messmer, Abteilung für Experimentelle Chirurgie, Ruprecht-Karls-Universitàt, Heidelberg, W. Germany; J.S. Meyer, Cerebrovascular Research Laboratories, Baylor College of Medicine, Houston, Texas, USA; M.A. Perego, Istituto Di Clinica Medica II, Università Degli Studi Di Roma, Rome, Italy; E. Rey, Department de Pharmacologie Clinique, Hôpital Saint Vincent de Paul, Paris, France; N. Toda, Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu, Japan; G. Trübestein, Facharzt für Innere Medizin, Medizinische Universitäuts-Poliklinik, Bonn, W. Germany; J.A. Vale, West Midland Poisons Unit, Dudley Road Hospital, Birmingham, England; P.M. Vanhoutte, Mayo Foundation, Rochester, Minnesota, USA; R. Verhaeghe, Centre for Thrombosis and Vascular Research, Department of Medical Research, University of Leuven, Leuven, Belgium.

‘Loftyl’, ‘Lofton’, ‘Bufedil’ (Abbott Laboratories); ‘Fonzylane’ (Laboratoires Lafon).

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Clissold, S.P., Lynch, S. & Sorkin, E.M. Buflomedil. Drugs 33, 430–460 (1987). https://doi.org/10.2165/00003495-198733050-00002

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