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Oral Naftidrofuryl

A Review of its Pharmacology and Therapeutic Use in the Management of Peripheral Occlusive Arterial Disease

  • Drug Evaluation
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Summary

Synopsis

Naftidrofuryl has been used for the treatment of intermittent claudication, a symptom of mild to moderate peripheral occlusive arterial disease (POAD), for at least 2 decades. As a serotonin 5-HT2 receptor antagonist, naftidrofuryl has vasoactive properties in addition to its favourable effects on oxidative metabolism, peripheral transcutaneous oxygen pressure and the rheological properties of platelets and erythrocytes. The drug may also reduce hypercholesterolaemia-induced intimai proliferation.

Clinical trials which conform best with European guidelines have shown that 3 and 6 months’ oral therapy with naftidrofuryl 600 or 633 mg/day (in 3 or 2 divided doses) increased pain-free walking distance to a greater extent than placebo administration in patients with POAD. Surgical revascularisation was required less often during 6 months of therapy with naftidrofuryl than in placebo recipients, confirming the superiority of naftidrofuryl treatment compared with placebo.

Available data provide some evidence of efficacy of the drug in the treatment of ischaemic rest pain and vascular ulceration. However, further trials are required before the usefulness of oral naftidrofuryl in severe POAD can be fully established.

When given orally, naftidrofuryl is well tolerated. Mild gastrointestinal effects are the most common adverse events, requiring withdrawal of therapy in approximately 1.2% of patients compared with 0.95% of placebo-treated patients.

In summary, oral naftidrofuryl improves the symptoms of intermittent claudication in patients with POAD with minimal risk of adverse effects. Therefore, in patients with Fontaine’ s classification stage II POAD for whom lifestyle modifications and management of concomitant disease have provided insufficient benefit, naftidrofuryl is potentially useful.

Pharmacodynamic Properties

The pathophysiological processes underlying the development of peripheral occlusive arterial disease (POAD) are complex and multifactorial. However, serotonin (5-hydroxytryptamine; 5-HT) appears to play a major role in vasoconstriction and platelet aggregation, 2 important components of the cascade of events leading to atherosclerosis. Therefore, the antagonistic effect of naftidrofuryl at the 5-HT2 receptors on vascular smooth muscle cells and platelets provides the likely mechanism of its action.

Naftidrofuryl is a vasoactive agent which inhibits serotonin-induced contractions in vessels from humans and various animal species. Naftidrofuryl also increases the efficiency of aerobic metabolism in oxygen-depleted tissues, as evidenced by drug-induced reductions in lactate: pyruvate ratios in healthy volunteers during exercise. The most important marker of the favourable effect of naftidrofuryl on oxidative metabolism is peripheral transcutaneous oxygen pressure. It appears that naftidrofuryl selectively improves the transcutaneous oxygen pressure in areas of ischaemia, including areas of ulceration, regardless of whether the drug has any effect on arterial blood flow.

Naftidrofuryl has favourable rheological effects. It inhibits serotonin-induced, but not spontaneous or epinephrine (adrenaline)-induced, aggregation of platelets in vitro and ex vivo. Naftidrofuryl reduces aggregability of erythrocytes and their rigidity was reduced by administration of a single oral 600mg dose. Finally, naftidrofuryl has been shown to have antiatherosclerotic effects in rats and hamsters.

Pharmacokinetic Properties

Mean maximal plasma concentrations (Cmax) after oral administration of 100mg of the drug are approximately 200 μg/L in healthy volunteers. Naftidrofuryl appears to be distributed to and stored in fatty tissue.

Naftidrofuryl is metabolised primarily by plasma pseudo-cholinesterases to 3 major metabolites. No evidence to date suggests that there is saturation of metabolism. The plasma elimination half-life of naftidrofuryl is approximately 1.2 to 2 hours, necessitating 3 times daily administration of the drug. Formulation of the drug in a hydrocolloidal matrix may provide an opportunity to reduce the frequency of administration to twice daily.

In elderly patients, following intravenous therapy, the Cmax of naftidrofuryl is higher and the plasma elimination half-life longer (2.33 vs 0.81 hours) than in healthy volunteers. Therefore, dosage reduction may be required in the elderly.

Therapeutic Efficacy

Rigorous recommendations for the assessment of pharmacological intervention in POAD have been developed because of the unpredictable course of the disease and the beneficial effects of nondrug therapy such as physical exercise. Ideally, placebo-controlled, double-blind, parallel-group studies should be undertaken, patients should have stable disease before randomisation and a standardised method of assessing pain-free walking distance should be used.

Only the efficacy of orally administered naftidrofuryl is discussed in this review because of the recent withdrawal of the intravenous formulation. The results of 4 studies which fulfilled most of the above criteria demonstrated that oral administration of naftidrofuryl 600 or 633 mg/day in 2 or 3 divided doses increased pain-free walking distance in patients with intermittent claudication to a greater extent than placebo after 3 and 6 months. Maximal walking distance after treatment with naftidrofuryl was also significantly increased compared with that observed in placebo recipients after 6, but not 3, months. In one of the 6-month studies conforming to trial guidelines, naftidrofuryl treatment reduced the number of surgical revascularisation procedures required compared with placebo (12 vs 30%). Crossover studies have confirmed that naftidrofuryl improves maximal walking distance compared with placebo. Double-blind, placebo-controlled, parallel-group trials which lacked a run-in phase (and therefore did not ensure patients had stable disease) demonstrated that naftidrofuryl 400 or 600 mg/day was effective for improving walking time in patients aged >60 years.

In a meta-analysis of the 4 trials mentioned earlier, treatment type (i.e. naftidrofuryl vs placebo) was the most discriminatory factor for improvement in walking distance (improvement of 95.6 vs 41.2m), with severity of disease (reflected in initial walking distance) the next most important factor (those patients who could walk further at baseline improved more during the trial than others). Results of studies in patients with more severe POAD have been less convincing.

For the treatment of ischaemic rest pain, naftidrofuryl (200mg twice daily by intravenous infusion followed by 200mg 3 times daily orally) has produced equivocal results. However, oral naftidrofuryl 600 mg/day does improve healing of vascular ulcers after 2 or 3 months compared with placebo (improvement of 56 vs 41% after 2 months in 1 study). Further suitably designed trials are required before the place of oral naftidrofuryl in these conditions can be clarified.

Tolerability

After oral administration of naftidrofuryl, the most common adverse events are gastrointestinal (e.g. epigastric pain, nausea, indigestion and digestive difficulties). However, these adverse events seldom result in drug withdrawal. For example, in a meta-analysis of placebo-controlled studies, 1.2% of patients receiving oral naftidrofuryl 600 mg/day compared with 0.95% of controls withdrew from therapy as a result of gastrointestinal effects.

Other adverse events which occur less commonly after oral administration of the drug include cutaneous effects (e.g. flushing), acute hepatic necrosis and oesophageal ulceration. Deliberate or accidental overdose with oral or intravenous naftidrofuryl can cause severe cardiovascular disorders.

As a result of severe cardiac and neurological toxicity following intravenous bolus administration of naftidrofuryl, the parenteral formulations of the drug were withdrawn from the European market in 1995.

Dosage and Administration

For the treatment of patients with mild to moderate POAD, it is recommended that naftidrofuryl is given orally in a dosage of 300 to 600 mg/day in 3 divided doses, swallowed whole. Because the metabolism of naftidrofuryl may be reduced in the elderly, the dosage may need to be decreased in these patients. It is no longer recommended that the drug be given intravenously.

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    Lee B. Barradell & Rex N. Brogden

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Various sections of the manuscript reviewed by: M.A. Barradas, Department of Chemical Pathology and Human Metabolism, Royal Free Hospital School of Medicine, London, England; M-P. Colgan, Department of Vascular Disease, St. James’ Hospital, Dublin, Ireland; E. Housley, Clinic for Peripheral Vascular Diseases, Royal Infirmary of Edinburgh, Edinburgh, Scotland; R. Karnik, K A Rudolfstiftung, Juchgassegasse, Wein, Austria; F. Kuzuya, Nagoya University, Nakatsugawa Municipal Hospital, Komanba, Nakatsugawa-shi, Gifu, Japan; D.P. Mikhailidis, Department of Chemical Pathology and Human Metabolism, Royal Free Hospital School of Medicine, London, England; R. Nishigaki, School of Pharmaceutical Sciences, Toho University, Miyama, Funabashi, Chiba, Japan; O. Pastoris, Universita Di Pavia, Istituto Di Farmacologia, Pavia, Italy; L. Walmsley, Department of Pharmacokinetics, Huntingdon Life Sciences Ltd., Huntingdon, England.

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Barradell, L.B., Brogden, R.N. Oral Naftidrofuryl. Drugs & Aging 8, 299–322 (1996). https://doi.org/10.2165/00002512-199608040-00005

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