Validated spectrofluorimetric and resonance Rayleigh scattering methods for determining naftidrofuryl in varied pharmaceutical samples based on its interaction with erythrosin B.

Naftidrofuryl is a vasodilator medication used for treating cerebral and peripheral vascular diseases. In this study, two spectroscopical techniques, spectrofluorimetric and resonance Rayleigh scattering (RRS), were utilized to quantify naftidrofuryl in its pharmaceutical samples. The developed methodologies in this study rely on a facile process of forming an association complex between erythrosine B reagent and naftidrofuryl under acidic conditions. The fluorimetric assay is based on the ability of naftidrofuryl to quench and decrease the native fluorescence intensity of the reagent when measured at λ emis . = 550 nm ( λ excit . = 526 nm). Under similar reaction conditions, the RRS method relies on the observed amplification in the RRS spectrum of the reagent at a wavelength of 577 nm following its interaction with naftidrofuryl. The methods exhibited linearity within the ranges 0.2-1.6 µg/ml (r2  = 0.999) and 0.1-1.4 µg/ml (r2  = 0.9994), with limit of quantitation values of 0.146 and 0.099 µg/ml, and limit of detection values of 0.048 and 0.032 µg/ml, for the fluorometric and the RRS methods, respectively. Moreover, the quenching between the dye and naftidrofuryl was studied using Stern-Volmer analysis, and the methodologies were experimentally optimized and validated. Additionally, acceptable recoveries were achieved when the procedures were applied to determine naftidrofuryl in pharmaceutical samples.

Protective role of naftidrofuryl against methotrexate-induced testicular damage via the amelioration of the p53/miRNA-29a/CDC42 apoptotic pathway, inflammation, and oxidative stress.

This study aimed to assess the possible protective effects of naftidrofuryl (Naf) against methotrexate (MTX)-induced testicular toxicity in rats. Male rats were randomly distributed into four groups: control, Naf, MTX, and MTX+Naf groups. MTX administration induced oxidative stress, inflammation, and apoptosis in the testicular tissue, while pretreatment with Naf attenuated these pathways. Naf pretreatment significantly decreased malondialdehyde and interleukin-6 contents, microRNA-29a (miRNA-29a) expression level, and nuclear factor kappa B and p53 immunostaining in the testicular tissues compared to the MTX group. Conversely, it significantly increased Johnsen's score, serum testosterone level, serum total antioxidant capacity, testicular superoxide dismutase activity, testicular catalase activity, and testicular cell division cycle 42 (CDC42) expression compared to the MTX group. In conclusion, Naf exerted a significant protective effect against MTX-induced testicular toxicity via antioxidant and anti-inflammatory mechanisms and modulating the p53/miRNA-29a/CDC42 apoptotic pathway.

The vasodilator naftidrofuryl attenuates short-term brain glucose hypometabolism in the lithium-pilocarpine rat model of status epilepticus without providing neuroprotection.

Status epilepticus (SE) triggered by lithium-pilocarpine is a model of epileptogenesis widely used in rats, reproducing many of the pathological features of human temporal lobe epilepsy (TLE). After the SE, a silent period takes place that precedes the occurrence of recurrent spontaneous seizures. This latent stage is characterized by brain glucose hypometabolism and intense neuronal damage, especially at the hippocampus. Importantly, interictal hypometabolism in humans is a predictive marker of epileptogenesis, being correlated to the extent and severity of neuronal damage. Among the potential mechanisms underpinning glucose metabolism impairment and the subsequent brain damage, a reduction of cerebral blood flow has been proposed. Accordingly, our goal was to evaluate the potential beneficial effects of naftidrofuryl (25 mg/kg i.p., twice after the insult), a vasodilator drug currently used for circulatory insufficiency-related pathologies. Thus, we measured the effects of naftidrofuryl on the short-term brain hypometabolism and hippocampal damage induced by SE in rats. 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) neuroimaging along with various neurohistochemical assays aimed to assess brain damage were performed. SE led to both severe glucose hypometabolism in key epilepsy-related areas and hippocampal neuronal damage. Although naftidrofuryl showed no anticonvulsant properties, it ameliorated the short-term brain hypometabolism induced by pilocarpine. Strikingly, the latter was neither accompanied by neuroprotective nor by anti-inflammatory effects. We suggest that naftidrofuryl, by acutely enhancing brain blood flow around the time of SE improves the brain metabolic state but this effect is not enough to protect from the damage induced by SE.

Comparison of Cilostazol and Naftidrofuryl in an Experimental Acute Ischemia-Reperfusion Model.

INTRODUCTION: Naftidrofuryl and cilostazol are drugs with proven efficacy in the treatment of claudication in peripheral vascular disease. In this experimental study, we evaluated the effects of naftidrofuryl and cilostazol in ischemia-reperfusion (IR) injury on various tissues. MATERIALS AND METHODS: 40 male albino Wistar rats (8-12 weeks old, 250-350 g.) are randomly divided into 4 groups: Control (Group 1), sham (group 2), cilostazol pre-treatment (group 3), naftidrofuryl pre-treatment (group 4). During 21 days placebo is given to group 2, 12 mg/kg/day cilostazol is given to group 3, 50 mg/kg/day naftidrofuryl is given to group 4 orally. Ischemia and reperfusion are induced at the lower hind limb in Groups 2, 3 and 4. Ischemic muscle, kidney, liver, heart, brain and blood samples are obtained. The total antioxidant capacity, oxidant levels and oxidative stress index are studied for each group. RESULTS: Both drugs have protective effects of remote organ injury following IR. Systemic effects are similar to each other, both have protective effects of IR injury. It showed no statistical significance in the total antioxidant capacity. Total oxidant levels are significantly affected by cilostazol in the heart (p < 0.01) and by naftidrofuryl in the liver (p < 0.01). The effect on oxidative stress was only significant with cilostazol on the heart (p < 0.01). CONCLUSION: Cilostazol and naftidrofuryl had beneficial effects in all tissues against tissue damage caused by IR injury. In ischemic muscle, kidney and heart cilostazol had improved outcomes comparing to naftidrofuryl. Naftidrofuryl had benefits over cilostazol in liver tissue.

Peripheral arterial disease: diagnosis and management

This guideline covers diagnosing and managing peripheral arterial disease (PAD) in people aged 18 and over. Rapid changes in diagnostic methods, endovascular treatments and vascular services associated with new specialties in surgery and interventional radiology have resulted in considerable uncertainty and variation in practice. This guideline aims to resolve that uncertainty and variation. In December 2020, we reviewed our guidance on opioids for non-cancer pain in response to a Public Health England evidence review on dependence on, and withdrawal from, prescribed medicines. To support discussion with patients about opioid prescribing, and safe withdrawal management, we are developing guidance on safe prescribing and withdrawal management of prescribed drugs associated with dependence and withdrawal and shared decision making. In the meantime, we have added links in this guideline to other NICE guidelines and other resources that support this aim'.

[Naftidrofuryl in arterial obstructive disease: A systematic revue of the literature]. / Naftidrofuryl dans l'artériopathie oblitérante des membres inférieurs : une revue systématique de la littérature.

INTRODUCTION: Arterial obstructive disease is a disease affecting 11 % of the general population. This prevalence is constantly increasing. Nafronyl is still prescribed despite a decreasing reimbursement rate since 2005. The objective of this study was to summarize data from the scientific literature on the efficacy and safety of nafronyl used for the treatment of peripheral arterial obstructive disease. METHOD: A systematic review was made on EMBASE, MEDLINE and the Cochrane Library. Randomized controlled trials, systematic reviews and meta-analyses comparing naftidrofuryl with placebo were included. The main outcome was an improvement in the maximum walking distance or pain free walking distance. The quality of the reviews was analysed using a standardised reading grid. Only the best study was retained. RESULTS: Among 193articles, one meta-analyses were selected. Naftidrofuryl improved the initial pain free walking distance by 60 % at six months, without a demonstrated increase in the risk of adverse reactions. CONCLUSION: The efficacy of naftidrofuryl over the maximum walking distance in peripheral arterial obstructive disease appears similar to physical exercise or simvastatin.

Prostanoids for critical limb ischaemia.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) is a common cause of morbidity and mortality due to cardiovascular disease in the general population. Although numerous treatments have been adopted for patients at different disease stages, no option other than amputation is available for patients presenting with critical limb ischaemia (CLI) unsuitable for rescue or reconstructive intervention. In this regard, prostanoids have been proposed as a therapeutic alternative, with the aim of increasing blood supply to the limb with occluded arteries through their vasodilatory, antithrombotic, and anti-inflammatory effects. This is an update of a review first published in 2010. OBJECTIVES: To determine the effectiveness and safety of prostanoids in patients with CLI unsuitable for rescue or reconstructive intervention. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (January 2017) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1). In addition, we searched trials registries (January 2017) and contacted pharmaceutical manufacturers, in our efforts to identify unpublished data and ongoing trials. SELECTION CRITERIA: Randomised controlled trials describing the efficacy and safety of prostanoids compared with placebo or other pharmacological control treatments for patients presenting with CLI without chance of rescue or reconstructive intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. We resolved disagreements by consensus or by consultation with a third review author. MAIN RESULTS: For this update, 15 additional studies fulfilled selection criteria. We included in this review 33 randomised controlled trials with 4477 participants; 21 compared different prostanoids versus placebo, seven compared prostanoids versus other agents, and five conducted head-to-head comparisons using two different prostanoids.We found low-quality evidence that suggests no clear difference in the incidence of cardiovascular mortality between patients receiving prostanoids and those given placebo (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.41 to 1.58). We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared with placebo (RR 0.97, 95% CI 0.86 to 1.09). Adverse events were more frequent with prostanoids than with placebo (RR 2.11, 95% CI 1.79 to 2.50; moderate-quality evidence). The most commonly reported adverse events were headache, nausea, vomiting, diarrhoea, flushing, and hypotension. We found moderate-quality evidence showing that prostanoids reduced rest-pain (RR 1.30, 95% CI 1.06 to 1.59) and promoted ulcer healing (RR 1.24, 95% CI 1.04 to 1.48) when compared with placebo, although these small beneficial effects were diluted when we performed a sensitivity analysis that excluded studies at high risk of bias. Additionally, we found evidence of low to very low quality suggesting the effects of prostanoids versus other active agents or versus other prostanoids because studies conducting these comparisons were few and we judged them to be at high risk of bias. None of the included studies assessed quality of life. AUTHORS' CONCLUSIONS: We found high-quality evidence showing that prostanoids have no effect on the incidence of total amputations when compared against placebo. Moderate-quality evidence showed small beneficial effects of prostanoids for rest-pain relief and ulcer healing when compared with placebo. Additionally, moderate-quality evidence showed a greater incidence of adverse effects with the use of prostanoids, and low-quality evidence suggests that prostanoids have no effect on cardiovascular mortality when compared with placebo. None of the included studies reported quality of life measurements. The balance between benefits and harms associated with use of prostanoids in patients with critical limb ischaemia with no chance of reconstructive intervention is uncertain; therefore careful assessment of therapeutic alternatives should be considered. Main reasons for downgrading the quality of evidence were high risk of attrition bias and imprecision of effect estimates.

Application of π acceptors to the spectrophotometric and spectrofluorimetric determination of vincamine and naftidrofuryl oxalate in their pharmaceutical preparations.

Three different spectrophotometric and two spectrofluorimetric methods have been developed and validated for the determination of vincamine (VN) and naftidrofuryl oxalate (NF) in tablets. The spectrophotometric methods depend on charge transfer complex formation between each of VN and NF with 7,7,8,8-tetracyano-quinodimethane (TCNQ), 2,6-dichloroquinone-4-chloroimide (DCQ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at 843, 580 and 588 nm, respectively. The spectrofluorimetric methods are based on the formation of charge transfer complex between each of the two drugs and TCNQ, with measurement of the fluorophore formed at 312/375 and 284/612 nm, respectively, or with DDQ at 400/475 and 284/396 nm, respectively. In the spectrophotometric measurements, Beer's law was obeyed at concentration ranges of 1.5-16, 10-180 and 12-140 µg/ml for VN with TCNQ, DCQ, and DDQ, respectively. For NF, the corresponding concentrations were 2-28, 5-75 and 25-150 µg/ml with TCNQ, DCQ, and DDQ, respectively. In the spectrofluorimetric measurements, the ranges for VN were 0.05-0.9 and 0.3-4 µg/ml with TCNQ and DDQ, respectively, whereas for NF the ranges were 0.05-0.85 and 0.5-8 µg/ml with TCNQ and DDQ, respectively. The different experimental parameters affecting the development and stability of the formed color or fluorophore were studied and optimized and the molar ratios of the complexes were calculated. The proposed methods were validated according to ICH guidelines and were successfully applied for the determination of VN and NF in their tablet dosage forms.

Incidentally diagnosed melorheostosis of upper limb: case report.

BACKGROUND: Melorheostosis is quite a rare bone disease with still unclear ethiology. Although multifocal affection is highly debilitating with unfavorable prognosis, there is no clear consensus about therapeutical approach. There is still insufficient evidence in the literature for almost a century after the first description. Affected bone has a typical appearance of melting wax. Diagnosis is usually incidental with pain as a leading symptom. Diagnosis itself is relatively easy, routine X-ray examination is sufficient. Even though it could be easily overlooked and mistaken with other diseases. Melorheostosis is incurable, the therapy is mostly focused on maintaining patient quality of life. Presented case is unique in terms of extent of the affection (index finger, metacarp shaft, carpal bones, forearm, humerus and whole scapula) in combination with osteopoikilotic islands in other 3 regions (vertebrae, manubrium sterni and left collar bone). Currently there is only one such a case published in the literature (Campbell), but without osteopoikilotic islands. CASE PRESENTATION: Melorheostosis was diagnosed in 26-year old female after injury as an incidental finding. This was quite surprising as the patient already suffered by limited movement in the upper limb and pain before the injury. Detailed examination were performed to confirm the diagnosis, no family history was found. Pharmacotherapy with bisphosphonates, non-steroidal antirheumatics and vasodilatans/rheologic drugs seemed to be effective to maintain the relatively good quality of patient life and good performance in daily routine. Questionable is further development of patient performance status and sustainability of conservative treatment in the long term follow up. CONCLUSION: Conservative treatment with bisphopshonates and COX-2 inhibitors in combination with naftidrofuryl can delay surgery solution.

Non-Invasive Therapy of Peripheral Arterial Disease.

Peripheral arterial disease (PAD) is a significant cause of morbidity and mortality worldwide. Lifestyle changes, like the cessation of the use of tobacco as well as a modification of dietary and exercise habits, can be the most cost-effective interventions in patients with PAD. Smocking cessation is the most important intervention, since it increases survival in these patients. Antiplatelet therapy is an essential component in the treatment of peripheral arterial disease (PAD) of the lower extremities. In addition to delaying arterial obstructive progression, these agents are most usefull in reducing adverse cardiovascular events such as non-fatal myocardial infarction (MI), stroke and vascular death. Mainstay of treatment continues to be aspirin monotherapy (75-325mg daily). Current treatment for lower extremity PAD is directed towards the relief of symptoms and improvement in QoL. The two agents which have consistently been found to be most efficient in achieving these goals are cilostazol and naftidrofuryl oxalate. Naftidrofuryl oxalate may emerge as the most efficient and cost-effective treatment for symptom relief.

[Use of naftidrofuryl in angiology].

The review analyses the role of serotonin in the development of pathological processes in angiological patients, showing its negative role in aggravating chronic and acute ischaemia of various organs (brain, myocardium, extremities) both at the expense of vasoconstriction and due to an increase in blood platelet aggregation of blood platelets and erythrocytes, followed by analysis of clinical efficacy of naftidrofuryl) - serotonin 5-HT2 receptor antagonist. Results of numerous randomized trials confirmed its efficacy and safety in treatment of angiological patients, being superior to other vasotropic drugs (cilostazol, pentoxyphyllin, nicotinic acid).

The limits of evidence in drug approval and availability: a case study of cilostazol and naftidrofuryl for the treatment of intermittent claudication.

PURPOSE: Despite numerous efforts to develop effective medications for the treatment of intermittent claudication (IC) over the past 4 decades, a gold standard medical management option has yet to be defined. Although not life-threatening, IC interferes with mobility and activities of daily living, significantly impairing quality of life and potentially causing depression. Cilostazol, the leading pharmacologic agent for IC in the United States, was approved by the US Food and Drug Administration (FDA) in 1999 based on controversial data. Meanwhile, naftidrofuryl, the first-line pharmacologic agent for IC in the United Kingdom and Europe, has never been approved by the FDA and therefore is not available in the United States. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect impossible. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted, because the manufacturers of these agents have much to lose and little to gain from such a study. OBJECTIVE: This article provides an overview of the pharmacology of cilostazol and naftidrofuryl, and the clinical studies leading to their approval and clinical acceptance. It further explores the possible sources of bias in analyzing these clinical trials, some of which have been brought to light by the National Institute for Health and Clinical Excellence (NICE) of the United Kingdom in its technology appraisal guidance. It also speculates the ways in which economic incentives may affect drug-marketing decisions. METHODS: A literature review of pharmacology and clinical trials for cilostazol and naftidrofuryl was performed in PubMed. The majority of included clinical trials were initially identified through the most recent Cochrane review articles as well as the FDA's approval packet for cilostazol. The technology appraisal guidance of the National Institute for Health and Care Excellence of the United Kingdom and the manufacturer's response to this guidance document were located via an online search engine. FINDINGS: The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect difficult. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted. IMPLICATIONS: The history of the evaluation, approval, and marketing of these drugs illustrates the limitations of data in the regulatory approval and marketing of agents whose benefit is subjective and difficult to quantify. Implementation of a standardized protocol with strict eligibility criteria, objective quantifiable measurement of drug effect, and validated endpoints will eventually allow development of an ideal pharmacotherapy for IC.

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

[Clinical studies in peripheral arterial occlusive disease: update from the aspects of a meta-narrative review]. / Klinische Studien bei peripherer arterieller Verschlusskrankheit: Update unter den Aspekten eines meta-narrativen Reviews.

BACKGROUND: Atherosclerosis is a systemic disease. Its association with the metabolic syndrome requires a multimodal therapy setting, to alleviate symptoms and for primary and secondary prevention. In the planning of the therapy, information about evidence of the interventions and a rationale for reasonable combinations are important. METHOD: For compiling a meta-narrative review (MNR) on the evidence of complementary and conventional pharmaco-therapy in peripheral arterial occlusive disease (PAOD), the literature was searched for meta-analyses of randomized controlled trials (RCTs). These were evaluated taking into account network-pharmacological aspects and research parameters. RESULTS: 4 suitable meta-analyses were found. In comparison to placebo, treatments with verum showed a significant improvement of the maximum walking distance of 63.5 m (95% confidence interval (CI) 27.11-99.91 m; Padma 28, Tibetan Formula), 41.3 m (95% CI -7.1-89.7 m; cilostazol, phosphodiesterase IIl inhibitor), 43.8 m (95% CI 14.1-73.6 m; pentoxifylline, rheological drug), and 71.2 m (95% CI 13.3-129.0 m; naftidrofuryl, rheological drug). Only for Padma 28, clinical relevance, defined as an increase of the maximum walking distance by >100 m, was analyzed and reached by 18.2% of the verum and 2.1% of the placebo patients (odds ratio 10; 95% CI 3.03-33.33). 1 conventional and 1 complementary drug additionally showed to have significant pleiotropic effects (Padma 28 and cilostazol (e.g. reduction of triglycerides)). CONCLUSIONS: According to meta-analytic evidence, naftidrofuryl and Padma 28 show clinically relevant efficacy for the treatment of early stages of PAOD. The extent to which the theoretically possible combination of different drugs contributes to improve the systemic disease under a network-pharmacological rationale remains to be shown in a multi-armed RCT.

A validated HPLC method for the simultaneous determination of naftidrofuryl oxalate and its degradation product (metabolite), naftidrofuryl acid: applications to pharmaceutical tablets and biological samples.

A simple, sensitive, and selective reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous determination of naftidrofuryl oxalate (NF) and its hydrolytic degradation product (metabolite), naftidrofuryl acid (NFA). Chromatographic separation was achieved on Spheri-5 RP-C8 (5 µm) (220 × 4.6 mm i.d.) column using a mobile phase composed of acetonitrile, 0.05 M sodium acetate and triethylamine (40 : 60 : 0.1, by volume) adjusted to pH 5.5 using glacial acetic acid. The mobile phase was pumped at flow rate 1.5 ml/min. The UV detector was set at 225 nm and quantification of the analytes was based on measuring the peak areas. The method was proved to be accurate and precise with linearity ranges of 0.1-25 and 0.2-25 µg ml(-1) for NF and NFA, respectively. The limits of detection were 0.03 and 0.04 µg ml(-1) for NF and NFA, respectively. The method was applied to serve three goals: (1) stability-indicating assay of the parent drug NF in its pharmaceutical formulation, (2) determination of the degradation product NFA down to a level of 0.005% in the presence of large excess of the parent drug, and (3) drug monitoring of naftidrofuryl and its metabolite, naftidrofuryl acid, in human plasma/urine samples taken from a healthy volunteer treated with 200 mg oral dose of naftidrofuryl oxalate. The proposed method proved to be accurate, precise, and reliable in all these application fields.

Naftidrofuryl for intermittent claudication.

BACKGROUND: Lifestyle changes and cardiovascular prevention measures are a primary treatment for intermittent claudication (IC). Symptomatic treatment with vasoactive agents (Anatomic Therapeutic Chemical Classification (ATC) for medicines from the World Health Organisation class CO4A) is controversial. OBJECTIVES: To evaluate evidence on the efficacy and safety of oral naftidrofuryl (ATC CO4 21) versus placebo on the pain-free walking distance (PFWD) of people with IC by using a meta-analysis based on individual patient data (IPD). SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9).For the original review the authors handsearched the European Journal of Vascular and Endovascular Surgery (1984 to 1994) and checked relevant bibliographies. They contacted the registration holder of naftidrofuryl and the authors of identified trials for any unpublished data. SELECTION CRITERIA: We included only randomized controlled trials (RCTs) with low or moderate risk of bias for which the IPD were available. DATA COLLECTION AND ANALYSIS: We collected data from the electronic data file or from the case report form and checked the data by a statistical quality control procedure. All randomized patients were analyzed following the intention-to-treat (ITT) principle. The geometric mean of the relative improvement in PFWD was calculated for both treatment groups in all identified studies.The effect of the drug was assessed compared with placebo on final walking distance (WDf) using multilevel and random-effect models and adjusting for baseline walking distance (WD0). For the responder analysis, therapeutic success was defined as an improvement of walking distance of at least 50%. MAIN RESULTS: We included seven studies in the IPD (n = 1266 patients). One of these studies (n = 183) was only used in the sensitivity analysis so that the main analysis included 1083 patients. The ratio of the relative improvement in PFWD (naftidrofuryl compared with placebo) was 1.37 (95% confidence interval (CI) 1.27 to 1.49, P < 0.001). The absolute difference in responder rate, or proportion successfully treated, was 22.3% (95% CI 17.1% to 27.6%). The calculated number needed to treat was 4.5 (95% CI 3.6 to 5.8). AUTHORS' CONCLUSIONS: Oral naftidrofuryl has a statistically significant and clinically meaningful, although moderate, effect of improving walking distance in the six months after initiation of therapy for people with intermittent claudication. Access by researchers to data from RCTs that are suitable for IPD analysis should be possible through repositories of data from pharmacological trials. Regular formal appraisal of the balance of risk and benefit is needed for older pharmaceutical products.