Article

The effect of inositol nicotinate (Hexopal) in patients with Raynaud's phenomenon. A placebo-controlled study

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Abstract

A double-blind placebo-controlled study of the effect of inositol nicotinate (Hexopal) in the treatment of Raynaud's phenomenon is described. Sixty-five patients, 20 males 45 females, aged 18-75 years, weighing 40-100 kg were enrolled by 45 General Practitioners in East Anglia, Scotland and North Midlands. They were given either Hexopal or placebo 4 × 500 mg tablets twice daily for three months. The two groups were well matched for pre-treatment characteristics and well balanced for environmental temperature during the trial. After six weeks' treatment 14 out of 29 patients in each group had improved but at the end of the study 21 in the Hexopal group (78% of those remaining) had improved whilst the number in the placebo group remained at 14 (56% of those remaining). A statistically significant improvement in symptoms and reduction in frequency of Raynaud's attack was seen only in the Hexopal group. Compared with placebo, symptoms were significantly better with Hexopal after three months of treatment. This study, conducted as far as possible under natural conditions in the cold season, produced further confirmation that Hexopal not only reduced the severity of Raynaud's symptoms but also the frequency of Raynaud's attacks.

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... [28] The second RCT (65 people, 54 with primary Raynaud's phenomenon) found that, compared with placebo, more people taking inositol nicotinate 2 g twice daily improved over 12 weeks (as measured by a 5-point scale from 0 [no problem] to 5 [very severe]), but the difference was not significant (19/34 [56%] people scored 0-1 with inositol v 11/33 [33%] with placebo; RR 1.58, 95% CI 0.90 to 2.76; calculated from data in the paper; see comment below). [29] Harms: ...
... [28] In the second RCT, three people taking inositol nicotinate withdrew from the trial because of gastrointestinal disturbance or dizziness, compared with one person taking placebo. [29] Comment: ...
... The second RCT included people with secondary Raynaud's phenomenon, so results may not be fully applicable in people with primary Raynaud's phenomenon. [29] These data are insufficient to draw any conclusions. ...
Article
Introduction: Raynaud's phenomenon is an episodic vasospasm of the peripheral arteries, causing pallor followed by cyanosis and redness with pain and sometimes paraesthesia. On rare occasions it can lead to ulceration of the fingers and toes (and in some cases of the ears or nose). This review focuses on primary (idiopathic) Raynaud's phenomenon occurring in the absence of an underlying disease. The prevalence of primary Raynaud's phenomenon varies by sex, country, and exposure to workplace vibration. Methods and outcomes: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for primary Raynaud's phenomenon? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions: In this systematic review we present information relating to the effectiveness and safety of the following interventions: amlodipine, diltiazem, exercise, inositol nicotinate, keeping warm, moxisylyte (thymoxamine), naftidrofuryl oxalate, nicardipine, nifedipine, prazosin, and smoking cessation.
Chapter
Sometimes Raynaud’s Phenomenon (RP) is symptomatic enough to warrant pharmacological treatment. The principles of RP treatment are to decrease the frequency of attacks, lessen the duration of attacks, and to prevent or treat complications especially after failure of conservative treatment (staying warm, avoiding stress and other precipitators, and smoking cessation). In general secondary RP is more severe than primary and the majority of patients with both primary and secondary RP do not require drug treatment. However, the most severe RP patients are often those with arterial occlusion/obliteration such as those with systemic sclerosis associated RP. First line drug treatment is initiation of dihydropyridine class of calcium channel blockers (CCBs), where the most studied is nifedipine. Achievable goals of treatment with CCBs may be a 1/3 reduction in frequency of attacks. Other CCBs could be considered such as amlodipine, felodipine, and nicardipine. If this class is not effective or not tolerated (due to side effects such as hypotension and peripheral edema), then in moderate to severe secondary RP, PDE5 inhibitors are considered and or prostacyclins such as intravenous iloprost. In mild RP, PDE5 inhibitors or losarten (an angiotension II inhibitor) or fluoxetine (a selective serotonin reuptake inhibitor) may be considered with some positive randomized controlled trial data. Topical nitrates may be helpful, but there can be dose dependent side effects such as headache and hypotension. Angiotensin-converting-enzyme inhibitors have mostly negative data. Trends in treatment of uncomplicated moderate to severe RP are using combinations of drugs if tolerated and after obtaining a partial response with CCBs such as adding PDE5 inhibitors. Complications of secondary RP (both prevention and treatment) are discussed in Chap. 19.
Article
Background: Many different drugs have been suggested for the symptomatic treatment of primary Raynaud's phenomenon. Apart from calcium channel blockers, which are considered the drugs of choice, the evidence of the effects of alternative pharmacological treatments is limited. Objectives: To assess the effects of various drugs with vasodilator actions on primary Raynaud's phenomenon. Search strategy: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 24 July 2007), and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 3, 2007). In addition, we searched MEDLINE (January 1966 to July 2007), EMBASE (1980 to July 2007) and reference lists of relevant articles. We contacted pharmaceutical companies. There were no language restrictions. Selection criteria: Randomised controlled trials evaluating the effects of oral formulations of any drug with vasodilator effects on subjective symptoms in primary Raynaud's phenomenon. Treatment with, or comparison with, calcium channel blockers was not assessed in this review. Data collection and analysis: Both authors assessed the trials for inclusion and their quality. One author (BV) extracted the data MS checked the results. Data extraction included adverse events. we contacted trial authors for missing data. Main results: Eight studies involving 290 participants were included. Two trials examined the effects of captopril, the rest were single trials on single drugs. All comparisons were with placebo. The methodological quality of most trials was poor. Enalapril was associated with a small increase in the frequency of attacks per week (difference in means 0.8; 95% CI 0.43 to 1.17). The difference between the intervention groups on a subjective improvement score was non-significant. There was a significant effect of buflomedil on the frequency of attacks per week (weighted mean difference (WMD) -8.8; 95% CI -17.55 to -0.09), but there was no evidence of effect on the severity score. The proportion with fewer attacks was significantly higher on moxisylyte than on placebo (relative risk (RR) 4.33; 95% CI 1.36 to 13.81). For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks. Beraprost and moxisylyte gave significantly more adverse effects than placebo. Authors' conclusions: Poor methodological quality, small sample sizes and the limited data available resulted in low precision of the statistical results and limited value of the overall results . The overall results show that there is no evidence for an effect of vasodilator drugs on primary Raynaud's phenomenon.
Article
Full-text available
Primary Raynaud’s phenomenon is common, particularly in younger women, and may be familial. Vasospasm is not confined to the digits and may involve, for example, the tongue and nose, and also visceral organs like the heart, oesophagus or lung and cerebral circulation. Symptoms tend to be milder in primary compared with secondary Raynaud’s phenomenon, which is associated with other disorders such as the connective tissue diseases. Indeed, the severity of symptoms often acts as the predictor for the much later onset of the associated systemic disease. Occupational Raynaud’s phenomenon is related to the use of vibrating instruments, and a significant proportion of patients may be cured by an early change in job. In those over 60 years of age, Raynaud’s phenomenon is commonly a result of atherosclerotic obstructive arterial disease, and screening for and treatment of the risk factors is appropriate. The best-studied mechanisms in Raynaud’s phenomenon involve the blood and vascular endothelium. Microcirculatory flow may be impeded by activated platelet clumps, rigid red and white blood cells and damaged endothelium. These platelet clumps, white blood cells and damaged endothelium also release vasoactive/vasoconstrictive compounds which may additionally trigger the clotting cascade and thrombosis. Initial management for mild disease should focus on support and advice regarding avoidance of known precipitating factors, including vasospastic drugs. Cold protection with warming agents, ‘Abel’ shoes and also electrically heated gloves and socks is effective, but may be too cumbersome and inconvenient for some patients. Simple vasodilators like naftidrofuryl, inositol nicotinate and possibly pentoxifylline (oxpentifylline) are useful in mild disease, with adverse effects like headache and flushing being less problematic. The ‘gold standard’ of Raynaud’s phenomenon treatment is nifedipine, a calcium channel antagonist/blocker. Full dosage, however, can be limited by ankle swelling, headache and flushing, but adverse effects may be reduced by using the ‘retard’ or long-acting preparations. Adverse effects are also reduced with the newer calcium channel antagonists like diltiazem but at the expense of efficacy. Useful, enhanced benefit is also achieved by combination therapy with vasodilators. Newer treatments include the prostaglandin analogues which are effective but disadvantaged by their parenteral route of administration, and lack of licence in some countries. Oral preparations are, however, being studied and are in the pipeline. Essential fatty acid supplementation is mildly effective, while ketanserin and calcitonin gene—related peptide both look promising. Lumbar sympathectomy retains its important role in the treatment of Raynaud’s phenomenon involving the lower limbs. Satisfactory symptomatic relief is now possible for many patients with Raynaud’s phenomenon and this should certainly be the aim for all patients seeking medical help.
Article
Many different drugs have been suggested for the symptomatic treatment of primary Raynaud's phenomenon. Apart from calcium channel blockers, which are considered the drugs of choice, the evidence of the effects of alternative pharmacological treatments is limited. This is an update of a review first published in 2008. To assess the effects of various drugs with vasodilator actions on primary Raynaud's phenomenon. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched 14 May 2012), CENTRAL (Issue 4, 2012) and clinical trials databases. We contacted one pharmaceutical company and one trial author for additional information. In addition, the reference lists of relevant studies were searched for additional citations. There were no language restrictions. Randomised controlled trials evaluating the effects of oral formulations of any drug with vasodilator effects on subjective symptoms in primary Raynaud's phenomenon. Treatment with, or comparison with, calcium channel blockers was not assessed in this review. Two members of the review team independently assessed the trials for inclusion and their quality and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data. Eight studies involving 290 participants were included. Two trials examined the effects of captopril, the rest were single trials on single drugs. All comparisons were with placebo. The methodological quality of most trials was poor.Enalapril was associated with a small increase in the frequency of attacks per week (difference in means 0.8; 95% CI 0.43 to 1.17). The difference between the intervention groups on a subjective improvement score was non-significant. There was a significant effect of buflomedil on the frequency of attacks per week (weighted mean difference (WMD) -8.8; 95% CI -17.55 to -0.09), but there was no evidence of effect on the severity score. The proportion with fewer attacks was significantly higher on moxisylyte than on placebo (relative risk (RR) 4.33; 95% CI 1.36 to 13.81). For captopril, beraprost, dazoxiben and ketanserin there was no evidence of an effect on the frequency, severity or duration of attacks. Beraprost and moxisylyte gave significantly more adverse effects than placebo. Poor methodological quality, small sample sizes and the limited data available resulted in low precision of the statistical results and limited value of the overall results .The overall results show that there is no evidence for an effect of vasodilator drugs on primary Raynaud's phenomenon.
Article
Current thinking on the general approaches to handling patients with Raynaud's disease is briefly described, and the principles of management discussed. The various categories of drug treatment available - vasodilators, especially those active on the smallest blood vessels, drugs acting on endothelium and platelets and their products, rheologically active drugs and some whose action it is difficult to classify - are mentioned. By far the most widely tested drugs in this field are the dihydropyridine-like slow calcium channel antagonists, of which nifedipine is probably the best known. Side effects are common and the optimal dosage and drug formulation are yet to be achieved. Serotonin antagonists (naftidrofuryl, ketanserin) look promising, although ketanserin is not generally available yet. Drugs active in the sympathetic control of vascular tone may well be best reserved for the most severe forms of Raynaud's, especially perhaps those associated with tissue loss in the secondary disease. Older vasodilators, such as glyceryl trinitrate (nitroglycerin) and some of the nicotinic acid derivatives, have not been studied of late but the transdermal applications of glyceryl trinitrate at least sound attractive. Drugs active in the cyclo-oxygenase systems, especially those with prostacyclin-like activity or thromboxane antagonists, are obviously promising; however, their unavailability in oral, sublingual or transdermal forms limits comment on them at present. Non-drug approaches such as biofeedback control of vascular responses may be interesting in a small number of patients, but the advice to 'keep warm' (and how to achieve this) is probably the most valuable suggestion that can be given to patients with Raynaud's disease.
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