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Off-Label Drug Uses - Tadalafil: Raynaud Phenomenon
Abstract
Off-Label Drug Uses
This Hospital Pharmacy feature is extracted from Off-Label DrugFacts, a quarterly publication available from Wolters Kluwer Health. Off-Label DrugFacts is a practitioner-oriented resource for information about specific FDA-unapproved drug uses. This new guide to the literature will enable the health care professional/clinician to quickly identify published studies on off-label uses and to determine if a specific use is rational in a patient care scenario. The most relevant data are provided in tabular form, so the reader can easily identify the scope of information available. A summary of the data—including background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations—precedes each table of published studies. References direct the reader to the full literature for more comprehensive information prior to patient care decisions. Direct questions or comments regarding “Off-Label Drug Uses” to hospitalpharmacy@drugfacts.com .
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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.
Raynaud’s phenomenon (RP) is characterised by sensitivity to cold temperatures associated with either biphasic or uniphasic change in colour of the digits. Since few studies are available which include older adults, the prevalence of RP in the older adult population is estimated from surveys or studies of the general population. The causes of RP in older adults may differ significantly from those in young adults and, therefore, so would the evaluation of RP. Because of comorbities that accompany advancing age, the managment of RP in older adult patients must take into consideration toxicity and adverse reactions that may develop, especially in the frail individual. Although nonpharmacological therapy is preferable, slow-release calcium antagonists provide a relatively well tolerated and effective treatment for moderate to severe RP in older adult patients. Aggressive treatment including hospitalisation is appropriate for older adult patients during periods of critical digital ischaemia associated with RP.
Raynaud's Phenomenon (RP) is a relatively common problem which may be troublesome and difficult to treat in a minority of patients. The state of the art in 1998 focusses on three key areas: the clinical spectrum of RP; its progression and prognosis; and its treatment. RP is a systemic disease, with a multifactorial aetiology and vasospasm affects not just the digits and skin but also major organs including the heart, lungs and kidneys. It is important to distinguish primary from secondary RP. RP may predate an associated connective tissue disease by many years and markers for this include severe RP symptoms with trophic skin changes, serological abnormalities and abnormal nailfold capillaries. Repeated attacks of vasospasm may cause ischaemic reperfusion injury to the endothelium, resulting in a vicious and self propagating cycle of cause and effect. Nifedipine remains the "gold standard" of treatment but a number of new and promising drugs, eg relaxin, are currently under investigation. "Vasodilator-plus...
The literature on Raynaud's phenomenon (RP) describes a complex and confusing picture of abnormalities that has suggested a multifactorial aetiology. Current research suggests that the underlying disorder is related to a local fault at the level of the digital microcirculation. It is likely that many of the biological changes described in RP are secondary manifestations of this primary abnormality. The strong familial relationship of RP suggests a genetic link although this has not yet been characterized. An overactivity of the sympathetic nervous system appears less likely as a candidate for the primary abnormality and dysfunction at the level of the nerve, and vessel wall may be more important. Digital cutaneous neurones show a deficient release of the vasodilatory calcitonin gene related peptide in PR. This may represent a primary fault that is confounded by other factors, which are influenced by cold or emotional triggers. Vasoconstricting substances such as catecholamines, endothelin-1 and 5-hydroxytryptamine, which may all be released in response to cold exposure, could cause digital artery closure and the associated symptoms of RP. In some cases, this would trigger a cascade of neutrophil and platelet activation, which through the release of inflammatory mediators, contribute to the endothelial damage seen with more severe RP. It is hypothesised that disturbance to the intricate functioning of the endothelium, and secondary compensation at local or systemic level, may appear over time. There is, therefore, still a need to differentiate the true aetiological factors from those that are causal associations with Raynaud's phenomenon. Progress is slowly being made with better understanding of the intricacies between these factors and the microcirculation. Deepening our comprehension of the `normal' mechanisms that influence microvascular blood flow is necessary to develop a better understanding of the pathophysiology of Raynaud's phenomenon.
The literature on Raynaud's phenomenon (RP) describes a complex and confusing picture of abnormalities that has suggested a multifactorial aetiology. Current research suggests that the underlying disorder is related to a local fault at the level of the digital microcirculation. It is likely that many of the biological changes described in RP are secondary manifestations of this primary abnormality. The strong familial relationship of RP suggests a genetic link although this has not yet been characterized. An overactivity of the sympathetic nervous system appears less likely as a candidate for the primary abnormality and dysfunction at the level of the nerve, and vessel wall may be more important. Digital cutaneous neurones show a deficient release of the vasodilatory calcitonin gene related peptide in PR. This may represent a primary fault that is confounded by other factors, which are influenced by cold or emotional triggers. Vasoconstricting substances such as catecholamines, endothelin-1 and 5-hydroxytryptamine, which may all be released in response to cold exposure, could cause digital artery closure and the associated symptoms of RP. In some cases, this would trigger a cascade of neutrophil and platelet activation, which through the release of inflammatory mediators, contribute to the endothelial damage seen with more severe RP. It is hypothesised that disturbance to the intricate functioning of the endothelium, and secondary compensation at local or systemic level, may appear over time. There is, therefore, still a need to differentiate the true aetiological factors from those that are causal associations with Raynaud's phenomenon. Progress is slowly being made with better understanding of the intricacies between these factors and the microcirculation. Deepening our comprehension of the 'normal' mechanisms that influence microvascular blood flow is necessary to develop a better understanding of the pathophysiology of Raynaud's phenomenon.
Raynaud's phenomenon (RP) is very often the first manifestation of SSc preceding the onset of all the other signs and symptoms of the disease. Two structures are involved in the pathogenesis of RP: the endothelium and the peripheral nervous system (PNS). The hypothesis is that SSc modifies consistently the activity of both these systems leading eventually to RP. The disease, through the injury to the endothelium, jeopardizes the basilar endothelial-dependent vascular tone control. An increase of endothelin, a potent endothelial-derived vasoconstrictor, and the reduction of nitric oxide, one of the main endothelial vasodilators, are two key events involved in the genesis of RP. The PNS is also targeted by the disease as demonstrated by the high incidence of neuropathy in SSc patients. A marked reduction of sensory fibres has been detected in SSc skin. Thus, the involvement of nerve terminals reduces the vasodilatory, endothelial dependent or independent, potential of the neuropeptides released by sensory nerve endings. Indeed, an increased sensitivity of alpha 2 adrenoceptors mediated vasoconstriction has been shown in SSc skin. The complex vasodilatory network formed by the interaction between the endothelium and the PNS seems greatly damaged by SSc leading inesorably toward vascular tone dysfunction clinically evident as RP.
The Raynaud's phenomenon often accompanies systemic rheumatic diseases and is also known as a vascular side effect of chemotherapy. Therapy of the Raynaud's phenomenon with nitrates or calcium-channel-blockers is rarely beneficial. In contrast, the PDE-V-inhibitor sildenafil seems to be effective in these patients. For the first time we report on a patient with Raynaud's phenomenon due to chemotherapy not responding to sildenafil but to the new PDE-V-inhibitor tadalafil in an equivalent dosage. Measurement with a laser Doppler revealed an increased blood flow and a reduction of symptoms. Therefore, therapy of Raynaud's phenomenon with the new PDE-V-inhibitor tadalafil seems to be an effective treatment option in patients not responding to sildenafil.