JFS R: Concise Reviews/Hypotheses in Food Science

Raynaud’s Phenomenon and the Possible Use of Foods CHRIS I. WRIGHT, CHRISTINE I. KRONER, AND RICHARD DRAIJER R: Concise Reviews in Food Science

ABSTRACT: In this article we focus on the possible use of foods to alleviate Raynaud’s phenomenon (RP). RP is evoked, predominately, by cold and results in a potent vascular constriction of the microvascular blood vessels in the hands, thus leading to reduced hand blood flow and the elevation of pain sensation. To alleviate RP by diet, food components need to be able to promote hand skin blood flow, which may be achieved using fish oil, garlic, ginkgo biloba, L-carnitine, or inositol nicotinate, or to increase hand skin temperature, using evening primrose oil, ginkgo biloba, or inositol nicotinate. Although there are a number of studies documenting such improvements with these ingredients, they often are poorly designed. Hence, there is a need for more controlled studies to substantiate their use, but also to test alternative foods or target new ones. Therefore, we also discuss some alternate food options and briefly outline clinical drugs for the treatment of RP, as their mechanisms of action may also be possible targets for food. It is the intention of this article to address the research needs of this field and to provide a better understanding of alternative options for those with RP. Keywords: Raynaud’s, vascular constriction, dietary intervention, nutraceutical, functional foods

Introduction Mahoney 1999; Generini and others 2003; Herrick 2003); however, lit- here are a growing number of studies focusing on the con- tle work has been published on the use of foods as a complementary Tceivable health benefits of foods, botanicals, and supplements treatment for RP patients or as a safeguard for those at high or future (Boelsma and others 2001; Green and others 2003). Some studies risk of developing it. Indeed, women are known to have a higher risk have reported beneficial effects in patients with Raynaud’s phenom- of developing RP than men. Others at risk include members of fam- enon (RP), which is perhaps the best-known cold-related circulatory ilies in which RP is already prevalent and people living in cold cli- disorder (Raynaud 1888), estimated to affect about 10% of the popu- mates (Belch and others 1996). For those affected by the primary lation (Belch 1997). RP is defined as episodic “attacks” of vasoconstric- condition, treatment is obviously based on its proper diagnosis and tion of the microvessels in the hand to cold or emotional stimuli this can entail a period of some 2 y (Coffman 1989; Turton and oth- (Bounameaux and others 1986; Coffman 1989; Darton and others ers 1998; Mahoney 1999). In those who do not seek treatment, the 1991; Belch 1997; Turton and others 1998). During such attacks, pe- condition worsens, but if treatment is sought, significant improve- ripheral sympathetic efferent activity is increased (Bongard and others ments occur in most cases. Hence, food components may help those 1993; Allen and others 2002; Malpas 2004), blood vessels narrow, and people at future risk as well as those already suffering. this leads to a reduction in the volume of blood flowing through the In this review, we discuss the prevalence and risk of RP, outline hands and fingers (and even the ears, nose, tongue, and lips). This the clinical strategies used to treat RP, detail the scientific findings leads to discoloration of the skin of the hands, which can turn white as of food intervention trials, and discuss possible future directions a result of vascular narrowing or collapse, or blue due to insufficient ox- for foods in this area. ygen delivery to tissue, or red, which is indicative of blood flow resto- ration after an attack of RP (Mahoney 1999). Raynaud’s Phenomenon Vasospasms, which are characteristic of RP, can occur several times each day, which means repeated attacks of ischemia fol- Primary and secondary RP lowed by periods of tissue reperfusion (Cerinic and others 1997). Cold is the main trigger for sporadic vasospasms in both primary Both stages can have serious consequences. Indeed, repeated and secondary RP, although emotional stress and excitement, par- bouts of ischemia lead to tissue damage, swelling, and ulceration, ticularly in the primary condition, also trigger events (Coffman whereas repeatedly exposing the endothelium to free-radical–in- 1989; Belch and others 1996; Landry and others 1996; Belch 1997; duced oxidative stress can result in connective tissue diseases such Turton and others 1998; Mahoney 1999; Generini and others 2003; as systemic sclerosis (Block and others 2001). To make things worse, Herrick 2003). The differentiation of these 2 conditions is based on vasospasm of the fingers may be a component of more widespread the presence or absence of an underlying vascular disorder. The vasospasm and so digital pain may be accompanied by other prob- primary form is thus not associated with any other condition, lems such as headaches and migraine, or even atypical angina or whereas the secondary form is. Also, the secondary condition has pulmonary hypertension (Block and others 2001). been associated with impaired endothelial function and flow and RP has received a lot of research interest (Landry and others 1996; changes in blood rheology (Mahoney 1999). Still, the mechanisms explaining the secondary condition are not fully understood. MS 20040728 Submitted 11/5/04, Revised 1/28/05, Accepted 2/22/05. The authors are with Unilever Health Inst., Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands. Direct inquiries to author Draijer (E-mail: Diagnosing RP [email protected]). The diagnosis of primary RP is based on the criteria suggested by

© 2005 Institute of Food Technologists Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R67 Further reproduction without permission is prohibited Published on Web 4/28/2005 R: Concise Reviews in Food Science Raynaud’s phenomenon and foods . . .

Allen and Brown (Allen and others 1932; Coffman 1989): cold and/ cases (Mahoney 1999). RP attacks can also be alleviated, in part, by or stress elicit at least 2 of the 3 color changes (white, blue, or red); avoiding conditions in which sympathetic activity is elevated, such episodes occur periodically over the course of at least a 2-y period; as stress and smoking (Generini and others 2003). Other approaches attacks occur in the hands as well as the feet; there are strong and may be to wear heated gloves or more layers of clothing (Belch and symmetrical pulses; there is no evidence of digital pitting, ulcer- others 1996) or apply topical skin creams containing nitrous oxide, ations, or gangrene; nailfold capillaries appear normal; subjects which will promote skin blood flow (Tucker and others 1999). have a negative antinuclear antibody test (a titer of less than 1:100); and Westegren erythrocyte sedimentation rate is normal (<20 mm/ Pharmacological approaches h) (LeRoy and others 1992). Those falling outside these criteria fall Clinically, drugs promoting a generalized peripheral vasodilata- under the criteria for secondary RP but may also include a number tion and an increased flow of blood would be of benefit to those with of abnormalities relating to the esophagus, small intestines, colon, RP (Cerinic and others 1997; Tucker and others 1999; Herrick 2003). lungs heart, and kidneys (LeRoy and others 1992). Indeed, a wide range of compounds has been used to try and achieve such effects. Examples including niacin, calcium channel Prevalence of RP blockers (Gasser 1991), angiotensin-converting enzyme inhibitors In the general public, RP is estimated to be prevalent in some (Cerinic and others 1997; Herrick 2003), sympathetic alpha-1 (Ma- 4% to 15% of people and is obviously higher in colder environments honey 1999) and alpha-2 antagonists (Herrick 2003), prostaglandins (Coffman 1989; Landry and others 1996; Leppert and others 1997). (Murai and others 1989; Lau and others 1991; Saito and others 1994; It is estimated that between 50% and 90% of all RP cases are related Belch and others 1995) and calcitonin gene-related peptide (Bunker to the primary condition and that women are some 5 to 7 times more and others 1993; Szallasi and others 2000; Herrick 2003). Other drugs likely to develop the primary form that are men (Belch 1997). The may be of benefit, but instead of evoking a vasodilatation, they work average age at which RP is diagnosed is between 20 and 40 y, with to block the vascular actions of vasoconstrictors (such as serotonin symptoms being worse if the age of onset is younger than 30 y [Mahoney 1999] and endothelin-1 [Herrick 2003]). Other drugs may (Belch 1997). In such cases, associated symptoms worsen with age be of benefit as they afford additional benefits such as a reduction and there is a strong likelihood of developing associated vascular in the frequency of RP attacks or their severity (for example, antiox- disease (Belch and others 1996; Turton and others 1998; Mahoney idants [Herrick and others 2000] and serotonin and endothelin-1 1999). The age of onset for RP is known to be lower in females than receptor antagonists). For other drugs (for example, nicotine [Usuki males, and lower in those females in colder climates (Leppert and and others 1998]), further substantiation is required before they can others 1997; Maricq and others 1997). Once diagnosed, about 3 of be considered treatment options for RP. And finally, a number of the 10 people with primary RP go on to develop its secondary form. RP previously mentioned compounds can be associated with unwanted attacks are related to geographical location, but this has no bearing adverse effects (for example, headaches, dizziness, diarrhea, aggra- on their severity (Maricq and others 1997). Finally, studies assess- vation, sleep disorders, postural hypotension, and itching), which ing the familial predisposition of primary RP (Freedman and others can restrict their use in some subjects. 1996) have documented a significant familial aggregation of prima- ry RP, but as yet no causative gene has been identified. Sympathetic nerve dissection The last resort to alleviate RP is surgery, whereby sympathetic nerves Prognosis for RP are dissected to provide some symptomatic relief to the affected area Once diagnosed, the prognosis for RP is very good. Primary RP (Cerinic and others 1997). Cervicothoracic sympathectomy (sympa- has the best prognosis and is associated with only a small chance thetic nerve dissection) is considered effective for between months (approximately 1%) of developing serious complications. In such and years, but unfortunately symptoms do gradually return. The al- cases, medication can be avoided by taking a number of precau- ternative is lumbar sympathectomy because this provides long-term tions to avoid and limit the effect of the trigger for RP events. Anoth- symptomatic relief in around 90% of cases (Mahoney 1999). er option for this primary condition is obviously the use of foods and hence the context of this review. Such an approach seems attractive Raynaud’s Phenomenon and the Use of Foods for primary RP but may also be useful for those who develop RP or he vascular effect of foods has been investigated in a number who have cold hands or a complementary approach for those who Tof studies, and those relating to RP or skin blood flow and tem- are already using medications. For those that have the secondary perature are also discussed. condition, the prognosis is not as clear-cut because it depends on the severity of RP and other underlying conditions such as sclero- Fish oil derma, lupus, or Sjögren syndrome (Turton and others 1998). Background. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the omega-3 fatty acids found in fatty fish modulate Non-food Approaches for vascular tone possibly by increasing prostaglandin production and Treating Raynaud’s Phenomenon thereby decreasing resting vascular tone. The cardiovascular ben- here are a wide variety of approaches utilized to treat RP and efits associated with EPA and DHA are believed to include slowing Tthese fall into 3 broad categories, lifestyle changes, drug inter- the progression of athersclerosis and reducing blood clotting (von ventions and dissection of sympathetic nerves to the region that is Schacky and others 1999). affected. These are discussed in further detail below because they Studies. Two studies have assessed the effects of fish oil on the offer physiological targets that may be new targets for food. microcirculation (Table 1). The 1st was a double-blind placebo-con- trolled trial. RP patients consumed 12 standardized fish oil capsules Lifestyle and behavioral changes (containing 3.96 g of EPA and 2.64 g of DHA) per day for 12 wk. Com- Temperature biofeedback is an example of a behavioral change. pared with placebo, fish oil was shown to delay the onset time for RP Those that use this method learn to self-hand warm in controlled and to promote digital blood flow and increase digital systolic pres- environmental conditions; this is extremely effective since it is sure during cold exposure (DiGiacomo and others 1989). The 2nd claimed to reduce the frequency of RP attacks in about 66% to 92% of study was a single blind study, and 0.15 g/kg (of body weight) of a

R68 JOURNAL OF FOOD SCIENCE—Vol. 70, Nr. 4, 2005 URLs and E-mail addresses are active links at www.ift.org Raynaud’s phenomenon and foods . . . standardized fish oil supplement was consumed for 3 wk by healthy uted to its flavone glycosides and terpene lactones (for example, the volunteers. This supplement, when compared with control levels, ginkgolides and bilobalides) (Kleijnen and others 1992). A standard- was shown to increase erythrocyte velocity, to increase plasma cho- ized extract of GB comprises 24% flavone glycosides and 6% terpene lesterol and low-density lipoprotein levels, and to decrease plasma lactones. It is suggested that flavone glycosides attribute for GB’s triglycerides (Bruckner and others 1987). antioxidant activity and mild inhibiting effect on platelet aggrega- Conclusions. Both studies found a tendency for fish oil to im- tion (Yoshikawa and others 1999). They are also suggested to provide provement microcirculatory blood flow dynamics and this implicates some safeguard against diseases such as atherosclerosis and diabet- their potential use by RP patients. However, in the 2nd study, this ic retinopathy. The terpene lactones apparently increase brain effect was not significantly different from the placebo effect. At blood flow circulation and also help maintain normal nerve fiber R: Concise Reviews in Food Science present, further studies are required to prove the efficacy of fish oils. activity. In addition, GB might be capable of modulating vascular tone (Mehlsen and others 2002) and increasing the elasticity of blood Evening primrose oil (EPO) vessels (Költringer and others 1989). Background. EPO is derived from EPO plant seeds, and like Studies. Two studies have tested the microvascular responses to black currant seed oil and borage oil, EPO contains gamma linolenic GB (Table 1). The 1st, conducted in 10 patients with primary RP, was acid, which the body converts to a hormone-like substance called a single-blind placebo-controlled study (Muir and others 2002). prostaglandin E1 (Belch and others 2000). Vascularly, this prostag- Consumption of 120 mg of GB per day for 10 wk was shown to reduce landin is suggested as having anti-inflammatory properties, thins the mean number of vasospastic attacks per week when compared the blood, and dilates blood vessels (Belch and others 2000). with placebo. Also, significant reductions (compared with control Studies. One study has assessed EPO consumption in RP (Belch levels) in the mean duration of attacks, the subjective assessment of and others 1985); it was a double-blind placebo-controlled trial in RP severity, and fibrinogen levels were observed. The 2nd study in- 21 patients (Table 1). Supplements of EPO reduced the number vestigated the acute effects of GB. This was a double-blind placebo- and severity of RP attacks and the degree of coldness. However, no controlled study and was performed in 10 healthy subjects; 112.5 mg effect was found on digital blood flows or temperatures. of GB was shown to increase nailfold erythrocyte velocity compared Conclusions. EPO seems to be useful in providing symptomatic with control levels, and reached a maximum 1 h after consumption relief from RP, but this effect is not dependent on changes in flow (Jung and others 1990b). and the mechanism for this effect needs further investigation. Conclusions. The chronic consumption of GB helps reduce the symptoms of RP, and its short-term consumption promotes mi- Garlic crovascular flow. Whether consumption of GB for extended periods Background. A number of studies document the positive vascu- affects microvascular flow still needs to be determined. lar effects of garlic. Garlic is reported to lower blood cholesterol and triglyceride levels, inhibit platelet aggregation, increase fibrinolysis Ginkgo biloba and ginseng (GBG) and accordingly slow blood coagulation, act as a mild antihyperten- Background. There are 2 forms of ginseng, the American and sive agent and antioxidant, and reduce arterial plaque formation in Asian varieties. American ginseng contains ginsenosides and might the elderly. reduce fatigue and stress levels. It has also been suggested to en- Studies. Three studies (Table 1) have assessed the effects of garlic hance exercise performance, but such effects are not consistent, on the microcirculation of the hands (Jung and others 1991; since it has been found show no effect in healthy people (Morris Kiesewetter and others 1991; Wohlrab and others 2000). Its acute and others 1996; Vogler and others 1999). effects were assessed in 2 studies (Jung and others 1991; Wohlrab Studies. In healthy subjects, the effect of short-term GBG inges- and others 2000), one of which determined the long-term influence tion was tested (Kiesewetter and others 1992). This was a double- of garlic consumption (Kiesewetter and others 1991). In the long- blind placebo-controlled study in which subjects consumed either term study, 120 patients with an underlying vascular disorder con- a moderate or high dose of GBG (Table 1). When compared with sumed 800 mg of garlic per day for 4 wk (Kiesewetter and others placebo, high doses (120 mg of GB and 200 mg of ginseng) signifi- 1991). This double-blind placebo-controlled trial showed that long- cantly increased erythrocyte blood velocity, decreased erythrocyte term garlic consumption, compared with placebo, increased eryth- rigidity, and decreased spontaneous platelet aggregations. High rocyte velocity and decreased spontaneous thrombocyte aggregation doses were also reported to significantly decrease arterial blood and diastolic blood pressure. In addition, garlic affected blood fluid- pressures, but only compared with control levels and not placebo. ity, decreasing plasma viscosity. Similar effects on erythrocyte veloc- Conclusions. Acute consumption of GB promotes beneficial ef- ity were found in 2 short-term intervention studies (Jung and others fects on the microcirculation, but whether it has the same effects 1990a; Jung and others 1991; Wohlrab and others 2000). In the 1st when taken long-term or when taken by those with RP has yet to be (Jung and others 1991), which was a double-blind placebo-controlled investigated. trial in 10 healthy volunteers, 900 mg of garlic increased erythrocyte velocity and precapillary arteriolar diameter and decreased plasma L-carnitine (L-C) viscosity. The 2nd study (Wohlrab and others 2000), which did not Background. The brain, liver, and kidneys manufacture L-C from include a placebo control and included 10 healthy subjects, reported the amino acids lysine and methionine, which is believed to play a that 600 mg of garlic induced peak effects on erythrocyte velocity role in the release of energy from fat. It does this by transporting fat- and capillary diameters 30 min after consumption. ty acids into the mitochondria and hence much of the body’s L-C is Conclusions. The long-term and short-term consumption of found in skeletal and cardiac muscles. This compound, and L-C de- garlic seems to promote the flow of peripheral blood and might rivatives, are especially interesting because they are suggested to benefit those with RP, those with an underlying vascular disorder, protect the heart against ischemia (Lango and others 2001) and/or and healthy people suffering from cold hands. reperfusion ischemia (Cui and others 2001). Hence, it is plausible that L-C, or a derivative of L-C, may safeguard against tissue damage Ginkgo biloba (GB) due to impaired microvascular function and blood flow (for example, Background. The medicinal benefits of GB can probably be attrib- as happens in systemic sclerosis [Hahn and others 1998]).

URLs and E-mail addresses are active links at www.ift.org Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R69 R: Concise Reviews in Food Science Raynaud’s phenomenon and foods . . .

Table 1—A summary of the study outcomes from human trials that have incorporated the use of foods to alleviate Raynaud’s phenomenona Study Ingredient Design n Status Dose Duration DiGiacomo Fish oil R, DB, 32 PRP/SRP 12 capsules per day 1. Weeks 0 to 6, fish oil or olive oil and others CO, PL containing 3.96 g 2. Weeks 6 to 12, interventions 1989) EPA and 2.64 g DHA crossed over 3. Weeks 12 to 17, only olive oil 3. Time to onset of RP (46.5 min versus 31.3 min) Outcome Significant improvements to a cold water challenge after 6 wk 1. Digital systolic blood pressure (43 versus 10 mm Hg) at 10 °C 2. Digital arterial blood flow at 40 °C (11.0%/min versus 8.0%/min), 15 °C (3.3%/min versus 0.8%/min), and 10 °C (2.6%/min versus 1.3%/min) Not significantly changed 1. Frequency of RP attacks 2. Severity of RP attacks 3. Plasma viscosity 4. Complete blood cell count 5. Westergren sedimentation rate 6. Platelet count Bruckner and Fish oil R, SB, 21 Healthy 1.5 g/10 kg/d 3 wk others 1987 P, PL Outcome Significant changes 1. Increased erythrocyte velocity 2. Decreased plasma triglycerides 3. Increased plasma cholesterol 4. Increased levels of low-density lipoproteins Not significantly changed 1. Mean arterial blood pressures 2. Blood viscosity Belch and Evening R, DB, 21 PRP/SRP 12 capsules per day 1. 2 wk of olive oil only others 1985 primrose oil P, PL giving a total of 540 mg 2. 8 wk of olive or evening primrose oil of gamma-linolenic acid Outcomes Significant changes 1. The frequency and duration of RP attacks were decreased comparedwith placebo (results are not reported here as they were presented as percent changes from pre-intervention values) 2. Decrease in the severity of RP (visual analogue scales) 3. Decrease in the degree of coldness Not significantly changed 1. Finger blood flow 2. Hand temperatures Kiesewetter Garlic R, DB, 60 Vascular disorder 800 mg of a 1.1 wwk washout phase and others 1991 PD, PL (i.e., increased standardized 2.4 weeks ntervention period spontaneous garlic powder aggregation) (containing 1.3 mg dl-1 of Allicin) Outcomes Significant changes 1. Decreased spontaneous thrombocyte aggregation (18 versus approximately 41%) 2. Increased erythrocyte velocity (0.94 versus approximately 0.70 mm/s) 3. Decreased plasma viscosity (1.21 versus approximately 1.25 mPas) 4. Decreased diastolic blood pressure (67 versus 74 mm Hg) 5. Reduction in glucose levels (79.0 versus approximately 89.0 mg/dL) Not significantly changed 1. Systolic blood pressure 2. Total cholesterol tended to decrease 3. Erythrocyte aggregation 4. Hematocrit 5. Triglycerides, fibrinogen and leukocyte adhesion 6. Leukocyte and thrombocyte counts Jung and Garlic R, DB, 10 Healthy Capsules containing 5 h others 1991 CO, PL 900 mg of Chinese garlic Outcomes Significant changes 1. Erythrocyte velocity (0.90 mm/s versus 0.70 mm/s) 2. Precapillary arteriolar diameter (25.1 versus 23.2 ␮m) 3. Hematocrit (42.3% versus 43.5%) 4. Plasma viscosity (1.24 versus 1.28) Not significantly changed 1. Tissue plasminogen activator activity (2.27 U/mL versus 2.01I U/mL) 2. Tissue plasminogen activator inhibitor (4.80 AU/mL versus 6.36 AU/mL)

(continued on next page)

R70 JOURNAL OF FOOD SCIENCE—Vol. 70, Nr. 4, 2005 URLs and E-mail addresses are active links at www.ift.org Raynaud’s phenomenon and foods . . .

Study Ingredient Design n Status Dose Duration Wohlrab and Garlic SIT 10 Healthy Tablets containing 6 h others 2000 600 mg of a dried ethanol-water extract of fresh garlic were consumed with 50 mL of tap water Outcomes Significant changes

1. Percent increase in erythrocyte velocity, which peaked 30 min after ingestion R: Concise Reviews in Food Science 2. Percentage increase after 30 min in arterial and venous capillary diameters, relative to control levels. After 2 h they were significantly reduced compared with pre-intervention levels 3. Percent increases in transcutaneous partial oxygen levels after 2 h and a significant drop after 6 h Not significantly changed 1. Veno-arterial reflex to a orthostatic challenge 2. Vasomotion 3. Reactive hyperthermic hyperemia Muir and Ginkgo biloba R, DB, 22 PRP 120 mg of a 1. 2-wk assessment period others 2002 PD, PL standardized extract 2.10 wk of intervention (Seredin) was consumed 3 times per day Outcomes Significant changes 1. Reduction in mean number of vasospastic attacks a wk (5.8/wk versus 13.2/wk) 2. Reduction in the mean duration of attacks 3. Percentage reduction in personal severity scores for symptoms 4. Reduction in mean fibrinogen levels Not significantly changed 1. Median number of attacks per week 2. The percentage aggregation response to adenosine diphosphate Jung and Ginkgo biloba R, SB, 10 Healthy Standardized 4 h others 1990b CO, PL preparationin a 45 mL solution (112.5 mg; LI 1370,Kaveri) Outcomes Significant changes 1. Increased erythrocyte velocity, with a peak effect after 1 h Not significantly changed 1. Systolic and diastolic blood pressures 2. Heart rate 3. Hematocrit 4. Plasma viscosity 5. Erythrocyte rigidity 6. Thrombocyte and leukocyte counts 7. Spontaneous thrombocyte aggregation 8. Circulating thrombocyte aggregates 9. Capillary diameter Kiesewetter Combined R, CO, PL 10 Healthy A low (60 mg of 1 h (a pilot study, investigating its and others 1992 ginkgo biloba ginkgo biloba and effects over a 3-h period showed and ginseng 100 mg of ginseng) it had peak effects 1 h after or high dose consumption) (120 mg and 200 mg, respectively) was taken with 200 mL of water Outcomes Significant changes 1. High dose increased erythrocyte velocity (0.86 mm/s versus 0.52 mm/s) 2. High dose decreased erythrocyte rigidity (1.01 versus 1.06 arbitrary units) 3. High dose decreased spontaneous platelet aggregation (14.7 versus 15.8 arbitrary units) 4. High dose decreased systolic and diastolic blood pressure 5. Low dose decreased only systolic blood pressure 6. High and low doses decreased circulating platelet aggregates Not significant 1. Erythrocyte aggregation Gasser and L-carnitine SIT 12 PRP 3 capsules per day 20 d others 1997 containing 1 g L-carnitine Outcomes Significant changes 1. Erythrocyte velocity was elevated during a transient cold intervention, compared with pre-intervention values 2. Recovery time following cold stimulus was shorter after intervention period 3. Number of capillaries still remaining open during cold stimulus was higher in intervention group 4. Systolic blood pressure was lower after intervention

(continued on next page)

URLs and E-mail addresses are active links at www.ift.org Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R71 R: Concise Reviews in Food Science Raynaud’s phenomenon and foods . . .

Not significantly changed 1. Diastolic blood pressure 2. Heart rate 3. Digital temperatures Study Ingredient Design n Status Dose Duration Ring and Inositol SIT 6 patients Patients had 3 g/d-1 of a 36 wk and others 1977 hexanicotinate and signs of RP standardized 10 controls and control extract (Hexopal) subjects were in solution healthy Outcomes Only trends in hand temperatures were reported 1. Patients had colder hands before intervention 2. After 1 wk, the hand temperatures of patients increased 3. After 3 wks, hand temperatures returned to near pre-intervention levels 4. After 7 wk, they tended to increase again 5. After 9 mo, only 2 patients left in study and hand temperatures remained elevated 6. In 4 patients that dropped out, hand temperatures were decreased relative to control subjects Ring and Inositol SIT 20 patients Patients had RP 4 g/d-1 of a 36 wk others 1981 hexanicotinate and 10 and controls standardized were healthy extract (Hexopal) in solution or as tablets Outcomes Significant changes 1. Improved phalanx to dorsal hand temperature ratio after a transient cold challenge 2. Improvement in subjective measures of coldness, numbness, and pain in the hands of Raynaud’s patients Not significantly changed 1. Ratio of phalanx to dorsal hand temperature under resting conditions 2. No significant change for subjective measures assessing burning sensation of the hands of Raynaud’s patients Holti 1979 Inositol SB 20 PRP/SRP 4 g/d-1 of a 1. 4 wk wash-out period hexanicotinate standardized extract 2. 12 wk of intervention (Hexopal) Outcomes Significant changes 1. Resting finger temperatures when compared with pre-intervention values 2. Improved resting digital skin heat clearance 3. Improved digital skin heat clearance to localized warming of the skin 4. Time to Raynaud’s attacks was prolonged 5. Decreased triglycerides and fibrinogen levels 6. Improved symptomatic assessments of pain on exposure to cold, coldness of extremities, paraesthesiae, and frequency and severity of Raynaud’s attacks Not significantly changed 1. Finger temperature to localized heating of the skin 2. Reactive hyperemic responses following a period of 5 min of hand circulation occlusion 3. Plasma viscosity Sunderland Inositol R, DB, 23 PRP 4 g/d of a 1. 2 wk wash-out period and others 1988 hexanicotinate PD, PL standardized 2. 12 wk of intervention extract (Hexopal) Outcomes Significant changes 1. The percentage number of Raynaud’s attacks decreased Not significantly changed 1. The duration of Raynaud’s attacks 2. Subjective improvement of symptoms 3. Hand and finger temperature assessments 4. Finger blood flow 5. Plasma prostaglandin I2 metabolites, serum thromboxane, plasma fibrinogen, plasminogen, and plasminogen activator activity were unchanged Aylward 1979 Inositol SIT 20 PRP 2 g/d to 4 g/d 9 mo hexanicotinate of Hexopal Outcomes Significant changes 1. After 2 mo, resting digital blood flows were improved 2. After 2 mo there was an increase in the hyperemic flow response to a 40 s period of hypoemia 3. Within 3 mo, serum cholesterol, triglycerides, and plasma fibrinogen levels decreased 4. Improvement in subjective assessments of severity of symptoms Not significantly changed 1. Hand blood flow 2. No consistent changes in systolic or diastolic blood pressures aNumbers in parentheses indicate a significant difference compared with placebo (that is, test versus placebo). CO = crossover; DB = double-blind; PD = parallel designed; PL = placebo; PRP = primary Raynaud’s phenomenon; R = randomized; RP = Raynaud’s phenomenon; SB = single blind; SIT = simply intervention tested (that is, lacking any control and intervention design); SRP = secondary Raynaud’s phenomenon.

R72 JOURNAL OF FOOD SCIENCE—Vol. 70, Nr. 4, 2005 URLs and E-mail addresses are active links at www.ift.org Raynaud’s phenomenon and foods . . .

Studies. With respect to RP and the microcirculation, 1 study has safeguard against diabetes and reduce the development of pe- investigated L-C (Table 1), and this was performed in 12 RP pa- ripheral sympathetic dystrophy. Few studies have investigated the tients who were asked to consume 1 g of L-C 3 times per day for 20 effect of vitamin C on the microcirculatory flow of blood in the hand d (Gasser and others 1997). The authors reported a number of vas- (Daanen 2003). If it is capable of promoting peripheral blood flow cular improvements. Erythrocyte velocity increased, as did the then it would be of potential use in RP. perfusion of blood during a simulated cold intervention. Other Studies. Single, high oral doses (2 g) have been shown to dilate benefits were a reduction in the time taken for blood flow to recover radial conduits, and this effect was more marked than that induced to normal values after the application of the cold stimulus and a by diltiazam (a calcium channel blocker) (Drossos and others 2003). decrease in systolic blood pressure. Vitamin C has also been shown to inhibit radial artery vasospasm R: Concise Reviews in Food Science Conclusions. Overall, L-C was shown to improve tissue perfusion (Drossos and others 2003) and might provide symptomatic relief in and to reduce the recovery time after a cold pressor test. In this RP. Another study (Purkayastha and others 1999) assessed vaso- study, the cold pressor was used to simulate a vasospastic attack. constrictor responses to cold immersion and a change in altitude, in Therefore, the decrease in recovery time represents the protection subjects consuming vitamin C (500 mg/d), vitamin E (400 mg/d), or provided by L-C against potential ischemic tissue damage. Howev- a combination of the two. At high altitude (3700 m versus 200 m), er, the down side of this story is the lack of concurrent studies, and those subjects consuming vitamins E and C seemed to maintain so more and better-designed studies are needed to confirm such better hand blood perfusion and higher skin temperatures. In a benefits. pilot study (Shand and others 2003), the vascular effects of a vita- min C (240 mg/d) and pine bark extract (480 mg/d) were assessed Inositol hexaniacinate and reported to decrease blood pressure and plasma viscosity and

Background. Vitamin B3 comes in 2 basic forms, niacin (or nicotin- to increase blood flow and forearm hyperemic responsiveness. ic acid) and niacinamide (or nicotinamide). Inositol hexaniacinate Whether this was due to the vitamin C or the pine bark extract is

(IH) is a variant of niacin. In vivo, water-soluble vitamin B3 is used in unclear, but more controlled studies will be able to assess this. the release of energy from carbohydrates and fat and to process al- Conclusions. Vitamins C might promote peripheral dilation and cohol. Niacin, but not niacinamide, is associated with vascular ben- even reduce vasospastic episodes. Thus, it may be of benefit in RP, efits because it is implicated in the regulation of cholesterol. but further research into its putative benefits needs further re- Studies. Table 1 outlines the 5 studies that investigated the ef- search before firm conclusions can be made. fects of IH in RP, and 4 of them can be criticized because they are lacking a study control (Ring and others 1977, 1981; Aylward 1979; Other Benefits that Foods May Provide Holti 1979; Sunderland and others 1988). The conclusions of these o far we have focused on foods that may promote vascular dila- studies were as follows. In RP, symptomatic improvements were Station and this is the main approach to RP (Block and others reported when IH was consumed for 3 (Holti 1979; Sunderland and 2001). However, foods that serve to protect the endothelium against others 1988) and 9 mo (Ring and others 1977, 1981; Aylward 1979). reperfusion injury (that may lead to conditions such as systemic scle- Two studies (Aylward 1979; Holti 1979) assessed responses of flow, rosis [Simonini and others 1999, 2000]) may benefit those with RP. and increases were reported after 2, 3, and 9 mo of consumption Two strategies may be considered in such cases. The 1st is to sustain (Aylward 1979; Holti 1979). Four studies have assessed hand skin or improve normal endothelial function using food compounds (Root temperature responses and they reported little (Holti 1979) or no and others 2004) or to limit oxidative stress by increasing the intake effect after 12 wk of consumption (Sunderland and others 1988) or of antioxidants (for example, vitamins C and E). Both approaches an increase after 9 mo of usage (Ring and others 1977, 1981). may be a safeguard against potential dysfunction, but whether they Symptomatic improvements were also assessed, and 3 of the 4 are effective for existing damage is unclear. In the case of systemic studies reported symptomatic improvements over the course of the sclerosis, Herrick and others (2000) suggested that treatment with intervention (Aylward 1979; Holti 1979; Ring and others 1981), and antioxidants is needed early in the progression of a disease to be the other found little or no effect with IH (Sunderland and others effective. Hence, the continuous use of foods rich in antioxidants 1988). Unfortunately, these were not very well designed or con- may be an ideal candidate for preventing putative damage. Another trolled intervention studies and so better-designed intervention option for those with RP may be to combine foods, or to incorporate trials need to be performed to support their findings. foods that vasodilate and also work as antioxidants. Conclusions. IH may improve RP-related cold symptoms and even promote microcirculatory blood flow; however, firm conclu- Future Directions and Research Needs sions cannot be drawn from the present studies due to their design cientific investigators have provided some evidence that di- limitations. Setary ingredients or compounds may be beneficial for those with RP. Other options to explore may be to determine whether Other Foods foods having effects in other circulations, such as the eyes and the he foods already discussed may not be the only options avail- lower limbs, also exhibit their influence on the microvessels of the Table as other foods or foods based on the structure of compounds, hands or feet (for example, determine whether they have homog- may have effects on the microcirculation, and might be more potent enous effects). Another approach may be to target foods that have vasodilators or provide better symptomatic relief than those detailed effects on specific receptors involved in the manifestation of RP. For previously. One example compound may be vitamin C. example, screening for foods that affect peripheral alpha-2 recep- tors, which are suggested to be hypersensitive in RP (Turton and Vitamin C others 1998) and may be of use in attenuating vascular constriction Background. Vitamin C has been suggested, at least, to contrib- to cold. Presently, a great deal of research is focusing on the vascu- ute to a number of vascular health benefits, which include the re- lar functions of foods, of which this review is one. However, in the duction of LDL cholesterol oxygenation, arterial wall stiffness, and field of RP, more research is still required because available studies platelet aggregation. It is also suggested to improve nitric oxide can be criticized for one of the following design limitations: that it activity and reverse dysfunctional endothelial cells. As well, it might was not very well designed, meaning that sample sizes were too

URLs and E-mail addresses are active links at www.ift.org Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R73 R: Concise Reviews in Food Science Raynaud’s phenomenon and foods . . .

small, subjects were not homogenous, only acute effects of the Bongard O, Bounameaux H. 1993. Clinical investigation of skin microcircula- tion. Dermatology 186:6–11. treatment were tested, or studies were not placebo-controlled. Also, Bounameaux HM, Hellemans H, Verhaege R. 1986. Digital pressure and flow those that are available need further substantiation. Therefore, in measurement upon local cooling in Raynaud’s disease. Effect of naftidrofuryl. Int Angiol 5:39–44. line with the increasing public interest in the health benefits of Bruckner G, Webb P, Greenwell L, Richardson D. 1987. Fish oil increases periph- botanicals, supplements, and foods, better-designed studies need eral capillary blood cell velocity in humans. Atherosclerosis 66:237–45. Bunker CB, Reavley C, O’Shaughnessy DJ, Dowd PM. 1993. Calcitonin gene- to be conducted, and more dietary interventions need to be as- related peptide in treatment of severe peripheral vascular insufficiency in sessed. Such research will permit health care professionals to prop- Raynaud’s phenomenon. Lancet 342:80–2. erly inform patients on scientific evidence, but may also be of value Cerinic MM, Generini S, Pignone A. 1997. New approaches to the treatment of Raynaud’s phenomenon. Curr Opin Rheumatol 9:544–56. to food manufacturers. Indeed, there is a growing demand for so- Coffman J. 1989. Raynaud’s phenomenon. New York: Oxford Univ. Press. called healthy foods, and fortification with ingredients may serve Cui J, Das DK, Bertelli A, Tosaki A. 2001. Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and ap- to improve health and wellness. optotic cardiomyocyte death in isolated rat hearts. Cardiovasc Res 254:227–34. Daanen HAM. 2003. Finger cold-induced vasodilation: a review. Eur J Appl Phys- iol 89:411–26. Conclusions Darton K, Black CM. 1991. Pyroelectric vidicon thermography and cold challenge number of ingredients have been investigated and shown to quantify the severity of Raynaud’s phenomenon. Br J Rheumatol 30:190–5. DiGiacomo RA, Kremer JM, Shah DM. 1989. Fish-oil dietary supplementation in Ahave positive effects on the microcirculation. Indeed, from re- patients with Raynaud’s phenomenon: a double-blind, controlled, prospec- viewing the available literature, it is evident that beneficial effects tive study. Am J Med 86:158–64. Drossos GE, Toumpoulis IK, Katritsis DG, Ioannidis JP, Kontogiorgi P, Svarna E. can be achieved via promoting microcirculatory flow, improving 2003. Is vitamin C superior to diltiazem for radial artery vasodilation in pa- hand skin temperature, or simply providing symptomatic relief tients awaiting coronary artery bypass grafting? J Thorac Cardiovasc Surg (Table 1). Indeed, fish oil, garlic, ginkgo biloba, L-carnitine, and 125:330–5. Freedman R, Mayes M. 1996. Familial aggregation of primary Raynaud’s dis- inositol nicotinate have been reported to improve flow (that is, ease. Arthrit Rheumat 39:1189–91. erythrocyte velocity or microcirculatory blood flow). Evening prim- Gasser P. 1991. Reaction of capillary blood cell velocity in nailfold capillaries to nifedipine and ketanserin in patients with vasospastic disease. J Int Med Res rose oil, ginkgo biloba, and inositol nicotinate have been found to 19:24–31. provide some symptomatic relief from cold, and increases in hand Gasser P, Martina B, Dubler B. 1997. Reaction of capillary blood cell velocity in nailfold capillaries to L-carnitine in patients with vasospastic disease. Drugs skin temperature have been documented in those taking inositol Exp Clin Res 23:39–43. nicotinate. A number of these studies, however, were not well con- Generini S, Del Rosso A, Pignone A, Cerinic MM. 2003. Current treatment op- tions in Raynaud’s phenomenon. Curr Treatment Options Cardiovasc Med trolled. Some ingredients need further validation or more studies 5:147–61. need to be performed to confirm what is already known. Green MR, Ouderaa Fvd. 2003. Nutrigenetics: where next for the foods industry? Pharmacogenomics 3:191–3. At the present time, more ingredients with beneficial effects in RP Hahn M, Heubach T, Steins A, Junger M. 1998. Hemodynamics in nailfold capillar- need to be identified, and others need more rigorous testing (for ex- ies of patients with systemic scleroderma: synchronous measurements of cap- ample, vitamin C and/or bioflavonoids, and nicotine-like com- illary blood pressure and red blood cell velocity. J Invest Dermatol 110:982–5. Herrick AL. 2003. Treatment of Raynaud’s phenomenon: new insights and de- pounds). Possible options for foods may be the targeting of vasoactive velopments. Curr Rheumatol Rep 5:168–74. receptors (which requires further research into the possible effect of Herrick AL, Hollis S, Schofield D, Rieley F, Blann A, Griffin K, Moore T, Braganza JM, Jayson MI. 2000. A double-blind placebo-controlled trial of antioxidant ther- foods on specific receptors) or to increase the consumption of foods apy in limited cutaneous systemic sclerosis. Clin Exp Rheumatol 18:349–56. with associated benefits to those with RP (that is, the intake of antiox- Holti G. 1979. An experimentally controlled evaluation of the effect of inositol nicotinate upon the digital blood flow in patients with Raynaud’s phenome- idants to delay or deter the onset of systemic sclerosis). What is clear is non. J Int Med Res 7:473–83. that further research into this field is needed. Such knowledge will Jung EM, Jung F, Mroietz C, Kiesewetter H, Pindur G, Wenzel E. 1991. Influence of garlic powder on cutaneous microcirculation. A randomised placebo-con- enable general practitioners to inform their patients properly, improve trolled double-blind study in apparently healthy subjects. Arzneimittelfors- the knowledge of alternative approaches to health, and detail the chung 41:626–30. Jung F, Jung EM, Mrowietz C, Kiesewetter H, Wenzel E. 1990a. Influence of garlic health-related benefits of foods to the food manufacturer. powder on cutaneous microcirculation: a randomised, placebo-controlled, double-blind, crossover study in apparently healthy subjects. Br J Clin Pract Acknowledgments Suppl 69:30–5. Jung F, Mrowietz C, Kiesewetter H, Wenzel E. 1990b. Effect of ginkgo biloba on We are grateful for informal discussions with Drs. F. McGlone (Uni- fluidity of blood and peripheral microcirculation in volunteers. Arzneimit- lever Research and Development, Port Sunlight, U.K.), E. de Groot telforschung 40:589–93. Kiesewetter H, Jung F, Mrowietz C, Wenzel E. 1992. Hemorrheological and circu- (Amsterdam Medical Center), M.G. Egbrink and A.J. Houben (Univ. latory effects of gincosan. Int J Clin Pharmacol Therap Toxicol 30:97–102. of Maastricht), and Prof. H.A. Daanen (TNO Human Factors, Soest, Kiesewetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E. 1991. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. The Netherlands). This research was funded by a Marie Curie fel- Int J Clin Pharmacol Therap Toxicol 29:151–5. lowship awarded to Dr. C.I. Wright. Kleijnen J, Knipschild P. 1992. Ginkgo biloba. Lancet 340:1136–9. Költringer P, Eber O, Langsteger W, Wakonig P, Klima G, Rothlauer W. 1989. Mik- rozirkulation und viskoelastizität des vollblutes unter ginkgo-biloba-extrakt. References Perfusion 1:28–30. Allen E, Brown G. 1932. Raynaud’s disease: a critical review of minimal requi- Landry G, Edwards J, Porter J. 1996. Current management of Raynaud’s syn- sites for diagnosis. Am J Med Sci 183:187–95. drome. Adv Surg 30:333–47. Allen J, Frame JR, Murray A. 2002. Microvascular blood flow and skin tempera- Lango R, Smolenski RT, Narkiewicz M, Suchorzewska J, Lysiak-Szydlowska W. ture changes in the fingers following a deep inspiratory gasp. Physiol Measur 2001. Influence of L-carnitine and its derivatives on myocardial metabolism 23:365–73. and function in ischemic heart disease and during cardiopulmonary bypass. Aylward M. 1979. Hexopal in Raynaud’s disease. J Int Med Res 7:484–91. Cardiovasc Res 51:21–9. Belch J. 1997. Raynaud’s phenomenon. Cardiovasc Res 33:25–30. Lau CS, McLaren M, Saniabadi A, Scott N, Belch JJF. 1991. The pharmacological Belch JJ, Ho M. 1996. Pharmacotherapy of Raynaud’s phenomenon. Drugs 52:682– effects of cicaprost, an oral prostacyclin analogue, in patients with Raynaud’s 95. syndrome secondary to systemic sclerosis - a preliminary study. Clin Exp Rheu- Belch JJ, Shaw B, O’Dowd A, Saniabadi A, Leiberman P, Sturrock RD, Forbes CD. matol 9:271–3. 1985. Evening primrose oil (Efamol) in treatment of Raynaud’s phenomenon: Leppert J, Ringqvist A, Ahlner J, Myrdal U, Walker-Engström M, Wennmalm A, a double blind study. Thrombosis Haemostasis 54:490–4. Ringqvist I. 1997. Seasonal variations in cyclic GMP response on whole-body Belch JJF, Capell HA, Cooke ED, Kirby JDT, Lau CS, Madhok R, Murphy E, Steinberg cooling in women with primary Raynaud’s phenomenon. Clin Sci 93:175–9. M. 1995. Oral iloprost as a treatment for Raynaud’s syndrome: a double blind LeRoy EC, Medsger TA. 1992. Raynaud’s phenomenon: a propsal for classifica- multicentre placebo controlled study. Ann Rheumatic Dis 54:197–200. tion. Clin Exp Rheumatol 10:485–8. Belch JJF, Hill A. 2000. Evening primrose oil and borage oil in rheumatologic Mahoney B. 1999. Raynaud’s syndrome. Podiatry encyclopedia [serial online]. conditions. Am J Clin Nutr 71:352S–6S. Perth, Western Australia: School of Physiotherapy, Curtin Univ. of Technology Block JA, Sequeira W. 2001. Raynaud’s phenomenon. Lancet 357:2042–8. Available from: www.podiatry.curtin.edu.au/encyclopedia/raynauds. Assessed Boelsma E, Hendriks HFJ, Roza L. 2001. Nutritional skin care: health effects of Apr 22, 2005. micronutrients and fatty acids. Am J Clin Nutr 73:853–64. Malpas SC. 2004. What sets the long-term level of sympathetic nerve activity: is

R74 JOURNAL OF FOOD SCIENCE—Vol. 70, Nr. 4, 2005 URLs and E-mail addresses are active links at www.ift.org Raynaud’s phenomenon and foods . . .

there a role for arterial baroreceptors? Am J Physiol 286:R1–R12. Simonini G, Cerinic MM, Generini S, Zoppi M, Anichini M, Cesaretti C, Pignone Maricq H, Carpentier P, Weinrich M, Keil J, Palesch Y, Biro C, Vionnet-Fuasset M, A, Falcini F, Lotti T, Cagnoni M. 1999. Oxidative stress in systemic sclerosis. Jiguet M, Valter I. 1997. Geographic variation in the prevalence of Raynaud’s Molec Cell Biochem 196:85–91. phenomenon: a 5 region comparison. J Rheumatol 24:879–89. Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM. 2000. Emerging po- Mehlsen J, DrabæK H, Wiinberg N, Winther K. 2002. Effects of a ginkgo biloba tentials for an antioxidant therapy as a new approach to the treatment of sys- extract on forearm hemodynamics in healthy volunteers. Clin Physiol Funct temic sclerosis. Toxicology 155:1–15. Imag 22:375–8. Sunderland GT, Belch JJ, Sturrock RD, Forbes CD, McKay AJ. 1988. A double blind Morris AC, Jacobs I, McLellan TM, Klugerman A, Wang LC, Zamecnik J. 1996. No randomised placebo controlled trial of hexopal in primary Raynaud’s disease. ergogenic effect of ginseng ingestion. Int J Sports Nutr 6:263–71. Clin Rheumatol 7:46–9. Muir AH, Robb R, McLaren M, Belch JJ. 2002. The use of ginkgo biloba in Raynaud’s Szallasi A, Di Marzo V. 2000. New perspectives on enigmatic vanilloid receptors. disease: a double-blind placebo-controlled trial. Vasc Med (Lond) 7:265–67. Trends Neurosci 23:491–7.

Murai C, Sasaki T, Osaki T, Hatakeyama A, Shibata S, Yoshinaga K. 1989. Oral Tucker AT, Pearson RM, Cooke ED, Benjamin N. 1999. Effect of nitric-oxide gen- R: Concise Reviews in Food Science limaprost for Raynaud’s phenomenon. Lancet 2:1218. erating system on microcirculatory blood flow in skin of patients with severe Purkayastha SS, Sharma RP, Ilavazhagan G, Sridharan K, Ranganathan S, Selva- Raynaud’s syndrome: a randomised trial. Lancet 354:1670–5. murthy W. 1999. Effect of vitamin C and E in modulating peripheral vascular Turton EPL, Kent PJ, Kester RC. 1998. The etiology of Raynaud’s phenomenon. response to local cold stimulus in man at high altitude. Jpn J Physiol 49:159–67. Cardiovasc Surg 6:431–40. Raynaud AGM. 1888. On local asphyxia and symmetrical gangrene of the ex- Usuki K, Kanekura T, Aradono K, Kanzaki T. 1998. Effects of nicotine on periph- tremities. London: New Sydenham Society. 121 p. eral cutaneous blood flow and skin temperature. J Dermatol Sci 16:173–81. Ring EF, Porto LO, Bacon PA. 1981. Quantitative thermal imaging to assess inos- Vogler BK, Pittler MH, Ernst E. 1999. The efficacy of ginseng. A systematic review itol nicotinate treatment for Raynaud’s syndrome. J Int Med Res 9:393–400. of randomised clinical trials. Eur J Clin Pharmacol 55:567–75. Ring EFJ, Bacon PA. 1977. Quantitative thermographic assessment of inositol von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. 1999. The effect of nicotinate therapy in Raynaud’s phenomena. J Int Med Res 5:217–22. dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, dou- Root M, Anderson JJB. 2004. Dietary effects on nontraditional risk factors for ble-blind, placebo-controlled trial. Ann Intern Med 130:554–62. heart disease. Nutr Res 24:827–38. Wohlrab J, Wohlrab D, Marsch WC. 2000. Acute effect of a dried ethanol-water

Saito S, Shimada H. 1994. Effect of prostaglandin E1 analogue administration on extract of garlic on the microhaemovascular system in skin. Arzneimittelfor- peripheral skin temperature at high altitude. Angiology 45:455–60. schung 50: 606-612. Shand B, Strey C, Scott R, Morrison Z, Gieseg S. 2003. Pilot study on the clinical Yoshikawa T, Naito Y, Kondo M. 1999. Ginkgo biloba leaf extract: review of biolog- effects of dietary supplementation with enzogenol®, a flavonoid extract of ical actions and clinical applications. Antioxidants Redox Signal 1:469–80. pine bark and vitamin C. Phytother Res 17:490–4.

URLs and E-mail addresses are active links at www.ift.org Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R75