Veterinary Dermatology 2004, 15 , 99 –107 Treatment of dermatophytosis in dogs and cats: review of published studies Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, ( Received 31 January 2003; accepted 24 July 2003) Abstract The recent literature
Journal5-6.newEffects of Black Currant Anthocyanoside
Intake on Dark Adaptation and VDT
Work-induced Transient Refractive
Alteration in Healthy Humans
Hitoshi Nakaishi, MD, DMSC, Hitoshi Matsumoto, MS,
Shigeru Tominaga, MS, and Masao Hirayama, PhD
AbstractThe effects of oral intake of a black currant anthocyanoside (BCA) concentrate on darkadaptation, video display terminal (VDT) work-induced transient refractive alteration,and subjective asthenopia symptoms (visual fatigue) were examined in a double-blind,placebo-controlled, crossover study with healthy human subjects. In a dark adaptationstudy, intake of BCA at three dose levels (12.5-, 20-, and 50 mg/subject, n = 12) appearedto bring about dose-dependent lowering of the dark adaptation threshold. Statisticalanalysis comparing the values before and after intake indicated there was a significantdifference at the 50 mg dose (p= 0.011). Comparing the refraction values for the dominanteye, BCA intake (50 mg/subject, n = 21) resulted in no decrease in the average valueafter the visual task; whereas, a placebo trial resulted in a large decrease in the averagevalue, resulting in borderline significance (p = 0.064). In the assessment of subjectiveasthenopia symptoms by questionnaire, significant improvement was recognized onthe basis of the statements regarding the eye and lower back after BCA intake.
(Altern Med Rev 2000;5(6):553-562) Introduction
In the previous decade, the rapid spread of computers and video display terminals (VDTs) in the home and workplace has led to an increase in ocular and visual problems, including eyediscomfort, blurring of distant objects, eye strain, and asthenopia (visual fatigue).1,2 Regardingnutritional mitigation of visual function problems, several dietary constituents, such as caro-tenoids,3 long-chain polyunsaturated fatty acids,4 and anthocyanosides5 have been shown to Hitoshi Nakaishi, MD, DMSC – Ophthalmologist and lecturer, University of Tsukuba (Department of Public Health, Collegeof Medical Technology and Nursing) Correspondence address: 3-8-15, Hon-Amanuma, Suginami-ku, Tokyo 167-0031,Japan Hitoshi Matsumoto, MS – Chemist and researcher, Nutritional Science Center, Bio Science Laboratories, Meiji Seika KaishaLtd Correspondence address: 5-3-1, Chiyoda, Sakadoshi, Saitama 350-0289, Japan. Email:email@example.com Shigeru Tominaga, MS – Agricultural chemist and chief researcher, Nutritional Science Center, Bio Science Laboratories,Meiji Seika Kaisha, Ltd Masao Hirayama, PhD – Natural products chemist and director of the R&D Management Division, Bio Science Laboratories,Meiji Seika Kaisha, Ltd Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000 Page 553
Figure 1: HPLC Profile of a Powdered
Concentrate of BCA. Assignment: (a)
D3G, (b) D3R, (c) C3G, and (d) C3R.
to evaluate the functions of anthocyanosidepreparations with different compositions in affects physiological activity. Black currant(Ribes nigrum L.) fruits and juice, known tobe rich in anthocyanosides, are commonlyconsumed in many parts of the world.11 In the present study, a powdered concentrate of BCAwas developed from a commercial source,12 which was found to consist of fouranthocyanoside components, having a simplecomposition compared with bilberry, which has fifteen anthocyanoside components. Itssimple composition is assumed to facilitateevaluation of the structure-activity relationship in studies on the physiological activity andbioavailability of the components.
myopic shift of refractive status following anextended and/or continuous near visual task is thought to be the most reliable indicator ofvisual fatigue.13 However, there have been no reports on the measurement of the alteration complex from bilberry (Vaccinium myrtillus or shift after oral intake of anthocyanosides.
L.) fruits has been reported to enhance visual This paper reports that oral intake of BCA acuity at night.6 This effect is reported to be brought about lowering of the dark adaptation exerted through acceleration of rhodopsin re- threshold in a double-blind, placebo-con- generation7 and/or activation of retinal en- trolled, crossover study with human subjects, zymes.8 Although the number of scientific re- and that the intake of BCA counteracted the ports is few, this information has attracted transient myopic shift of refractive status af- much interest in screening anthocyanoside ho- ter visual tasks such as VDT operation. In ad- mologues to identify the active compound(s).
dition, assessment utilizing a questionnaire This information also suggests that intake of exhibited that BCA intake prevented or im- anthocyanoside-rich foods may have previ- proved subjective symptoms of visual fatigue ously unknown effects in terms of preventing visual problems attributable to working withcomputers and VDTs.
Test sample of BCA
anthocyanoside-rich foods and fruits, and the pared from a commercially available black currant juice by the method developed in a preparation process. As the anthocyanoside previous study.12 The concentrate contains 9.2- composition is assumed to play an important percent BCA, consisting of delphinidin 3- role in terms of the physiological activity rutinoside (D3R, 4.61%), delphinidin 3-glu- displayed (such as the French paradox9 of red coside (D3G, 1.36%), cyanidin 3-rutinoside wine and antioxidant activity10), it is important Page 554 Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 1: The Composition of the Test Samples (capsules and
juice) used for the Dark Adaptation Study and the Transient
Refractive Alteration Study.
Type and composition of test sample, g/subject 1. The amount in the case of a dose of 50 mg BCA/subject. In case of a dose of 25 or 12.5 mg of BCA, the value is reduced to a half and a quarter of that shown, respectively.
(C3R, 2.83%), and cyanidin 3-glucoside (C3G, 0.40%), as shown by the HPLC profile in Fig- anthocyanosides (vegetables, fruits, and juice).
ure 1. As test samples, capsules were used for All tests were started between 9 a.m. and 11 the dark adaptation study and juice was used for the transient refractive alteration study. Foreach study, a placebo was prepared so as to Study design
have a taste and color equivalent to those of the test sample. The compositions of the test trolled, crossover study in which the subjects samples and placebo preparations are shown were assigned to four groups: one group given in Table 1. All other nutrients, reagents, and placebo and three groups given doses of BCA chemicals used were purchased from commer- concentrate (540, 270, and 135 mg/subject, corresponding to 50, 25, and 12.5 mg BCA/subject). Each dose of BCA or placebo was Dark Adaptation Study
eight females; body weight, 52-70 kg; age, 24- 51; mean 33.3 years old) showing no patho- logical ocular signs participated in this study.
The study was conducted according to the prin- Helsinki and Tokyo; i.e., informed consent was obtained after full explanation of the nature of the procedure to each subject. On the day be-fore the experiment subjects were asked to Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000 Page 555
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 2: Age, Sex, and Refractive Status of Individual
Subjects in a Transient Refractive Alteration Study.
answer concerningthe direction. The di-rection of the bars domly (vertical, hori-zontal, right diagonal, Transient
20-25; mean 20.9 years old) were enrolled in the study. They were confirmed to be free of sured binocularly with a Goldmann-Weekers any ocular diseases, refractive errors (high Adaptometer (Haag-Streit, Switzerland). Af- myopia more than 4 diopter, hyperopia more ter brief pre-adaptation in complete darkness than 1 diopter, or astigmatism of which the for two minutes, the subjects looked for ten strongest curvature was more than 1.5 diopter), minutes into the center of a white sphere with or presbyopia at the time of enrollment, as luminance of 2000 asb (light adaptation). Next, shown in Table 2. All of the subjects gave writ- during dark adaptation, a circular test field with ten informed consent according to the Decla- 11 degrees of arc with dark and light bars (con- rations of Helsinki and Tokyo prior to the start trast 100%, width 1.5 cm) was presented cen- trally at a distance of 30 cm, and the dark ad-aptation threshold was measured during each Study design
ten seconds of the first ten minutes until the cone-rod break time, then each minute until crossover study with subjects assigned to ei- 30 minutes after the start. The dark adaptation ther a BCA or a placebo group. The subjects threshold was determined by increasing the were asked to avoid caffeine, nicotine, and light intensity of the light bars until the sub- foods rich in anthocyanosides (vegetables, ject perceived the bars and gave the correct fruits, and juice) for 24 hours before the study.
Page 556 Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission The subjects were given a cup of juice (200 in UP mode and the mean of the five fusing values was determined. Third, subjective fa- subject, corresponding to 50 mg of BCA/sub- tigue symptoms were assessed by a question- ject) or placebo, the compositions of which naire consisting of five statements concerning are shown in Table 1. Regarding the question- the fatigue symptoms of the head and/or neck, naire for the assessment of subjective astheno- arm, eye, shoulder, and lower back. The mag- pia symptoms, the subjects were instructed to respond by placing a mark showing the mag- terms of VAS by having the subject place a nitude of the symptoms on a Visual Analog mark on a 100 mm horizontal line indicating a continuum from no fatigue (left end) to strong fatigue (right end). The subject’s re- sponse to each statement was defined as the fraction values for the dominant eye, flicker distance (in millimeters) from the left end of Statistical Analyses
before and after intake of the test samples (BCA concentrate or placebo). Comparisonwas made by means of a paired-t test.
BCA Test Sample
BCA concentrate used in this study was 9.2percent by HPLC analysis.12 As shown in Fig- Variables Measured
ure 1, the concentrate consisted of four com- sisted of a simple calculation test on a VDT, component was quantified by HPLC. The re- modifying the Kraepelin test method.15 The sults of analysis of the BCA test samples (cap- task was loaded for two hours without a pause, sules and juice) are shown in Table 1. In prepa- and measurements were carried out for three ration of the juice-type test samples, sucrose, items. First, the spherical (R) and cylindrical citric acid, and coloring pigments were added (C) refraction of the dominant eye was mea- to make the placebo’s taste and color identical sured by means of an autorefractometer (Nidek AR-600A, Japan) according to the method ofNakamura and Uosato.16 The refraction value Dark Adaptation Study
for the dominant eye was evaluated in terms of the spherical equivalent of (S + C/2). Sec- healthy volunteers were measured as the vi- ond, the M value (flicker value) was mea- sual threshold after 30 minutes of dark adap- sured using critical flicker fusion (CFF) de- tation, before and two hours after intake of termined via a Flicker 501 (Takei Kiki Kogyo, BCA (at three dose levels: 50, 25, and 12.5 Japan) according to the method reported by mg/subject) or placebo. The results are sum- Ogasawara et al.17 This measurement was car- marized in Table 3. Figure 2 shows the typical ried out five times with the signal frequency profile of dark adaptation threshold values Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000 Page 557
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 3: Dark Adaptation Values Measured Before and After Intake of BCA
or Placebo in a Dark Adaptation Study.
Dark adaptation value, mean–SD of log asb; (p value)1 1. The results of statistical analysis, independently carried out in each vertical row, are shown in parentheses.
2. Statistical p value for "after intake" vs "before intake" in each horizontal row.
during the 30-minute period before and after at only one dose level of BCA (50 mg/sub- BCA intake in the case of one subject. The mean standard deviation before intake rangedfrom 2.056 ± 0.209 (placebo) to 2.016 ± 0.170 Transient Refractive Alteration
(BCA, 25 mg/subject). No significant differ- ence was found among the four groups as a individual subjects are shown in Table 2. Re- standard deviation after intake among the four fraction values for the dominant eye (desig- groups showed a decrease from 2.018 ± 0.218 nated as diopter (D)), measured before (M 1) (placebo) to 1.923 ± 0.167 (BCA, 50 mg/sub- ject) with increasing doses of BCA. This dose- dependent decrease of the threshold was as- sociated with expansion of the change in the intake resulted in no decrease in the average refraction values for the dominant eye (M ) value after the visual task (from M 1 of -0.432 from -0.038 ± 0.106 (placebo) to -0.115 ± ± 0.602 D to M 2 of –0.402 ± 0.643 D, p = 0.131 (BCA, 50 mg/subject), comparing the 0.598), whereas in the placebo trial after the values before and after intake. At the BCA dose visual task there was a large decrease in the level of 50 mg/subject, compared to the pla- refraction values, exhibiting borderline signifi- cebo, there was a significant difference (p = cance (from M 1 of –0.384 ± 0.536 D to M 2 0.014) in the threshold values after intake, but of –0.503 ± 0.579 D, p = 0.064). Average In comparing the statistical p values obtained placebo were –0.030 ± 0.252 D and 0.119 ± in analysis of the data after intake versus be- 0.278 D, respectively, and a statistically sig- fore intake among four dose levels of BCA, a nificant difference was evident (p = 0.006).
significant difference (p = 0.011) was evident Page 558 Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Figure 2: Typical Dark Adaptation Threshold
Before (continuous line) and After (dotted line) BCA Intake in the Case of One Subject During against 42.83 ± 33.55 mm, p =0.052; change, 19.16 ± 22.74 against 35.48 ± 30.87 mm, p =0.025).
adaptation threshold after 30minutes, shows the visual thresh- every dose level (50, 25, and12.5 mg/subject), and that intake threshold (p = 0.011); the resultis a statistically significant im-provement in dark adaptation ues and the assessment of subjective visual threshold began in the first 10 minutes of cone fatigue symptoms before and after the task in break and continued until the end of the ex- the subjects given BCA or placebo are sum- amination, 30 minutes after the start (Figure marized in Table 5. The average flicker values 2). As this feature is consistent with that ob- after the task were 34.39 ± 3.51 and 34.13 ± served in a study on bilberry anthocyanosides,4 2.90 Hz, respectively, and the changes com- oral intake of anthocyanosides is thought to paring the values before and after were small, affect preferably rod components involved in within one Hz. Statistical analysis exhibited dark adaptation. However, not all studies have no significant difference in these parameters found positive improvements with bilberry extracts; for example, one in which research- values obtained in assessment of subjective ers reported no improvement in night visual asthenopia symptoms for each of the five state- ments, all average values after the task were higher than those before the task in both the In a transient refractive alteration study, it was shown that oral intake of BCA average value in the case of every statement (50 mg/subject) has the effect of preventing after BCA intake was smaller than that after myopic refractory shift after visual tasks on placebo intake. Statistical analysis of the data VDTs. This is the first scientific report of di- on each statement showed a significant differ- etary anthocyanosides having such a preven- ence between BCA intake and placebo intake tive effect, except for a recent report19 on bil- in two statements, one regarding the eye (af- berry anthocyanosides which had the effect of ter, 47.31 ± 24.72, against 56.72 ± 25.24 mm, promoting recovery of visual acuity in cases Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000 Page 559
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Table 4: Refraction Values for the Dominant Eye, Measured
Before and After the Task in Subjects Given BCA or Placebo, and the Change in Refractive Alteration. 1) data could be ex-plained as a hyper-opic shift rather 1) Mtra1 and Mtra2 are the measured values and DMtra is the change (Mtra1-Mtra2).
3) Statistical analysis of Mtra2 and DMtra was independently carried out for each dominant eye comparing the BCA and placebo groups. a,b,a),b) Values with different superscript letters are significantly different (p<0.05). Superscript letters without and with parentheses show the results of statistical analysis of refraction is re-ported to comprisethe major part ofvisual fatigue.20 of pseudomyopia in primary school students upon oral intake every day for eight weeks.
BCA and placebo, and the latter provided in- teresting information through analysis of the dietary anthocyanosides may serve as a new five statements. As shown in Table 5, all aver- means of preventing myopic refractory shift age values after the task were found to be during visual tasks or promoting visual recov- smaller than those before the task, thus the task ery. If so, effects such as improvement of dark applied was considered to give the subject an adaptation and rhodopsin regeneration can be adequate load to induce visual fatigue. BCA intake resulted in a significant difference in Page 560 Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission promoted recovery from or servedto prevent VDT work-induced tran- ferent (p<0.05). Superscript letters without and with ferent superscript letters are significantly dif 2) Statistical analysis comparing the values after the test and the change in values was independently carried out in each hori parentheses indicate the results of statistical analysis of the values after the test and the change in values, respectively Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000 Page 561
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission References
Kirshner B, Guyatt GH. A methodologicalframework for assessing health indices. J Tyrrell RA, Leibowitz HW. The relation of vergence effort to reports on visual fatigue Japan Psychotechnology Institute. Uchida- following prolonged near work. Hum Factors Kraepelin psychological test data book. Tokyo: Murata K, Araki S, Yokoyama K, et al.
Nakamura Y, Uosato H. Auto-accomodometer.
fatigue assessed by visual evoked potential, near point distance and critical flicker fusion.
Ind Health 1996;34:61-69.
Ogasawara K, Oohira A, Ozawa T. Thesignificance of CFF for evaluation of astheno- pia due to VDT work. Jap J Traumatol Occup against age-related macular degeneration by carotenoids and antioxidant vitamins. Am JClin Nutr 1995;62:1448S-1461S.
Muth ER, Laurent JM, Jasper P. The effect ofbilberry nutritional supplementation on night Neuringer M. Infant vision and retinal function visual acuity and contrast sensitivity. Altern in studies of dietary long-chain polyunsatu- rated fatty acids: methods, results, andimplications. Am J Clin Nutr 2000;71:256S- Kajimoto O, Sasaki K, Takahashi T. Recovery effect of VMA intake on visual acuity ofpseudomyopia in primary school students. J Morazzoni P, Bombardelli E. Vaccinium New Rem & Clin 2000;49:72-79. [Article in myrtillus L. Fitoterapia 1996;67:3-29.
Jayle PGE, Aubert L. Action des glycosides Simonson E, Brozek J. Flicker fusion fre- d’anthicyanes sur la vision scopique et quency: background and applications. Physiol mesopique du sujet normal. Therapie Tronche P, Bastidem P, Komor J. Effect ofanthocyanin glycosides on the kinetics ofregeneration of the crimson retina in the rabbit.
C R Soc Biol 1967;161:2473-2475.
Virmaux N, Bizec JC, Nullans G, et al.
Modulation of rod cyclic GMP-phosphodi-esterase activity by anthocyanin derivatives.
Biochem Soc Trans 1990;18:686-687.
Renaud S, de Logeril M. Wine, alcohol,platelets, and the French paradox for coronaryheart disease. Lancet 1992;339:1523-1526.
Tsuda T, Ohshima K, Kawakishi S, Osawa T.
Oxidative pigments isolated from the seeds ofPhaseolus vulgaris L. J Agric Food Chem1994;42:248-251.
Banaszczyk J, Plocharski W. Suitability ofblackcurrants for juices and clear nectarsproduction. Fruit Process 1996;6:321-325.
Matsumoto H, Hanamura S, Kishi M, et al. Apreparative-scale isolation of four anthocyanincomponents in blackcurrant (Ribes nigrum L.)fruits. J Agric Food Sci Submitted for publica-tion, 2000.
Grandjean E, Vigliani E, ed. Ergonomic aspectof VDTs. London: Taylor and Francis Co.;1980.
Page 562 Alternative Medicine Review ◆ Volume 5, Number 6 ◆ 2000
Copyright2000 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
T I P S H E E T www.healthinaging.org Expert information from Healthcare Professionals Who Specialize in the Care of Older Adults Ten Medications Older Adults Should Avoid or Use with Caution Because older adults often experience chronic health conditions that require treatment with multiple medications, there is a greater likelihood of experiencing unwanted drug side effects. Ol