Skip to main content
NCBI home page
Annals of Vascular Diseases logoLink to Annals of Vascular Diseases
. 2014 Jul 30;7(3):266–273. doi: 10.3400/avd.oa.14-00055

Examination of Clinical Efficacy of Keishibukuryogan on Non-Specific Complaints Associated with Varicose Veins of the Lower Extremity

Shinobu Hayashi 1,✉, Shintaro Shibutani 1, Hirotoki Okubo 1, Tatsuya Shimogawara 1, Tsuyoshi Ichinose 1, Yasuhiro Ito 1, Kouki Mihara 1, Tomohisa Egawa 1, Atsushi Nagashima 1, Hideaki Obara 2, Yuko Kitagawa 2
PMCID: PMC4180688  PMID: 25298828

Abstract

The subjective symptoms of varicose veins of the lower extremity often include malaise, numbness, coldness, pain, and pruritus of the lower extremity, and relieving these complaints is important in managing the quality of life of patients. We have examined the clinical efficacy of keishibukuryogan, a Kampo prescription for improving oketsu (impaired microcirculation, congestion), on non-specific complaints associated with varicose veins of the lower extremity. Keishibukuryogan was administered to 30 patients with non-specific complaints associated with varicose veins of the lower extremity for 12 weeks, resulting in improvements in the scores of subjective symptoms, severity of varicose veins, and oketsu as well as an increase in skin perfusion pressure. And especially the effect was remarkable in female. In addition, oketsu was shown to be involved in the subjective symptoms associated with varicose veins of the lower extremity, demonstrating efficacy of keishibukuryogan. No adverse drug reaction or abnormal laboratory result was observed in patients receiving keishibukuryogan, and the rate of general improvement and usefulness was 73.3%. It was suggested that keishibukuryogan was useful to improve the symptoms of patients with non-specific complaints associated with varicose veins of the lower extremity especially in female patients. (*English translation of Jpn J Phlebol 2013; 24: 303-310)

Keywords: varicose veins of the lower extremity, keishibukuryogan, Kampo prescription, non-specific complaints, oketsu

Introduction

The subjective symptoms of varicose veins of lower extremity often include malaise, numbness, coldness, pain, and pruritus of lower extremity. At our department, surgical treatment is performed for varicose veins of lower extremity including stripping, catheter venous ablation (laser therapy), and sclerotherapy. The waiting time for surgery, however, is more than nine months due to a large number of patients for whom surgery is indicated because the incidence of varicose vein of lower extremity is very high. As a result, the management of patients’ quality of life (QOL) during the waiting time has been an issue.

Our department has experienced many cases in which the symptoms associated with varicose vein were alleviated by the administration of a Kampo prescription, keishibukuryogan, combined with the compression therapy using elastic compression stockings for medical use.

In order to determine the clinical usefulness of keishibukuryogan for the non-specific complaints associated with varicose vein of lower extremity (malaise, numbness, coldness, pain, and pruritus) and its usefulness as a drug to improve oketsu (impaired microcirculation and non-physiological blood congestion) in patients with varicose vein of lower extremity, we examined the association between oketsu and varicose vein of lower extremity.

Subjects and Methods

The study included 30 patients who met the following four criteria among 163 patients with varicose vein of lower extremity who visited our outpatient department between December 2010 and August 2011: (1) having non-specific complaints (malaise, numbness, coldness, pain, and pruritus), (2) having a varicose vein of C3 or severer (CEAP classification), (3) being suitable for receiving keishibukuryogan for consecutive 12 weeks, and (4) taking no other Kampo prescriptions.

All the diagnoses of varicose vein were made based on ultrasonographic results, and its severity was evaluated according to CEAP (clinical sign, etiologic classification, anatomical distribution, pathophysiologic dysfunction) classification.1)

Having given informed consent for the study, the patients started to take keishibukuryogan extract fine granules (KB-25, Kracie Pharmaceutical, Ltd., Tokyo, Japan) 6 g/day divided in two doses, a regimen selected with a consideration to the patients’ medication compliance. The administration period was 12 weeks. Evaluation was conducted of changes in subjective symptoms (Visual Analogue Scale [VAS]2)), severity of varicose vein (CEAP classification), and oketsu score (modification of the oketsu score by Terasawa, et al.3) [Table 1]) before and after the administration, and blood tests (peripheral blood, biochemical test, prothrombin time-international normalized ratio [PT-INR], activated partial thromboplastin time [APTT], fibrin degradation product [FDP], and D-dimer, etc.) and skin perfusion pressure (SPP) test (using SensiLaseTM PAD 3000 [VÄSAMED, Inc., Eden Prairie, Minnesota, USA]) were conducted.

graphic file with name avd-07-266-t001.jpg

Open in a new tab

The degree of overall improvement was evaluated according to the following criteria with a greater weight attached to the improvements in subjective symptoms and severity of varicose vein:

Markedly improved: VAS score of 0 is recorded in any item of subjective symptoms, and the severity of varicose vein is improved.

Improved: VAS score of 0 is recorded in any item of subjective symptoms, or the severity of varicose vein is improved.

Somewhat improved: VAS score of 0 is not recorded in any item of subjective symptoms, but the scores are improved and the severity of varicose vein is unchanged.

Unchanged: The VAS scores of subjective symptoms are unchanged or worsened, and the severity of varicose vein is unchanged.

Worsened: The VAS scores of subjective symptoms are unchanged or worsened, and the severity of varicose vein is worsened.

The use of concomitant Kampo prescriptions other than keishibukuryogan was prohibited. The concomitant use of anticoagulant or antiplatelet agents was also prohibited as a general rule. If its use, however, was unavoidable and any of these agents was used, a change in its regimen between before and after administration was not allowed. All the patients underwent concomitant compression therapy with elastic compression stockings.

Statistical analysis was conducted using Stat View for Windows version 4.54 (Abacus Concepts, Inc., Piscataway, New Jersey, USA). Paired t-test (intragroup comparison) and unpaired t-test (intergroup comparison) were used for VAS scores of subjective symptoms and oketsu scores as well as for skin perfusion pressure, Wilcoxon signed rank test for severity of varicose vein and oketsu scores by item, as well as laboratory results of coagulation system, and χ2 test for degree of improvement. Statistical significance was considered to be present when risk rate was less than 5%.

Results

1. Patients’ background

The patients’ background is shown in Table 2.

1.

Open in a new tab

2. VAS scores of subjective symptoms

The VAS scores of the subjective symptoms showed a significant improvement (p <0.01) in the total point of malaise, numbness, coldness, pain, and pruritus. Among the scores by symptom, those of malaise (p <0.01) and numbness (p <0.05) showed a significant improvement (Fig. 1A). The analysis of the sex difference in efficacy demonstrated that a significant improvement was recognized in the total point (p <0.001) and all the scores by symptom (p <0.05 for each score) for women, while little improvement was recognized in the total point and all the scores by symptom for men (Fig. 1B).

Fig. 1.

Fig. 1

Open in a new tab

Visual analogue scale (VAS) scores of subjective symptoms. (A) The VAS scores of the subjective symptoms showed a significant improvement in the total point of malaise, numbness, coldness, pain, and pruritus. Among the scores by symptoms, those of malaise and numbness showed a significant improvement. *: p <0.05; **: p <0.01; paired t-test, mean ± SD. (B) In female patients the VAS scores of the subjective symptoms showed a significant improvement in total and each of symptoms. *: p <0.05; **: p <0.01; ***: p <0.001; paired t-test.

3. Severity of varicose vein

Among 17 patients (56.7%) who showed an improvement in the severity of varicose vein, three patients (10.0%) achieved a two-level improvement. An overall significant improvement was recognized in the scores after administration compared with those before administration (p <0.001). No sex difference was observed in the improvement of varicose vein severity (data not shown).

4. Oketsu score

An overall significant improvement was recognized in the oketsu scores (p <0.001). A significant improvement was also observed in each of male and female patients (p <0.001) although the total oketsu score of male patients was different from that of female patients (Fig. 2).

Fig. 2.

Fig. 2

Open in a new tab

Scores of oketsu. An overall significant improvement was recognized in the scores of oketsu. A significant improvement was also observed in each of male and female patients. ***: p <0.001; paired t-test, mean ± SD.

5. Laboratory results of coagulation system

The overall level of FDP was significantly increased (p <0.05), and an increase of the level was also observed in female group, but both the levels were within the reference range. No significant change was observed in other parameters (data not shown).

6. Skin perfusion pressure (SPP)

Overall, significant increases were observed in the skin perfusion pressure measurements of dorsal (p <0.01) and plantar (p <0.001) regions and the average of both measurements (p <0.001) (Fig. 3A). Significant increases were recognized in female group (p <0.01 for dorsal and planter, p <0.001 for average) but not in male group. The level of dorsal region and the average level before administration were significantly lower in female group than in male group (p <0.01) (Fig. 3B).

Fig. 3.

Fig. 3

Open in a new tab

Skin perfusion pressure. (A) Significant increases were observed in the skin perfusion pressure measurements of dorsal and plantar regions and the average of both measurements. **: p <0.01; ***: p <0.001; paired t-test, mean ± SD. (B) In terms of sex, skin perfusion pressure improved significantly in female. Before administration, skin perfusion pressure measurements of dorsal regions and the average of dorsal and plantar regions in female patients were significantly lower than those in male. **: p <0.01; ***: p <0.001; paired t-test, ††: p <0.01, unpaired t-test, mean ± SD.

7. Correlation between improvement level in oketsu scores and that in VAS scores of subjective symptoms

A significant correlation was recognized between the improvement level (the improvement level equals to the level before administration minus the level after administration) in oketsu scores and that in subjective symptoms induced by keishibukuryogan (r = 0.471, p <0.01, data not shown).

8. Correlation between change in skin perfusion pressure and improvement level in VAS scores of subjective symptoms

No significant correlation was recognized between the change in skin perfusion pressure (the level of change equals to the level after administration minus the level before administration) and the improvement level of subjective symptoms (r = 0.145, p = 0.444, data not shown).

9. Safety

No adverse event that was considered to be related to keishibukuryogan was observed in the reports of adverse drug reactions and laboratory tests.

10. Degree of overall improvement

Overall, markedly improved, improved, somewhat improved, unchanged, and worsened results were observed in 5, 17, 3, 5, and 0 patients, respectively, with the improvement rate (improved or better) of 73.3%. Those results were observed in 0, 6, 0, 2, and 0 patients, respectively for men, and 5, 11, 3, 3, and 0 patients, respectively for women, with a significantly better overall improvement in women than in men (p <0.001).

11. Degree of usefulness

The degree of usefulness, which is an integration of the degree of overall improvement and safety, was evaluated as very useful in 5 patients, useful in 17, somewhat useful in 3, and not useful in 5, with the usefulness (useful or better) ratio of 73.3%. Similarly to the degree of overall improvement, a significantly higher ratio was recognized in women than in men (p <0.001).

Discussion

Keishibukuryogan is a Kampo prescription for improving impaired microcirculation and congestive condition. It consists of five herbal components: tonin, shakuyaku, and botampi effective for improving congestion and resolving hematomas, keihi effective for blood circulation promotion with its vasodilating action, and bukuryo for diuresis and antiedematous action. Shakuyaku and botampi also have anti-inflammatory, analgesic, and antipyretic effects.4)

Various researchers have ever reported on the administration of keishibukuryogan for varicose vein of lower extremity. Okuma, et al.5) reported that the prevention rate of thrombi by sclerotherapy for varicose vein of lower extremity combined with keishibukuryogan was higher than that by sclerotherapy without keishibukuryogan. Makita, et al.6) described the improvement of coldness and purpura in patients with varicose vein of lower extremity associated with intermittent claudication. Furthermore, Hirano, et al.7) reported on the case of a patient with varicose vein of lower extremity due to diabetes mellitus in which the administration of keishibukuryogan improved the symptoms of varicose vein and a surgery was avoided. On the other hand, Koike, et al.8) concluded that keishibukuryogan was not effective for relieving the subcutaneous hematoma after stripping.

The studies on the effect of keishibukuryogan for sensory disturbance include that on arteriosclerosis obliterans of lower extremities reported by Yokokawa, et al.9) and that in patients with cerebral stroke reported by Fujita, et al.10) The authors of the both studies estimated that keishibukuryogan with its effects to promote blood fluidity and peripheral blood flow contributed to the alleviation of the subjective symptoms of the patients by improving coldness and numbness. Various effects of keishibukuryogan have so far been reported: decrease in blood viscosity,11) dilation of arteries,11) inhibition of platelet aggregation,12,13) and promotion of erythrocyte deformability14) in the field of basic pharmacology, and increase in blood flow rate,15) decrease in blood viscosity,15–17) inhibition of platelet aggregation,17) inhibition of erythrocyte aggregation,15) promotion of erythrocyte deformability,18) and decrease in hematocrit level15) in the field of clinical pharmacology. These factors may contribute to the effect of keishibukuryogan to increase peripheral blood flow. Also in our study, the improvement of the subjective symptoms associated with varicose vein of lower extremity was considered to be due to the effect of keishibukuryogan to increase peripheral blood flow (microcirculation improving effect) because a significant increase in skin perfusion pressure was observed after the administration of keishibukuryogan. No significant correlation was, however, recognized between the change in skin perfusion pressure and the improvement of subjective symptoms. Since an increase in skin perfusion pressure was observed, the possibility is suggested that keishibukuryogan may be indicated not only for varicose vein of lower extremity, but also for peripheral artery disease (PAD) and diabetic leg lesions, and studies on the efficacy for these diseases are warranted in the future. The efficacy of keishibukuryogan in the field of vascular surgery is described in reports on the improvement of swollen lower extremities in patients with deep venous thrombosis19) and the alleviation of swollen lower extremities after knee replacement surgery20) in addition to the reports mentioned before. Moreover, Niimi, et al.21) reported on the case of a patient who had been unable to walk after high ligation surgery, but recovered the walking ability one year after the administration of keishibukuryogan. In all of these cases, no major adverse drug reaction was described. Thus, keishibukuryogan may be a product that can be used widely and safely in the field of vascular surgery.

Keishibukuryogan is a major prescription for improving a condition called “oketsu” in Oriental medicine,22) and is most frequently used in patients with oketsu having moderate physical fitness. Oketsu, which is a concept equivalent to impaired microcirculation in Western medicine, is one of the pathological entities unique to Oriental medicine and is very important as a clinical concept.23) Varicose vein of lower extremity can be, consequently, interpreted as oketsu in the venous system in Oriental medicine. Studies on oketsu are represented by reports by Terasawa, et al.,3) who analyzed oketsu from the viewpoint of Western medicine, and completed an oketsu score as a diagnostic criteria of oketsu. This oketsu score is frequently used also in the modern Kampo medicine as a tool for evaluating oketsu.9,24) In our study, we simplified the oketsu score by Terasawa, et al. to be used for evaluating, in particular, symptoms related to varicose vein of lower extremity. The results obtained by using the simplified score showed a significant correlation between the improvement of subjective symptoms and that of oketsu scores. Oketsu was shown to be involved in the subjective symptoms associated with varicose vein of lower extremity, and keishibukuryogan was demonstrated to be useful for non-specific complaints in patients with varicose vein of lower extremity. The transition of oketsu scores for different findings observed during our study revealed significant improvements after the keishibukuryogan administration in five findings in addition to the finding “many capillary vessels standing out (like sludge worms)” (data not shown). The finding “many capillary vessels standing out (like sludge worms)” is equivalent to a finding called “sairaku” in Kampo medicine, which is very similar to the finding of web-type varicose vein of lower extremity. The observed improvement in this finding is interesting in terms of the similarities recognized between Oriental and Western medicines. Niimi, in fact, has proposed the potential efficacy of keishibukuryogan for reducing web-type varicose vein of lower extremity.25)

Our study suggested that keishibukuryogan has only a minor clinical implication for laboratory parameters since the FDP level remained within the reference value even after a significant increase was observed. The impacts of keishibukuryogan on the laboratory parameters of coagulation system are shown in reports on shortened PT in disseminated intravascular coagulation (DIC) model rats,26) shortened PT in patients taking warfarin,27) and increased D-dimer in patients having received knee replacement surgery.20) On the other hand, reports on blood coagulation factors in patients receiving keishibukuryogan described decreased fibrinogen in patients with lacunar infarct,18) improved reduction of thrombotest results and AT-III activity in rats with high blood viscosity,28) improved reduction of fibrinogen and platelet in DIC model rats.26) These reports will lead to an assumption that the effects of keishibukuryogan on the coagulation system vary according to the conditions, and these effects will help correct an unbalanced status by exerting impacts both on coagulation and fibrinolysis. Further studies will be, however, needed to examine the effects of keishibukuryogan on the blood coagulation system in patients with varicose vein of lower extremity.

Our study demonstrated improvements in CEAP classification and skin perfusion pressure, objective indices of varicose vein severity, on the basis of which the possibility was suggested that keishibukuryogan would be clinically useful for not only relieving subjective symptoms, but also improving varicose vein of lower extremity itself. Moreover, an improvement in the VAS score of pruritus was also recognized in seven out of eight patients who had been categorized into CEAP classification C4 (skin lesions [lipodermatosclerosis, pigmentation, eczema]) before administration, and achieved an improvement of one level or more (data not shown), showing a relationship between the varicose vein severity determined according to CEAP classification and the improvement in subjective symptoms.

Keishibukuryogan is often used in women to treat conditions such as menopausal symptoms, menstrual abnormality, and uterine leiomyoma. In our study, the female subjects achieved a better improvement of the VAS score for subjective symptoms and a larger increase in skin perfusion pressure than the male subjects did. In particular, subjective symptoms were hardly relieved in male subjects, while they were relieved in female subjects, suggesting a potential sex difference in the effects of keishibukuryogan for patients with varicose vein of lower extremity. Female sex hormone (progesterone) is considered to be one of the important causes of varicose vein of lower extremity.29) Keishibukuryogan is, on the other hand, considered to be a luteinizing hormone-releasing hormone (LH-RH) antagonist that inhibits the secretion of LH and follicle-stimulating hormone (FSH).30) Thus, the inhibitory effect of keishibukuryogan on progesterone secretion may be involved in the sex difference in efficacy observed in our study. Furthermore, although elastic compression stockings were concomitantly used in all the subjects in the study, their effects may not be different between the male and female subjects. The results obtained from the study may suggest an objective efficacy of some extent by keishibukuryogan even though the study was not a comparative one with a group not receiving keishibukuryogan.

Our department uses Kampo prescriptions in many patients presenting the subjective symptoms associated with venous thromboembolism (VTE) or lymphedema other than varicose vein of lower extremity, and the usefulness of Kampo medicine seems to be demonstrated by the high satisfaction of patients. In the clinical setting of vascular surgery department, we experience many cases in which complaints of patients cannot be resolved by an approach of Western medicine alone. Our study showed that the administration of keishibukuryogan may be useful for relieving subjective symptoms, an important issue in treating patients presenting non-specific complaints associated with varicose vein of lower extremity, and that it is considered to be particularly effective for female patients.

Conclusion

Oketsu, a concept in Kampo medicine, was suggested to be involved in the subjective symptoms associated with varicose vein of lower extremity. Keishibukuryogan, which is a drug for improving oketsu, is useful in patients presenting non-specific complaints associated with varicose vein of lower extremity. Keishibukuryogan may be particularly effective for female patients.

Disclosure Statement

All authors have no conflict of interest.

Footnotes

*

This article is English translation of Jpn J Phlebol 2013; 24: 303-310.

References

  1. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004; 40: 1248-52 [DOI] [PubMed] [Google Scholar]
  2. Ogawa S. Concept of change has altered: New key words 100 + α, 1st ed Tokyo: Shinko Trading Company, Publication Department of Medical Books, 2008: 118-9 [Google Scholar]
  3. Terasawa K, Shinoda H, Imadaya A, et al. Symptom analysis of oketsu syndrome and proposal of its diagnostic criteria. Kampo Medicine 1983; 34: 1-17 [Google Scholar]
  4. Yasui H. Guide for Clinical Application of Kampo Prescriptions, ver.1. Tokyo: Korin, 2004: 92-3 [Google Scholar]
  5. Okuma M, Shindo K, Ishida O, et al. Sclerotherapy for varicose vein—summary of 50 cases. Skin Research 1995; 37: 651-7 [Google Scholar]
  6. Makita K. Kampo therapy for varicose vein of lower extremity, coldness, and purpura. The Journal of Traditional Sino-Japanese Medicine Extra Edition 1992; 13: 158-61 [Google Scholar]
  7. Hirano Y. Two cases of diabetes mellitus avoiding surgery for varicose vein of lower extremity by administration of keishibukuryogan. Kampo Medicine 1993; 33: 29-34 [Google Scholar]
  8. Koike Y, Jojima K, Niimi M. Effect of keishibukuryogan on cutaneous hematoma after stripping for varicose vein of lower extremity. Journal of Japanese College of Surgeons 2011; 36: 127-31 [Google Scholar]
  9. Yokokawa K, Horio T, Boku T, et al. Efficacy of keishibukuryogan for arteriosclerosis obliterans of lower extremity. Progress in Medicine 2007; 27: 2625-37 [Google Scholar]
  10. Fujita K, Yamamoto T, Kamezaki T, et al. Efficacy of keishibukuryogan, a traditional Japanese herbal medicine, in treating cold sensation and numbness after stroke: clinical improvement and skin temperature normalization in 22 stroke patients. Neurol Med Chir (Tokyo) 2010; 50: 1-5; discussion 5-6 [DOI] [PubMed] [Google Scholar]
  11. Goto H, Shimada Y, Sekiya N, et al. Effects of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats. Phytomediocine 2004; 11: 188-95 [DOI] [PubMed] [Google Scholar]
  12. Terasawa K, Kimura M, Sakuragawa N, et al. Effects of anti-“Oketsu” drugs on blood coagulation and fibrinolysis. Yakugaku Zasshi 1983; 103: 313-8 (in Japanese) [DOI] [PubMed] [Google Scholar]
  13. Nishimoto T, Kai C, Sasabe A, et al. Effect of anti-oketsu drugs on platelet function (first report)—platelet coagulation inhibitory effect of keishibukuryogan and kanshinnigoho—. Journal of Medical and Pharmaceutical Society for Wakan-yaku, 1985; 2: 596-7 [Google Scholar]
  14. Orita M, Abe H, Arichi S, et al. Effect of keishibukuryogan on erythrocyte deformability. Journal of Traditional Medicines 1984; 1: 243-8 [Google Scholar]
  15. Itoh T, Terasawa K, Kohta K, et al. Effects of Keishi-bukuryo-gan and Trapidil on the microcirculation in patients with cerebro-spinal vascular disease. Journal of Traditional Medicines 1992; 9: 40-6 [Google Scholar]
  16. Tosa H, Hiyama Y, Itoh T, et al. Effects of Keishi-bukuryo-gan on patients with cerebro-spinal vascular disease. Journal of Traditional Medicines 1989; 6: 13-9 [Google Scholar]
  17. Tosa H, Toriizuka K, Terasawa K, et al. The effects of Keishi-bukuryo-gan on blood viscosity, platelet functions and blood coagulation in normal subjects. Journal of Traditional Medicines 1987; 4: 172-9 [Google Scholar]
  18. Hikiami H, Goto H, Sekiya N, et al. Comparative efficacy of Keishi-bukuryo-gan and pentoxifylline on RBC deformability in patients with “oketsu” syndrome. Phytomedicine 2003; 10: 459-66 [DOI] [PubMed] [Google Scholar]
  19. Uchida N. Therapeutic effect of keishibukuryogan on swelling caused by deep vein thrombosis. Jpn J Phlebol 2009; 20: 1-6 (in Japanese) [Google Scholar]
  20. Tamaya M, Maeda M, Mori N, et al. Effect of Kampo prescription (keishibukuryogan) to relieve postoperative swelling of lower extremity. Journal of Orthopedics and Traumatology 2006; 49: 751-3 [Google Scholar]
  21. Niimi M, Shirato H, Kawahara M, et al. A case of a patient who had been unable to walk after high ligation surgery for deep venous thrombosis, but recovered the walking ability after administration of keishibukuryogan. Jpn J Vasc Surg 2010; 19: 404 [Google Scholar]
  22. Takayama K. Guidance for Common Kampo Prescriptions, 47th ed.Tokyo: Organization for Kampo Medicine, Kampo Sanko-juku, 2010: 274-5 [Google Scholar]
  23. Terasawa K. Wakan Medical Practice Learned from Cases, 2nd ed.Tokyo: Igaku-shoin, 2000: 45 [Google Scholar]
  24. Egashira Y, Nishiyama K. Approach to oketsu state using coagulation indices in patients with steroid-dependent asthma. Kampo and Immuno-allergy 1997; 11: 40-9 [Google Scholar]
  25. Niimi M. Do Kampo prescriptions work? From the viewpoint of vascular surgery and transplantation immunity. Kampo & the Newest Therapy 2008; 17: 71-9 [Google Scholar]
  26. Kubo M, Matsuda H, Nagao T, et al. Effect of keishibukuryogan to improve general condition. Proc Symp WAKAN-YAKU 1983; 16: 171-6 [Google Scholar]
  27. Endo M, Hayasaki T, Oikawa T, et al. A case in which Kampo medicine affected warfarin control. Journal of Traditional Medicines 2008; 25: 122-4 [Google Scholar]
  28. Tani T, Iwanaga M, Ono T, et al. Effect of steroids on blood property and improving effect of keishibukuryogan. Journal of Traditional Medicines 1984; 1: 50-1 [Google Scholar]
  29. Began JJ. Surgical management of primary and recurrent varicose veins. Gloviczki P James S Yao T eds. Handbook of Venous Disorders, 2nd ed.Great Britain: Arnold, 2001: 289-302 [Google Scholar]
  30. Sakamoto S, Kudo H, Kawasaki T, et al. Effects of a Chinese herbal medicine, keishi-bukuryo-gan, on the gonadal system of rats. J Ethnopharmacol 1988; 23: 151-8 [DOI] [PubMed] [Google Scholar]

Articles from Annals of Vascular Diseases are provided here courtesy of Editorial Committee of Annals of Vascular Diseases

RESOURCES