Efficacy of combination therapy with unkeito and boiogito for menopausal arthralgia: A retrospective observational study.

Context: Arthralgia affects menopausal patients. Aim: Here, we report a retrospective observational study evaluating the therapeutic efficacy of a combination of unkeito and boiogito for menopausal arthralgia. Settings and Design: Patients treated with a combination of unkeito and boiogito for menopausal arthralgia between April 2020 and October 2022 at three Japanese Kampo outpatient clinics were retrospectively examined. Treatment effectiveness was determined based on the patient's description of pain. Adverse events associated with this treatment regimen were also recorded. The study design was approved by the Tokai University Ethics Committee (Approval number: 22R196). Methods and Material: This study was conducted by retrospectively analysing the medical records of patients who attended the three medical facilities. All patients received Kampo medicines based on traditional medical diagnoses. Outpatients with a diagnosis of menopausal arthralgia were selected, and information on those who were treated with a combination of unkeito and boiogito was collected. Statistical Analysis: The age, height, and weight of all patients are represented as the mean ± standard deviation. Statistical analyses were not performed in this study as there was no comparison group. Results: During the study period, nine patients with menopausal arthralgia received the unkeito and boiogito combination. Four patients showed a "significant" response to the combination treatment, four showed an "effective" response, and one patient showed an "ineffective" response. One patient reported headache as an adverse event. Conclusion: The combination of unkeito and boiogito may be effective in the treatment of menopausal arthralgia.

Unkeito promotes follicle development by restoring reduced follicle-stimulating hormone responsiveness in rats with polycystic ovary syndrome.

Background: Polycystic ovary syndrome (PCOS) is a common disorder resulting in irregular menstruation and infertility due to improper follicular development and ovulation. PCOS pathogenesis is mediated by downregulated follicle-stimulating hormone receptor (FSHR) expression in granulosa cells (GCs); however, the underlying mechanism remains elusive. Unkeito (UKT) is a traditional Japanese medicine used to treat irregular menstruation in patients with PCOS. In this study, we aimed to confirm the effectiveness of UKT in PCOS by focusing on follicle-stimulating hormone (FSH) responsiveness. Methods: A rat model of PCOS was generated by prenatal treatment with 5α-dihydrotestosterone. Female offspring (3-week-old) rats were fed a UKT mixed diet or a normal diet daily. To compare the PCOS phenotype in rats, the estrous cycle, hormone profiles, and ovarian morphology were evaluated. To further examine the role of FSH, molecular, genetic, and immunohistological analyses were performed using ovarian tissues and primary cultured GCs from normal and PCOS model rats. Results: UKT increased the number of antral and preovulatory follicles and restored the irregular estrous cycle in PCOS rats. The gene expression levels of FSHR and bone morphogenetic protein (BMP)-2 and BMP-6 were significantly decreased in the ovarian GCs of PCOS rats compared to those in normal rats. UKT treatment increased FSHR staining in the small antral follicles and upregulated Fshr and Bmps expression in the ovary and GCs of PCOS rats. There was no change in serum gonadotropin levels. In primary cultured GCs stimulated by FSH, UKT enhanced estradiol production, accompanied by increased intracellular cyclic adenosine monophosphate levels, and upregulated the expression of genes encoding the enzymes involved in local estradiol synthesis, namely Cyp19a1 and Hsd17b. Furthermore, UKT elevated the expression of Star and Cyp11a1, involved in progesterone production in cultured GCs in the presence of FSH. Conclusions: UKT stimulates ovarian follicle development by potentiating FSH responsiveness by upregulating BMP-2 and BMP-6 expression, resulting in the recovery of estrous cycle abnormalities in PCOS rats. Restoring the FSHR dysfunction in the small antral follicles may alleviate the PCOS phenotype.

Unkeito Suppresses RANKL-Mediated Osteoclastogenesis via the Blimp1-Bcl6 and NF-κB Signaling Pathways and Enhancing Osteoclast Apoptosis.

Osteoporosis is a common bone disease, particularly in menopausal women. Herein, we screened four Kampo medicines (Unkeito (UKT), Kamishoyosan (KSS), Kamikihito (KKT), and Ninjinyoeito (NYT)), frequently used to treat menopausal syndromes, for their effects on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in RAW 264 cells. Considering that UKT exhibited the most potent effect, we examined its effect on RANKL-induced osteoclastogenesis, the induction of osteoclast apoptosis, and the mechanisms underlying its effects. UKT inhibits RANKL-induced osteoclast differentiation in the early stage and decreases osteoclast-related genes, including tartrate-resistant acid phosphatase (Trap), dendritic cell-specific transmembrane protein (Dcstamp), matrix metalloproteinase-9 (Mmp9), and cathepsin K (Ctsk). Specifically, UKT inhibits the nuclear factor of activated T cells 1 (NFATc1), which is essential for osteoclastogenesis. UKT increases Bcl6, which antagonizes NFATc1 and Dc-stamp, thereby blocking the progression of osteoclasts to maturation. UKT also decreased nuclear translocation by downregulating the activity of p65/NF-κB. In addition, UKT enhances mononuclear osteoclast apoptosis via activation of caspase-3. Herein, we demonstrate that UKT suppresses RANKL-mediated osteoclastogenesis via the Blimp1-Bcl6 and NF-κB signaling pathways and enhances mononuclear osteoclast apoptosis. Furthermore, UKT prevents bone loss in OVX mice. Thus, UKT might be a potential therapeutic agent for postmenopausal osteoporosis.

Twenty Cases of 20 Women Treated with a Regimen of Herbal Medicine According to the Treatment Stage of in vitro Fertilization or Microinsemination / 日本東洋医学雑誌

This report describes 20 women who underwent in vitro fertilization or microinsemination while receiving a regimen of herbal medicine, of which contents varied according to the treatment stage. Until the ova were harvested, in order to promote maturation, patients were treated with hachimijiogan for reinforcing kidney yang, and keishibukuryogan for removing blood stasis. Following this, during the period between harvesting and implantation, they were treated either exclusively with unkeito for warming meridians, dissipates cold, and replenishes blood, or with unkeito in combination with keishibukuryogan. Following implantation, they were treated with tokishakuyakusan to induce uterine relaxation. The treatment regimen was determined based on traditional herbal evidence of infertile patient's blood stasis and kidney deficiency. We adjusted applied dose depending on the conditions of patients. Fourteen of the 20 women tested positive for pregnancy; 10 of them carried to term, whereas in 4 of them, the pregnancy ended in abortion or miscarriage. Anti-Müllerian hormone concentration, endometrial thickness, estimated follicle count, recovered ova count, fertilized ova count, and numbers of ova to reach the early-embryo stage and blastocyst stage were compared between the continuing pregnancy and the non-pregnancy groups. Improvements were observed in all values after combined use of traditional herbal medicines, except in the case of endometrial thickness, and significant differences appeared in recovered ova count and fertilized ova count. These observations suggest that a regimen of herbal medicine adapted to the various stages of in vitro fertilization may be a useful complementary therapy during pregnancy.

<b>Three Cases of Trigger Finger which were Successfully Treated with U</b><b>nkeito</b> / 日本東洋医学雑誌

Trigger finger develops because of stenosis around the A1 annular ligament, which causes inhibition of smooth expansion and contraction of the finger. It is effectively treated by an anti-inflammatory analgesic and/or steroid infusion, and by Western style medical surgery. Here, we report 3 cases of trigger finger effectively treated with unkeito. The first case was a 71-year-old female who had been treated with Kampo medicine for an enlarged feeling in the abdomen. She complained of trigger finger, in the knuckle of her right third finger, dry lips, and hot flashes in her hands and feet. The second case was a 56-year-old female who had been treated with Kampo medicine for polyarticular pain in her fingers. She complained of trigger finger of the left fourth finger and hot flashes in her hands. The third case was a 71-year-old female who had been treated for chronic renal failure. She complained of trigger finger in the left first finger and dry skin but had neither hot flashes in the hands nor dry lips. One of the target symptoms of unkeito is hot flashes in the hands and dry lips. Unkeito is composed of herbs which improve <i>ketsu </i>deficiency, <i>oketsu</i>, inflammation, and dry skin. It is possible that these actions of unkeito are effective in trigger finger as well.

Practice of the Assimilation of Kampo and Western Medicine / 日本東洋医学雑誌

Chinese herbal remedy (KAMPO) is no longer an out-of-date medicine. It is now transforming into a new medical care system that attracts world-wide attention. The therapeutic system of Oriental Medicine is different in various aspects from that of Occidental Medicine. In this regard, appropriate harmonization of East and West (Oriental Medicine and Occidental Medicine) by comparison with merits and demerits in the understanding of diseases, methods of consultation, usage of drugs, etc. is expected to improve the quality of medical care. Considering that most of the drugs used in the Occidental Medicine are based on “single effective ingredient” that is artificially synthesized while herbal drugs are produced by combining crude drugs that contain various ingredients, the method of administration should naturally be changed.Such stance of Kampo medicine is based on the “respect for and understanding of individual constitution and disposition while paying attention to the gender difference and individuality” with the patient as the protagonist (treatment that is centered on client) and is also based on understanding and respecting the gender difference and individuality that are the basis of so-called “Science and Art” of practical medicine.

Endocrinological actions of Unkei-to, a herbal medicine, and its clinical usefulness in anovulatory and/or infertile women.

Kampo medicine (Chinese herbal medicine) has been reported to be effective in the treatment of pituitary-ovarian dysfunction in young women and in the treatment of undefined symptoms in perimenopausal women. It has been considered that both the diagnosis and treatment of ovulatory failure in adolescent girls or young women are necessary for the sake of future fertile capacity. However, treatment for the above patients is not easy as steroid hormones and strong stimulators of ovulation should not be recommended because of the several side-effects it causes. Furthermore, young women, especially teenagers, seem to be reluctant to visit gynecology clinics. A number of herbal medicines have been used for many centuries in China and Japan for the treatment of menstrual disorders and infertility. In general, the traditional Chinese herbal prescriptions are rather inexpensive and safe with little side-effects, and have properties for normalizing biological balances. Unkei-to is known to stimulate the synthesis and release of gonadotropins in the rat pituitary. In humans, Unkei-to is known to be effective in various menstrual disorders, abnormal uterine bleeding, and infertility. In the treatment of ovulatory failure, recent dynamic studies have revealed the mechanism by which Unkei-to stimulates the diencephalon-pituitary-ovarian axis in humans. In this paper, we critically review the clinical data available (to date) in order to assess the efficacy of Unkei-to in inducing ovulation in several types of ovulatory disturbances. (Reprod Med Biol 2003; 2: 45-61).

The Effects of Unkei-To on Patients with Primary Sjoegren's Syndrome / 日本東洋医学雑誌

Unkei-to was used successfully to treat three patients with primary Sjögren's syndrome (pSjS). The first case was a 67-year-old woman. In April 1993, she visited Tonami General Hospital with the symptom of dry eyes. Her condition was diagnosed as pSjS from being antinuclear antibody (ANA) positive, dry eye, and decrease of saliva secretion. She used eye drops, but her dry eye did not improve, she visited our department in June 1995. Administration of Unkei-to improved her symptoms after 6 months of treatment.<br>The second case was a 73-year-old woman. In 1987, she was treated in our hospital for lumbago based on spondylosis. In 1991, she began to suffer from pain and swelling of the right sterno-clavicular joint (RSCJ) and was admitted. She was anti-SS-A/Ro ANA positive, schirmer's test was positive, lymphocyte infiltration was observed by lip biopsy, and thus pSjS was diagnosed. Treatment with Unkei-to resulted in the improvement of pain and swelling of RSCJ, as well as a decrease in serum C-reactive protein. But a favorable effect on dry mouth was not attained in this case.<br>The third case involved a 39-year-old woman who began to experience polyarthralgia and dry mouth in June 1991. She visited a neighborhood hospital and was diagnosed as pSjS from hyper γ-globulinemia, anti SS-A ANA positivity, and decrease of saliva secretion. She first visited our hospital in March 1994. We administered Keishikaryojutubu-to and improvement of polyarthralgia was observed. Subsequently, she suffered from symptoms of dry eye and dry mouth. We treated her with Unkei-to, which improved the symptoms of dryness, but not polyarthralgia in this case.<br>These observations suggest that Unkei-to might be a useful agent for the treatment of pSjS.

A Case of Female Infertility Treated with Unkei-to after Clomifene-induced Ovarian Hyperstimulation Syndrome / 日本東洋医学雑誌

A 26-year-old woman visited our hospital complaining of infertility. Initially treatment was given based on clomiphene for induction of ovulation. However, she suffered from ovarian hyperstimulation syndrome (OHSS) due to the clomiphene, accompanied by abdominal pain. Unkei-to was decided on as the best mode of treatment since clomiphene could not be continued. The patient's basal body temperature (BBT) returned to its biphasic cycle. Three months later, natural pregnancy occurred that resulted in the birth of a healthy boy by normal delivery.<br>Unkei-to is frequently given for a variety of gynecological disorders, such as irregular menstruation, dysmenorrhea, discharge, climacteric disturbance, etc.<br>Although induction of ovulation is often a necessary and effective infertility therapy, multiple pregnancies and OHSS can be problematic. The present case suggests that Unkei-to may be effective for infertility involving clomiphene-induced OHSS