Combined Extract of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi Improved Hot Flashes and Depression in an Ovariectomized Rat Model of Menopause

Menopause leads to ovarian hormone loss, which causes symptoms such as weight gain, hot flashes, and depression. Exploring nutraceuticals is important for treating menopausal symptoms that extensively impact women’s quality of life. We hypothesized that a combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi (LEPE) would alleviate menopausal symptoms in an ovariectomized menopausal rat model. Bilateral ovariectomy was performed and animals were assigned to five groups: (1) Sham, (2) Vehicle, (-) Control, (3) LEPE (100 mg/kg bw), (4) LEPE (200 mg/kg bw), and (5) Estradiol (3 μg/kg bw). LEPE was orally administered daily for 12 weeks. LEPE supplementation did not affect growth performance (body weight and feed intake) or body composition (lean mass and fat in tissue). LEPE did not cause deviations in aspartate aminotransferase, alanine aminotransferase, estradiol, and follicle-stimulating hormone levels, indicating no hepatotoxicity or endocrine disturbance. LEPE decreased type I collagen (CTX-1) but did not affect bone mineral density or osteocalcin. LEPE decreased tail temperature and increased rectal temperature, improving menopause-related vasomotor symptoms. Furthermore, LEPE ameliorated depression-related behavior, including in forced swimming and tail suspension tests. Thus, LEPE may improve menopausal symptoms by enhancing vasomotor symptoms and depression in an ovariectomized rat menopause model.

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The Effect Combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi Extract on Menopause Symptoms in an Ovariectomized Rat Model

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_040 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 330-330

Author(s):

Eun Young Kang ◽

Hyun Kyung Kim ◽

Gwang-woong Go

Keyword(s):

Rat Model ◽

Hot Flashes ◽

Menopausal Symptoms ◽

Vasomotor Symptoms ◽

Type I ◽

Pueraria Lobata ◽

Female Rat ◽

Mineral Density ◽

Eclipta Prostrata ◽

Menopausal Depression

Abstract Objectives Menopause causes ovarian hormone decline, followed by symptoms including weight gain, bone loss, hot flashes, and menopausal depression. We had a purpose that a combination of Leonurus japonicus Houtt, Eclipta prostrata L., and Pueraria lobata Ohwi (LEPE) would alleviate menopausal symptoms in an ovariectomized menopausal rat model. Methods Female rat underwent surgery to resect bilateral ovarian and were randomly assigned to five groups: (1) Sham, (2) Vehicle, negative control, (3) LEPE (100 mg/kg bw), (4) LEPE (200 mg/kg bw), and (5) Estradiol (E2, 3 μg/kg bw). LEPE was orally gavaged daily for 12 weeks. Results There is no effect on growth performance, including body weight and feed intake, or body composition, including lean mass and fat in tissue. LEPE did not cause hepatotoxicity (aspartate aminotransferase and alanine aminotransferase) and endocrine disturbance (estradiol, follicle-stimulating hormone levels, and uterine weight). Despite decreasing type I collagen (CTX-1), LEPE did not affect bone mineral density and osteocalcin. LEPE supplement reduced the tail temperature and increased the rectal temperature, improving menopause-associated vasomotor symptoms such as hot flashes and night sweat. Furthermore, LEPE relieved behavior related to menopausal depression, including in forced swimming and tail suspension tests. Conclusions These findings suggest that LEPE ameliorates menopausal symptoms via improving menopause-associated vasomotor symptoms and depression behavior in a female rat model of surgical menopause. Funding Sources This research was funded by Nong Shim.

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Bulletin of Russian State Medical University ◽

10.24075/10.24075/brsmu.2021.003 ◽

2021 ◽

Author(s):

MV Osikov ◽

EV Davydova ◽

KS Abramov

Keyword(s):

Bone Healing ◽

Standard Therapy ◽

Type I Collagen ◽

Femoral Shaft ◽

Control Group ◽

Blood Levels ◽

Type I ◽

Mineral Density ◽

Fracture Consolidation ◽

To Receive

Efferent physical therapy holds promise as an adjunct to the combination treatment of femoral fractures in young, working-age individuals. The aim of the study was to investigate the dynamics of bone turnover markers at different stages of femoral fracture consolidation in patients undergoing ozone therapy. The study enrolled 20 men (group 2, 47.8 ± 3.5 years) with a femoral shaft fracture (AO/ASIF 32А, 32В). The control group (group 1, 46.8 ± 3.7 years) comprised 10 healthy males. Subgroup 2a (n = 10) was assigned to receive standard therapy; subgroup 2b (n = 10) was assigned to receive standard therapy complemented by minor autohemotherapy (MAHT) at 20 mg/L ozone concentrations. On days 7, 30 and 90, fracture consolidation was assessed on the RUST scale and blood levels of С-terminal telopeptides of type I collagen (bCTx, pg/ml) and procollagen type I carboxy-terminal propeptide (PICP, ng/ml) were measured. On day 7, the total RUST score in subgroups 2a and 2b was 4 points; on day 30, it was 6.5 and 8.7 points, respectively, and on day 90, it reached 10 and 11.5 points, respectively. Bone mineral density was as high as 90% in the MAHT subgroup vs. 78% in subgroup 2а, indicating faster bone healing. On day 30, bCTx levels in subgroup 2b were higher than in subgroup 2a (2289.4 [2145.3; 2365.4] vs. 1894.6 [1745.3; 2098.2], respectively. On day 7, PICP was significantly elevated in subgroup 2b in comparison with subgroup 2a; its levels peaked on days 30 and 90 (day 30: 268.3 [231.2; 286.3] vs. 183.2 [174.6; 195.6]; day 90: 584.6 [512.3; 589.3] vs. 351.2 [312.3; 369.4]. Thus, MAHT produces a positive effect on the quality and intensity of bone healing in men with isolated closed femoral shaft fractures.

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Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5521562 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Minsun Kim ◽

MinBeom Kim ◽

Jae-Hyun Kim ◽

SooYeon Hong ◽

Dong Hee Kim ◽

...

Keyword(s):

Bone Loss ◽

Rat Model ◽

Osteoclast Differentiation ◽

Ovariectomized Rat ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Mineral Density ◽

Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

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Effects of denosumab in Japanese rheumatoid arthritis patients treated with conventional anti-rheumatic drugs: 36-month extension of a phase 3 study

The Journal of Rheumatology ◽

10.3899/jrheum.201376 ◽

2021 ◽

pp. jrheum.201376

Author(s):

Yoshiya Tanaka ◽

Tsutomu Takeuchi ◽

Satoshi Soen ◽

Hisashi Yamanaka ◽

Toshiyuki Yoneda ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Type I Collagen ◽

Joint Destruction ◽

Term Treatment ◽

Drug Discontinuation ◽

Type I ◽

Mineral Density ◽

Phase 3 ◽

Long Term Treatment

Objective To evaluate safety and efficacy of long-term denosumab 60 mg every 6 (Q6M) or 3 months (Q3M) in rheumatoid arthritis (RA) patients. Methods This 12-month, randomised, double-blind, placebo-controlled, multicentre phase 3 trial with an open-label extension period from 12 to 36 months (DESIRABLE) enrolled Japanese RA patients treated with placebo for 12 months then denosumab Q6M (P/Q6M) or denosumab Q3M (P/Q3M); denosumab Q6M for 36 months (Q6M/Q6M); or denosumab Q3M for 36 months (Q3M/Q3M). Efficacy was assessed by van der Heijde modified total Sharp (mTSS), bone erosion (ES), and joint space narrowing (JSN) scores. Results Long-term treatment better maintained mTSS and ES suppression in the P/Q3M and Q3M/Q3M versus P/Q6M and Q6M/Q6M groups; changes from baseline in total mTSS at 36 months were 2.8 (standard error 0.4), 1.7 (0.3), 3.0 (0.4), and 2.4 (0.3), respectively; corresponding changes in ES were 1.3 (0.2), 0.4 (0.2), 1.4 (0.2), and 1.1 (0.2). No JSN effect was observed. Bone mineral density consistently increased in all groups after denosumab initiation, regardless of concomitant glucocorticoid administration. Serum C-telopeptide of type I collagen decreased rapidly at 1-month post-denosumab administration (both in the initial 12- month [Q3M, Q6M groups] and long-term treatment [P/Q3M, P/Q6M groups] phases). Adverse event incidence leading to study drug discontinuation was similar across treatment groups. Conclusion Denosumab treatment maintained inhibition of progression of joint destruction up to 36 months. Based on effects on ES progression, higher dosing frequency at an earlier treatment stage may be needed to optimise treatment. Denosumab was generally well tolerated.

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EFFECTS OF BISPHOSPHONATES ON OSTEOPOROSIS INDUCED BY DUCHENNE MUSCULAR DYSTROPHY: A PROSPECTIVE STUDY

Endocrine Practice ◽

10.4158/ep-2020-0073 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1477-1485

Author(s):

Wen-bin Zheng ◽

Yi Dai ◽

Jing Hu ◽

Di-chen Zhao ◽

Ou Wang ◽

...

Keyword(s):

Bone Mineral Density ◽

Vitamin D ◽

Alkaline Phosphatase ◽

Duchenne Muscular Dystrophy ◽

Zoledronic Acid ◽

Muscular Dystrophy ◽

Bone Mineral ◽

Type I Collagen ◽

Type I ◽

Mineral Density

Objective: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neuromuscular disease that brings a significantly increased risk of osteoporosis and bone fractures. We prospectively evaluated the effects of oral and intravenous bisphosphonates on the bones of children with DMD. Methods: This study included a total of 52 children with DMD. They were divided into zoledronic acid (ZOL), alendronate (ALN), and control groups according to bone mineral density (BMD) and history of fragility fractures. For 2 years, all patients took calcium, vitamin D, and calcitriol. Meanwhile, 17 patients received infusions of ZOL, and 18 patients received ALN. BMD, serum levels of alkaline phosphatase (ALP) and the cross-linked C-telopeptide of type I collagen (β-CTX) were evaluated. Results: After 24 months of treatment, the percentage changes in lumbar spine BMD were 23.2 ± 9.7% and 23.6 ± 8.8% in the ZOL and ALN groups (all P<.01 vs. baseline). The increases did not differ between the ZOL and ALN groups, but were significantly larger than those of the control group ( P<.01). Serum β-CTX and ALP levels, respectively, were decreased by 44.4 ± 18.0% and 31.9 ± 26.7% in the ZOL group and by 36.0 ± 20.3% and 25.8 ± 14.4% in the ALN group (all P<.01 vs. baseline). Conclusion: Zoledronic acid and alendronate had similar protective effects to increase bone mineral density and reduce bone resorption in children with DMD, which were superior to treatment of calcium, vitamin D, and calcitriol. Abbreviations: 25OHD = 25 hydroxyvitamin D; ALN = alendro-nate; ALP = alkaline phosphatase; ALT = alanine aminotransferase; BMD = bone mineral density; BP = bisphosphonate; Ca = calcium; β-CTX = cross-linked C-telopeptide of type I collagen; DMD = Duchenne muscular dystrophy; FN = femoral neck; GC = glucocorticoid; LS = lumbar spine; ZOL = zoledronic acid

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Ojayeonjonghwan, an oriental medicine composed of five seeds, protects against vasomotor and neurological disorders in estrogen-deficient rats

Experimental Biology and Medicine ◽

10.1177/1535370219827847 ◽

2019 ◽

Vol 244 (3) ◽

pp. 193-206 ◽

Cited By ~ 2

Author(s):

Byoung-Seob Ko ◽

Jin Ah Ryuk ◽

Joo Tae Hwang ◽

Ting Zhang ◽

Xuangao Wu ◽

...

Keyword(s):

Normal Control ◽

Memory Function ◽

Hot Flashes ◽

Menopausal Symptoms ◽

Control Group ◽

Oriental Medicine ◽

Mineral Density ◽

Ovx Rats ◽

Serum Serotonin ◽

Normal Controls

The different ojayeonjonghwan remedies all contain five fruit and seed water extracts, and they have been used for reproductive health in men and women. We hypothesized that the two OJa remedies would differently improve the early menopause-related vasomotor and neurological symptoms in estrogen-deficient animals. Ovariectomized (OVX) rats had either 0.5% dextrin (OVX-control), conjugated equine estrogen (150 μg/kg body weight; positive-control), 0.5% ojayeonjonghwan remedy-1 (OJa1), or 0.5% ojayeonjonghwan remedy-2(OJa2) in high-fat diet for 12 weeks. Normal-control rats (sham operation) were fed the same high-fat diet as OVX-control rats. Tail skin temperature, depressiveness, memory function, and body composition were determined. The mRNA expressions of hippocampal serotonin receptor (5HT)1A and 5HT2A and brain-derived neurotrophic factor(BDNF) were measured. OJa1 and OJa2 groups had lower tail skin temperatures than OVX-control. Bone mineral density (BMD) and lean body mass (LBM) measured by DEXA increased only in OJa2, and were similar to the positive- and normal-controls ( P < 0.05). In the forced swim test immobile time, an index of depressiveness was much lower in OJa1 and OJa2 than the control group. Memory as measured by passive avoidance, water maze, and Y maze tests was impaired in the OVX-control group, compared to the normal-control ( P < 0.05), but normalized in OJa1 comparable to the positive- and normal-control groups. The neurological impairments were associated with serum serotonin levels and 5HT2A mRNA expression in the midbrain, and decreased hippocampal BDNF mRNA and protein expressions in the OVX-control group compared to normal-controls ( P < 0.05). OJa1 increased serum serotonin levels and 5HT2A expression in the midbrain, and hippocampal BDNF expression to similar levels as normal-controls ( P < 0.05). In conclusion, OJa1 and OJa2 improved hot flashes and depression and maintained BMD and LBM. OJa2 prevented the impairment of memory function in OVX rats. OJa1 and OJa2 have the potential to be effective therapies for postmenopausal vasomotor and neurological symptoms. Impact statement Menopausal symptoms impair the quality of life of many women, and although conventional treatments are often effective, their use is limited by adverse effects. Ojayeonjonghwan, OJa, is a traditional Oriental medicine that is used for both male and female reproductive health and has a long history of safe use. We evaluated the effectiveness of two variations of OJa (OJa1 and OJa2) for treating menopausal symptoms in ovariectomized (OVX) rats. Both OJa preparations were effective for relieving indicators of hot flashes and depression, and for preventing loss of bone mineral density and lean body mass. Only OJa 2 prevented memory dysfunction. These results show that the traditional Oriental medicine, Ojayeonjonghwan, has the potential to relieve menopausal symptoms in women and should be further evaluated in human clinical trials as an alternative to convention therapies in women for whom conventional therapies are not indicated or found to be ineffective.

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Reduced Bone Mineral Density and Increased Bone Metabolism Rate in Young Adult Patients with 21-Hydroxylase Deficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-2823 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4453-4458 ◽

Cited By ~ 47

Author(s):

Mariateresa Sciannamblo ◽

Gianni Russo ◽

Debora Cuccato ◽

Giuseppe Chiumello ◽

Stefano Mora

Keyword(s):

Bone Mineral Density ◽

Alkaline Phosphatase ◽

Bone Metabolism ◽

Type I Collagen ◽

Whole Body ◽

Type I ◽

Healthy Controls ◽

Mineral Density ◽

Specific Alkaline Phosphatase ◽

Bone Specific Alkaline Phosphatase

Abstract Context: Patients with congenital adrenal hyperplasia (CAH) receive glucocorticoids as replacement therapy. Glucocorticoid therapy is the most frequent cause of drug-induced osteoporosis. Objective: The objective of the study was to evaluate bone mineral density (BMD) and bone metabolism in CAH patients. Design: This was a cross-sectional observational study. Setting: The study was conducted at a referral center for pediatric endocrinology. Patients and Other Participants: Thirty young patients with the classical form of CAH (aged 16.4–29.7 yr) treated with glucocorticoid from diagnosis (duration of treatment 16.4–29.5 yr) and 138 healthy controls (aged 16.0–30.0 yr) were enrolled. Main Outcome Measures: BMD was measured in the lumbar spine and whole body by dual-energy x-ray absorptiometry. Bone formation and resorption rates were estimated by serum measurements of bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen, respectively. Results: CAH patients were shorter than controls (women −6.8 and men −13.3 cm). Therefore, several methods were used to account for the effect of this difference on bone measurements. Whole-body BMD measurements were significantly lower, compared with controls (P < 0.03), after controlling for height (on average −2.5% in females and −9.3% in male patients). No differences were found in lumbar spine measurements. Bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen serum concentrations were higher in CAH patients than control subjects (P < 0.04). BMD measurements and bone metabolism markers did not correlate with the actual glucocorticoid dose or mean dose over the previous 7 yr. Conclusions: Young adult patients with the classical form of CAH have decreased bone density values, compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

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Treatment of Glucocorticoid-Induced Osteoporosis with Bisphosphonates Alone, Vitamin D Alone or a Combination Treatment in Eastern Asians: A Meta-Analysis

Current Pharmaceutical Design ◽

10.2174/1381612825666190619125426 ◽

2019 ◽

Vol 25 (14) ◽

pp. 1653-1662

Author(s):

Junjie Wang ◽

Hongzhuo Li

Keyword(s):

Vitamin D ◽

Femoral Neck ◽

Combination Treatment ◽

Type I Collagen ◽

Meta Analysis ◽

Type I ◽

Mineral Density ◽

Bone Specific Alkaline Phosphatase ◽

Asian Populations ◽

Significant Difference

Background: Glucocorticoid (GC)-induced osteoporosis and fractures have become a serious problem for Eastern Asians. Bisphosphonates (BPs), vitamin D and a combination treatment are effective methods to prevent and treat GC-induced osteoporosis. Objective: The study aimed to compare the efficacy of BPs, vitamin D and a combination treatment for preventing and managing GC-induced osteoporosis in Eastern Asians. Methods: A comprehensive search in the PubMed, EMBASE, Web of Science and Cochrane CENTRAL databases was undertaken for randomized controlled trials (RCTs) on the effect of BPs, vitamin D and the combination treatment on GCs-induced osteoporosis in Eastern Asian populations. Primary outcome measures were the change in bone mineral density (BMD) and bone turnover markers. The final search was performed in March 2019. Results: Nine RCTs were included. A total of 545 patients met the inclusion criteria. Compared with vitamin D, BPs and the combination treatment significantly alleviated osteoporosis of the spine and femoral neck in Eastern Asians with GC-induced osteoporosis. At the same time, the change in serum bone-specific alkaline phosphatase (BAP) and serum C-telopeptide of type I collagen (CTX) levels was observed to be significantly less with BPs and the combination treatment with vitamin D alone. No significant difference was found between BPs and the combination treatment in the markers mentioned above. Conclusion: Compared with vitamin D alone, BPs alone and the combination treatment were significantly effective on Eastern Asians with GC-induced osteoporosis. Compared with the combination treatment, BPs alone were observed to be effective enough to increase the BMDs of the spine and femoral neck on both sides and thus prevent GC-induced osteoporosis in Eastern Asians.

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A Special Ingredient (VtR) Containing Oligostilbenes Isolated fromVitis thunbergiiPrevents Bone Loss in Ovariectomized Mice:In VitroandIn VivoStudy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/409421 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 8

Author(s):

Yu-Ling Huang ◽

Yen-Wenn Liu ◽

Yu-Jou Huang ◽

Wen-Fei Chiou

Keyword(s):

Type I Collagen ◽

Ethanol Extract ◽

Serum Levels ◽

Bone Diseases ◽

Nodule Formation ◽

Type I ◽

Mineral Density ◽

Osteoporosis Therapy ◽

Interleukin 7 ◽

Induced Changes

Vitis thunbergiiis used in Taiwan as a botanical supplement for inflammatory bone diseases. This study aims to examine its direct effect on bone metabolism. Three-month-old female mice were randomly divided into ovariectomized control (OVX), sham operated (SHAM), and ovariectomy treated with either 17β-estradiol or a special ingredient (VtR) fractionated from an ethanol extract ofV. thunbergiistarted two weeks after ovariectomy. VtR treatment for 8 weeks significantly ameliorated the deterioration of bone mineral density and reversed all the ovariectomy-induced changes in μ-CT parameters. The antiosteoporotic effect of VtR accompanied decrease in serum levels of C-terminal telopeptides of type I collagen (CTx), interleukin-7, and ration of RANKL/osteoprotegerin (OPG) but rise in osteocalcin concentration. Sparse calcified microarchitecture and less alkaline-phosphatase- (ALP-) positive cells were observed at the femur and vertebral sites in OVX mice while VtR remarkably restored such variation. HPLC analysis showed (+)-vitisin-A, (−)-vitisin-B, and ampelopsin C predominated in VtR. Both (−)-vitisin B and ampelopsin C increased ALP activity and bone nodule formation in cultured osteoblasts. Instead of stimulating osteoblastogenesis, (+)-vitisin A dramatically repressed osteoclasts differentiation and bone resorption. The results suggested VtR composed of diverse components to reciprocally drive osteoblastogenesis and interdict osteoclastogenesis may serve as a potential botanic drug for osteoporosis therapy.

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Selective Delivery of Estradiol to Bone by Aspartic Acid Oligopeptide and Its Effects on Ovariectomized Mice

Endocrinology ◽

10.1210/endo.142.3.8024 ◽

2001 ◽

Vol 142 (3) ◽

pp. 1228-1233 ◽

Cited By ~ 48

Author(s):

Koichi Yokogawa ◽

Kazuhiro Miya ◽

Tohru Sekido ◽

Yasuhiko Higashi ◽

Masaaki Nomura ◽

...

Keyword(s):

Type I Collagen ◽

Bone Matrix ◽

Type I ◽

Dependent Manner ◽

Messenger Rnas ◽

Half Time ◽

Mineral Density ◽

Ovariectomized Mice ◽

Acidic Oligopeptide ◽

Pharmacological Potential

Abstract We have developed a novel osteotropic prodrug of estradiol (E2) conjugated with l-Asp-hexapeptide (E2·3D6), which has very low affinity for estrogen receptors, and in this study, we examined its pharmacokinetic behavior and pharmacological potential. After a single iv injection of E2·3D6 to mice, the half-time for elimination from plasma was about 100 min; however, E2 was selectively delivered to the bone and eliminated very slowly, declining to the endogenous level at about 7 days. After a single iv injection of E2, the half-time in plasma was about 70 min, whereas E2 was highly distributed to the uterus, and the bone concentration of E2 was only slightly increased at 6 h. When E2 (0.37 μmol/kg, sc, every third day) or E2·3D6 (0.11 to 1.1 μmol/kg, sc, every seventh day) was administered to OVX mice for 4 weeks, E2 increased the bone mineral density (BMD) together with weights of liver and uterus, whereas E2·3D6 increased only the BMD, in a dose-dependent manner. E2·3D6 enhanced the expression of messenger RNAs of bone matrix proteins (osteopontin, bone sialoprotein, type I collagen α) of OVX mice at 4 h after administration, but E2 did very slightly. These results indicate that the E2 prodrug was delivered to the bone, where it gradually released E2, thereby ameliorating bone loss. This acidic oligopeptide appears to be a good candidate for selective drug delivery to bone.

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