Lack of change of cancellous bone volume with short-term use of the new immunosuppressant rapamycin in rats

Summary Immunosuppressants have adverse effects on bone mineral metabolism in animal and human studies, with corticosteroids producing low-turnover osteopenia, and cyclosporin-A (CsA) producing high-turnover osteopenia. Rapamycin (RAPA) is a new immunosuppressant reported to be at least 10 times more potent than CsA, and acts via a different pathway to CsA and the other new immunosuppressant FK506. This study investigated the effects of RAPA on bone mineral metabolism in the rat. Forty-two, 10-week-old, male Sprague Dawley rats were divided into three groups, and treated according to the following protocol: group A (control) received RAPA vehicle by daily gavage for 14 days (n = 12); group B (high dose RAPA) received RAPA 2.5 mg/kg/day by daily gavage for 14 days (n = 15); group C (low dose RAPA) received RAPA 1.25 mg/kg/day by daily gavage for 14 days (n = 15). Rats were weighed and bled on days 0, 7, and 14 for measurement of blood ionized calcium, bone Gla protein (BGP), parathyroid hormone (PTH), and 1,25(OH)₂D. Tibial bone histomorphometry was determined on day 14 after double-calcein labeling. Weight gain was similar in the two groups treated with RAPA compared with control animals. High-dose RAPA (group B) transiently depressed serum BGP levels on day 7, with elevated blood ionized calcium levels on day 7, and lowered 1,25(OH)₂D levels on day 14. Serum PTH levels were unchanged. Low dose RAPA (group C) did not affect calciotropic hormones. Histomorphometric analyses of tibial metaphyses revealed that parameters of bone formation and resorption were not significantly different in the groups treated with RAPA (group B and C) compared with control animals (group A). Trabecular bone volume (BV/TV) in group B (high-dose RAPA) (15.39 ± 1.01%) and C (low-dose RAPA) (15.38 ±0.57%) was not significantly altered compared with group A (control) (16.42 ± 0.86%). Short-term treatment with RAPA, unlike CsA, does not result in excess resorption and loss of bone volume. The depressed serum 1,25(OH)₂D levels seen with high-dose RAPA therapy may adversely effect bone mineral metabolism in the long term.Presented in part at the American Federation for Clinical Research National Meeting. May 1992, Baltimore, MD     

The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention

The menopausal transition is associated with decreased ovarian function and concomitant decline in estrogen production, which may result in physiological effects such as hot flashes, reduced bone mass, and altered lipid profile. It is well established that these unfavorable changes are effectively offset with estrogen therapy (ET) or, in women with a uterus, estrogens in combination with a progestin (hormone therapy). Selective estrogen receptor (ER) modulators (SERMs), which exhibit both ER agonist and antagonist activities depending on the target tissue, have been regarded as offering the potential to provide the benefits of ET and hormone therapy with an improved safety and tolerability profile. To date, no SERM alone has demonstrated an ideal benefit-risk profile for menopausal therapy. The tissue-selective estrogen complex, or the pairing of a SERM with estrogens, may provide an optimal blend of ER agonist and antagonist activities. We evaluated the physiological profile of this novel therapeutic paradigm by using various in vivo models to assess uterine, vasomotor, lipid, and skeletal responses to a tissue-selective estrogen complex partnering bazedoxifene with conjugated estrogens (CE). Bazedoxifene at 3.0 mg/kg effectively antagonized CE-induced uterine stimulation without reversing the positive effects of CE on vasomotor instability. When paired with CE, bazedoxifene at 3.0 mg/kg reduced total cholesterol levels by up to 20% compared with CE alone and significantly increased total bone density relative to control. These preclinical findings showed that the appropriate dose combination of bazedoxifene/CE exhibits positive vasomotor, lipid, and skeletal responses with minimal uterine stimulation.     

Picrorhiza kurroa Inhibits Experimental Arthritis Through Inhibition of Pro‐inflammatory Cytokines,Angiogenesis and MMPs

The present study investigates the anti‐arthritic activity of Picrorhiza kurroa (PK), on formaldehyde and adjuvant‐induced arthritis (AIA) in rat. Administration of Picrorhiza kurroa rhizome extract (PKRE) significantly inhibited joint inflammation in both animal models. In AIA‐induced arthritic rat, treatment with PKRE considerably decreased synovial expression of interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), tumor necrosis factor receptor‐1 (TNF‐R1) and vascular endothelial growth factor as compared with control. The anti‐arthritic activity was found to be well substantiated with significant suppression of oxidative and inflammatory markers as there was decreased malonaldehyde, Nitric oxide, tumor necrosis factor alpha levels accompanied with increased glutathione and superoxide dismutase, catalase activities. Additionally, PKRE significantly inhibited the expression of degrading enzymes, matrix metalloproteinases‐3 and matrix metalloproteinases‐9 in AIA‐induced arthritic rat. Histopathology of paw tissue displayed decreased inflammatory cell infiltration as compared with control. Taken together, these results demonstrated the anti‐arthritic activity of PKRE against experimental arthritis, and the underlying mechanism behind this efficacy might be mediated by inhibition of inflammatory mediators and angiogenesis, improvement of the synovium redox status and decreased expression of matrix metalloproteinases. Copyright © 2015 John Wiley & Sons, Ltd.     

Comparative studies of different organs of Nyctanthes arbortristis in modulation of cytokines in murine model of arthritis

Objective To study the modulation effect of pro-and anti-inflammatory cytokines following long term use of water soluble ethanol extracts from different organs of Nyctanthes arbortristis(NAT) in mouse model of arthritis. Methods Arthritis was induced in mice by two injections of Freund's complete adjuvant on days 0 and 12 in the sub-planter surface of the right hind paw. Results Injection of adjuvant resulted in a maximum primary edema of the footpad with erythema,and edema and distortion of joints of the right hind paw after 24-48 hours. Second injection of FCA led to the formation of secondary swellings persisting more than four weeks that spread onto the other hind limb but to a lesser extent. Histological analysis of the ankle on day 47 showed marked evidence of cartilage destruction in association with pannus formation and moderate bone resorption. Proinflammatory cytokine levels in the inflamed joint homogenate were elevated on days 2,14,and 47. Oral administration of leaf and fruit extracts in arthritic mice reduced joint homogenate levels of tumor necrosis factor-α,interleukin-1β,and interleukin-6 on days 2,14,and 47 in comparison to untreated arthritic mice. Interleukin-10 level was elevated in the inflamed joint on days 2,14,and 47 in comparisons to untreated arthritic mice. Conclusion Evidence of lesser inflammation of the footpad and joint and associated histological observation support the therapeutic benefit of leaf and fruit extracts from Nyctanthes arbortristis. This study helps in understanding the mechanism of anti-inflammatory action of Nyctanthes arbortristis in the light of pro-and anti-inflammatory cytokine balance.     

Some substituted 1,3,4-thiadiazoles: a novel centrally acting agents

In the present study, a series of 2-amino-5-sulphanyl-1,3,4-thiadiazole derivatives were synthesized in good yields and the structure of these compounds were established by means of FT-IR, ¹H/¹³C NMR, mass, and elemental analysis. The synthesized compounds were screened pharmacologically to evaluate their central nervous system activity. The purpose of this study was to evaluate the title compounds on Central Nervous System activity by varying the substituents in the thiadiazole scaffold. Three of the tested compounds (centrally acting agents) 2a, 2d, and 2g exhibited excellent antidepressant, anxiolytic, and anticonvulsant activity in comparison to the reference drugs.     

Neural innervation of white adipose tissue and the control of lipolysis

White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS–norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured electrophysiologically and neurochemically (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracers revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.     

AGC of a two‐area multi‐source power system interconnected via AC/DC parallel links under restructured power environment

In this paper, automatic generation control (AGC) of a two‐area multi‐source power system interconnected via alternating current/direct current (AC/DC) parallel links under restructured power environment is proposed. Each area is equipped with multipower generating sources such as thermal and hydro/gas. To execute the different market contracts in restructured power system, the optimal regulators are designed and implemented using optimal control theory. It is observed that the system dynamic results effectively satisfy the AGC requirements in restructured power system, as well as the system dynamic performance is improved by using AC/DC parallel links in comparison with that obtained with AC link as an area interconnection between the control areas. Furthermore, the eigenvalue study is performed to examine the system stability with and without AC/DC parallel links. Finally, the effectiveness of the optimal regulators is checked for the system under study with physical constraints like time delay, boiler dynamics, generation rate constraints, and governor dead band nonlinearity and variations in system parameters from the nominal values. It is shown that the optimal regulators optimized for linear system are robust enough and work well in the proposed realistic AGC system incorporating physical constraints and wide variations in parameters. Copyright © 2015 John Wiley & Sons, Ltd.