Decreasing in intelligence of adult and old mice induced by glucocorticoid and its mechanism

Immunosuppresion and decrease in intellgence of adult and old mice were induced by glucocorticoids (GCOR, sc, 4 mg kg~(-1), qd×28 d). Calcium fluoresence indicator Fura 2-AM was used to measure free intracellular calcium ([Ca~(2 )]_i.Programmed cell death (PCD) or apoptosis was measured by electron microscopy and flow cytometry.The results showed that GCOR caused immunosupression and decrease in intelligence as well as PCD of hippocaripus in mature and old mice.In vivo     

XW630, a conjugate of tetracycline and estrone, in treatment of osteoporosis in overiectomized rats

AIM: To study the effects of XW630 on the bone formation inoveriectomized (OVX ) rats and in human osteoblast--likeosteosarcoma cell line TE85. METHODS: The OVX rats wereobtained by abdominal oopholectomy. The static and dynamichistomorphometric studies were performed by bi-labeledtetracycline methods.The iNOS activity was determined by     

Risedronate,a novel pyridinyl bisphosphonate for the treatment of osteoporosis and Paget’s disease of bone

Osteoporosis and Paget’s disease of bone are the most common metabolic bone diseases. They cause considerable disability and pain, and reduce quality of life. The elderly are at greatest risk of osteoporotic fractures, and in an ageing world population, the burden of the disease is likely to increase. Bisphosphonates are known to be effective antiresorptive agents for the treatment of Paget’s disease of bone, postmenopausal osteoporosis (PMO) and corticosteroid-induced osteoporosis (CIO). However, some bisphosphonates have been associated with troublesome gastrointestinal side-effects. Risedronate is a novel pyridinyl bisphosphonate recently approved in the USA for the treatment of Paget’s disease, and is under development for the treatment of PMO and CIO. Risedronate is effective and well-tolerated in the treatment of Paget’s disease. It has the shortest treatment regimen of any oral bisphosphonate; a two month course of therapy results in sustained remission, as determined by biochemical indices. The results of recent clinical trials suggest that risedronate is also an effective, well-tolerated therapy for PMO and CIO. Risedronate represents an advance in the therapeutic options available for the treatment of Paget’s disease, and is expected to be of further value for treatment of PMO and CIO when it receives approval for use in these conditions.     

Patient‐perceived problems, compliance, and the outcome of hypertension treatment

Objective: To study the associations between the outcome of antihypertensive therapy with both patient-perceived problems and patient initiated modification of dosage instructions. Design and methods: In this cross-sectional survey, all chronic hypertensives aged less than 75 years (n = 971) visiting nine Finnish pharmacies between May and September of 1996 were asked to participate. Of the 866 agreeing to participate, 482 returned the questionnaire (56%). After excluding persons with missing data, the final study population consisted of 428 hypertensive patients. Information on problems with treatment, the modification of dosage instructions, and blood pressure levels was based on patient self-reports.Results: Two-thirds (68%) of the study population reported suffering from one or more problems. The most common problems were symptoms of high blood pressure and adverse drug effects. Thirty-one percent of the male respondents and 21% of the female respondents reported having modified their dosage instructions. Only 36% of the patients had reached the goal blood pressure (<160/90 mmHg). Patients having problems with hypertension treatment were significantly more likely to have modified their dosage instructions than those without problems (3+ problems, adjusted OR=4.8). Not reaching goal blood pressure levels was sigfinicantly associated with both high number of patient-perceived problems (3+ problems, adjusted OR=2.1) and modification of dosage instructions (adjusted OR=1.9).Conclusion: The poor outcome in antihypertensive therapy is associated with both patient-perceived problems and patient initiated modification of dosage instructions.     

Prevention of γ-radiation induced cellular genotoxicity by tempol: Protection of hematopoietic system

Tempol (TPL) under in vitro conditions reduced the extent of gamma radiation induced membrane lipid peroxidation and disappearance of covalently closed circular form of plasmid pBR322. TPL protected cellular DNA from radiation-induced damage in various tissues under ex vivo and in vivo conditions as evidenced by comet assay. TPL also prevented radiation induced micronuclei formation (in peripheral blood leucocytes) and chromosomal aberrations (in bone marrow cells) in whole body irradiated mice. TPL enhanced the rate of repair of cellular DNA (blood leucocytes and bone marrow cells) damage when administered immediately after radiation exposure as revealed from the increased Cellular DNA Repair Index (CRI). The studies thus provided compelling evidence to reveal the effectiveness of TPL to protect hematopoietic system from radiation injury.     

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1–34 for the treatment of osteoporosis

Osteoporosis treatment with PTH 1–34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1–34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1–34 nasal spray formulation bioactivity. The chemically synthesised PTH 1–34 had an EC₅₀ of 0.76 nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol^® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1–34 within an in vitro cell culture model (p > 0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol^® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1–34 into the blood via intranasal delivery produced a Cmax of 2.1 ± 0.5 ng/ml compared to 13.7 ± 1.6 ng/ml with Solutol^® HS15 enhancer (p = 0.016) and a Cmax14.8 ± 8 ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol^® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol^® HS15 formulation therefore demonstrated potential as a PTH 1–34 nasal spray formulation for the treatment of osteoporosis.     

Aspirin enhances protective effect of fish oil against thrombosis and injury‐induced vascular remodelling

Background and Purpose

Although aspirin (acetylsalicylic acid) is commonly used to prevent ischaemic events in patients with coronary artery disease, many patients fail to respond to aspirin treatment. Dietary fish oil (FO), containing ω3 polyunsaturated fatty acids (PUFAs), has anti‐inflammatory and cardio‐protective properties, such as lowering cholesterol and modulating platelet activity. The objective of the present study was to investigate the potential additional effects of aspirin and FO on platelet activity and vascular response to injury.

Experimental Approach

Femoral arterial remodelling was induced by wire injury in mice. Platelet aggregation, and photochemical‐ and ferric chloride‐induced carotid artery thrombosis were employed to evaluate platelet function.

Key Results

FO treatment increased membrane ω3 PUFA incorporation, lowered plasma triglyceride and cholesterol levels, and reduced systolic BP in mice. FO or aspirin alone inhibited platelet aggregation; however, when combined, they exhibited synergistic suppression of platelet activity in mice, independent of COX‐1 inhibition. FO alone, but not aspirin, attenuated arterial neointimal growth in response to injury. Strikingly, a combination of FO and aspirin synergistically inhibited injury‐induced neointimal hyperplasia and reduced perivascular inflammatory reactions. Moreover, co‐administration of FO and aspirin decreased the expression of pro‐inflammatory cytokines and adhesion molecules in inflammatory cells. Consistently, a pro‐resolution lipid mediator‐Resolvin E1, was significantly elevated in plasma in FO/aspirin‐treated mice.

Conclusions and Implications

Co‐administration of FO and low‐dose aspirin may act synergistically to protect against thrombosis and injury‐induced vascular remodelling in mice. Our results support further investigation of adjuvant FO supplementation for patients with stable coronary artery disease.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

AA

arachidonic acid

CO

coconut oil

CVD

cardiovascular disease

DHA

docosahexaenoic acid

EPA

eicosapentaenoic acid

FO

fish oil

HDLC

high‐density lipoprotein cholesterol

LDLC

low‐density lipoprotein cholesterol

PCI

percutaneous coronary intervention

PUFA

polyunsaturated fatty acid; TG, triglyceride

Tables of Links

Combination therapy: the Holy Grail for the treatment of postmenopausal osteoporosis?

Agents for the treatment of osteoporosis are divided into broad categories according to whether the predominant effect is to inhibit bone resorption (antiresorptive drugs) or stimulate bone formation (osteo-anabolic drugs). However, due to the coupling of these two components of bone remodeling, drugs that inhibit bone resorption generally also reduce bone formation, and those that stimulate bone formation also increase bone resorption. Since these synchronous changes may limit the beneficial effects of treatment, researchers have undertaken a search for combinations of antiresorptive and osteo-anabolic drugs given concurrently, sequentially, intermittently, or cyclically that could partially or totally uncouple bone resorption and bone formation. This offers the potential for greater increases in bone mineral density (BMD), restoration of lost structural elements, and perhaps greater reduction in fracture risk than monotherapy with currently approved drugs. While some methods of combining drugs have been shown to enhance BMD response and perhaps extend the duration of osteo-anabolic effects compared to monotherapy, none have been proven to provide greater reduction of fracture risk. Upon completion of a course of osteo-anabolic therapy with daily subcutaneous parathyroid hormone, antiresorptive therapy must be started in order to prevent subsequent loss of BMD.     

Alendronate with and without cholecalciferol for osteoporosis: results of a 15‐week randomized controlled trial*

ABSTRACT

Objective: Many osteoporosis patients have low 25-hydroxyvitamin D (25OHD) and do not take recommended vitamin D amounts. A single tablet containing both cholecalciferol (vitamin D₃) and alendronate would improve vitamin D status concurrently, with a drug shown to reduce fracture risk. This study assessed the efficacy, safety, and tolerability of a once-weekly tablet containing alendronate 70?mg and cholecalciferol 70 μg (2800 IU) (ALN + D) versus alendronate 70?mg alone (ALN).

Methods: This 15‐week, randomized, double-blind, multi-center, active-controlled study was conducted during a season when 25OHD levels are declining, and patients were required to avoid sunlight and vitamin D supplements for the duration of the study. Men (?n = 35) and postmenopausal women (n = 682) with osteoporosis and 25OHD ≥ 9?ng/mL were randomized to ALN + D (?n = 360) or ALN (n = 357).

Main outcome measures: Serum 25OHD, parathyroid hormone, bone-specific alkaline phosphatase (BSAP), and urinary N‐telopeptide collagen cross-links (NTX).

Results: Serum 25OHD declined from 22.2 to 18.6?ng/mL with ALN (adjusted mean change = –3.4;95% confidence interval [CI]: –4.0 to –2.8), and increased from 22.1 to 23.1?ng/mL with ALN + D (adjusted mean change = 1.2; 95% CI: 0.6 to 1.8). At 15 weeks, adjusted mean 25OHD was 26% higher (?p < 0.001, ALN + D versus ALN), the adjusted relative risk (RR) of 25OHD < 15?ng/mL (primary endpoint) was reduced by 64% (incidence 11% vs. 32%; RR = 0.36; 95% CI: 0.27 to 0.48 [?p < 0.001]), and the RR of 25OHD < 9?ng/mL (a secondary endpoint) was reduced by 91% (1% vs. 13%; RR = 0.09; 95% CI: 0.03 to 0.23 [?p < 0.001]). Antiresorptive efficacy was unaltered, as measured by reduction in bone turnover (BSAP and NTX).

Conclusion: In osteoporosis patients who avoided sunlight and vitamin D supplements, this once-weekly tablet containing alendronate and cholecalciferol provided equivalent antiresorptive efficacy, reduced the risk of low serum 25OHD, improved vitamin D status over 15 weeks, and was not associated with hypercalcemia, hypercalciuria or other adverse findings, versus alendronate alone.

Trial registration: ClinicalTrials.gov identifier: NCT00092066.     

Recent advances in pharmacologic prevention and treat ment of osteoporosis

１ＩｎｔｒｏｄｕｃｔｉｏｎＯｓｔｅｏｐｏｒｏｓｉｓｉｓａｒｅｄｕｃｔｉｏｎｉｎｂｏｎｅｍａｓｓａｎｄａｃｈａｎｇｅｉｎｍｉｃｒｏａｒｃｈｉｔｅｃｔｕｒｅ，ｗｈｉｃｈｉｎｃｒｅａｓｅｓｔｈｅｓｕｓｃｅｐｔｉｂｉｌｉｔｙｏｆｆｒａｃｔｕｒｅｓ．Ｏｓｔｅｏｐｏｒｏｓｉｓｉｓｔｈｅｍｏｓｔｃｏｍｍｏｎｍｅｔａｂｏｌｉｃｂｏｎｅｄｉｓｅａｓｅｉｎｔｈｅｄｅｖｅｌｏｐｅｄｗｏｒｌｄａｎｄｉｓｉｎｃｒｅａｓｉｎｇｌｙｒｅｃｏｇｎｉｓｅｄａｓａｎｉｍｐｏｒｔａｎｔｐｕｂｌｉｃｈｅａｌｔｈｐｒｏｂｌｅｍ．Ｏｓｔｅ…     

A comparison of teriparatide and calcitonin therapy in postmenopausal Asian women with osteoporosis: a 6‐month study

ABSTRACT

Objective: The number of hip fractures is expected to double in the next 20 years, with current estimates that Asia will account for 37% of these cases. As bone mineral density (BMD) may be used as a measure of fracture risk, we sought to compare the effects of teriparatide with salmon calcitonin treatment on changes in BMD, biochemical bone markers, and safety in postmenopausal Asian women with osteoporosis.

Methodology: A total of 104 patients (?n = 47 teriparatide [20?µg/day subcutaneously] and n = 57 calcitonin [100?IU/day subcutaneously]) were enrolled in Hong Kong, Singapore, Philippines, Malaysia, and Thailand. Calcium (≥ 500?mg/day) and vitamin D (200–400?IU/day) supplements were taken throughout the 6‐month controlled, randomized study.

Results: Teriparatide was associated with a 5.03 ± 4.77% increase in lumbar spine BMD (?p < 0.0001, mean ± SD change from baseline), whereas changes in lumbar spine BMD for patients on calcitonin were not statistically significant (mean change of 0.36 ± 4.12%, p = 0.16). Comparison of the two groups indicated that teriparatide treatment improved lumbar spine BMD statistically significantly more than calcitonin (?p < 0.0001). No statistically significant changes were observed for total hip or femoral neck BMD. Serum bone-specific alkaline phosphatase (BSAP) increased by 55.9% (median change from baseline, p < 0.0001) in the teriparatide group, and remained stable with calcitonin (5.0% change, p = 0.24); osteocalcin increased by 156.15% (median change from baseline, p < 0.0001) with teriparatide, and decreased with calcitonin (–15.25%, p = 0.03). Similar rates of adverse events were observed, with nausea and dizziness the most commonly reported for both groups (teriparatide versus calcitonin, 13.0% versus 23.2% p = 0.21, 10.9% versus 21.4% p = 0.19, respectively). There were no clinically relevant changes observed in laboratory parameters.

Conclusions: Both treatments were similarly tolerated, however teriparatide was associated with greater increases in lumbar spine BMD and bone formation markers, demonstrating the unique mechanism of action and safety of this treatment for osteoporosis in these Asian women.     

Src inhibitors: drugs for the treatment of osteoporosis, cancer or both?

Src was one of the first proto-oncogenes to be identified and is a prototype of non-receptor type tyrosine kinases. The role of Src in bone metabolism first became apparent in Src-deficient mice and has been confirmed using low-molecular-weight Src inhibitors in animal models of osteoporosis. At the cellular level, it is well established that Src plays an important role in proliferation, and adhesion and motility. In addition, recent data indicate an involvement of Src in cell survival and intracellular trafficking in various specialized cell types. These new findings suggest that Src inhibitors might have therapeutic value in the suppression of tumor growth, tumor angiogenesis and bone resorption.     

Research progress in prevention and treatment of acute kidney injury induced by intravenous injec‑ tion of iodine contrast agentsCSCD

Post‑contrast acute kidney injury (PC‑AKI) is one kind of the serious adverse reactions of iodine contrast agents. With the rapid development of computed tomography technology, the use of intrave‑ nous iodine contrast agents has significantly increased. Although the incidence is very low, PC‑AKI after intravenous injection has attracted attention. At present, there is no effective treatment measure which is evidence‑based for PC‑AKI. Effective risk prediction and prevention of PC‑AKI are important measures to reduce the occurrence risk and relieve the kidney injury. Rehydration therapy is currently recommended in clinical practice for the prevention and treatment of PC‑AKI. In recent years, there are also many scholars studying the prevention and treatment measures such as remote ischemic precondition, drug therapy, and renal replacement therapy. © 2023 Chinese Medical Association. All rights reserved.