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1.
G protein-coupled receptors as anabolic drug targets in osteoporosis.
Diepenhorst, N, Rueda, P, Cook, AE, Pastoureau, P, Sabatini, M, Langmead, CJ
Pharmacology & therapeutics. 2018;:1-12
Abstract
Osteoporosis is a progressive bone disorder characterised by imbalance between bone building (anabolism) and resorption (catabolism). Most therapeutics target inhibition of osteoclast-mediated bone resorption, but more recent attention in early drug discovery has focussed on anabolic targets in osteoblasts or their precursors. Two marketed agents that display anabolic properties, strontium ranelate and teriparatide, mediate their actions via the G protein-coupled calcium-sensing and parathyroid hormone-1 receptors, respectively. This review explores their activity, the potential for improved therapeutics targeting these receptors and other putative anabolic GPCR targets, including Smoothened, Wnt/Frizzled, relaxin family peptide, adenosine, cannabinoid, prostaglandin and sphingosine-1-phosphate receptors.
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2.
Salivary hypofunction: An update on therapeutic strategies.
Salum, FG, Medella-Junior, FAC, Figueiredo, MAZ, Cherubini, K
Gerodontology. 2018;(4):305-316
Abstract
OBJECTIVE To perform a literature review addressing the therapeutic strategies for salivary hypofunction. BACKGROUND Qualitative and quantitative salivary dysfunctions predispose to changes in the oral mucosa and teeth, cause impairment to oral functions and negative impact on quality of life. MATERIALS AND METHODS A MEDLINE/PubMed search was conducted using the terms "Xerostomia" AND, "Saliva Artificial" OR, "Citric Acid," "Malic Acid," "Chewing Gum," "Acupuncture" OR, "Pilocarpine" OR, "Bethanechol" OR, "Cevimeline" OR, "Hyperbaric Oxygen Therapy" OR, "Stem Cell Therapy" OR "Genetic Therapy" and their Mesh Terms. RESULTS We selected 25 clinical trials investigating the effects of salivary substitutes, chewing gum, malic and citric acids, pilocarpine, cevimeline, bethanechol, acupuncture, hyperbaric oxygen therapy and regenerative therapies on salivary hypofunction. In most studies, the number of participants was low and the follow-up times short. The therapeutic modalities were classified according to the level of evidence on salivary dysfunction. CONCLUSIONS Pilocarpine and cevimeline had the strongest evidence of beneficial effect on salivary hypofunction. Citric and malic acids increase salivary flow but also increase the risk of erosion and dental caries. There are no controlled clinical trials supporting the efficacy of acupuncture, stem cell therapy and gene therapy on salivary dysfunction, although clinical observations suggest a promising effect. There is no evidence supporting salivary substitutes, chewing gum, bethanechol or hyperbaric oxygen on the treatment of salivary hypofunction.
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3.
First case of drug eruption due to ipragliflozin: Case report and review of the literature.
Saito-Sasaki, N, Sawada, Y, Nishio, D, Nakamura, M
The Australasian journal of dermatology. 2017;(3):236-238
Abstract
Ipragliflozin is a new drug for the treatment of diabetes mellitus. Its action of sodium-glucose cotransporter 2 (SGLT2) inhibition induces glucosuria and decreases blood glucose levels. We report the first case of ipragliflozin-related eczematous drug eruption and a review of the past literature on drug eruptions caused by SGLT2 inhibitors.
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4.
Biodesulfurization: a model system for microbial physiology research.
Kilbane, JJ, Stark, B
World journal of microbiology & biotechnology. 2016;(8):137
Abstract
Biological desulfurization (biodesulfurization) of dibenzothiophene (DBT) by the 4S pathway is a model system for an enviromentally benign way to lower the sulfur content of petroleum. Despite a large amount of effort the efficiency of the 4S pathway is still too low for a commercial oil biodesulfurization process, but the 4S pathway could potentially be used now for commercial processes to produce surfactants, antibiotics, polythioesters and other chemicals and for the detoxification of some chemical warfare agents. Proteins containing disulfide bonds are resistant to temperature, pH, and solvents, but the production of disulfide-rich proteins in microbial hosts is challenging. The study of the 4S pathway can provide insights as to how to maximize the production of disulfide-rich proteins. Engineering of the operon encoding the 4S pathway to contain a greater content of methionine and cysteine may be able to link use of DBT as a sole sulfur source to increasing 4S pathway activity by increasing the nutritional demand for sulfur. This strategy could result in the development of biocatalysts suitable for use in an oil biodesulfurization process, but the study of the 4S pathway can also lead to a better understanding of microbial physiology to optimize activity of a mult-step co-factor-requiring pathway, as well as the production of highly stable industrially relevant enzymes for numerous applications.
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5.
Rivaroxaban in patients with a recent acute coronary syndrome event: integration of trial findings into clinical practice.
Shivu, GN, Ossei-Gerning, N
Vascular health and risk management. 2014;:291-302
Abstract
Despite significant advances in the management of acute coronary syndrome (ACS) and long-term antiplatelet therapy after an ACS event, patients continue to be at risk of further cardiovascular events. There is evidence that recurrent events are at least partly attributed to the persistent activation of the coagulation system after ACS. Various anticoagulants, including vitamin K antagonists (VKAs) and non-VKA oral anticoagulants, have been evaluated in patients post-ACS, in combination with antiplatelet therapy. The desired outcome would be a further reduction of recurrent cardiovascular events with low or acceptable levels of bleeding complications. Here, we provide an overview of the current clinical trial data of non-VKA oral anticoagulants, focusing on rivaroxaban in particular, for secondary prevention in patients with a recent ACS event.
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6.
[Molecular mechanisms of action of bisphosphonates and strontium ranelate].
Vengerovskiĭ, AI, Khlusov, IA, Nechaev, KA
Eksperimental'naia i klinicheskaia farmakologiia. 2014;(9):43-6
Abstract
Bisphosphonates are chemical analogs of isoprene lipids, which competitively decrease the activity of farnesyl diphosphate synthase in osteoclasts and thus retard prenylation. The non-prenylated small GTPases cannot attach to the membrane of osteoclasts, which decreases their resorptive function and accelerates apoptosis. Strontium ranelate activates the Wnt signal pathway (with participation of calcium-sensitive receptor), increases the replication activity (by changing the function of RANKL/RANK/OPG system) thus suppressing the apoptosis of osteoblasts, and retards the resorptive function by accelerating the apoptosis of osteoclasts.
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7.
Advantages and limitations of the new anticoagulants.
Schulman, S
Journal of internal medicine. 2014;(1):1-11
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Abstract
During recent years, three new anticoagulants (dabigatran, rivaroxaban and apixaban) have been introduced to the market, probably with one more anticoagulant (edoxaban) in the next 2 years. This review is not intended to compare the efficacy and risks of these new agents, but rather to detail the advantages and limitations. The pharmacokinetic characteristics of these drugs have few drug and food interactions, predictable dose responses, and rapid onset and offset, thus resulting in simplified management of the patient requiring anticoagulant therapy. No routine laboratory monitoring is required. A somewhat unexpected, but exciting observation involving the new anticoagulants, is the uniform reduction in intracranial bleeding by one-half compared with warfarin. The potential limitations of the new anticoagulants include uncertainty regarding assessment of drug levels, safe drug levels for major surgery, management of major bleeding, renal dependence, multiple dose regimens, adherence in the absence of frequent monitoring and unknown, rare side effects that were not captured in the trials. This review should clarify some of these concerns.
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8.
[The combined use of bisphosphonates and strontium ranelate with osseosubstituting materials].
Khlusov, IA, Vengerovsky, AI, Novitsky, VV
Vestnik Rossiiskoi akademii meditsinskikh nauk. 2014;(11-12):128-32
Abstract
In review the possibility of biomaterials osseointegration improvement with help of bisphosphonates or strontium ranelate is discussed. For this purpose, they are added to hydroxyapatite used for implants coating, or are included as a component of bulk calcium phosphate materials. Strontium is employed as a compound of biodegradable metal alloys, also. Combined use of carrier (implant) with bisphosphonates or strontium ranelate promotes controlling local delivery of pharmaceutical molecules into lesion, enhances the therapy efficiency, and decreases a dose and systemic toxicity of the drugs. Bisphosphonates and strontium ranelate increase the mass, a count and thickness of bone trabeculas, improve the bone biomechanical properties in the place of implants fixation, and diminish the bone fracture risk. Main studies are devoted to pharmacologic mechanisms of implants osseointegration improvement. Bisphosphonates as isoprenoid lipids chemical analogues diminish by concurrent principle the osteoclastsfarnesylpyrophosphate synthase activity and inhibit the prenylation. Unprenylated small GTPases don't fasten onto osteoclasts membrane that weakens cellular resorptive activity and accelerates their apoptosis. Strontium ranelate enhances osteoblasts replicative activity and suppresses their apoptosis, also retards osteoclasts resorptive function and accelerates their apoptosis. Its effects are conditioned by activating Wnt-signaling pathway by means of calcium-sensing receptor and by changing the RANKL/RANK/OPG system.
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9.
Meta-analysis of efficacy and safety of rivaroxaban compared with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation.
Aryal, MR, Ukaigwe, A, Pandit, A, Karmacharya, P, Pradhan, R, Mainali, NR, Pathak, R, Jalota, L, Bhandari, Y, Donato, A
The American journal of cardiology. 2014;(4):577-82
Abstract
Several studies have been conducted to study the efficacy and safety of rivaroxaban in the atrial fibrillation periprocedural ablation period with similar rates of thromboembolism and major bleeding risks compared with warfarin or dabigatran. We sought to systematically review this evidence using pooled data from multiple studies. Studies comparing rivaroxaban with warfarin or dabigatran in patients undergoing catheter ablation for atrial fibrillation were identified through electronic literature searches of MEDLINE, EMBASE, clinicaltrials.gov, and the Cochrane library up to March 2014. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 3,575 patients, thromboembolism (composite of stroke, transient ischemic attack, and systemic and pulmonary emboli) occurred in 3 of 789 patients (0.4%) in the rivaroxaban group and 10 of 2,786 patients (0.4%) in the warfarin group (RR 0.71, 95% CI 0.26 to 1.96, I(2) = 0%, p = 0.51). Major hemorrhage occurred in 9 of 749 patients (1.2%) in the rivaroxaban group and 22 of 975 patients (2.3%) in the warfarin group (RR 0.49, 95% CI 0.24 to 1.02, I(2) = 0%, p = 0.06). Furthermore, direct efficacy and safety comparisons between rivaroxaban and dabigatran showed nonsignificant differences in rates of thromboembolism (0.5% vs 0.4%, respectively, RR 1.12, 95% CI 0.25 to 4.99, I(2) = 0%, p = 0.88) and major bleeding (1.0% vs 1.6%, respectively, RR = 0.71, 95% CI 0.16 to 3.15, I(2) = 22%, p = 0.66). In conclusion, our study suggests that patients treated with rivaroxaban during periprocedural catheter ablation have similar rates of thromboembolic events and major hemorrhage. Similar results were seen in direct comparisons between dabigatran and rivaroxaban.
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10.
Novel oral anticoagulants in secondary prevention of stroke.
Diener, HC, Easton, JD, Hankey, GJ, Hart, RG
Best practice & research. Clinical haematology. 2013;(2):131-9
Abstract
In patients with atrial fibrillation (AF) oral anticoagulation with vitamin-K antagonists (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention yielding a 60-70% relative reduction in stroke risk compared with placebo, as well as a mortality reduction of 26 percent. Vitamin-K antagonists have a number of well documented shortcomings. Recently the results of randomised trials for three new oral anticoagulants that do not exhibit the limitations of vitamin-K antagonists have been published. These include direct factor Xa inhibitors (rivaroxaban and apixaban) and a direct thrombin inhibitor (dabigatran). The studies (RE-LY, ROCKET-AF, ARISTOTLE, AVERROES) provide promising results for the new agents, including higher efficacy and a significantly lower incidence of intracranial bleeds compared with warfarin or aspirin. The new drugs show similar results in secondary as well as in primary stroke prevention in patients with AF. Apixaban was demonstrated to be clearly superior to aspirin and had the same rate of major bleeding complications. Meta-analyses show that the novel anticoagulants are superior to warfarin for the reduction of stroke, major bleeding and intracranial bleeds. New anticoagulants add to the therapeutic options for patients with AF, and offer a number of advantages over warfarin, for both the clinician and patient, including a favorable bleeding profile and convenience of use. Aspirin is no longer an option in secondary stroke prevention in patients with atrial fibrillation. Consideration of these new anticoagulants will improve clinical decision making.