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Trends in Food Science & Technology     Hybrid Journal   (Followers: 18, SJR: 1.824, h-index: 92)
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Trends in Immunology     Full-text available via subscription   (Followers: 30, SJR: 5.842, h-index: 163)
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Trends in Neurosciences     Full-text available via subscription   (Followers: 22, SJR: 8.438, h-index: 203)
Trends in Parasitology     Full-text available via subscription   (Followers: 8, SJR: 1.866, h-index: 95)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 16, SJR: 4.091, h-index: 152)
Trends in Plant Science     Full-text available via subscription   (Followers: 19, SJR: 5.147, h-index: 147)
Trials in Vaccinology     Open Access  
Tribology and Interface Engineering Series     Full-text available via subscription   (Followers: 3)
Tribology Intl.     Hybrid Journal   (Followers: 17, SJR: 1.25, h-index: 56)
Tribology Series     Full-text available via subscription   (Followers: 2)
Tsinghua Science & Technology     Full-text available via subscription   (SJR: 0.173, h-index: 16)
Tuberculosis     Hybrid Journal   (Followers: 4, SJR: 1.077, h-index: 59)
Tunnelling and Underground Space Technology     Hybrid Journal   (Followers: 3, SJR: 1.208, h-index: 35)
Tzu Chi Medical J.     Full-text available via subscription   (SJR: 0.106, h-index: 6)
Ultramicroscopy     Hybrid Journal   (Followers: 2, SJR: 1.603, h-index: 71)
Ultrasonics     Hybrid Journal   (Followers: 4, SJR: 0.639, h-index: 51)
Ultrasonics Sonochemistry     Hybrid Journal   (Followers: 2, SJR: 1.267, h-index: 60)
Ultrasound Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.162, h-index: 5)
Ultrasound in Medicine & Biology     Full-text available via subscription   (Followers: 6, SJR: 0.864, h-index: 85)
Urban Forestry & Urban Greening     Hybrid Journal   (Followers: 7, SJR: 0.755, h-index: 22)
Urologic Clinics of North America     Full-text available via subscription   (Followers: 1, SJR: 0.626, h-index: 57)
Urologic Oncology: Seminars and Original Investigations     Hybrid Journal   (Followers: 5)
Urological Science     Full-text available via subscription   (Followers: 1, SJR: 0.109, h-index: 1)
Urology     Hybrid Journal   (Followers: 166, SJR: 1.036, h-index: 129)
Urology Case Reports     Open Access  
Utilities Policy     Hybrid Journal   (Followers: 1, SJR: 0.719, h-index: 22)
Vaccine     Hybrid Journal   (Followers: 10, SJR: 1.36, h-index: 117)
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Value in Health     Hybrid Journal   (Followers: 15)
Vascular Pharmacology     Hybrid Journal   (Followers: 2, SJR: 0.923, h-index: 65)
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Video J. and Encyclopedia of GI Endoscopy     Open Access  
Virology     Hybrid Journal   (Followers: 15, SJR: 1.428, h-index: 126)
Virus Research     Hybrid Journal   (Followers: 2, SJR: 0.999, h-index: 72)
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Wave Motion     Hybrid Journal   (Followers: 2, SJR: 0.855, h-index: 34)
Wavelet Analysis and Its Applications     Full-text available via subscription   (Followers: 3)
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Web Semantics: Science, Services and Agents on the World Wide Web     Hybrid Journal   (Followers: 10, SJR: 3.259, h-index: 42)
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Wine Economics and Policy     Open Access   (Followers: 3)
Women and Birth     Full-text available via subscription   (Followers: 6, SJR: 0.392, h-index: 13)
Women's Health Issues     Full-text available via subscription   (Followers: 5, SJR: 0.71, h-index: 32)
Women's Studies Intl. Forum     Hybrid Journal   (Followers: 2, SJR: 0.407, h-index: 24)
World Crop Pests     Full-text available via subscription   (Followers: 1)
World Development     Hybrid Journal   (Followers: 43, SJR: 1.488, h-index: 82)
World Neurosurgery     Hybrid Journal   (Followers: 1, SJR: 0.525, h-index: 57)
World Patent Information     Hybrid Journal   (Followers: 8, SJR: 0.319, h-index: 16)
World Psychiatry     Full-text available via subscription   (Followers: 3, SJR: 2.526, h-index: 24)
World Pumps     Full-text available via subscription   (Followers: 2)
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Zeitschrift für Medizinische Physik     Full-text available via subscription   (Followers: 1, SJR: 0.406, h-index: 15)
Zoologischer Anzeiger - A J. of Comparative Zoology     Hybrid Journal   (Followers: 1, SJR: 0.533, h-index: 24)
Zoology     Hybrid Journal   (Followers: 6, SJR: 0.538, h-index: 28)

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Journal Cover Pharmacological Research
   [5 followers]  Follow    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
     ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
     Published by Elsevier Homepage  [2573 journals]   [SJR: 1.248]   [H-I: 76]
  • Chronic heart damage following doxorubicin treatment is alleviated by
           lovastatin
    • Abstract: Publication date: Available online 21 November 2014
      Source:Pharmacological Research
      Author(s): Christian Henninger , Stefanie Huelsenbeck , Philip Wenzel , Moritz Brand , Johannes Huelsenbeck , Arno Schad , Gerhard Fritz
      The anticancer efficacy of anthracyclines is limited by cumulative dose-dependent early and delayed cardiotoxicity resulting in congestive heart failure. Mechanisms responsible for anthracycline-induced heart damage are controversially discussed and effective preventive measures are preferable. Here, we analyzed the influence of the lipid lowering drug lovastatin on anthracycline-induced late cardiotoxicity as analyzed three month after treatment of C57BL/6 mice with five low doses of doxorubicin (5×3mg/kg BW; i.p.). Doxorubicin increased the cardiac mRNA levels of BNP, IL-6 and CTGF, while the expression of ANP remained unchanged. Lovastatin counteracted these persisting cardiac stress responses evoked by the anthracycline. Doxorubicin-induced fibrotic alterations were neither detected by histochemical collagen staining of heart sections nor by analysis of the mRNA expression of collagens. Extensive qRT-PCR-array based analyses revealed a large increase in the mRNA level of heat shock protein Hspa1b in doxorubicin-treated mice, which was mitigated by lovastatin co-treatment. Electron microscopy together with qPCR-based analysis of mitochondrial DNA content indicate that lovastatin attenuates doxorubicin-stimulated hyperproliferation of mitochondria. This was not paralleled by increased expression of oxidative stress responsive genes or senescence-associated proteins. Echocardiographic analyses disclosed that lovastatin protects from the doxorubicin-induced decrease in the left ventricular posterior wall diameter (LVPWD), while constrictions in fractional shortening (FS) and ejection fraction (EF) evoked by doxorubicin were not amended by the statin. Taken together, the data suggest beneficial effects of lovastatin against doxorubicin-induced delayed cardiotoxicity. Clinical studies are preferable to scrutinize the usefulness of statins for the prevention of anthracycline-induced late cardiotoxicity.
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      PubDate: 2014-11-24T01:33:35Z
       
  • Erratum to “Muscarinic receptors stimulate cell proliferation in the
           human urothelium-derived cell line UROtsa” [Pharmacol. Res. 64
           (2011) 420–425]
    • Abstract: Publication date: Available online 22 October 2014
      Source:Pharmacological Research
      Author(s): Nicola Arrighi , Serena Bodei , Alessandra Lucente , Martin C. Michel , Danilo Zani , Claudio Simeone , Sergio Cosciani Cunico , PierFranco Spano , Sandra Sigala



      PubDate: 2014-11-24T01:33:35Z
       
  • The emerging role of redox-sensitive Nrf2–Keap1 pathway in diabetes
    • Abstract: Publication date: Available online 29 October 2014
      Source:Pharmacological Research
      Author(s): Elango Bhakkiyalakshmi , Dornadula Sireesh , Palanisamy Rajaguru , Ramasamy Paulmurugan , Kunka Mohanram Ramkumar
      The pathogenic processes involving in the development of diabetes range from autoimmune destruction of pancreatic β-cells with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The major contributing factor for excessive β-cell death includes oxidative stress-mediated mitochondrial damage, which creates an imbalance in redox homeostasis. Yet, β-cells have evolved adaptive mechanisms to endure a wide range of stress conditions to safeguard its potential functions. These include ‘Nrf2/Keap1’ pathway, a key cellular defense mechanism, to combat oxidative stress by regulating phase II detoxifying and antioxidant genes. During diabetes, redox imbalance provokes defective Nrf2-dependent signaling and compromise antioxidant capacity of the pancreas which turnout β-cells to become highly vulnerable against various insults. Hence, identification of small molecule activators of Nrf2/Keap1 pathway remains significant to enhance cellular defense to overcome the burden of oxidative stress related disturbances. This review summarizes the molecular mechanism behind Nrf2 activation and the impact of Nrf2 activators in diabetes and its complications.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Immunization in cancer patients: Where we stand
    • Abstract: Publication date: Available online 25 October 2014
      Source:Pharmacological Research
      Author(s): Christine Robin , Florence Beckerich , Catherine Cordonnier
      An increasing proportion of cancer patients benefit from new treatment strategies. However, infection remains a main cause of morbidity and mortality, either due to the underlying diseases, to treatment, or both. Although most opportunistic infections are sofar not routinely preventable by vaccines, community infections such as invasive pneumococcal disease and influenza may be avoided by vaccines in many instances. The immune response of cancer patients to vaccines is almost constantly depressed when compared to the one of healthy individuals of the same age range. However, they may, in many cases, reach seroprotection. This article addresses the rationale to develop and implement immunization programs in cancer patients, including patients with hematologic malignancies and recipients of stem cell transplantation, and the main specificities of this patient population regarding vaccines, and the potential approaches to improve the immune response. The Infectious Diseases Society of America has recently published guidelines for vaccination of the immunocompromised hosts. Although many questions remain to be clarified, oncologists and hematologists should be encouraged to implement these guidelines in their therapeutic programs and to develop prospective studies covering unsolved issues.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Novel therapeutic approaches for diabetic nephropathy and retinopathy
    • Abstract: Publication date: Available online 29 October 2014
      Source:Pharmacological Research
      Author(s): Vera Usuelli , Ennio La Rocca
      Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • EP2 and EP4 receptors mediate PGE2 induced relaxation in murine colonic
           circular muscle: Pharmacological characterization
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): M. Martinez-Cutillas , N. Mañé , D. Gallego , M. Jimenez , M.T. Martin
      Background Prostaglandin E2 (PGE2) is a regulator of gastrointestinal motility that might be involved in impaired motor function associated to gut inflammation. The aim of the present work is to pharmacologically characterize responses to exogenous and endogenous PGE2 in the mouse colon targeting EP2 and EP4 receptors. Methods Wild type (WT) and EP2 receptor knockout (EP2-KO) mice were used to characterize PGE2 and butaprost (EP2 receptor agonist) effects on smooth muscle resting membrane potential and myogenic contractility in circularly oriented colonic preparations. Results In WT animals, PGE2 and butaprost concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. Combination of both EP2 (PF-04418948 0.1μM) and EP4 receptor antagonists (L-161,982 10μM) was needed to block both electrical and mechanical PGE2 responses. Butaprost inhibitory responses (both electrical and mechanical) were totally abolished by PF-04418948 0.1μM. In EP2-KO mice, PGE2 (but not butaprost) concentration-dependently inhibited spontaneous contractions and hyperpolarized smooth muscle cells. In EP2-KO mice, PGE2 inhibition of spontaneous contractility and hyperpolarization was fully antagonized by L-161,982 10μM. In WT animals, EP2 and EP4 receptor antagonists caused a smooth muscle depolarization and an increase in spontaneous mechanical activity. Conclusions PGE2 responses in murine circular colonic layer are mediated by post-junctional EP2 and EP4 receptors. PF-04418948 and L-161,982 are selective EP2 and EP4 receptor antagonists that inhibit PGE2 responses. These antagonists might be useful pharmacological tools to limit prostaglandin effects associated to dismotility in gut inflammatory processes.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Immunogenicity of meningococcal quadrivalent (serogroup A, C, W135 and Y)
           tetanus toxoid conjugate vaccine: Systematic review and meta-analysis
    • Abstract: Publication date: Available online 30 October 2014
      Source:Pharmacological Research
      Author(s): Paolo Pellegrino , Valentina Perrone , Sonia Radice , Annalisa Capuano , Emilio Clementi
      Meningococcal meningitis represents one of the leading cause of bacterial meningitis in developed countries. Among the thirteen described serogroups, only five are usually responsible of invasive infections making immunisation against multiple serogroups the best strategy to protect individuals from this disease. Herein we carried out a systematic review and meta-analysis, in accordance with the PRISMA statement, of the recently EU-licensed meningococcal ACWY-tetanus toxoid conjugate vaccine (MenACWY-TT). We included 15 randomised clinical trials, comparing MenACWY-TT and Men-PS (ten studies), MenACWY-TT and MenC-CRM197 (four studies) and MenACWY-TT and MenACWY-DT (one study). All studies included in the meta-analysis showed high immunogenicity for MenACWY-TT vaccines in all tested serogroups. Our results suggest that the MenACWY-TT vaccine is as immunogenic as the other commercial avaiable meningococcal vaccines.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Is narcolepsy a classical autoimmune disease'
    • Abstract: Publication date: Available online 29 October 2014
      Source:Pharmacological Research
      Author(s): María-Teresa Arango , Shaye Kivity , Yehuda Shoenfeld
      Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness. It is caused by the loss of orexin producing neurons in the lateral hypothalamus. Current evidences suggest an autoimmune mediated process causing the specific loss of orexin neurons. The high association of the disease with the HLA DQB1*06:02, as well as the link with environmental factors and are important clues supporting this theory. Recently, the association between the occurrence of the disease and vaccination campaign after the 2009 H1N1 pandemic highlighted the importance to increase the knowledge in the Pandora box of the vaccines. This review discusses the last finding regarding the pathogenesis of the disease and its relationship with the H1N1 vaccines.


      PubDate: 2014-11-24T01:33:35Z
       
  • On pharmacologist and vaccines: Present and future challenges
    • Abstract: Publication date: Available online 10 November 2014
      Source:Pharmacological Research
      Author(s): Paolo Pellegrino , Annalisa Capuano , Sonia Radice



      PubDate: 2014-11-24T01:33:35Z
       
  • Ongoing pharmacovigilance on vaccines
    • Abstract: Publication date: Available online 10 November 2014
      Source:Pharmacological Research
      Author(s): Carmela Santuccio , Francesco Trotta , Patrizia Felicetti
      Vaccines represent a specific subgroup of drugs characterised by peculiar features that should be taken into account during adverse events surveillance. In this review, we analyse and discuss specific requirements of vaccine pharmacovigilance, including the needs of guarantee a safer use of vaccines and preserving public confidence in immunisation programmes. Key elements for the routine safety monitoring, new regulations and some available tools are taken into account. Finally, our experience in vaccine pharmacovigilance is shortly described.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Tranilast: A review of its therapeutic applications
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Sara Darakhshan , Ali Bidmeshki Pour
      Tranilast (N-[3′,4′-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. Initially, tranilast was identified as an anti-allergic agent, and used in the treatment of inflammatory diseases, such as bronchial asthma, atypical dermatitis, allergic conjunctivitis, keloids and hypertrophic scars. Subsequently, the results showed that it could be also effective in the management of a wide range of conditions. The beneficial effects of tranilast have also been seen in a variety of disease states, such as fibrosis, proliferative disorders, cancer, cardiovascular problems, autoimmune disorders, ocular diseases, diabetes and renal diseases. Moreover, several trials have shown that it has very low adverse effects and it is generally well tolerated by patients. In this review, we have attempted to accurately summarize previously published studies relating to the use of tranilast for a range of disorders and discuss the drug's possible mode of action. The major mode of the drug's efficacy appears to be the suppression of the expression and/or action of the TGF-β pathway, but the drug affects other factors as well. The findings presented in this review demonstrate the potential of tranilast for the control of a vast array of pathological situations, furthermore, it is a prescribed drug without severe side effects.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Hyperoxic gassing with Tiron enhances bradykinin-induced
           endothelium-dependent and EDH-type relaxation through generation of
           hydrogen peroxide
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Pui San Wong , Richard E. Roberts , Michael D. Randall
      Oxygenation with 95%O2 is routinely used in organ bath studies. However, hyperoxia may affect tissue responses, particularly in studies which involve reactive oxygen species (ROS). Here, the effects of the antioxidant, Tiron, were investigated under different gassing conditions in the porcine isolated coronary artery (PCA). Distal PCAs from male and female pigs were mounted in a wire myograph gassed with either 95%O2/5%CO2 or 95% air/5%CO2 and pre-contracted with U46619. Concentration–response curves to bradykinin were constructed in the presence of Tiron (1mM), a cell permeable superoxide scavenger and catalase (1000Uml−1) to breakdown H2O2. The H2O2 level in Krebs’–Henseleit solution was detected using Amplex Red. Bradykinin produced concentration-dependent vasorelaxations in male and female PCAs when gassed with either 95%O2 or air, with no differences in the R max or EC50. Tiron increased the potency of bradykinin only when gassed with 95%O2 in PCAs from both sexes. At 95%O2, catalase prevented the leftward shift caused by Tiron in both sexes indicating that catalase prevented the formation of H2O2 by Tiron. In female PCAs, addition of catalase to Tiron significantly reduced the R max. In the EDH-type response (using L-NAME and indomethacin), Tiron enhanced the potency of the bradykinin-induced vasorelaxation when gassed with 95%O2 in PCAs from both sexes. Biochemical analysis using Amplex Red demonstrated that H2O2 was generated in Krebs’–Henseleit solution when gassed with 95%O2, but not with air. Therefore, hyperoxic gassing conditions could alter the environment generating superoxide within the Krebs’–Henseleit buffer, which may, in turn, influence the in vitro pharmacological responses.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Diacerein is a potent and selective inhibitor of palmitoylethanolamide
           inactivation with analgesic activity in a rat model of acute inflammatory
           pain
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Stefania Petrosino , Akbar Ahmad , Gabriele Marcolongo , Emanuela Esposito , Marco Allarà , Roberta Verde , Salvatore Cuzzocrea , Vincenzo Di Marzo
      Palmitoylethanolamide (PEA) is produced by mammalian cells from its biosynthetic precursor, N-palmitoyl-phosphatidyl-ethanolamine, and inactivated by enzymatic hydrolysis to palmitic acid and ethanolamine. Apart from fatty acid amide hydrolase (FAAH), the N-acylethanolamine-hydrolyzing acid amidase (NAAA), a lysosomal enzyme, was also shown to catalyze the hydrolysis of PEA and to limit its analgesic and anti-inflammatory action. Here we report the finding of a new potential inhibitor of NAAA, EPT4900 (4,5-diacetyloxy-9,10-dioxo-anthracene-2-carboxylic acid, diacerein). EPT4900 exhibited a high inhibitory activity on human recombinant NAAA over-expressed in HEK293 cells (HEK-NAAA cells). EPT4900 selectively increased the levels of PEA in intact HEK-NAAA cells, and inhibited inflammation as well as hyperalgesia in rats treated with an intraplantar injection of carrageenan. This latter effect was accompanied by elevation of PEA endogenous levels in the paw skin.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial
           dysfunction through mitochondrial biogenesis improvement
    • Abstract: Publication date: January 2015
      Source:Pharmacological Research, Volume 91
      Author(s): Pedro Bullón , Lourdes Román-Malo , Fabiola Marín-Aguilar , José Miguel Alvarez-Suarez , Francesca Giampieri , Maurizio Battino , Mario D. Cordero
      Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications.
      Graphical abstract image

      PubDate: 2014-11-24T01:33:35Z
       
  • Editorial Board
    • Abstract: Publication date: November 2014
      Source:Pharmacological Research, Volume 89




      PubDate: 2014-10-12T13:10:52Z
       
  • JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced
           peripheral neuropathy
    • Abstract: Publication date: Available online 7 October 2014
      Source:Pharmacological Research
      Author(s): A. Khasabova Iryna , Xu Yao , Justin Paz , Cutler T. Lewandowski , Amy E. Lindberg , Lia Coicou , Natasha Burlakova , Don A. Simone , Virginia S. Seybold
      Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl- sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.
      Graphical abstract image

      PubDate: 2014-10-12T13:10:52Z
       
  • A role for the sodium pump in H2O2-induced vasorelaxation in porcine
           isolated coronary arteries
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): P.S. Wong , M.J. Garle , S.P.H. Alexander , M.D. Randall , R.E. Roberts
      Hydrogen peroxide (H2O2) has been proposed to act as a factor for endothelium-derived hyperpolarization (EDH) and EDH may act as a ‘back up’ system to compensate the loss of the NO pathway. Here, the mechanism of action of H2O2 in porcine isolated coronary arteries (PCAs) was investigated. Distal PCAs were mounted in a wire myograph and pre-contracted with U46619 (1nM–50μM), a thromboxane A2-mimetic or KCl (60mM). Concentration–response curves to H2O2(1μM–1mM), bradykinin (0.01nM–1μM), sodium nitroprusside (SNP) (10nM–10μM), verapamil (1nM–10μM), KCl (0–20mM) or Ca2+-reintroduction (1μM–10mM) were constructed in the presence of various inhibitors. Activity of the Na+/K+-pump was measured through rubidium-uptake using atomic absorption spectrophotometry. H2O2 caused concentration-dependent vasorelaxations with a maximum relaxation (R max) of 100±16% (mean±SEM), pEC50 =4.18±0.20 (n =4) which were significantly inhibited by PEG-catalase at 0.1–1.0mM H2O2 (P <0.05). 10mM TEA significantly inhibited the relaxation up to 100μM H2O2 (P <0.05). 60mM K+ and 500nM ouabain significantly inhibited H2O2-induced vasorelaxation producing a relaxation of 40.8±8.5% (n =5) and 47.5±8.6% (n =6) respectively at 1mM H2O2 (P <0.0001). H2O2-induced vasorelaxation was unaffected by the removal of endothelium, inhibition of NO, cyclo-oxygenase, gap junctions, SKCa, IKCa, BKCa Kir, KV, KATP or cGMP. 100μM H2O2 had no effects on the KCl-induced vasorelaxation or Ca2+-reintroduction contraction. 1mM H2O2 inhibited both KCl-induced vasorelaxation and rubidium-uptake consistent with inhibition of the Na+/K+-pump activity. We have shown that the vascular actions of H2O2 are sensitive to ouabain and high concentrations of H2O2 are able to modulate the Na+/K+-pump. This may contribute towards its vascular actions.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Computational modelling approaches to vaccinology
    • Abstract: Publication date: Available online 16 September 2014
      Source:Pharmacological Research
      Author(s): Francesco Pappalardo , Darren Flower , Giulia Russo , Marzio Pennisi , Santo Motta
      Excepting the Peripheral and Central Nervous Systems, the Immune System is the most complex of somatic systems in higher animals. This complexity manifests itself at many levels from the molecular to that of the whole organism. Much insight into this confounding complexity can be gained through computational simulation. Such simulations range in application from epitope prediction through to the modelling of vaccination strategies. In this review, we evaluate selectively various key applications relevant to computational vaccinology: these include technique that operates at different scale that is, from molecular to organisms and even to population level.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Can vaccines interact with drug metabolism?
    • Abstract: Publication date: Available online 26 September 2014
      Source:Pharmacological Research
      Author(s): Paolo Pellegrino , Emilio Clementi , Annalisa Capuano , Sonia Radice
      Vaccines are safe and efficacious in reducing the burden of several serious infections affecting children and adults. Due to their efficacy, vaccines are often administered in patients with chronic diseases, likely to be under poly-therapy. Because of several case reports indicating changes in drug metabolism after vaccination, the hypothesis of an interaction between vaccines and specific drugs has been put forward. These interactions are conceivably of great concern, especially in patients treated with molecules characterised by a narrow therapeutic index. Herein, we review and systematise the available evidence on vaccine–drug interactions. The picture that emerges indicates that reduction in the activity of specific CYPs following vaccination may occur, most likely via interferon γ overproduction, and for specific drugs such as anticonvulsivant and theophylline may have significant clinical relevance. Clinical interaction between vaccines and drugs that are metabolised by cytochromes uninfluenced by INFγ levels, such as warfarin, are instead unlikely to happen. Further studies are however needed to gain a complete picture of vaccine–drug interactions and define their relevance in terms of possible negative clinical impact.
      Graphical abstract image

      PubDate: 2014-10-12T13:10:52Z
       
  • Predicting post-vaccination autoimmunity: Who might be at risk?
    • Abstract: Publication date: Available online 30 September 2014
      Source:Pharmacological Research
      Author(s): Alessandra Soriano , Gideon Nesher , Yehuda Shoenfeld
      Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in improving public health. However, adverse effects, including autoimmune conditions may occur following vaccinations (autoimmune/inflammatory syndrome induced by adjuvants – ASIA syndrome). It has been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents, as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately, vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior post-vaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases; presence of autoantibodies; carrying certain genetic profiles, etc.).


      PubDate: 2014-10-12T13:10:52Z
       
  • Rutin has intestinal antiinflammatory effects in the CD4+ CD62L+ T cell
           transfer model of colitis
    • Abstract: Publication date: Available online 2 October 2014
      Source:Pharmacological Research
      Author(s): Cristina Mascaraque , Carlos Aranda , Borja Ocón , María Jesús Monte , María Dolores Suárez , Antonio Zarzuelo , José Juan García Marín , Olga Martínez-Augustin , Fermín Sánchez de Medina
      Rutin, one of the most abundant flavonoids in nature, has been shown to exert intestinal antiinflammatory effects in experimental models of colitis. Our aim was to study the antiinflamatory effect of rutin in the CD4+ CD62L+ T cell transfer model of colitis, one of the closest to the human disease. Colitis was induced by transfer of CD4+ CD62L+ T cells to Rag1−/− mice. Rutin was administered by gavage as a postreatment. Treatment with rutin improved colitis at the dose of 57mg/kg/day, while no effect was noted with 28.5mg/kg/day. Therapeutic benefit was evidenced by a reduced disease activity index, weight loss and damage score, plus a 36% lower colonic myeloperoxidase and a 54% lower alkaline phosphatase activity. In addition, a decreased secretion of proinflammatory cytokines (IFNγ and TNFα) by mesenteric lymph node cells was observed ex vivo. The colonic expression of proinflammatory genes, including IFNγ, TNFα, CXCL1, S100A8 and IL-1β, was significantly reduced by more than 80% with rutin as assessed by RT-qPCR. Flavonoid treated mice exhibited decreased activation of splenic CD4+ cells (STAT4 phosphorylation and IFNγ expression) and reduced plasma cytokine levels. This effect was also apparent in mucosal lymphocytes based on reduced STAT4 phosphorylation. The protective effect was comparable to that of 3mg/kg/day budesonide. Rutin had no effect on splenocytes or murine T cells in vitro, while its aglycone, quercetin, exhibited a concentration dependent inhibition of proinflammatory cytokines, including IFNγ. Rutin but not quercetin showed vectorial basolateral to apical transport in IEC18 cells, associated with reduced biotransformation. We conclude that rutin exerts intestinal antiinflammatory activity in chronic, T lymphocyte dependent colitis via quercetin release and actions involving mucosal and lymph node T cells. Our results suggest that rutin may be useful in the management of inflammatory bowel disease in appropriate dosage conditions.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Hydrocodone Extended-Release: Pharmacodynamics, Pharmacokinetics and
           Behavioral Pharmacology of a Controversy
    • Abstract: Publication date: Available online 6 October 2014
      Source:Pharmacological Research
      Author(s): Harry J. Gould III , Dennis Paul
      Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro®, an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDA's Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to Expert Panel's opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Histamine in the locus coeruleus promotes descending noradrenergic
           inhibition of neuropathic hypersensitivity
    • Abstract: Publication date: Available online 7 October 2014
      Source:Pharmacological Research
      Author(s): Hong Wei , Cong-Yu Jin , Hanna Viisanen , Hao-Jun You , Antti Pertovaara
      Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1–10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Fenofibrate and dipyridamole treatments in low-doses either alone or in
           combination blunted the development of nephropathy in diabetic rats
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Pitchai Balakumar , Rajavel Varatharajan , Ying Hui Nyo , Raja Renushia , Devarajan Raaginey , Ann Nah Oh , Shaikh Sohrab Akhtar , Mani Rupeshkumar , Karupiah Sundram , Sokkalingam A. Dhanaraj
      Low-doses of fenofibrate and dipyridamole have pleiotropic renoprotective actions in diabetic rats. This study investigated their combined effect relative to their individual treatments and lisinopril in rats with diabetic nephropathy. Streptozotocin (55mg/kg, i.p., once)-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Diabetic rats after 10 weeks developed nephropathy with discernible renal structural and functional changes as assessed in terms of increase in kidney weight to body weight ratio (KW/BW), and elevations of serum creatinine, urea and uric acid, which accompanied with elevated serum triglycerides and decreased high-density lipoproteins. Hematoxylin–eosin, periodic acid Schiff and Masson trichrome staining confirmed renal pathological changes in diabetic rats that included glomerular capsular wall distortion, mesangial cell expansion, glomerular microvascular condensation, tubular damage and degeneration and fibrosis. Low-dose fenofibrate (30mg/kg, p.o., 4 weeks) and low-dose dipyridamole (20mg/kg, p.o., 4 weeks) treatment either alone or in combination considerably reduced renal structural and functional abnormalities in diabetic rats, but without affecting the elevated glucose level. Fenofibrate, but not dipyridamole, significantly prevented the lipid alteration and importantly the uric acid elevation in diabetic rats. Lisinopril (5mg/kg, p.o., 4 weeks, reference compound), prevented the hyperglycemia, lipid alteration and development of diabetic nephropathy. Lipid alteration and uric acid elevation, besides hyperglycemia, could play key roles in the development of nephropathy. Low-doses of fenofibrate and dipyridamole treatment either alone or in combination markedly prevented the diabetes-induced nephropathy. Their combination was as effective as to their individual treatment, but not superior in preventing the development of diabetic nephropathy.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Identification of up- and down-regulated proteins in doxorubicin-resistant
           uterine cancer cells: Reticulocalbin-1 plays a key role in the development
           of doxorubicin-associated resistance
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Eugenie Wong Soon May , Szu-Ting Lin , Chi-Chen Lin , Jo-Fan Chang , Eric Hung , Yi-Wen Lo , Li-Hsun Lin , Ren-Yu Hu , Chi-Lun Feng , Dai-Ying Lin , Shine-Bei Wu , Wen-Chi Lee , Kevin W. Lyu , Hsiu-Chuan Chou , Hong-Lin Chan
      Drug resistance is a frequent cause of failure in cancer chemotherapy treatments. In this study, a pair of uterine sarcoma cancer lines, MES-SA, and doxorubicin-resistant partners, MES-SA/DxR-2μM cells and MES-SA/DxR-8μM cells, as a model system to investigate resistance-dependent proteome alterations and to identify potential therapeutic targets. We used two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) to perform this research and the results revealed that doxorubicin-resistance altered the expression of 208 proteins in which 129 identified proteins showed dose-dependent manners in response to the levels of resistance. Further studies have used RNA interference, H2A.X phosphorylation assay, cell viability analysis, and analysis of apoptosis against reticulocalbin-1 (RCN1) proteins, to prove its potency on the formation of doxorubicin resistance as well as the attenuation of doxorubicin-associated DNA double strand breakage. To sum up, our results provide useful diagnostic markers and therapeutic candidates such as RCN1 for the treatment of doxorubicin-resistant uterine cancer.
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      PubDate: 2014-10-12T13:10:52Z
       
  • Des-Arg9-bradykinin causes kinin B1 receptor mediated
           endothelium-independent contractions in endotoxin-treated porcine coronary
           arteries
    • Abstract: Publication date: December 2014
      Source:Pharmacological Research, Volume 90
      Author(s): Amar S. More , Hye Min Kim , Gilson Khang , Tobias Hildebrandt , Christian Bernlöhr , Henri Doods , Paul M. Vanhoutte , Dongmei Wu
      This study examined responses of isolated pig coronary arteries after kinin B1 receptor induction by endotoxin. Des-Arg9-bradykinin (DBK) induced concentration-dependent, endothelium-independent contractions in lipopolysaccharide (LPS)-treated but not untreated arterial rings. The B1-receptor antagonist SSR240612, but not the B2-receptor antagonist HOE140, prevented the endothelium-independent contractions to DBK. The DBK-induced contractions were blocked by indomethacin (nonselective cyclooxygenase [COX] inhibitor), celecoxib (selective COX-2 inhibitor), and terbogrel (thromboxane-prostanoid [TP] receptor antagonist) but not valeryl salicylate (selective COX-1 inhibitor), AH6809 (an E prostanoid [EP] and PGD2 receptor [DP1] receptor antagonist), AL 8810 (a selective PGF2α [FP] receptor antagonist), or RO1138452 (a selective I prostanoid [IP] receptor antagonist). They were attenuated by N-(p-amylcinnamoyl) anthranilic acid (ACA), and by DETCA plus tiron but not by l-NAME. Quantitative RT-PCR revealed excessive up-regulations of mRNA expressions of B1 receptors, COX-2, and thromboxane A synthase 1 (TBXAS1) following LPS incubation, but not of B2 receptors or COX-1. The present data demonstrate that B1 receptors are coupled to COX-2 in causing endothelium-independent contractions in endotoxin-treated pig coronary arteries. Accordingly, kinin B1 receptor induction during inflammation may have a pathological significance in the vasculature, particular in coronary arteries with dysfunctional endothelial cells.
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      PubDate: 2014-10-12T13:10:52Z
       
  • The effect of peroxynitrite decomposition catalyst MnTBAP on aldehyde
           dehydrogenase-2 nitration by organic nitrates: Role in nitrate tolerance
    • Abstract: Publication date: Available online 28 August 2014
      Source:Pharmacological Research
      Author(s): Vincenzo Mollace , Carolina Muscoli , Concetta Dagostino , Luigino Antonio Giancotti , Micaela Gliozzi , Iolanda Sacco , Valeria Visalli , Santo Gratteri , Ernesto Palma , Natalia Malara , Vincenzo Musolino , Cristina Carresi , Saverio Muscoli , Cristiana Vitale , Daniela Salvemini , Francesco Romeo
      Bioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo. Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4h. This was expressed by attenuation of platelet aggregation induced by thrombin (40U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event in GTN tolerance, an effect counteracted both in vitro and in vivo by novel peroxynitrite decomposition catalyst.
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      PubDate: 2014-09-02T02:39:30Z
       
  • Indole-3-carbinol induces cMYC and IAP-family downmodulation and promotes
           apoptosis of Epstein–Barr virus (EBV)-positive but not of
           EBV-negative Burkitt's lymphoma cell lines
    • Abstract: Publication date: Available online 30 August 2014
      Source:Pharmacological Research
      Author(s): Gema Perez-Chacon , Cristobal de los Rios , Juan M. Zapata
      Indole-3-carbinol (I3C) is a natural product found in broadly consumed plants of the Brassica genus, such as broccoli, cabbage, and cauliflower, which exhibits anti-tumor effects through poorly defined mechanisms. I3C can be orally administered and clinical trials have demonstrated that I3C and derivatives are safe in humans. In this study we show that I3C efficiently induces apoptosis in cell lines derived from EBV-positive Burkitt's lymphomas (virus latency I/II), while it does not have any cytotoxic activity against EBV-negative Burkitt's lymphomas and immortalized EBV-infected lymphoblastoid cell lines (virus latency III). The effect of I3C in EBV-positive Burkitt's lymphoma is very specific, since only I3C and its C6-methylated derivative, but not other 3-substituted indoles, have an effect on cell viability. I3C treatment caused apoptosis characterized by loss of mitochondria membrane potential and caspase activation. I3C alters the expression of proteins involved in the control of apoptosis and transcription regulation in EBV-positive Burkitt's lymphoma cell lines. Among those, cMYC, cIAP1/2 and XIAP downmodulation at mRNA and protein level precede apoptosis induction, thus suggesting a role in I3C cytotoxicity. We also showed that I3C and, more particularly, its condensation dimer 3,3′-diindolylmethane (DIM) prolonged survival and reduced tumor burden of mice xenotransplanted with EBV-positive Burkitt's lymphoma Daudi cells. In summary these results, together with previous reports from clinical trials indicating the lack of toxicity in humans of I3C and derivatives, support the use of these compounds as a new therapeutic approach for treating patients with endemic (EBV-positive) Burkitt's lymphoma.
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      PubDate: 2014-09-02T02:39:30Z
       
  • Novel Therapeutic Strategies for Ischemic Heart Disease
    • Abstract: Publication date: Available online 1 September 2014
      Source:Pharmacological Research
      Author(s): Adam J. Perricone , Richard S. Vander Heide
      Despite significant advances in the physician's ability to initiate myocardial reperfusion and salvage heart tissue, ischemic heart disease remains one of the leading causes of death in the United States. Consequently, alternative therapeutic strategies have been intensively investigated, especially methods of enhancing the heart's resistance to ischemic cell death - so called “cardioprotective” interventions. However, although a great deal has been learned regarding the methods and mechanisms of cardioprotective interventions, an efficacious therapy has yet to be successfully implemented in the clinical arena. This review discusses the current understanding of cardioprotection in the context of ischemic heart disease pathophysiology, highlighting those elements of ischemic heart disease pathophysiology that have received less attention as potential targets of cardioprotective intervention.


      PubDate: 2014-09-02T02:39:30Z
       
  • Clinical evidence of statin therapy in non-dyslipidemic disorders
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Nicola Ferri , Alberto Corsini
      The clinical benefits of statins are strongly related to their low density lipoprotein cholesterol (LDL-C) lowering properties. However, considering that the pharmacological target of statins, the 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase, is one of the upstream enzyme of the mevalonate pathway, its inhibition may determine a substantial impoverishment of additional lipid moieties required for a proper cellular function. From this hypothesis, several experimental and clinical evidences have been reported indicating additional effects of statins beyond the LDL-C lowering, in particular anti-inflammatory and immunomodulatory effects. Thus statin therapy, indicated for hyperlipidemic patients for primary and secondary prevention of coronary heart disease (CHD) has begun to be considered effective in other diseases not necessarily linked to altered lipid profile. In the present review we summarized the current clinical evidence of the efficacy and safety profile of statins in a variety of diseases, such as rheumatoid arthritis, venous thromboembolism, liver diseases, polycystic ovary syndrome, and age-related macular degeneration. As discussed in the review, pending large, well designed, randomized trials, it is reasonable to conclude that there is no definitive evidence for the use of statins in the aforementioned diseases.
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      PubDate: 2014-08-16T01:35:57Z
       
  • Cardiovascular effects of statins, beyond lipid-lowering properties
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Christos G. Mihos , Andres M. Pineda , Orlando Santana
      The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as ‘statins’, are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid-lowering properties, which include enhancement of endothelial function, anti-inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits.


      PubDate: 2014-08-16T01:35:57Z
       
  • Editorial Board
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87




      PubDate: 2014-08-16T01:35:57Z
       
  • The pharmacogenomics of statins
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Ingrid C. Gelissen , Andrew J. McLachlan
      The statin class of cholesterol-lowering drugs have been used for decades to successfully lower plasma cholesterol concentrations and cardiovascular risk. Adverse effects of statins are generally considered mild, but increase with age of patients and polypharmacy. One aspect of statin therapy that is still difficult for prescribers to predict is the individual's response to statin therapy. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect statin efficacy and safety. In this review, a number of candidates that affect statin pharmacokinetics and pharmacodynamics are discussed. Some of these candidates, in particular those involved in import and efflux of statins, have now been linked to increased risk of side effects. Furthermore, pharmacogenomic studies continue to reveal new players that are involved in the fine-tuning of the complex regulation of cholesterol homeostasis and response to statins.
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      PubDate: 2014-08-16T01:35:57Z
       
  • Editorial Board
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88




      PubDate: 2014-08-16T01:35:57Z
       
  • The pharmacology of statins
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Cesare R. Sirtori
      Statins, inhibitors of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme, are molecules of fungal origin. By inhibiting a key step in the sterol biosynthetic pathway statins are powerful cholesterol lowering medications and have provided outstanding contributions to the prevention of cardiovascular disease. Their detection in mycetes traces back to close to 40 years ago: there were, originally, widely opposing views on their therapeutic potential. From then on, intensive pharmaceutical development has led to the final availability in the clinic of seven statin molecules, characterized by differences in bioavailability, lipo/hydrophilicity, cytochrome P-450 mediated metabolism and cellular transport mechanisms. These differences are reflected in their relative power (mg LDL-cholesterol reduction per mg dose) and possibly in parenchymal or muscular toxicities. The impact of the antagonism of statins on a crucial step of intermediary metabolism leads, in fact, both to a reduction of cholesterol biosynthesis as well as to additional pharmacodynamic (so called “pleiotropic”) effects. In the face of an extraordinary clinical success, the emergence of some side effects, e.g. raised incidence of diabetes and cataracts as well as frequent muscular side effects, have led to increasing concern by physicians. However, also in view of the present relatively low cost of these drugs, their impact on daily therapy of vascular patients is unlikely to change.


      PubDate: 2014-08-16T01:35:57Z
       
  • Statins: From cholesterol-lowering drugs to novel immunomodulators for the
           treatment of Th17-mediated autoimmune diseases
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Cristina Ulivieri , Cosima T. Baldari
      Statins, a class of drugs that act as inhibitors of cholesterol biosynthesis and protein isoprenylation, have been proposed as immunomodulatory agents due to their potent effects both on T lymphocytes and on antigen presenting cells. Unfortunately to date the benefits of statin therapy have not been unequivocally established due to contrasting results obtained in the setting of several autoimmune diseases. A major hurdle is our limited mechanistic understanding of the pleiotropic mechanisms underlying statin-mediated immunomodulation. Accumulating evidence has highlighted two CD4+ T cell subsets, the Th17 and Treg cells, as important disease-related targets of statins. Here we shall review recent findings on the activity of statins on Th17 and Treg differentiation and effector function. Statin-based therapies of multiple sclerosis, a Th17 cell-mediated autoimmune disease, and of Systemic Lupus Erithematosus, characterized by a Th17/Treg imbalance, will be also discussed, based on animal models and clinical trials.
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      PubDate: 2014-08-16T01:35:57Z
       
  • Statins, bone metabolism and treatment of bone catabolic diseases
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Yijia Zhang , Aaron D. Bradley , Dong Wang , Richard A. Reinhardt
      The discovery that statins had bone anabolic properties initiated many investigations into their use for treatment of bone catabolic diseases, such as osteoporosis. This paper reviews the molecular basis of statin's role in bone metabolism, and animal and human studies on the impact of systemic statins on osteoporosis-induced bone fracture incidence and healing, and on bone density. Limitations of systemic statins are described along with alternative dosing strategies, including local applications and bone-targeting systemic preparations. The principal findings of this review are: (1) traditional oral dosing with statins results in minimal efficacy in the treatment of osteoporosis; (2) local applications of statins show promise in the treatment of accessible bony defects, such as periodontitis; and (3) systemically administered statins which can target bone or inflammation near bone may be the safest and most effective strategy in the treatment of osseous deficiencies.
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      PubDate: 2014-08-16T01:35:57Z
       
  • Statins role in the prevention and treatment of sepsis
    • Abstract: Publication date: October 2014
      Source:Pharmacological Research, Volume 88
      Author(s): Paul P. Dobesh , Keith M. Olsen
      Sepsis is a complex disease with typically poor outcomes. While the onset of sepsis is typically infectious, the detrimental consequences follow pathogen toxin release that produces activation of numerous cytokines and a pro-inflammatory response. These same cytokines also stimulate activation of coagulation and inhibit natural fibrinolysis. Despite decades of research targeted against these pathways the development of sepsis and mortality in patients with sepsis remains high. While statins were developed for reducing cholesterol in patients with atherosclerotic disease, we now know they have a number of other properties which may be helpful in the prevention and treatment of sepsis. Statins have demonstrated the ability to reduce a number of pro-inflammatory cytokines known to be detrimental in the development and progression of sepsis. Statins have also demonstrated the ability to limit the coagulation response and promote fibrinolysis in the setting of sepsis. Based on these encouraging pharmacologic properties of statins a number of trials have been conducted evaluating the impact of statins on the prevention and treatment of sepsis. Most of the trials to date have been retrospective cohort trials, with very few prospective randomized trials. While some trials fail to demonstrate a benefit of statins, most trials suggest a reduction in the development of sepsis and/or other important sepsis related outcomes. While the laboratory and early clinical experience with statins are encouraging, randomized controlled trials will be need to fully define the role of statins in the prevention and treatment of sepsis.
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      PubDate: 2014-08-16T01:35:57Z
       
  • Erratum to “Protection afforded by pre- or post-treatment with
           4-phenylbutyrate against liver injury induced by acetaminophen overdose in
           mice” [Pharmacol. Res. 87 (2014) 26–41]
    • Abstract: Publication date: Available online 4 August 2014
      Source:Pharmacological Research
      Author(s): Daisuke Shimizu , Yoichi Ishitsuka , Keishi Miyata , Yoshiro Tomishima , Yuki Kondo , Mitsuru Irikura , Takao Iwawaki , Yuichi Oike , Tetsumi Irie



      PubDate: 2014-08-08T00:57:05Z
       
  • Pharmacological activation of AMPK ameliorates perivascular
           adipose/endothelial dysfunction in a manner interdependent on AMPK and
           SIRT1
    • Abstract: Publication date: Available online 7 August 2014
      Source:Pharmacological Research
      Author(s): Yan Sun , Jia Li , Na Xiao , Meng Wang , Junping Kou , Lianwen Qi , Fang Huang , Baolin Liu , Kang Liu
      Adipose and endothelial dysfunction is tightly associated with cardiovascular diseases in obesity and insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and SIRT1 activities implicated in adipocytokine expression and endothelial homeostasis under inflammatory conditions by using salicylate, metformin, AICA riboside (AICAR) and resveratrol as AMPK activating agents. We prepared conditioned medium (CM) by stimulating PVAT with palmitic acid (PA) and observed the effects of AMPK activating agents on adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of resveratrol and metformin in fructose-fed rats. We observed that PA stimulation induced inflammation and dysregulation of adipocytokine expression accompanied with reduced AMPK activity and SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory adipocytokines, and upregulated adiponectin and PPARγ expression in PVAT in an AMPK/SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with AMPK inhibitor compound C or SIRT1 inhibitor nicotinamide. Long-term fructose-feeding in rats induced dysregulation of adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by oral administration of resveratrol and metformin. Altogether, pharmacological activation of AMPK beneficially regulated adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/SIRT1- interdependent manner.
      Graphical abstract image

      PubDate: 2014-08-08T00:57:05Z
       
  • The flavonoid quercetin induces acute vasodilator effects in healthy
           volunteers: correlation with beta-glucuronidase activity
    • Abstract: Publication date: Available online 27 July 2014
      Source:Pharmacological Research
      Author(s): Almudena Perez , Susana Gonzalez-Manzano , Rosario Jimenez , Rocío Perez-Abud , Jose M. Haro , Antonio Osuna , Celestino Santos-Buelga , Juan Duarte , Francisco Perez-Vizcaino
      Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). Design double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26±5 years, 6 female) were given a capsule containing placebo, 200 or 400mg of quercetin in random order in three consecutive weeks. At 2h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1μM for 200 and 400mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA.
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      PubDate: 2014-07-31T00:32:51Z
       
  • Statins in neurological disorders: An overview and update
    • Abstract: Publication date: Available online 19 June 2014
      Source:Pharmacological Research
      Author(s): Anna Maria Malfitano , Giuseppe Marasco , Maria Chiara Proto , Chiara Laezza , Patrizia Gazzerro , Maurizio Bifulco
      Statins have, at present, the potential to provide a new therapeutic target for various neurological diseases. It is well established that statins reduce cholesterol levels and prevent coronary heart disease. Moreover, evidence suggest that statins have additional properties such as endothelial protection via action on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These properties might have potential therapeutic implication not only in stroke but also in neurological disorders such as Alzheimer disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In addition to their potent anti-atherosclerotic and cardio-protective effects, compelling clinical and preclinical studies delineate the neuro-protective efficacy of statins in all these neurological disorders. It is apparent from these studies that most patients with central nervous system disorders probably benefit to some extent from lipid-lowering therapy. But data are not univocal, and we must also consider the adverse effects due to the administration of lipid-lowering therapy. Thus, in these scenarios the effectiveness of statins in treating stroke, Alzheimer's disease, Parkinson disease, multiple sclerosis, and primary brain tumors have to be conclusively proven in vivo and/or in adequate clinical trials.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Novel prospects of statins as therapeutic agents in cancer
    • Abstract: Publication date: Available online 5 July 2014
      Source:Pharmacological Research
      Author(s): Simona Pisanti , Paola Picardi , Elena Ciaglia , Alba D’Alessandro , Maurizio Bifulco
      Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed toward the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Statins in chronic kidney disease and kidney transplantation
    • Abstract: Publication date: Available online 1 July 2014
      Source:Pharmacological Research
      Author(s): Theodoros I. Kassimatis , David J.A. Goldsmith
      HMG-CoA reductase inhibitors (statins) have been shown to improve cardiovascular (CV) outcomes in the general population as well as in patients with cardiovascular disease (CVD). Statins’ beneficial effects have been attributed to both cholesterol-lowering and cholesterol-independent “pleiotropic” properties. By their pleiotropic effects statins have been shown to reduce inflammation, alleviate oxidative stress, modify the immunologic responses, improve endothelial function and suppress platelet aggregation. Patients with chronic kidney disease (CKD) exhibit an enormous increase in CVD rates even from early CKD stages. As considerable differences exist in dyslipidemia characteristics and the pathogenesis of CVD in CKD, statins’ CV benefits in CKD patients (including those with a kidney graft) should not be considered unequivocal. Indeed, accumulating clinical evidence suggests that statins exert diverse effects on dialysis and non-dialysis CKD patients. Therefore, it seems that statins improve CV outcomes in non-dialysis patients whereas exert little (if any) benefit in the dialysis population. It has also been proposed that dyslipidemia might play a causative role or even accelerate renal injury. Moreover, ample experimental evidence suggests that statins ameliorate renal damage. However, a high quality randomized controlled trial (RCT) and metaanalyses do not support a beneficial role of statins in renal outcomes in terms of proteinuria reduction or retardation of glomerular filtration rate (GFR) decline.
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      PubDate: 2014-07-27T00:24:02Z
       
  • Statin: New life for an old drug
    • Abstract: Publication date: Available online 14 July 2014
      Source:Pharmacological Research
      Author(s): Maurizio Bifulco , Akira Endo



      PubDate: 2014-07-27T00:24:02Z
       
  • Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal
           death through oxidative stress
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Elsa Gouix , Alain Buisson , André Nieoullon , Lydia Kerkerian-Le Goff , Joseph S. Tauskela , Nicolas Blondeau , Laurence Had-Aissouni
      Understanding the role of astrocytes in stroke is assuming increasing prominence, not only as an important component on its own within the neurovascular unit, but also because astrocytes can influence neuronal outcome. Ischemia may induce astrogliosis and other phenotypic changes, but these remain poorly understood, in part due to limitations in reproducing these changes in vitro. Dibutyryl cyclic AMP-differentiated cultured astrocytes are more representative of the in vivo astroglial cell phenotype, and were much more susceptible than undifferentiated astrocytes to an ischemic-like stress, oxygen-glucose deprivation (OGD). OGD altered the expression/distribution and activity of glial glutamate transporters, impaired cellular glutamate uptake and decreased intracellular levels of glutathione preferentially in differentiated astrocytes. Resistance to OGD was conferred by inhibiting caspase-3 with DEVD-CHO and oxidative stress by the antioxidant N-acetylcysteine (NAC). The resistance of undifferentiated astrocytes to OGD may result from a transient but selective morphological transformation into Alzheimer type II astrocytes, an intermediary stage prior to transforming into reactive astrocytes. Co-culture of neurons with OGD-exposed astrocytes resulted in neurotoxicity, but at surprisingly lower levels with dying differentiated astrocytes. The antioxidant NAC or the 5-LOX inhibitor AA861 added upon co-culture delayed (day 1) but did not prevent neurotoxicity (day 3). Astrocytes undergoing apoptosis as a result of ischemia may represent a transient neuroprotective mechanism via ischemia-induced release of glutathione, but oxidative stress was responsible for neuronal demise when ischemia compromised astrocyte supportive functions.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • N6-isopentenyladenosine affects cytotoxic activity and cytokines
           production by IL-2 activated NK cells and exerts topical anti-inflammatory
           activity in mice
    • Abstract: Publication date: Available online 22 July 2014
      Source:Pharmacological Research
      Author(s): Elena Ciaglia , Simona Pisanti , Paola Picardi , Chiara Laezza , Silvio Sosa , Aurelia Tubaro , Mario Vitale , Patrizia Gazzerro , Anna Maria Malfitano , Maurizio Bifulco
      N6-isopentenyladenosine (iPA) is a modified adenosine with an isopentenyl moiety derived from the mevalonate pathway which displays pleiotropic biological effects, including anti-tumor and anti-angiogenic activity. Previous evidence revealed a biphasic effect of iPA on phytohemagglutinin-stimulated lymphocytes, being pro-proliferative at low doses and anti-proliferative at high doses. Analogously, we have recently shown that low iPA concentrations (<1μM) increased the immune response of natural killer (NK) cells against cancer targets. In the present study, we evaluated the effect of iPA at high concentration (10μM) on IL-2-activated NK cells. iPA, inhibited NK cell proliferation and cytotoxicity against their conventional tumor target, human K562 cells. This inhibition was associated with decreased expression and functionality of NK cell activating receptors NKp44 and NKG2D as well as impaired cyto/chemokines secretion (RANTES, MIP-1α, TNF-α and IFN-γ). ERK/MAPK and STAT5 activation in IL-2-activated NK cells were inhibited by iPA. The results obtained in vitro were validated in vivo in the inflammatory murine model of croton oil-induced ear dermatitis. The topical application of iPA significantly reduced mouse ear oedema, thus suggesting anti-inflammatory properties of this molecule. These results show the ability of iPA to exert anti-inflammatory effects both in vitro and in vivo directly targeting NK cells, providing a novel pharmacological tool in those diseases characterized by a deregulated immune-response, such as cancer or inflammatory conditions.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • ErbB/HER protein-tyrosine kinases: Structures and small molecule
           inhibitors
    • Abstract: Publication date: September 2014
      Source:Pharmacological Research, Volume 87
      Author(s): Robert Roskoski Jr.
      The epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4). These receptors consist of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. The ErbB proteins function as homo and heterodimers. Growth factor binding to EGFR induces a large conformational change in the extracellular domain. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric dimer. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas. Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer and lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Moreover, monoclonal antibodies that target the extracellular domain of ErbB2 are used for the treatment of ErbB2-positive breast cancer and monoclonal antibodies that target ErbB1 and are used for the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them, and a current goal of research is to develop drugs that are effective against drug-resistant tumors.
      Graphical abstract image

      PubDate: 2014-07-27T00:24:02Z
       
  • In vivo sex differences in leukotriene biosynthesis in zymosan-induced
           peritonitis
    • Abstract: Publication date: Available online 1 June 2014
      Source:Pharmacological Research
      Author(s): Antonietta Rossi , Carlo Pergola , Simona Pace , Olof Rådmark , Oliver Werz , Lidia Sautebin
      Leukotrienes (LTs) are 5-lipoxygenase (5-LO) metabolites which are implicated in sex-dependent inflammatory diseases (asthma, autoimmune diseases, etc). We have recently reported sex differences in LT biosynthesis in in vitro models such as human whole blood, neutrophils and monocytes, due to down-regulation of 5-LO product formation by androgens. Here we present evidences for sex differences in LT synthesis and related inflammatory reactions in an in vivo model of inflammation (mouse zymosan-induced peritonitis). On the cellular level, differential 5-LO subcellular compartmentalization in peritoneal macrophages (PM) from male and female mice might be the basis for these differences. Sex differences in vascular permeability and neutrophil recruitment (cell number and myeloperoxidase activity) into peritoneal cavity were evident upon intraperitoneal zymosan injection, with more prominent responses in female mice. This was accompanied by higher levels of LTC4 and LTB4 in peritoneal exudates of female compared to male mice. Interestingly, LT peritoneal levels in orchidectomized mice were higher than in sham male mice. In accordance with the in vivo results, LT formation in stimulated PM from female mice was higher than in male PM, accompanied by alterations in 5-LO subcellular localization. The increased formation of LTC4 in incubations of PM from orchidectomized mice confirms a role of sex hormones. In conclusion, sex differences observed in LT biosynthesis during peritonitis in vivo may be related, at least in part, to a variant 5-LO localization in PM from male and female mice.
      Graphical abstract image

      PubDate: 2014-06-02T15:13:57Z
       
  • Statins and skeletal muscles toxicity: from clinical trials to everyday
           practice
    • Abstract: Publication date: Available online 13 May 2014
      Source:Pharmacological Research
      Author(s): Giuseppe Danilo Norata , Gianpaolo Tibolla , Alberico Luigi Catapano
      The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the results of observational studies and clinical trials provide compelling evidence that skeletal muscle toxicity is a frequent, dose-dependent, adverse event associated with all statins. It has been suggested that reduced availability of metabolites produced by the mevalonate pathway rather than intracellular cholesterol lowering per se might be the primary trigger of toxicity, however other alternative explanations have gained credibility in recent years. Aim of this review is: i) to describe the molecular mechanisms associated to statin induced myopathy including defects in isoprenoids synthesis followed by altered prenylation of small GTPase, such as Ras and Rab proteins; ii) to present the emerging aspects on pharmacogenetics, including CYP3A4, OATP1B1 and glycine amidinotransferase (GATM) polymorphisms impacting either statin bioavailability or creatine synthesis; iii) to summarize the available epidemiological evidences; and iii) to discuss the concepts that would be of interest to the clinicians for the daily management of patients with statin induced myopathy. The interplay between drug-environment and drug-drug interaction in the context of different genetic settings contribute to statins and skeletal muscles toxicity. Until specific assays/algorithms able to combine genetic scores with drug-drug-environment interaction to identify patients at risk of myopathies will become available, clinicians should continue to monitor carefully patients on polytherapy which include statins and be ready to reconsider dose, statin or switching to alternative treatments. The beneficial effects of adding agents to provide the muscle with the metabolites, such as CoQ10, affected by statin treatment will also be addressed.
      Graphical abstract image

      PubDate: 2014-05-16T03:59:20Z
       
 
 
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