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Basic & Clinical Pharmacology & Toxicology

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ISSN (Print) 1742-7835 - ISSN (Online) 1742-7843
Published by John Wiley and Sons

[1587 journals]

Purinoceptor‐mediated, Capsaicin‐resistant Excitatory Effect of Allyl Isothiocyanate on Neurons of the Guinea‐Pig Small Intestine
- Authors: Lorand Bartho; Elin Nordtveit, Veronika Szombati, Rita Benko
  Pages: n/a - n/a
  Abstract: Allyl isothiocyanate (AITC; 200 μM) caused atropine‐ and tetrodotoxin‐sensitive longitudinal muscle contraction on the guinea‐pig small intestine. The response was not influenced by hexamethonium, a functional blockade of capsaicin‐sensitive neurons or by antagonists acting at TRPV1 or TRPA1, but was abolished by the P2 purinoceptor antagonist PPADS (50 μM). It is concluded that cholinergic motoneurons are activated by a purinergic mechanism in the course of the AITC response, independently of capsaicin‐sensitive processes or even TRPA1.
  PubDate: 2013-02-26T05:01:34.315242-05:
  DOI: 10.1111/bcpt.12060
Antinociceptive and Anti‐inflammatory Activities of the Ethanolic Extract, Fractions and 8‐Methoxylapachenol from Sinningia allagophylla Tubers
- Authors: Felipe L. Barbosa; Lídia S. Mori, Dilamara Riva, Maria Élida A. Stefanello, Aleksander R. Zampronio
  Pages: n/a - n/a
  Abstract: This study investigated the antinociceptive and anti‐inflammatory activities of the ethanolic extract (EESAl), fractions and the compound 8‐methoxylapachenol (8ML) obtained from the tubers of Sinningia allagophylla. Male Swiss mice were treated with EESAl (3–300 mg/kg) or vehicle by oral route (p.o.) 1 hr before the injection of formalin 2.5% or carrageenan (Cg) into the hind paw. EESAl (3–30 mg/kg) reduced the inflammatory phase of the nociceptive behaviour induced by formalin (around 65% for all doses). EESAl (3–300 mg/kg, p.o.) also reduced Cg‐induced mechanical hyperalgesia and oedema in a dose‐dependent fashion but did not change the hot‐plate latency or the motor performance of the animals. Oral administration of petroleum ether fraction (PE, 3 mg/kg), but not in the methanolic fraction (30 mg/kg), reduced both Cg‐induced oedema and hyperalgesia. Compound 8ML isolated from PE (1.8 mg/kg, p.o.) abolished Cg‐induced hyperalgesia but also did not change hot‐plate latency or motor performance of the animals. 8ML administration into the paw (0.75–750 pg) dose‐dependently reduced Cg‐induced hyperalgesia. 8ML (750 pg) also blocked the hyperalgesia induced by tumour necrosis factor (TNF‐α), interleukin‐1β (IL‐1β) and prostaglandin E2 (PGE2) but failed to change the hyperalgesia induced by cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1) and dopamine (Dopa). These results suggest that EESAl has an important antinociceptive and anti‐inflammatory activity, the former one related, at least in part, to the reduction in the hyperalgesia. Similarly, 8ML reduced Cg‐induced oedema and mechanical hyperalgesia and seems to act in peripheral sites and on the prostaglandin rather than on the sympathetic component of the Cg‐inflammatory hyperalgesia.
  PubDate: 2013-02-25T08:30:33.199405-05:
  DOI: 10.1111/bcpt.12051
Non‐Fatal Suicidal Self‐Poisonings in Children and Adolescents over a 5‐Year Period (2007–2011)
- Authors: Sergey Zakharov; Tomas Navratil, Daniela Pelclova
  Pages: n/a - n/a
  Abstract: The objective of this study was to analyse non‐fatal suicidal self‐poisonings in children and adolescents and to identify commonalities that might direct preventive health efforts. From the database of the Czech Toxicological Information Center, the inquiries due to non‐fatal suicidal self‐poisonings in children (9–13 years old) and adolescents (14–18 years old) in 2007–2011 were evaluated. From 10,492 calls about suicide attempts, 2393 concerned children and adolescents (13.5% and 86.5%, respectively). Most suicide attempts were committed during the spring (31.3%). Among toxic agents, drugs were used in 97.8% of the cases. 63% of cases involved monopoisonings and combinations of more than three drugs (10.3%) were rare. The most frequent ingestions appeared using drugs affecting the nervous system and anti‐inflammatory non‐steroids. The dose was evaluated as toxic in 73.4% of the cases and as severely toxic in 3.0% of the cases. The symptoms of moderate and severe intoxications were present in 10.5% of the cases. First aid was provided in 5.6%, and gastric lavage was performed in 21.9% of the cases. Antidotes were indicated in 13.3% and secondary elimination methods in 4.4% of the cases. Mostly, one or two easily accessible drugs were used in suicide attempts, with paracetamol and ibuprofen were the most common ones. Only one in 10 children applied a non‐toxic dose. One‐fifth of the patients received medical care within 60 min. and one‐third later than 4 hr after exposure. The time criterion for gastric lavages was fulfilled in less than half of the cases, and in every fourth case, the procedure was performed when it was unlikely to be beneficial.
  PubDate: 2013-02-23T05:07:59.037293-05:
  DOI: 10.1111/bcpt.12047
Polybrominated Diphenyl Ether Congener (BDE‐100) Induces Mitochondrial Impairment
- Authors: Lílian Cristina Pereira; Alecsandra Oliveira Souza, Daniel Junqueira Dorta
  Pages: n/a - n/a
  Abstract: Brominated flame retardants are used in various consumer products to increase their resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are representatives of this class and among the most widely used congeners, and BDE‐100 is produced on a large scale. There is a lack of toxicological data about these compounds, which has recently become a matter of concern to the scientific community. The mitochondria are recognized as the main energy‐producing organelles, as well as playing a vital role in the maintenance of many cell functions. Therefore, mitochondria were used in the present work as an experimental model to evaluate the effects of the BDE‐100 congeners at concentrations ranging from 0.1 μM to 50 μM. The results showed that high concentrations of BDE‐100 were able to induce mitochondrial alterations. It was observed that the substance had an affinity for the hydrophilic portion of the mitochondrial membrane, as monitored by ANS, inhibiting the glutamate + malate‐stimulated mitochondrial respiration and also inducing dissipation of the mitochondrial membrane potential, deregulation of calcium homoeostasis and mitochondrial swelling, the latter being insensitive to cyclosporin A (CsA) but partially inhibited by Ruthenium Red and N‐ethyl maleimide. In addition, a significant reduction in mitochondrial ATP content was found, but on the other hand, no oxidative stress was observed after exposure of the mitochondria to BDE‐100. These results show the key role of mitochondria in the cytotoxicity induced by BDE‐100.
  PubDate: 2013-02-23T02:58:51.585346-05:
  DOI: 10.1111/bcpt.12046
Involvement Of Large‐Conductance Ca2+‐Activated K+ Channels In Both Nitric Oxide And Endothelium‐Derived Hyperpolarization‐Type Relaxation In Human Penile Small Arteries
- Authors: István Király; János Pataricza, Zoltán Bajory, Ulf Simonsen, András Varro, Julius Gy. Papp, Lászlo Pajor, Attila Kun
  Pages: n/a - n/a
  Abstract: Large‐conductance Ca2+‐activated K+ channels (BKCa), located on the vascular smooth muscle, play an important role in regulation of vascular tone. In penile corpus cavernosum tissue, opening of BKCa channels leads to relaxation of corporal smooth muscle which is essential during erection; however, there is little information on the role of BKCa channels located in penile vascular smooth muscle. This study was designed to investigate the involvement of BKCa channels in endothelium‐dependent and ‐independent relaxation of human intracavernous penile arteries. In human intracavernous arteries obtained in connection with transsexual operations, change of isometric force was recorded in microvascular myographs and endothelium‐dependent (nitric oxide (NO) and endothelium‐derived hyperpolarization (EDH)‐type) and ‐independent (NO‐donor) relaxation was measured in contracted arteries. In penile small arteries contracted with phenylephrine, acetylcholine evoked NO‐ and EDH‐type relaxations which were sensitive to iberiotoxin, a selective blocker of BKCa channels. Iberiotoxin also inhibited relaxations induced by a NO donor, sodium nitroprusside. NS11021, a selective opener of BKCa channels, evoked pronounced relaxations which were inhibited in the presence of iberiotoxin. NS13558, a BKCa inactive analogue of NS11021, failed to relax human penile small arteries. Our results show that BKCa channels are involved in both NO‐ and EDH‐type relaxation of intracavernous penile arteries obtained from healthy men. The effect of a selective opener of BKCa channels also suggests that direct activation of the channel may be an advantageous approach for treatment of impaired endothelium‐dependent relaxation often associated with erectile dysfunction.
  PubDate: 2013-02-18T03:30:29.770857-05:
  DOI: 10.1111/bcpt.12059
Reduction of Sympathetic Nerve Activity as a Possible Mechanism for the Hypothermic Effect of Oseltamivir, an Anti‐influenza Virus Drug, in Normal Mice
- Authors: Hideki Ono; Yui Iwajima, Yuko Nagano, Kaori Chazono, Yasuhiro Maeda, Masahiro Ohsawa, Shohei Yamamoto
  Pages: n/a - n/a
  Abstract: Oseltamivir, an anti‐influenza virus drug, has strong antipyretic effects in mice (Ono et al., 2008) and influenza patients. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose‐dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.‐preadministered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti‐nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms.
  PubDate: 2013-02-08T10:56:23.908878-05:
  DOI: 10.1111/bcpt.12058
Cinnabar is Different from Mercuric Chloride in Mercury Absorption and Influence on the Brain Serotonin Level
- Authors: Qi Wang; Xiaoda Yang, Baoxu Zhang, Xiuwei Yang, Kui Wang
  Pages: n/a - n/a
  Abstract: The toxicity of cinnabar, a naturally occurring mercury sulphide (HgS), has long been referred to soluble mercury chloride (HgCl2). To investigate whether the speciation of mercury plays a role in its disposition and toxicity, we hereby investigated and compared cinnabar with soluble HgCl2 and pure insoluble HgS in mice on mercury absorption, tissue distribution and in relation to the biological effects. The male C57BL/6J mice were treated by oral administration of various doses of cinnabar, with 0.01 g/kg of HgCl2 for comparison, or the same dose of cinnabar or pure HgS (0.1 g/kg), once a day for 10 consecutive days. The total mercury contents in serum and tissue (brain, kidney, liver) were measured by atomic fluorescence spectrometer (AFS). The biological effects investigated involved monoamine neurotransmitters (serotonin, 5‐HT) in brain as an indicator of therapeutic function, and serum alanine transaminase (ALT) as a marker of hepatic damage, blood urea nitrogen (BUN) and serum creatinine as markers for renal function. The mercury absorption of cinnabar or HgS was much less than that of HgCl2. The mercury levels in brains of the cinnabar group were only slightly changed and kept in a steady‐state with the dose elevated. Cinnabar or HgS suppressed brain 5‐HT levels. HgCl2 could not cause any changes in brain 5‐HT although the mercury level increased considerably. The results revealed that cinnabar or HgS is markedly different from HgCl2 in mercury absorption, tissue distribution and influence on brain 5‐HT levels, which suggests that the pharmacological and/or toxicological effects of cinnabar undertake other pathways from mercuric ions.
  PubDate: 2013-02-07T12:38:35.767431-05:
  DOI: 10.1111/bcpt.12045
Tissue Accumulation Kinetics of Ciclesonide‐active Metabolite and Budesonide in Mice
- Authors: Ulla Mårs; Roland d'Argy, Karin Hallbeck, Anna Miller‐Larsson, Staffan Edsbäcker
  Pages: n/a - n/a
  Abstract: Inhaled corticosteroids (ICS) are mainstay treatment of asthma and chronic obstructive pulmonary disease. However, highly lipophilic ICS accumulate in systemic tissues, which may lead to adverse systemic effects. The accumulation of a new, highly lipophilic ICS, ciclesonide and its active metabolite (des‐CIC) has not yet been reported. Here, we have compared tissue accumulation of des‐CIC and an ICS of a moderate lipophilicity, budesonide (BUD), after 14 days of once‐daily treatment in mice. Single, three or 14 daily doses of [3H]‐des‐CIC or [3H]‐BUD were administered subcutaneously to male CD1 albino mice, which were killed at 4 hr, 24 hr or 5 days after the last dose. Distribution of tissue concentration of radioactivity was studied by quantitative whole‐body autoradiography. Pattern of radioactivity distribution across most tissues was similar for both corticosteroids after a single as well as after repeated dosing. However, tissue concentration of radioactivity differed between des‐CIC and BUD. After a single dose, concentrations of radioactivity for both corticosteroids were low for most tissues but increased over 14 days of daily dosing. The tissue radioactivity of des‐CIC at 24 hr and 5 days after the 14th dose was 2–3 times higher than that of BUD in majority of tissues. Tissue accumulation, assessed as concentration of tissue radioactivity 5 days after the 14th versus 3rd dose, showed an average ratio of 5.2 for des‐CIC and 2.7 for BUD (p
  PubDate: 2013-02-07T12:32:15.127254-05:
  DOI: 10.1111/bcpt.12043
Total Synthetic Protoapigenone WYC02 Inhibits Cervical Cancer Cell Proliferation and Tumour Growth through PIK3 Signaling Pathway
- Authors: Yun‐Ju Chen; Nari Kay, Jinn‐Moon Yang, Chih‐Ta Lin, Hsueh‐Ling Chang, Yang‐Chang Wu, Chi‐Feng Fu, Yu Chang, Steven Lo, Ming‐Feng Hou, Yi‐Chen Lee, Ya‐Ching Hsieh, Shyng‐Shiou Yuan
  Pages: n/a - n/a
  Abstract: Flavonoids have been intensively explored for their anti‐cancer activity. In this study, a total synthetic flavonoid protoapigenone known as WYC02, was analysed for its potential anti‐cancer activity on human cervical cancer cells as well as the underlying mechanisms for these effects. Using the site‐moiety maps to explore the binding site similarity, pharmacophore and docking pose similarity. The effect of WYC02 on cell viability, migration, invasion, apoptosis as well as the underlying mechanisms were analysed in vitro using human cervical cancer cells. Effect of WYC02 on in vivo tumour growth was assessed in a tumour xenograft study. WYC02 inhibited cell proliferation, MMPs activity, migration and invasion in cervical cancer cells. We speculated that WYC02 might inhibit the activities of PIK3 family proteins including PIK3CA, PIK3CB, PIK3CD and PIK3CG. Indeed, WYC02 decreased the expression of PIK3 family proteins, especially PIK3CG, through ubiquitination and inhibited the activities of PIK3CG and PIK3 downstream molecules AKT1 and MTOR in cervical cancer cells. Furthermore, PIK3 signaling pathway was involved in the inhibitory effect of WYC02 on cervical cancer cell proliferation and tumour growth in vitro and in vivo. WYC02 inhibits cervical cancer cell proliferation and tumourigenesis via PIK3 signaling pathway and has the potential to be developed as a chemotherapeutic agent in cervical cancer.
  PubDate: 2013-02-06T10:47:37.026631-05:
  DOI: 10.1111/bcpt.12057
Extraction of Electronic Health Record Data in a Hospital Setting: Comparison of Automatic and Semi‐Automatic Methods Using Anti‐TNF Therapy as Model
- Authors: Thomas Cars; Björn Wettermark, Rickard E. Malmström, Gunnar Ekeving, Bo Vikström, Ulf Bergman, Martin Neovius, Bo Ringertz, Lars L. Gustafsson
  Pages: n/a - n/a
  Abstract: There is limited experience and methods for extractions of drug therapy data from electronic health records (EHR) in the hospital setting. We have therefore developed and evaluated completeness and consistency of an automatic versus a semi‐automatic extraction procedure applied on prescribing and administration of the TNF inhibitor infliximab using a hospital EHR system in Karolinska University Hospital, Sweden. Using two different extraction methods (automatic and semi‐automatic), all administered infusions of infliximab between 2007 and 2010 were extracted from a database linked to the EHR system in a large university hospital. Extracted data included encrypted personal identity number (PIN), date of birth, sex, time of prescription/administration, healthcare units, prescribed/administered dose, time of admission/discharge. The primary diagnosis (ICD‐10) for the treatment with infliximab was extracted by linking inflixmab infusions to their corresponding treatment episode. A total of 13,590 infusions of infliximab were administered during the period of 2007 to 2010. Of those were 13,531 (99.6%) possible to link to a corresponding treatment episode and a primary diagnosis was extracted for 13,530 infusions. Information on encrypted PIN, date of birth, time of prescription/administration, time of admission/discharge and healthcare unit was complete. Information about sex was missing in one patient only. Calculable information about dosage was extracted for 13,300 (98.3 %) of all linked infusions. This methodological study showed the potential to extract drug therapy data in a hospital setting. The semi‐automatic procedure produced an almost complete pattern of demographics, diagnoses and dosages for the treatment with infliximab.
  PubDate: 2013-02-03T20:55:28.126238-05:
  DOI: 10.1111/bcpt.12055
Metformin Induces Cytotoxicity by Down‐Regulating Thymidine Phosphorylase and ERCC1 Expression in Non‐Small Cell Lung Cancer Cells
- Authors: Jen‐Chung Ko; Yu‐Ching Huang, Huang‐Jen Chen, Sheng‐Chieh Tseng, Hsien‐Chun Chiu, Ting‐Yu Wo, Yi‐Jhen Huang, Shao‐Hsing Weng, Robin Y.Y. Chiou, Yun‐Wei Lin
  Pages: n/a - n/a
  Abstract: Metformin is an anti‐diabetic drug recently shown to inhibit cancer cell proliferation and growth, although the involved molecular mechanisms have not been elucidated. In many cancer cells, high expression of thymidine phosphorylase (TP) and ERCC1 are associated with poor prognosis. We used A549 and H1975 human non‐small cell lung cancer (NSCLC) cell lines to investigate the role of TP and ERCC1 expression in metformin‐induced cytotoxicity. Metformin treatment decreased cellular TP and ERCC1 protein and mRNA levels by down‐regulating phosphorylated MEK1/2‐ERK1/2 protein levels in a dose‐ and time‐dependent manner. The enforced expression of the constitutively active MEK1 (MEK1‐CA) vectors significantly restored cellular TP and ERCC1 protein levels and cell viability. Specific inhibition of TP and ERCC1 expression by siRNA enhanced the metformin‐induced cytotoxicity and growth inhibition. Arachidin‐1, an antioxidant stilbenoid, further decreased TP and ERCC1 expression and augmented metformin's cytotoxic effect, which was abrogated in lung cancer cells transfected with MEK1/2‐CA expression vector. In conclusion, metformin induces cytotoxicity by down‐regulating TP and ERCC1 expression in NSCLC cells.
  PubDate: 2013-01-31T07:31:12.730854-05:
  DOI: 10.1111/bcpt.12052
Tea Polyphenols Modulate Antioxidant Redox System on Cisplatin‐induced Reactive Oxygen Species Generation in a Human Breast Cancer Cell
- Authors: Vaiyapuri S. Periasamy; Ali A. Alshatwi
  Pages: n/a - n/a
  Abstract: Tea polyphenols (TPP) have potent antioxidant and anticancer properties, particularly in patients undergoing radiation or chemotherapy. However, few studies have been conducted on treatments using a combination of TPP and the conventional chemical anticancer drug cisplatin (CP). This study was designed to investigate the mechanism of the cytotoxicity of total TPP and CP, which may synergistically induce cell death in cancer cells. Here, breast cancer cells (MCF‐7) were treated with various concentrations of TPP alone or in combination with the chemotherapeutic drug CP. The effect of TPP on cell growth, intracellular reactive oxygen species (ROS) level, apoptosis and gene expression of caspase‐3, caspase‐8 and caspase‐9 and p53 was investigated. The MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay revealed that the MCF‐7 cells were less sensitive to growth inhibition by TPP treatment than either CP or the combination therapy. Propidium iodide nuclear staining indicated that exposure to this combination increased the proportion of apoptotic nuclei compared with a single‐agent treatment. Flow cytometry analysis was used to quantify changes in intracellular ROS. Detection of activated caspases by fluorescently labelled inhibitors of caspases (FLICA) combined with the plasma membrane permeability assay demonstrated that the percentage of early and late apoptotic/secondary necrotic cells was higher in the cells treated with the combination than in those treated with either TPP or CP alone. The combined TPP and CP treatment synergistically induced apoptosis through both caspase‐8 and caspase‐9 activation and p53 over‐expression. This suggests that TPP plus CP may be used as an efficient antioxidant‐based combination therapy for estrogen receptor (ER)‐positive and p53‐positive breast cancer.
  PubDate: 2013-01-24T12:25:57.762694-05:
  DOI: 10.1111/bcpt.12035
Kolaviron, a Natural Antioxidant and Anti‐Inflammatory Phytochemical Prevents Dextran Sulphate Sodium‐Induced Colitis in Rats
- Authors: Ebenezer O. Farombi; Isaac A. Adedara, Babajide O. AjayiZ, Omolola R. Ayepoola, Ewomazino E. Egbeme
  Pages: n/a - n/a
  Abstract: The beneficial effects of kolaviron, a natural biflavonoid from the seeds of Garcinia kola, have been attributed mainly to its antioxidant and anti‐inflammatory effects. The present study investigated these effects on dextran sulphate sodium (DSS)‐induced ulcerative colitis in rats. Sulfasalazine served as standard reference in this study. Kolaviron and sulfasalazine were separately co‐administered orally at 200 mg/kg and 500 mg/kg, respectively, to dextran sulphate sodium‐exposed rats for five days. The result indicated that kolaviron or sulfasalazine significantly prevented DSS‐induced body weight loss as well as the incidence of diarrhoea and bleeding in DSS‐exposed rats. Kolaviron suppressed the DSS‐mediated increase in colonic nitric oxide concentration and myeloperoxidase activity and significantly prevented the increase in inflammatory mediators, interleukin‐1β and tumour necrosis factor alpha, in the colon of DSS‐treated rats. The significant depletion in colonic antioxidant status in rats exposed to DSS alone was evident by marked reduction in colonic catalase and glutathione S‐transferase activities as well as glutathione content, leading to elevated hydrogen peroxide and lipid peroxidation levels. Histopathologically, DSS alone resulted in severe epithelial erosion, total absence of goblet cells, destruction of the crypts, necrotic and distorted glands, accompanied by marked cellular mononuclear cells infiltration. However, administration of kolaviron and sulfasalazine ameliorated DSS‐induced colitis by increasing the antioxidant status, decreased hydrogen peroxide and lipid peroxidation levels and attenuated the adverse effect of DSS on colon architecture. In conclusion, the anti‐colitis effect of kolaviron is related to its intrinsic anti‐inflammatory and anti‐oxidative properties.
  PubDate: 2013-01-22T02:27:06.099935-05:
  DOI: 10.1111/bcpt.12050
Quercetin decreases liver damage in mice with non‐alcoholic steatohepatitis
- Authors: Éder Marcolin; Luiz Felipe Forgiarini, Graziella Rodrigues, Juliana Tieppo, Greice Stefani Borghetti, Valquiria Linck Bassani, Jaqueline Nascimento Picada, Norma Possa Marroni
  Pages: n/a - n/a
  Abstract: Non‐alcoholic steatohepatitis (NASH) is a frequent condition in obese patients that may progress to end‐stage liver disease. This study was designed to evaluate the modulation of this condition by use of quercetin (Q), a flavonoid largely found in vegetable foods, with known antiinflammatory and antioxidant properties, in the experimental model of non‐alcoholic steatohepatitis (NASH) by using a diet deficient in methionine and choline (MCD). Male C57BL6 mice were divided into four groups (n=16): (i) Control plus vehicle (control ration plus carboxymethylcellulose 1% used as vehicle, CO + V); (ii) Control ration plus Q 50 mg/kg (CO + Q); (iii) MCD diet plus vehicle (NASH + V); and (iv) MCD diet plus Q (NASH + Q). Diets were administered for 4 weeks. At the end of the experimental period, liver alterations, bioindicators of oxidative stress and DNA damage were assessed. NASH was diagnosed in 100% of the mice that were fed the MCD diet. In addition, a significant increase in DNA damage in liver tissue from NASH + V group was observed in comparison to CO + V. The group NASH + Q showed a significant decrease in hepatic damage enzymes, lipoperoxidation, DNA damage and a lower degree of macrovesicular steatosis, ballooning and inflammatory process. These findings suggest that Q may have protective effects by improving liver integrity in NASH.
  PubDate: 2013-01-18T03:20:31.269355-05:
  DOI: 10.1111/bcpt.12049
Immunosuppressive Effect of Silymarin on MAPK Signaling Pathway: The Impact on T Cell Proliferation and Cytokine Production
- Abstract: Silymarin, a polyphenolic flavonoid derived from milk thistle (Silybum marianum), is known to have anti‐inflammatory, hepatoprotective and anticarcinogenic effects. In this study, the in vitro immunomodulatory effect of silymarin was investigated using human CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) from healthy individuals were activated with anti‐CD3 (5μg/ml) plus anti‐CD28 (2μg/ml) and treated with 10, 50 and 100μM silymarin. Cells were incubated 72 hr for proliferation assay using MTT and for viability analysis using PI staining and flow cytometry. Naive CD4+ T cell were also isolated from PBMCs, activated with PHA/anti‐CD28 and treated with 100μM silymarin for 72 hr. MAPKs activity of cell lysate from activated naive CD4+T cells was assessed using an ELISA‐based MAPkinase activity kit and Th1/Th2 related cytokines expression were determined by Multi‐Analyte ELISA array Kit. Results indicated a significant inhibition in proliferation of activated PBMC after 48‐hr incubation with 100μM silymarin without causing cell death. Moreover, MAPKs activity, (ERK1/2 and P38) and Th1‐ related cytokines (IL2, TNF‐α IFN‐γ) were significantly reduced in silymarin‐treated cells compared to control after 72 hr. This study shows that silymarin has the ability to inhibit T cell proliferation and pro‐inflammatory cytokine secretion in vitro. Furthermore, silymarin is able to inhibit ERK1/2 and P38 pathway activation in T cells stimulated through TCR engagement, a property that is likely associated with its ability to inhibit T cell proliferation and cytokine secretion. Therefore, Silymarin, as an immune‐response modifier, might be a valuable drug in therapeutic situations in which immunosuppression is required. This article is protected by copyright. All rights reserved.
The Role of NF‐κB1A Promoter Polymorphisms on Coronary Artery Disease Risk
- Abstract: Coronary artery disease (CAD), which is now regarded as a chronic inflammatory disease, is the leading cause of death worldwide. Nuclear factor (NF)‐κB is a transcription factor that plays an important role in the regulation of the immune system. NF‐κBIA is the inhibitory version of NF‐κB. This study is the first investigation of the association between CAD and NF‐κBIA ‐297 C/T, ‐826 C/T, ‐881 A/G polymorphisms in a Turkish population using PCR–RFLP method. The study population comprised 201 cases with CAD and 201 healthy controls. There was no significant difference in NF‐κB1A ‐297 C/T and ‐881 A/G in allele and genotype frequencies between case and control populations. The genotype frequency of NF‐κBIA ‐826TT in the patients with CAD was significantly higher than that of the controls (p=0.015, adjusted OR=7.09, 95% CI=1.95‐25.70). The CAD patients also had significantly higher carriage rate of NF‐κBIA ‐826T allele than the controls (p=0.03, OR=1.43, 95% CI=1.03–1.99). Linkage analysis indicated a close linkage among these three variants of NF‐κBIA (for case χ2=85.35 and p
β‐Cyclodextrin‐complexed (‐)‐linalool produces antinociceptive effect superior to that of (‐)‐linalool in experimental pain protocols
- Abstract: Many plants produce (‐)‐linalool, a plant‐derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti‐inflammatory and analgesic effects of (‐)‐linalool have been widely suggested for various studies. Poor chemical stability and short half‐life restrain the clinical applications of some essential oil and monoterpenes, including (‐)‐linalool. However, β‐cyclodextrin (β‐CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In the present study, the antinociceptive effect of (‐)‐linalool and (‐)‐linalool/β‐CD was examined using the acetic acid writhing reflex, formalin and hot plate tests in rodents. (‐)‐Linalool and (‐)‐linalool/β‐CD demonstrated strong antinociceptive activity in all the chemical‐ and heat‐induced mice models (p
Activity of Dexrazoxane and Amifostine against late Cardiotoxicity Induced by Combination of Doxorubicin with Cyclophosphamide In Vivo
- Abstract: Cardiotoxicity is one of the main limiting side effects of doxorubicin and cyclophosphamide (DC) treatment, and the present study was organized to identify cardioptotective activity of amifostine and dexrazoxane against DC combination. BalbC/NIH mice underwent DC treatment (DC group), pre‐treated with amifostine (ADC group) or dexrazoxane (IDC group), euthanized at 1.5 and 3 months after treatments when the grade of myocardial damage was analysed by light microscopy using the Billingham scoring method. DC treatment induced severe myocardial damae with one lethal event before evaluation at 3 months. Main characteristics of DC cardiotoxicity were polymorphic myocyte degeneration and alterations of blood vessels followed by ecchimoses, haemorrhage and thromboses. Polymorphism was also found in the IDC and ADC groups but its morphological patterns were different. In animals subject to IDC treatment, the blood vessels were better preserved than in the ADC group, whereas thrombosis was not seen in either of these two groups. Quantitatively, grade of myocardial injury in the ADC and IDC groups was significantly higher compared to the non‐treated group at both times of estimation, and significantly lower compared to the DC group at 1.5 months. At 3 months, significance against DC treatment was lost in the ADC group, while preserved in the IDC‐treated animals. Also, there was significant progression in the ADC group comparing scores between 1.5 and 3 months. These results revealed that the cardiotoxicity of DC combination displays specific morphological hallmark and evolution in time, different to those described after doxorubicin‐single treatment. Neither amifostine nor dexrazoxane prevented development of cardiomyopathy induced by DC treatment. This article is protected by copyright. All rights reserved.
Role of P‐glycoprotein in the Uptake/Efflux Transport of Oral Vitamin K Antagonists and Rivaroxaban through the Caco‐2 Cell Model
- Abstract: Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter‐ and intra‐individual variability. P‐glycoprotein could contribute to this variability. The aim of the present study was to investigate the involvement of P‐gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco‐2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P‐gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P‐gp inhibitor cyclosporine A (10 μM) and the more potent and specific P‐gp inhibitor valspodar (5 μM). Analytical quantification was performed by LC‐MS. With an efflux ratio of 1.7 and a significant decrease of the efflux (Papp B‐A), in the presence of P‐gp inhibitors at a concentration of 50 μM, acenocoumarol can be considered as a weak P‐gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P‐gp substrate. The P‐gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P‐gp inhibitors. In conclusion, none of the three VKAs tested are strong P‐gp substrates. However, acenocoumarol can be considered as a weak P‐gp substrate and phenprocoumon as a poor P‐gp substrate. This article is protected by copyright. All rights reserved.
Evaluation of the Potency of Two Novel Bispyridinium Oximes (K456, K458) in Comparison with Oxime K203 and Trimedoxime to Counteract Tabun‐induced Neurotoxicity in Rats
- Abstract: The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun‐induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the Functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 85% of LD50 value) were evaluated. Tabun‐induced neurotoxicity was monitored by the Functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun‐poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun‐induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun‐induced acute neurotoxic signs and symptoms. Their ability to decrease tabun‐induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203 but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings. This article is protected by copyright. All rights reserved.
Lenalidomide at Therapeutic and Supra‐therapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men
- Abstract: The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time‐matched changes from placebo in the baseline‐adjusted least‐squares mean QTcI were 60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug‐clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients. This article is protected by copyright. All rights reserved.
Intravenous Lipid Emulsion Entraps Amitriptyline into Plasma and Can Lower its Brain Concentration – an Experimental Intoxication Study in Pigs
- Abstract: Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well‐perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid® (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p
Statins and Cancer‐Related Mortality: An Open Question
- Abstract: HMG‐CoA reductase inhibitors, statins and pleiotropic effects have been associated with both increased and decreased cancer risk. This letter intends to contribute to ascertaining the real role of statins in cancer since there are conflicting results in the literature1. In the last volume of The Lancet Oncology, Cagney2 outlined the results of Nielsen and colleagues recently published in the New England Journal of Medicine3. The nationwide study suggests that statin use in patients with cancer is associated with a 15% reduction in cancer‐related mortality in the Danish population who had received a diagnosis of cancer between 1995 and 2007. The used databases virtually included all cancer diagnoses made during the 12‐year period and the follow‐up of 13 different types of cancers, but in our opinion, and according to Caporaso4, the study suffers from some important limitations, and numerous potential misjudgements should be taken into account. This article is protected by copyright. All rights reserved.
Melatonin Attenuates Isoflurane‐Induced Acute Memory Impairments in Aged Rats
- Abstract: Melatonin is an endogenous hormone with neuroprotective effects. Melatonin levels in elderly patients are reduced following surgeries that require anaesthesia. Whether reduced melatonin levels are important for postoperative cognitive dysfunction (POCD) remains unclear. Here, we investigated the effects of melatonin on cognitive dysfunctions induced by isoflurane and mechanisms underlying these effects. Seventy‐two 20‐month‐old Sprague‐Dawley rats were randomly divided into six groups (n=12). These groups included M1 and M10 groups that received intraperitoneal melatonin at 1 mg/kg or 10 mg/kg, respectively, and an ISO group that received 4 hr of inhaled 2% isoflurane. They also included M1+ISO and M10+ISO groups that received 1 mg/kg or 10 mg/kg of melatonin plus 4 hr of inhaled 2% isoflurane, respectively, and a control group that received an equal volume of saline. Injections were administered daily for 14 consecutive days. Memory was assessed in the Morris water maze. Plasma and hippocampi were harvested to determine melatonin concentrations and MT1/MT2 receptor expression. Rats treated only with isoflurane showed significantly longer latencies in Morris water maze test trials compared with the control group, with shorter time in the probe trial (p
Cardioprotective Effects of Nicorandil, a Mitochondrial Potassium Channel Opener against Doxorubicin‐induced Cardiotoxicity in Rats
- Abstract: Doxorubicin is a chemotherapeutic drug used to treat solid and haematopoietic tumours. Its use is limited by a major side effect of cardiotoxicity. It was reported that doxorubicin‐induced cardiotoxicity is mediated through oxidative stress coupled with impaired NO bioavailability and NF‐κB activation. Nicorandil, a mitochondrial ATP‐dependent potassium (KATP) channel opener, was reported to be cardioprotective on ischaemic myocardium. However, the effect of nicorandil against doxorubicin‐induced cardiotoxicity has not yet been clarified. Accordingly, six groups of rats were used. The first three groups were injected with vehicle, nicorandil (3 mg/kg) orally and doxorubicin (a single intraperitoneal injection of 20 mg/kg), respectively. Group four was treated with nicorandil whereas group five was treated with glibenclamide and then nicorandil starting two days before doxorubicin and continued for five consecutive days. Group six was treated with glibenclamide alone. At the end of the experiment, the rats were killed. Cardiac enzyme indexes were measured in serum. Heart tissues were processed for determination of nitrite/nitrate, NF‐κB protein expression, glutathione (GSH), lipid peroxide (TBARS) levels and superoxide production. In addition to body weight reduction, doxorubicin produced cardiotoxicity as indicated from the increase in lactate dehydrogenase (LDH), creatine kinase (CK) activities, TBARS, superoxide production, NF‐κB expression and caspase‐3 activity. Moreover, doxorubicin decreased GSH and nitrite/nitrate levels. Histopathological examination of doxorubicin‐treated hearts revealed degenerative changes. On the other hand, nicorandil protected cardiac tissues against doxorubicin cardiotoxicity as evidenced from normalization of cardiac biochemical and oxidative stress parameters and amelioration of histopathological changes. Glibenclamide, a blocker of the KATP channel, reversed most of the cardiac effects of nicorandil. This article is protected by copyright. All rights reserved.
Nephrectomised and Hepatectomised Animal Models as Tools in Preclinical Pharmacokinetics
- Abstract: Early understanding the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in the drug development process. In vitro methodologies can be used to investigate metabolic patterns but in general, they lack several aspects of the whole body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance to drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well‐balanced anaesthesia and adequate monitoring of the animals is also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post‐operative supportive care of the animals can increase the value of these models by minimising the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models. This article is protected by copyright. All rights reserved.
Channeling of Statin Use towards Low‐Risk Population and Patients with Diabetes
- Abstract: This study based on nationwide comprehensive health registers analysed trends in characteristics of statin users in the whole community‐dwelling population of Finland between 1999 and 2008. The annual number of incident users (defined as those purchasing statins for the first time ever) increased 1.6‐fold from 50,125 to 78,058 and that of ongoing users (including continuous users and re‐initiators) increased 4.6‐fold from 114,091 to 521,218. The proportion of incident users without cardiovascular disease (CVD) or diabetes increased from 23.6% to 27.8% while the proportion of those with diabetes increased from 15.7% to 19.5%. An increasing proportion of ongoing users had diabetes (from 13.8% to 22.8%). The proportion of ongoing users without CVD or diabetes remained below one‐fifth; however, their number increased fivefold. Over the study period, there was a clear shift toward prescribing of higher statin doses both among incident and ongoing users. In conclusion, statin use is expanding to individuals with low cardiovascular risk despite the fact that clinical guidelines emphasize interventions other than pharmacotherapy for this population. At the same time, statin use is increasingly targeted to patients with diabetes, a high‐risk group that is likely to benefit from it. This article is protected by copyright. All rights reserved.
Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMPK
- Abstract: Curcumin is a well‐known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high‐fat/cholesterol diet (HFD)‐induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body weight and adipose tissue weight of mice in the HFD+C group compared to the findings for the HFD group (p
L‐Amino Acid Oxidase Isolated from Bothrops pirajai Induces Apoptosis in BCR‐ABL Positive Cells and Potentiates Imatinib Mesylate Effect
- Abstract: Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of Philadelphia chromosome and by BCR‐ABL1, which encodes the BCR‐ABL oncoprotein. Although imatinib mesylate (IM) is effective for CML treatment, patients in accelerated and blastic phases of the disease are often refractory to this therapy and there are also cases of IM resistance in patients in the chronic phase. Therefore, potential new drugs are being investigated to improve the efficiency of the therapy of CML such as snake venoms and their compounds. In this investigation, Bothrops pirajai L‐amino acid oxidase (BpirLAAO‐I) effect on normal peripheral blood mononuclear cells (PBMC) and on BCR‐ABL+ cell line was assessed to explore its potential against leukaemic cells. MTT viability assay, lymphocyte subsets quantification and cell activation markers expression were performed to evaluate BpirLAAO‐I effect on normal PBMC. The effect of BpirLAAO‐I on HL‐60 and HL‐60.BCR‐ABL cell lines was assessed by apoptosis detection. BpirLAAO‐I was able to induce apoptosis in HL‐60 and HL‐60.BCR‐ABL cell lines in a dose‐dependent manner, promoted caspases 3, 8 and 9 activation and enhanced IM effect while not affecting the viability of normal cells. In addition, BpirLAAO‐I promoted immune cells activation and lymphocytes subsets changes on normal PBMC. The results indicate that BpirLAAO‐I induces apoptosis and potentiates IM effect on BCR‐ABL+ cells.
Pan‐BH3 Mimetic S1 Exhibits Broad‐Spectrum Antitumor Effects by Cooperation between Bax and Bak
- Abstract: Small molecule S1 is a pan‐BH3 mimetic that can bind anti‐apoptotic Bcl‐2, Bcl‐xL and Mcl‐1 proteins. Herein, different Bcl‐2 member expression cancer cell lines (NCI‐H345, MCF‐7, SMMC‐7721 and Hela), and cells deficient in Bax and/or Bak by shRNA were used to unravel the cascade of events by which S1 promotes apoptosis compared with Bcl‐2/Bcl‐xL inhibitor ABT‐737. We identified that S1 exhibited broader antitumour spectrum than ABT‐737 through disruption of more Bcl‐2 interactions including Mcl‐1/Bak interaction. Moreover, the individual and combined roles of Bax and Bak in S1‐induced apoptosis were revealed. Our results showed that S1 induced a Bak‐mediated apoptosis. Bak played a predominant role in either S1 or ABT‐737‐induced apoptosis through the cooperation with Bax on the formation of large oligomers on mitochondrial membrane.
In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development
- Abstract: The present study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and estrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Estrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine was observed. Finally, pup birth weight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic‐like doses.
Enantiomer Selective Glucuronidation of the Non‐Steroidal Pure Anti‐Androgen Bicalutamide by Human Liver and Kidney: Role of the Human UDP‐Glucuronosyltransferase (UGT)1A9 Enzyme
- Abstract: Bicalutamide (Casodex®) is a non‐steroidal pure anti‐androgen used in the treatment of localized prostate cancer. It is a racemate drug and its activity resides in the (R)‐enantiomer, with little in the (S)‐enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalyzed by UDP‐glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation.
Sex Difference in Formation of Propofol Metabolites: A Replication Study
- Abstract: Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men; an effect that may be inherent in sex differences in propofol metabolism.
Spinal RhoA/Rho Kinase Signaling Pathway may Participate in the Development of Bone Cancer Pain
- Abstract: It has been shown that activation of spinal RhoA/Rho kinase (ROCK) signaling pathway facilitates nociception in neuropathic and inflammatory pain, but its effects on bone cancer pain have not previously been studied. The present study was designed to examine the potential role of the spinal RhoA/ROCK signaling pathway in the development of bone cancer pain. A model for bone cancer was induced by injecting Walker 256 cells into the tibia of rats. On days 6, 9 and 15 after inoculation, the expression of spinal RhoA and ROCK2 protein levels were higher in the Walker 256 cells injected rats compared to the sham rats. On day 9, intrathecal injection of C3 exoenzyme (a RhoA inhibitor, 10 pg) significantly attenuated bone cancer pain behaviour as well as up‐regulation of spinal RhoA and ROCK2 protein levels. These effects were completely abolished by intrathecal pre‐treatment with U‐46619 (a RhoA agonist, 1.5 pg). These results suggest that the spinal RhoA/ROCK signaling pathway may be involved in the development of bone cancer pain. The findings of this study may lead to novel therapeutic strategies for prevention and/or treatment of bone cancer pain.
Pharmacokinetic‐Pharmacodynamic Modeling of Biomarker Response to Sitagliptin in Healthy Volunteers
- Abstract: Pharmacokinetic/pharmacodynamic (PK/PD) models can be useful tools in new drug development and also optimal drug therapy in patients. This study was designed to develop a PK/PD model of sitagliptin based on the physiology of incretin. The PK/PD data included information derived from two different studies. Study 1 was conducted as a one‐sequence, three‐period, repeated‐dose, dose escalation (sitagliptin 25, 50 and 100 mg q.d.) design in twelve healthy volunteers. Study 2 was a first‐in‐man study for the newly developed dipeptidyl peptidase‐4 (DPP‐4) inhibitor in healthy volunteers. In study 1, blood samples were collected to measure sitagliptin concentrations, DPP‐4 activity and active glucagon‐like peptide‐1 (GLP‐1) concentrations. In study 2, only data from the “placebo group” were used, and blood samples were collected to measure DPP‐4 activity, active GLP‐1 concentrations and glucose concentrations. A PK/PD analysis was conducted using a non‐linear mixed effects modeling approach. Sitagliptin pharmacokinetics was modeled using a two‐compartment model with first‐order absorption. Changes in DPP‐4 inhibition were linked to the PK model using a sigmoid Emax model, whereas the active GLP‐1 changes were explained using an indirect response model; this model incorporated the glucose and DPP‐4 inhibition models. The PK/PD model developed adequately described the changes in sitagliptin concentration, DPP‐4 inhibition and active GLP‐1 concentration in healthy volunteers.
Medication Reviews by Clinical Pharmacists at Hospitals Lead to Improved Patient Outcomes: A Systematic Review
- Abstract: Suboptimal medication use may lead to morbidity, mortality and increased costs. In order to reduce unnecessary patient harm, medicines management including medication reviews can be provided by clinical pharmacists. Some recent studies have indicated a positive effect of this service, but the quality and outcomes vary among studies. Hence, there is a need for compiling the evidence within this area. The aim of this systematic MiniReview was to identify, assess and summarise the literature investigating the effect of pharmacist‐led medication reviews in hospitalised patients.
Evaluation of the Antinociceptive Effects of Lidocaine and Bupivacaine on the Tail Nerves of Healthy Rats
- Abstract: This study was designed to develop a simple and effective model of tail nerve block without general anaesthesia and surgical incision, to assist in exploring and studying new local anaesthetics. Tail nerves of adult, male Sprague Dawley rats were blocked by injecting 1% lidocaine and 0.5% bupivacaine, respectively. To evaluate the tail nerve block model, the effects of tail nerve blocks induced by two classical local anaesthetics were assessed and compared by recording disappearance and recovery time of thermal and mechanical nociception. The results showed that thermal and mechanical nociception of the tail disappeared after application of local anaesthetics but were unchanged by normal saline. No abnormal results were found in both the 3‐day observation period and the pathological study, and pain thresholds of all rats recovered fully. We have thus developed an easily operated, reliable and reversible model of tail nerve block for conscious rats that can be used to evaluate efficacy, safety and pharmacokinetics of new local anaesthetics and additives.
Effects Of Antihypertensive And Triglyceride Lowering Agents On Splenocyte Apoptosis In Rats With Fatty Liver
- Abstract: Individuals with the metabolic syndrome (MS) and non‐alcoholic fatty liver disease (NFALD) have an increased incidence of infection and infection‐related mortality. Rats given fructose‐enriched diet (FED) develop the MS including NAFLD. In this study, we characterized changes in splenocyte apoptosis in FED rats given medications to treat various components of the MS. Apoptosis of splenocytes may induce immunosuppression. Splenocyte apoptosis was evaluated by activated caspase‐3 immunohistochemistry in the periarterial sheath (PALS), (a T‐cell area), follicles (B‐cell area), marginal (B‐cell area) and in the red pulp zones. FED administration caused an enormous increase in splenocyte apoptosis in all of the spleen zones: PALS (+2966%), follicles (+3025%), marginal (+5228%) and red pulp (+7000%). Administration of captopril to the FED rats was associated with a further increase in the splenocyte apoptosis only in the marginal (150%), PALS (+105%) and red pulp (+67%) zones. Bezafibrate administration to the FED rats was associated with no further increase in apoptosis rates. Amlodipine administration to the FED rats was associated with almost complete amelioration of the splenoctye apoptosis that was induced by the FED diet. These pharmacological manipulations were also associated with changes in the hepatic lipids composition and oxidative milieu that did not correlate to the changes in splenocyte apoptosis. NAFLD in FED rats is associated with an increase in splenic apoptosis. Agents administered to treat components of the MS in FED rats may lead to divergent changes in the splenic histology and splenocyte apoptosis.
Comparable Lumefantrine Oral Bioavailability when Co‐administered With Oil‐Fortified Maize Porridge or Milk in Healthy Volunteers
- Abstract: Co‐administration of artemether‐lumefantrine with milk is recommended to improve lumefantrine (L) absorption but milk may not be available in resource‐limited settings. This study explored the effects of cheap local food in Uganda on oral bioavailability of lumefantrine relative to milk. In an open‐label, four‐period cross‐over study, 13 healthy adult volunteers were randomized to receive a single oral dose of artemether‐lumefantrine (80 mg artemether / 480 mg lumefantrine) with water, milk, maize porridge or maize porridge with oil on separate occasions. Plasma lumefantrine was assayed using high‐performance liquid chromatography with ultraviolet detection. Pharmacokinetic exposure parameters were determined by non‐compartmental methods using WinNonlin. Peak concentrations (Cmax) and area under concentration‐time curve restricted to 48 hr post‐single dose (AUC(0‐48)) were selected for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. When artemether‐lumefantrine was administered with maize porridge plus oil, average bioequivalence ranges (means ratios 90% CI, 0.84 – 1.88 and 0.85 – 1.69 for Cmax and AUC(0‐48), respectively) were within and exceeded acceptance ranges relative to milk (90% CI, 0.80 – 1.25). Both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures (bioinequivalence) relative to milk. If milk is not available, it is thus possible to recommend fortification of carbohydrate rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine after artemether‐lumefantrine administration.
Fentanyl Pharmacokinetics is not Dependent on Hepatic Uptake by Organic Anion‐Transporting Polypeptide 1B1 in Humans
- Abstract: A recent study investigating the pharmacokinetics of fentanyl in Sprague‐Dawley rats suggested fentanyl to be a substrate of rat organic anion‐transporting polypeptide Oatp. In humans, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 (SLCO1B1) might modulate fentanyl pharmacokinetics and efficacy in humans. Sixteen healthy male and female volunteers, homozygous for SLCO1B1*1a (genetic wild type) (n=11) or *15 (deficient haplotype carrying the single nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n=5), were included in this randomized cross‐over study.