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  • Silibinin attenuates adipose tissue inflammation and reverses obesity and its complications in diet-induced obesity model in mice
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-23
    Mohammad Alsaggar; Shifa Bdour; Qutaibah Ababneh; Tamam El-Elimat; Nidal Qinna; Karem H. Alzoubi

    Obesity is a multifactorial chronic disease that comprises several pathological events, such as adipose hypertrophy, fatty liver and insulin resistance. Inflammation is a key contributer to development of these events, and therefore, targeting inflammation is increasingly considered for management of obesity and its complications. The aim of the current study was to investigate therapeutic outcomes of anti-inflammatory activities of the natural compound Silibinin in reversing obesity and its complication in mice. C57BL/6 male mice were fed high-fat diet for 8 weeks until development of obesity, and then injected with 50 mg/kg silibinin intraperitoneally twice per week, or vehicle for 8 weeks. Throughout the experiment, mice were continuously checked for body weight and food intake, and glucose tolerance test was performed toward the end of the experiment. Animals were sacrificed and serum and tissues were collected for biochemical, histological, and gene expression analysis to assess silibinin effects on adipose inflammation, fat accumulation, liver adipogenesis and glucose homeostasis. Silibinin treatment reversed adipose tissue inflammation and adipocyte hypertrophy, and blocked progression in weight gain and obesity development with no significant effects on rates of food intake. Silibinin also reversed fatty liver disease and restored glucose homeostasis in treated animals, and reversed hyperglycemia, hyperinsulinemia and hypertriglyceridemia. In this study, we demonstrated that silibinin as an anti-inflammatory therapy is a potential alternative to manage obesity, as well as its related complications. Moreover, silibinin-based therapies could further evolve as a novel treatment to manage various inflammation-driven disorders.

    更新日期:2020-01-23
  • In vitro and in situ study on characterization and mechanism of the intestinal absorption of 2,3,5,4′-tetrahydroxy-stilbene-2-O-β-D-glucoside
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-22
    Cheng Wang; Yimeng Zhou; Xiaohong Gong; Li Zheng; Yunxia Li

    2,3,5,4′-tetrahydroxystilbence-2-O-β-D-glucoside (TSG) is a polyhydroxyphenolic compound, which exhibited a broad spectrum of pharmacological activities, such as anti-inflammatory, anti-depression, anti-oxidation and anti-atherosclerosis. However, the compound had poor bioavailability and the underlying absorption mechanisms had not been studied. Therefore, the purpose of this study was to investigate the intestinal absorption mechanism of TSG. This study used Caco-2 cell monolayer model and single-pass intestinal perfusion model to explore the gastrointestinal absorption mechanisms of TSG. The effects of basic parameters such as drug concentration, time and pH on the intestinal absorption of TSG were analyzed by high performance liquid chromatography. The absorption susceptibility of TSG to three inhibitors, P-gp inhibitors verapamil hydrochloride and quinidine, and MRP2 inhibitor probenecid were also assessed. TSG was poorly absorbed in the intestines and the absorption of TSG in stomach is much higher than that in intestine. Both in vitro and in situ experiments showed that the absorption of TSG was saturated with increasing concentration and it was better absorbed in a weakly acidic environment pH 6.4. Moreover, TSG interacts with P-gp and MRP2, and TSG was not only the substrate of the P-gp and MRP2, but also affected the expression of P-gp and MRP2. It was concluded that the gastrointestinal absorption the most unique active ingredient and considered as the mechanisms of TSG involved processes passive transport and the participation of efflux transporters.

    更新日期:2020-01-23
  • Comparison of metamizole and paracetamol effects on colonic anastomosis and fibroblast activities in Wistar rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-13
    Eko Purnomo; Dwi Aris Agung Nugrahaningsih; Nunik Agustriani; Gunadi

    Leakage following colorectal anastomosis surgery causes various complications associated with high morbidity and mortality, especially in pediatric patients. It might be caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) as postoperative analgesics. This study aimed to compare the effect of metamizole and paracetamol on colonic anastomosis and fibroblast activities, including proliferation, migration, and collagen synthesis, in Wistar rats. Rats were divided into control, paracetamol and metamizole groups. The colonic anastomosis was evaluated by determining the integrity of the muscle layers, the formation of granulation tissue, and mucosal anastomosis. Fibroblast activities were analyzed by measuring the proliferation, migration, and collagen synthesis. Metamizole caused more damage to muscle layer integrity, more inhibition of granulation tissue formation in the anastomosis area and lower mucosal anastomosis compared with paracetamol and control groups. Metamizole had a higher cytotoxic effect than paracetamol, which suppressed the proliferation and migration of fibroblasts. Furthermore, both drugs did not affect the synthesis of collagen. Metamizole shows worse effects on the integrity of muscle layers, inhibition of granulation tissue formation, mucosal anastomosis, fibroblast proliferation, and migration, but not collagen synthesis, than paracetamol in Wistar rat intestines following colonic anastomosis. These findings might indicate that paracetamol is safer than metamizole as analgesic following colonic anastomosis.

    更新日期:2020-01-14
  • Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-09
    Miho Nakamura; Junya Nakade; Tadashi Toyama; Masaki Okajima; Takumi Taniguchi

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors inhibit SGLT2, which is expressed in the proximal renal tubule, and thus reduce blood glucose levels by enabling the urinary excretion of excess glucose. SGLT2 inhibitors have been reported to suppress the complications of diabetes and reduce overall mortality. However, little is known about the types of symptoms that may occur in response to an overdose of an SGLT2 inhibitor. Here, we describe a case of intoxication caused by an overdose of an SGLT2 inhibitor. An otherwise physically healthy adult woman ingested an overdose of ipragliflozin, an SGLT2 inhibitor, and a polypill of olmesartan medoxomil, and azelnidipine in a suicide attempt. Although her blood ipragliflozin concentration was very high (9516.3 ng/mL) upon hospital arrival, her initial blood glucose level was normal, and she did not exhibit symptoms such as hypoglycemia or polyuria. Moderate renal dysfunction associated with an estimated glomerular filtration rate of 42.3 mL/min/1.73 m2 was observed. Thirty-six hours after ingestion, her blood ipragliflozin concentration decreased to a level equivalent to that observed after a therapeutic dose and her renal function improved almost simultaneously. After improvement in her renal function, the osmotic diuretic effect of the drug progressed. Her blood glucose level declined slightly but was in the normal range due to glucose administration. During the clinical course, fatal hypoglycemia was not observed. Our case showed that an overdose of an SGLT2 inhibitor caused toxic effects on renal function, but severe hypoglycemia was not observed. Additional cases of intoxication from SGLT2 inhibitors alone would be helpful to clarify the mechanism of intoxication.

    更新日期:2020-01-11
  • The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-06
    Cecilia Nwadiuto Amadi; Wisdom Izuchukwu Nwachukwu

    Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

    更新日期:2020-01-07
  • Safety, tolerability, and pharmacokinetics of repeated oral doses of 2-hydroxybenzylamine acetate in healthy volunteers: a double-blind, randomized, placebo-controlled clinical trial
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-06
    Lisa M. Pitchford; Patricia M. Driver; John C. Fuller; Wendell S. Akers; Naji N. Abumrad; Venkataraman Amarnath; Ginger L. Milne; Sheau-Chiann Chen; Fei Ye; L. Jackson Roberts; M. Benjamin Shoemaker; John A. Oates; John A. Rathmacher; Olivier Boutaud

    2-Hydroxybenzylamine (2-HOBA) is a selective dicarbonyl electrophile scavenger being developed as a nutritional supplement to help protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline observed with Mild Cognitive Impairment or Alzheimer’s disease. This study evaluated the safety, tolerability, and pharmacokinetics of repeated oral doses of 2-HOBA acetate (500 or 750 mg) administered to healthy volunteers every eight hours for two weeks. The effects of 2-HOBA on cyclooxygenase function and cerebrospinal fluid penetrance of 2-HOBA were also investigated. Repeated oral administration of 2-HOBA was found to be safe and well-tolerated up to 750 mg TID for 15 days. 2-HOBA was absorbed within 2 h of administration, had a half-life of 2.10–3.27 h, and an accumulation ratio of 1.38–1.52. 2-HOBA did not interfere with cyclooxygenase function and was found to be present in cerebrospinal fluid 90 min after dosing. Repeated oral administration of 2-HOBA was found to be safe and well-tolerated. These results support continued development of 2-HOBA as a nutritional supplement. Studies are registered at ClinicalTrials.gov (NCT03555682 Registered 13 June 2018, NCT03554096 Registered 12 June 18).

    更新日期:2020-01-06
  • The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-03
    Zhaowei Zhang; Mingxiao Chen; Long Zhang; Qiang Zhao

    Clopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China. One hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected. The frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE. Our study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up. ChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.

    更新日期:2020-01-04
  • The effect of Liv-52 on liver ischemia reperfusion damage in rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2020-01-03
    Orhan Cimen; Hüseyin Eken; Ferda Keskin Cimen; Arif Burak Cekic; Nezahat Kurt; Asli Ozbek Bilgin; Bahadir Suleyman; Halis Suleyman; Renad Mammadov; Kamil Pehlivanoglu; Eray Kurnaz

    Liver ischemia reperfusion (I/R) damage which is frequently seen in clinical hepatobiliary surgeries has no effective treatment for it. Liv-52, known to have hepatoprotective effects, is a natural antioxidant drug licensed by the Ministry of Health of India. The aim of our study is to investigate the effect of Liv-52 on liver damage induced by I/R in rats. Albino Wistar male rats were divided into three groups; liver I/R (IR), 20 mg/kg Liv-52 + liver ischemia reperfusion (LIR) and sham operation applied to control group (HG). Liv-52 was administered to the LIR group (n = 6) 1 h prior to I/R application and distilled water was given orally to IR (n = 6) and HG (n = 6) groups as a solvent. Ischemia was determined as 1 h, and reperfusion was identified as 6 h in animals. Increased levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase, malondialdehyde, myeloperoxidase, and decreased levels of superoxide dismutase, and glutathione related enzymes caused by I/R application have been converged to healthy group level with Liv-52 treatment and the damage in liver tissue has been improved histopathologically. Liv-52 may be beneficial for preventing liver I/R damage in pre-surgery application.

    更新日期:2020-01-04
  • A phase 1, randomized, open-label, single-dose study to assess the relative bioavailability of a subcutaneous dose of FKB327 when administered using a prefilled syringe, a prefilled auto-injector, or a vial with disposable syringe in healthy subjects
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-30
    Jim Bush; Kazuki Kawakami; Rafael Muniz

    FKB327 is a biosimilar of the adalimumab reference product (RP). The primary objective was to assess the relative bioavailability of FKB327 after a single subcutaneous (SC) dose via prefilled syringe (PFS), auto-injector (AI), or vial with a disposable syringe (vial), in healthy subjects. This randomized, open-label, parallel-group, single SC-dose study was conducted in 195 healthy male and female subjects who were randomized 1:1:1 to receive FKB327 40 mg via PFS, AI, or vial. The primary pharmacokinetic (PK) parameters, areas under the serum concentration-time curve to the last detectable value (AUC0-t) and extrapolated to infinity (AUC0-∞), and maximum concentration (Cmax), were compared. Relative bioavailability was established if the ratio of geometric least squares (LS) means of the test product was within the predefined bioequivalence (BE) range of 0.80 to 1.25 of the RP for each comparison. Safety and immunogenicity were assessed. The mean serum FKB327 concentration-time profiles appeared similar across all 3 presentations. AUC0-t, AUC0-∞, and Cmax were within the predefined BE range for PFS compared with vial, suggesting comparable bioavailability. AUC0-∞ and Cmax of AI compared with vial and PFS were fully contained within BE range, although the upper limit of 90% confidence intervals of the geometric LS means ratios for AUC0-t was slightly high. Treatment-emergent adverse events in all 3 groups were mild, with no new safety concern with FKB327 identified. Similar immunogenicity was observed among administrations. Among all 3 delivery methods, PK characteristics, safety profiles, and immunogenicity were similar. EU Clinical Trials Registry EudraCTN2014–004469-26, registered October 14, 2014.

    更新日期:2019-12-31
  • SBF-1 inhibits contact hypersensitivity in mice through down-regulation of T-cell-mediated responses
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-21
    Wei Chen; Xianying Fang; Yuan Gao; Ke Shi; Lijun Sun; Biao Yu; Qiong Luo; Qiang Xu

    T lymphocytes play an important role in contact hypersensitivity. This study aims to explore the immunosuppressive activity of SBF-1, an analog of saponin OSW-1, against T lymphocytes in vitro and in vivo. Proliferation of T lymphocytes from lymph nodes of mice was determined by MTT assay. Flow cytometry analysis was performed to assess T cell activation and apoptosis. Levels of cytokines were determined by PCR and ELISA. BALB/c mice were sensitized and challenged with picryl chloride and thickness of left and right ears were measured. SBF-1 effectively inhibited T lymphocytes proliferation induced by concanavalin A (Con A) or anti-CD3 plus anti-CD28 at a very low dose (10 nM) but exhibited little toxicity in non-activated T lymphocytes at concentrations up to 10 μM. In addition, SBF-1 inhibited the expression of CD25 and CD69, as well as he phosphorylation of AKT in Con A-activated T cells. SBF-1 also induced apoptosis of activated T cells. In addition, SBF-1 also downregulated the induction of the T cell cytokines, IL-2 and IFN-γ in a dose-dependent manner. Furthermore, SBF-1 significantly suppressed ear swelling and inflammation in a mouse model of picryl chloride-induced contact hypersensitivity. Our findings suggest that SBF-1 has an unique immunosuppressive activity both in vitro and in vivo mainly through inhibiting T cell proliferation and activation. Its mechanism appears to be related to the blockage of AKT signaling pathway.

    更新日期:2019-12-21
  • KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Martyn Harvey; Jamie Sleigh; Logan Voss; Mike Bickerdike; Ivaylo Dimitrov; William Denny

    Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents. KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models. KEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5–10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats. KEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010.

    更新日期:2019-12-20
  • Evaluation of immunological, inflammatory, and oxidative stress biomarkers in gasoline station attendants
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Angela Maria Moro; Elisa Sauer; Natália Brucker; Mariele Feiffer Charão; Bruna Gauer; Sabrina Nunes do Nascimento; Gabriela Goethel; Marta Maria Medeiros Frescura Duarte; Solange Cristina Garcia

    Gasoline is a complex mixture of saturated and unsaturated hydrocarbons, in which aromatic compounds, such as BTX (benzene, toluene, and xylene) feature as the main constituents. Simultaneous exposure to these aromatic hydrocarbons causes a significant impact on benzene toxicity. In order to detect early alterations caused in gasoline station attendants exposed to BTX compounds, immunological, inflammatory, and oxidative stress biomarkers were evaluated. A total of 66 male subjects participated in this study. The gasoline station attendants (GSA) group consisted of 38 gasoline station attendants from Rio Grande do Sul, Brazil. The non-exposed group consisted of 28 subjects who were non-smokers and who had no history of occupational exposure. Environmental and biological monitoring of BTX exposure was performed using blood and urine. The GSA group showed increased BTX concentrations in relation to the non-exposed group (p < 0.001). The GSA group showed elevated protein carbonyl (PCO) levels and pro-inflammatory cytokines, decreased expression of CD80 and CD86 in monocytes, and reduced glutathione S-transferase (GST) activity compared to the non-exposed group (p < 0.05). BTX levels and trans,trans-muconic acid levels were positively correlated with pro-inflammatory cytokines and negatively correlated with interleukin-10 contents (p < 0.001). Increased levels of pro-inflammatory cytokines were accompanied by increased PCO contents and decreased GST activity (p < 0.001). Furthermore, according to the multiple linear regression analysis, benzene exposure was the only factor that significantly contributed to the increased pro-inflammatory cytokines (p < 0.05). Taken together, these findings show the influence of exposure to BTX compounds, especially benzene, on the immunological, inflammatory, and oxidative stress biomarkers evaluated. Furthermore, the data suggest the relationship among the evaluated biomarkers of effect, which could contribute to providing early signs of damage to biomolecules in subjects occupationally exposed to BTX compounds.

    更新日期:2019-12-19
  • Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Fabiana Gomes Nascimento Soares; Gabriela Göethel; Luciano Porto Kagami; Gustavo Machado das Neves; Elisa Sauer; Estefania Birriel; Javier Varela; Itamar Luís Gonçalves; Gilsane Von Poser; Mercedes González; Daniel Fábio Kawano; Fávero Reisdorfer Paula; Eduardo Borges de Melo; Solange Cristina Garcia; Hugo Cerecetto; Vera Lucia Eifler-Lima

    Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds. Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50). Toxicity assays: Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors. Two of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds. Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

    更新日期:2019-12-19
  • Evaluation of the acute toxicity, phototoxicity and embryotoxicity of a residual aqueous fraction from extract of the Antarctic moss Sanionia uncinata
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Andréia da Silva Fernandes; Lara Barroso Brito; Gisele Augusto Rodrigues Oliveira; Elisa Raquel Anastácio Ferraz; Heitor Evangelista; José Luiz Mazzei; Israel Felzenszwalb

    Ultraviolet (UV) radiation is the main exogenous inductor of skin damage and so photoprotection is important to control skin disorders. The Antarctic moss Sanionia uncinata is an important source of antioxidants and the photoprotective activity of its organic extracts has been investigated. This study aimed to evaluate the potential photoprotection, cytotoxicity and embryotoxicity of residual aqueous fraction (AF) from the moss S. uncinata. UV-visible spectrum and SPF (sun protection factor) were determined by spectrophotometry. Embryotoxicity potential was evaluated by Fish embryo-larval toxicity test using zebrafish (Danio rerio) as organism model. Cell death assays by water-soluble tetrazolium salt (WST-1) and lactate dehydrogenase (LDH) were investigated using HaCaT keratinocyte cell line cultured in monolayers and three dimensions (3D). Phototoxicity and association with UV-filters were performed by 3T3 neutral red uptake test. The AF showed sharp absorption bands in the UV region and less pronounced in the visible region. The SPF was low (2.5 ± 0.3), but the SPF values of benzophenone-3 and octyl-methoxycinnamate increased ~ 3 and 4 times more, respectively, in association with AF. The AF did not induce significant lethal and sublethal effects on zebrafish early-life stages. In monolayers, the HaCaT cell viability, evaluated by WST-1, was above 70% by ≤0.4 mg AF/mL after 48 and 72-h exposure, whereas ≤1 mg AF/mL after 24-h exposure. The LDH assay showed that the cell viability was above 70% by ≤0.4 mg AF/mL even after 72-h exposure, but ≤1 mg/mL after 24 and 48-h exposure. In 3D cell culture, an increased cell resistance to toxicity was observed, because cell viability of HaCaT cell by WST-1 and LDH was above ~ 90% when using ≤1 and 4 mg AF/mL, respectively. The AF demonstrated values of photo irritation factor < 2 and of photo effect < 0.1, even though in association with UV-filters. The residual AF absorbs UV-vis spectrum, increased SPF values of BP-3 and OMC and does not induce embryotoxicity to zebrafish early life-stage. The cell death assays allowed establishing non-toxic doses of AF and phototoxicity was not detected. AF of S. uncinata presents a good potential for skin photoprotection against UV-radiation.

    更新日期:2019-12-19
  • Nuclear factor erythroid 2 – related factor 2 and its relationship with cellular response in nickel exposure: a systems biology analysis
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Luisa Jiménez-Vidal; Pedro Espitia-Pérez; José Torres-Ávila; Dina Ricardo-Caldera; Shirley Salcedo-Arteaga; Claudia Galeano-Páez; Karina Pastor-Sierra; Lyda Espitia-Pérez

    Nickel and nickel-containing compounds (NCC) are known human carcinogens. However, the precise molecular mechanisms of nickel-induced malignant transformation remain unknown. Proposed mechanisms suggest that nickel and NCC may participate in the dual activation/inactivation of enzymatic pathways involved in cell defenses against oxidative damage, where Nuclear factor-erythroid 2 related factor 2 (Nrf2) plays a central role. For assessing the potential role of proteins involved in the Nrf2-mediated response to nickel and NCC exposure, we designed an interactome network using the STITCH search engine version 5.0 and the STRING software 10.0. The major NCC-protein interactome (NCPI) generated was analyzed using the MCODE plugin, version 1.5.1 for the detection of interaction modules or subnetworks. Main centralities of the NCPI were determined with the CentiScape 2.2 plugin of Cytoscape 3.4.0 and main biological processes associated with each cluster were assessed using the BiNGO plugin of Cytoscape 3.4.0. Water-soluble NiSO4 and insoluble Ni3S2 were the most connected to proteins involved in the NCPI network. Nfr2 was detected as one of the most relevant proteins in the network, participating in several multifunctional protein complexes in clusters 1, 2, 3 and 5. Ontological analysis of cluster 3 revealed several processes related to unfolded protein response (UPR) and response to endoplasmic reticulum (ER) stress. Cellular response to NCC exposure was very comparable, particularly concerning oxidative stress response, inflammation, cell cycle/proliferation, and apoptosis. In this cellular response, Nfr2 was highly centralized and participated in several multifunctional protein complexes, including several related to ER-stress. These results add evidence on the possible Ni2+ induced – ER stress mainly associated with insoluble NCC. In this scenario, we also show how protein degradation mediated by ubiquitination seems to play key roles in cellular responses to Ni.

    更新日期:2019-12-19
  • Gamma-hexalactone flavoring causes DNA lesion and modulates cytokines secretion at non-cytotoxic concentrations
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Luísa Zuravski; Taiane A. Escobar; Elizandra G. Schmitt; Queila D. F. Amaral; Fávero R. Paula; Thiago Duarte; Marta M. M. F. Duarte; Michel M. Machado; Luís F. S. Oliveira; Vanusa Manfredini

    The γ-hexalactone is a flavoring agent for alcoholic beverages, teas, breads, dairy products, coffees, buttery products among others. It presents low molecular weight and exhibits sweet fruity aroma with nuances of nuts. As far as we know, both literature and government regulations have gaps regarding the safe use of the γ-hexalactone. In this context, the main objective of this work was to evaluate the effects of γ-hexalactone through in silico and in vitro approaches. The in silico analysis was performed through four free online platforms (admetSAR, Osiris Property Explorer®, pkCSM platform and PreADMET) and consisted of comparative structural analysis with substances present in databases. The computational prediction was performed in the sense of complement and guide the in vitro tests. Regarding in vitro investigations, screening of cytotoxicity (assessed by cell proliferation and viability parameters) in lymphocytes exposed to γ-hexalactone for 72 h were carried out previously to determine non-cytotoxic concentrations. Following this screening, concentrations of 5.15, 0.515, and 0.0515 μM were selected for the study of the respective potentials: genotoxic (assessed by DNA comet assay), chromosomal mutation (analysis of micronucleus frequency) and immunomodulatory (cytokine quantification using ELISA immunoassay). The results of in vitro assays were compared by one-way analysis of variance (ANOVA), followed by Bonferroni’s post hoc test, conducted by statistic software. The platform PreADMET pointed out that γ-hexalactone is potentially mutagenic and carcinogenic. The comet assay data corroborate with these results demonstrating that γ-hexalactone at 5.15 μM caused lymphocytes DNA damage. In relation to cytokine secretion, the results indicate that lymphocytes were activated by γ-hexalactone at non-cytotoxic concentrations, involving an increase in the IL-1 levels in all tested concentrations, ranging from approximately 56 to 93%. The γ-hexalactone only at 5.15 μM induced increase in the levels of IL-6 (~ 60%), TNF-α (~ 68%) and IFN-γ (~ 29%), but decreased IL-10 (~ 46%) in comparison with the negative control (p < 0.05). No change was observed in total lymphocytes or in cell viability at the concentrations tested. In summary, the γ-hexalactone demonstrated immunomodulatory and genotoxic effects at non-cytotoxic concentrations in healthy lymphocytes.

    更新日期:2019-12-19
  • Melatonin-loaded lipid-core nanocapsules protect against lipid peroxidation caused by paraquat through increased SOD expression in Caenorhabditis elegans
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Mariele F. Charão; Gabriela Goethel; Natália Brucker; Karina Paese; Vera L. Eifler-Lima; Adriana R. Pohlmann; Silvia S. Guterres; Solange C. Garcia

    Melatonin has been described in the literature as a potent antioxidant. However, melatonin presents variable, low bioavailability and a short half-life. The use of polymeric nanoparticulated systems has been proposed for controlled release. Thus, the purpose of this study was to investigate the action of melatonin-loaded lipid-core nanocapsules (Mel-LNC) in the antioxidant system of Caenorhabditis elegans, and the possible protective effect of this formulation against lipid peroxidation caused by paraquat (PQ). The suspensions were prepared by interfacial deposition of the polymer and were physiochemically characterized. C. elegans N2 wild type and transgenic worm CF1553, muls84 [sod-3p::gfp; rol6(su1006)] were obtained from the Caenorhabditis Genetics Center (CGC). The worms were divided into 5 groups: Control, PQ 0.5 mM, PQ 0.5 mM + Mel-LNC 10 μg/mL, PQ + unloaded lipid-core nanocapsules (LNC), and PQ + free melatonin (Mel) 10 μg/mL. The lipid peroxidation was assessed through thiobarbituric acid (TBARS) levels and the fluorescence levels of the transgenic worms expressing GFP were measured. The LNC and Mel-LNC presented a bluish-white liquid, with pH values of 5.56 and 5.69, respectively. The zeta potential was − 6.4 ± 0.6 and − 5.2 ± 0.2, respectively. The mean particle diameter was 205 ± 4 nm and 203 ± 3 nm, respectively. The total melatonin content was 0.967 mg/ml. The TBARS levels were significantly higher in the PQ group when compared to the control group (p < 0.001). Mel-LNC reduced TBARS levels to similar levels found in the control group. Moreover, only Mel-LNC significantly enhanced the SOD-3 expression (p < 0.05). Mel-LNC was capable of protecting C. elegans from lipid peroxidation caused by PQ and this was not observed when free melatonin was used. Moreover, Mel-LNC increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3, demonstrating a possible mechanism of protection from PQ-induced damage. These findings demonstrated that melatonin, when associated with nanocapsules, had improved antioxidant properties and the protective activity against PQ-induced lipid peroxidation could be associated with the activation of antioxidant enzymes by Mel-LNC in C. elegans.

    更新日期:2019-12-19
  • Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    João Paulo Bianchi Ximenez; Jurandyr Moreira de Andrade; Maria Paula Marques; Eduardo Barbosa Coelho; Guilherme Suarez-Kurtz; Vera Lucia Lanchote

    Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35–50 years) or postmenopausal (n = 20; aged 60–79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays. Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [β-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (− 8.585 ± 3.060, p = 0.008). The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value. RBR-7tqc7k.

    更新日期:2019-12-19
  • In vitro toxic evaluation of two gliptins and their main impurities of synthesis
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Camila F. A. Giordani; Sarah Campanharo; Nathalie R. Wingert; Lívia M. Bueno; Joanna W. Manoel; Barbara Costa; Shanda Cattani; Marcelo Dutra Arbo; Solange Cristina Garcia; Cássia Virginia Garcia; Nádia Maria Volpato; Elfrides Eva Scherman Schapoval; Martin Steppe

    The presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). MTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated. Cytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 μM of sitagliptin and 10 μM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations. This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

    更新日期:2019-12-19
  • Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-19
    Bruna Candia Piccoli; Ana Lúcia Anversa Segatto; Cláudia Sirlene Oliveira; Fernanda D’Avila da Silva; Michael Aschner; João Batista Teixeira da Rocha

    Exposure to vinylcyclohexene (VCH) and methylmercury (MeHg+) can induce oxidative stress and gene modulation. Several studies have been evaluating the effects of VCH and MeHg+, but little is known about interactive effects between them. This work aimed to assess the exposure and co-exposure effects of MeHg+ and VCH on oxidative stress and gene modulation in Drosophila melanogaster. Reactive species production, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated after exposure and co-exposure to VCH (1 mM) and MeHg+ (0.2 mM) for one or three days in the head and body (thorax and abdomen) of flies. The expression of genes related to redox state and inflammatory response was evaluated after exposure and co-exposure to VCH and MeHg+ for three days. Survival decreased only in flies co-exposed to VCH and MeHg+ for three days. All treatments increased total reactive species production after one day of exposure. However, no significant changes were observed in the head after three days of exposure. One day of exposure to VCH caused an increase in the head GST activity, whereas MeHg+ induced an increase after three days of exposure. Regarding the body, all treatments increased GST activity after one day of exposure, but only the flies exposed to MeHg+ presented an increase in GST activity after three days of exposure. Treatments did not alter AChE activity in the head. As for gene expression, there was a significant increase in the Relish transcription factor gene in the flies’ body, but Nrf2, Keap1, Jafrac1, TrxR1, and NF-κβ were not altered. The results suggest that exposure to VCH and MeHg+ induce oxidative stress and activation of an inflammatory response in fruit flies.

    更新日期:2019-12-19
  • Thymoquinone ameliorates Pachycondyla sennaarensis venom-induced acute toxic shock in male rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-17
    Ibrahim M. Alhazza; Hossam Ebaid; Bahaa Abdel-Salam; Jameel H. Al-Tamimi; Iftekhar Hassan; Ahmed M. Rady; Ashraf M. A. Mashaly

    For many decades, the sting of Samsun ant (Pachycondyla sennaarensis) has been a serious clinical challenge for the people living in some of the major Middle East and Asian countries. In the present study, the therapeutic potential of Nigella sativa derived plant extract component, thymoquinone (TQ) has been tested against the Samsun ant venom (SAV) at the toxic dose in the rats. The adult male rats were divided into four groups (n = 10): control, SAV treated, SAV + TQ treated and TQ alone treated. It was found that the sub-lethal dose of SAV alters not only many of the kidney and liver function markers but also induces oxidative stress in the animals. Moreover, the SAV also disturbs various immunological parameters including expression of PMNs, CD-80, CD-86, interleukins and other cytokines compromising the affected organism towards mild to severe allergic reactions including life-risking anaphylaxis. The plant extract, TQ, effectively restores many of the biochemical and oxidative stress parameters comparable to the normal concomitant with improving the immunological aspects that might attributive in relieving from SAV-induced toxicity and allergic reactions in the affected organism to a greater extent. Hence, TQ has an excellent antidote property against SAV-induced toxicities in vivo. Although the study is a vivid indication of the potential therapeutic potential of TQ against the SAV induced in vivo toxicity, yet the actual mechanism of interaction translating the toxicity amelioration warrants further investigations.

    更新日期:2019-12-18
  • Complete atrioventricular block due to timolol eye drops: a case report and literature review
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-02
    Zhuoying Wang; Ian Denys; Feng Chen; Lijie Cai; Xuecui Wang; Daniel R. Kapusta; Yongliang Lv; Juan Gao

    Timolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block. A 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (− 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup. We conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.

    更新日期:2019-12-02
  • Analysis of apoptosis related genes in nurses exposed to anti-neoplastic drugs
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-12-02
    Maral Ramazani; Razieh Pourahmad Jaktaji; Farshad H. Shirazi; Maria Tavakoli-Ardakani; Ahmad Salimi; Jalal Pourahmad

    Anti-neoplastic agents are widely used in the treatment of cancer and some non-neoplastic diseases. These drugs have been proved to be carcinogens, teratogens, and mutagens. Concern exists regarding the possible dangers of the staff handling anti-cancer drugs. The long-term exposure of nurses to anti-neoplastic drugs is still a controversial issue. The purpose of this study was to monitor cellular toxicity parameters and gene expression in nurses who work in chemotherapy wards and compare them to nurses who work in other wards. To analyze the apoptosis-related genes overexpression and cytotoxicity effects, peripheral blood lymphocytes obtained from oncology nurses and the control group. Significant alterations in four analyzed apoptosis-related genes were observed in oncology nurses. In most individual samples being excavated, Bcl-2 overexpression is superior to that of Bax. Prominent P53 and Hif-1α up-regulation were observed in oncology nurses. Moreover, all cytotoxicity parameters (cell viability, ROS formation, MMP collapse, Lysosomal membrane damage, Lipid peroxidation, Caspase 3 activity and Apoptosis phenotype) in exposed oncology nurses were significantly (p < 0.001) higher than those of unexposed control nurses. Up-regulation of three analyzed apoptosis-related genes were observed in nurses occupationally exposed to anti-cancer drugs. Our data show that oxidative stress and mitochondrial toxicity induced by anti-neoplastic drugs lead to overexpression of apoptosis-related genes in oncology nurses.

    更新日期:2019-12-02
  • Sodium valproate induced acute pancreatitis in a bipolar disorder patient: a case report
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-11-29
    Wanli Huang; Xin Ren; Fang Shen; Baoping Xing

    Sodium valproate is one of the most widely used antiepileptics and mood stabilizers. However, this drug may induce acute pancreatitis. Few cases have been reported so far, mainly on the pediatric patients who underwent antiepileptic treatment. Hereby, we present a case of bipolar disorder with sodium valproate-induced acute pancreatitis. The patient is a 54-year-old Chinese male. He was diagnosed with bipolar disorder for more than 39 years. Since the first onset of the disease, he had several relapses. The patient had had sodium valproate to stabilize mood swings for a year before the occurrence of acute pancreatitis. But he did vomit once during the inpatient care period. Then he was referred to another hospital following a notably high level of amylase. The results of computed tomography demonstrated an increased pancreatic volume and swollen peripancreatic fat tissue. As a result, the patient was diagnosed with acute pancreatitis. Unlike other cases reported in literatures, the high amylase level did not revert to normal after the withdrawal of medications. The patient was discharged from hospital with a high level of amylase, and was placed under follow-up observations. Acute pancreatitis is considered as one of the idiosyncratic adverse reactions to antiepileptic drugs. Previous reports were mainly on the pediatric patients with increased propensity to idiosyncratic drug effects, or the adult chronic renal failure patients with sodium valproate-induced pancreatitis due to the retention of intermediate metabolites in their bodies. In this study, even though our patient exhibited no high risk of developing pancreatitis, he was treated for drug-induced acute pancreatitis in three hospitals. As rare as drug-induced acute pancreatitis can be, it should not be overlooked, Moreover, the mechanism of how sodium valproate induces acute pancreatitis remains unknown. Therefore, physicians need to consider the medical history of patients before prescribing this medication.

    更新日期:2019-11-30
  • Antihistamine effects and safety of fexofenadine: a systematic review and Meta-analysis of randomized controlled trials
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-11-29
    Cheng-zhi Huang; Zhi-hui Jiang; Jian Wang; Yue Luo; Hua Peng

    As a new generation antihistamine, fexofenadine has been widely used in allergic diseases. However, there is still a lack of collective evidence regarding the antihistamine effects and safety profiles of fexofenadine relative to other antihistamine drugs and placebo. Therefore, we aimed to systematically evaluate the antihistamine effects and safety of fexofenadine. An electronic literature search of randomized controlled trials (RCTs) was performed using Embase, Cochrane and PubMed from establishment to January 1st, 2018. RCTs comparing the antihistamine effects or safety (adverse events, sedative effects, and cognitive/psychomotor function) of fexofenadine with either other antihistamines or placebo for healthy subjects and patients with allergy were selected. Fifty-one studies of 14,551 participants met the inclusion criteria. When compared with the first-generation antihistamines, fexofenadine produced significantly lower adverse events frequency (OR = 0.446; 95% CI: 0.214 to 0.929, P = 0.031), significantly lower sedative effects frequency (OR = 0.265; 95% CI: 0.072 to 0.976, P = 0.046) and significantly less change of all cognitive/psychomotor function. When compared with the second-generation antihistamines, fexofenadine produced significantly marginal sedative effects (OR = 0.59; 95% CI, 0.38 to 0.93; P = 0.02) and significantly less change of most of the cognitive/psychomotor function. When compared with placebo, fexofenadine produced more significant antihistamine effects. Fexofenadine has a positive antihistamine effect, which is probably no worse than the second-generation antihistamines. Fexofenadine probably has a favorable safety profile, which is more likely better than that of the first-generation antihistamines. There is lack of data to support that fexofenadine has a better overall safety profile compared to the second-generation antihistamines, however, some presently available evidence on sedative effects and certain aspects of cognitive/psychomotor function favors fexofenadine. Therefore, fexofenadine may be worthy of recommendation for safety related workers.

    更新日期:2019-11-30
  • Characterization and preventability of adverse drug events as cause of emergency department visits: a prospective 1-year observational study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-04-27
    Ivan Lo Giudice; Eleonora Mocciaro; Claudia Giardina; Maria Antonietta Barbieri; Giuseppe Cicala; Maria Gioffrè-Florio; Giuseppe Carpinteri; Aulo Di Grande; Edoardo Spina; Vincenzo Arcoraci; Paola Maria Cutroneo

    Adverse drug events (ADEs) are a significant cause of emergency department (ED) visits, with a major impact on healthcare resource utilization. A multicentre observational study, aimed to describe frequency, seriousness and preventability of ADEs reported in four EDs, was performed in Sicily (Italy) over a 1-year period. Two trained monitors for each ED supported clinicians in identifying ADEs of patients admitted to EDs between June 1st, 2013 and May 31st, 2014 through a systematic interview of patients or their caregivers and with an additional record review. A research team analyzed each case of suspected ADE, to make a causality assessment applying the Naranjo algorithm and a preventability assessment using Schumock and Thornton criteria. Absolute and percentage frequencies with 95% confidence interval (CI) and medians with interquartile ranges (IQR) were estimated. Logistic regression models were used to evaluate independent predictors of serious and certainly preventable ADEs. Out of 16,963 ED visits, 575 (3.4%) were associated to ADEs, of which 15.1% resulted in hospitalization. ADEs were classified as probable in 45.9%, possible in 51.7% and definite in 2.4% of the cases. Moreover, ADEs were considered certainly preventable in 12.3%, probably preventable in 58.4%, and not preventable in 29.2% of the cases. Polytherapy influenced the risk to experience a serious, as well as a certainly preventable ADE. Whilst, older age resulted an independent predictor only of serious events. The most common implicated drug classes were antibiotics (34.4%) and anti-inflammatory drugs (22.6%). ADEs due to psycholeptics and antiepileptics resulted preventable in 62.7 and 54.5% of the cases, respectively. Allergic reactions (64%) were the most frequent cause of ADE-related ED visits, followed by neurological effects (10.2%) that resulted preventable in 1.9 and 37.3% of the cases, respectively. ADEs are a frequent cause of ED visits. The commonly used antibiotics and anti-inflammatory drugs should be carefully managed, as they are widely involved in mild to severe ADEs. Polytherapy is associated with the occurrence of serious, as well as certainly preventable ADEs, while older age only with serious events. A greater sensitivity to drug monitoring programs among health professionals is needed.

    更新日期:2019-11-28
  • Apigenin and hesperidin augment the toxic effect of doxorubicin against HepG2 cells
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-03
    Agnieszka Korga; Marta Ostrowska; Aleksandra Jozefczyk; Magdalena Iwan; Rafal Wojcik; Grazyna Zgorka; Mariola Herbet; Gemma Gomez Vilarrubla; Jaroslaw Dudka

    Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. Despite the fact that systematic chemotherapy with a doxorubicin provides only marginal improvements in survival of the HCC patients, the doxorubicin is being used in transarterial therapies or combined with the target drug – sorafenib. The aim of the study was to evaluate the effect of natural flavonoids on the cytotoxicity of the doxorubicin against human hepatocellular carcinoma cell line HepG2. The effect of apigenin and its glycosides - cosmosiin, rhoifolin; baicalein and its glycosides – baicalin as well as hesperetin and its glycosides – hesperidin on glycolytic genes expression of HepG2 cell line, morphology and cells’ viability at the presence of doxorubicin have been tested. In an attempt to elucidate the mechanism of observed results, the fluorogenic probe for reactive oxygen species (ROS), the DNA oxidative damage, the lipid peroxidation and the double strand breaks were evaluated. To assess impact on the glycolysis pathway, the mRNA expression for a hexokinase 2 (HK2) and a lactate dehydrogenase A (LDHA) enzymes were measured. The results were analysed statistically with the one-way analysis of variance (ANOVA) and post hoc multiple comparisons. The apigenin and the hesperidin revealed the strongest effect on the toxicity of doxorubicin. Both flavonoids simultaneously changed the expression of the glycolytic pathway genes - HK2 and LDHA, which play a key role in the Warburg effect. Although separate treatment with doxorubicin, apigenin and hesperidin led to a significant oxidative DNA damage and double strand breaks, simultaneous administration of doxorubicin and apigenin or hesperidin abolished these damage with the simultaneous increase in the doxorubicin toxicity. The obtained results indicate the existence of a very effective cytotoxic mechanism in the HepG2 cells of the combined effect of doxorubicin and apigenin (or hesperidin), not related to the oxidative stress. To explain this synergy mechanism, further research is needed, The observed intensification of the cytotoxic effect of doxorubicin by this flavonoids may be a promising direction of the research on the therapy of hepatocellular carcinoma, especially in a chemoembolization.

    更新日期:2019-11-28
  • Effects of neprilysin-renin inhibition in comparison with neprilysin-angiotensin inhibition on the neurohumoral changes in rats with heart failure
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-03
    Kawa Dizaye; Rojgar H. Ali

    The activation of neurohumoral compensatory mechanisms is a common physiological phenomenon in heart failure in order to make up for a failing heart, which will usually have a deteriorating effect on overall health condition. Many medications, such as neprilysin and angiotensin inhibitors, have recently been introduced to remediate neurohumoral changes. This study was conducted to evaluate the efficacy of the sacubitril-aliskiren combination versus the sacubitril-ramipril combination in the treatment of neurohumoral changes in rats with experimentally induced heart failure. Thirty Wister rats were randomly assigned into five groups each of six rats, the first group was the control group. Intraperitoneal isoprenaline injections of 5 mg/kg/day for 1 week were used to induce experimental models of heart failure in rats of the rest of experimental groups. The second group served as a positive control. Rats in the third, fourth, and fifth groups received oral daily dose of sacubitril 30 mg/kg/day, sacubitril-aliskiren 30,10 mg/kg/day, and sacubitril-ramipril 30/10 mg/kg/day respectively, for 2 weeks. Induction of heart failure in rats has significantly increased circulating NT-proBNP (980 ± 116.71 pg/ml), MMP9 (15.85 ± 0.57 ng/ml), troponin-I (3.09 ± 0.147 ng/ml), CK-MB (31.55 ± 1.69 ng/ml), renin (736 ± 45.8 pg/ml), urea (52.1 ± 1.57 mg/dl), and creatinine (0.92 ± 0.04 mg/dl). Significant decreases in glomerular filtration rate (7.031 ± 1.6 ml/hr./kg), urine flow (0.2761 ± 0.06 ml/h/kg), total solute excretion (0.11 ± 0.03 meq/m), and mean blood pressure (83.5 ± 2.6 mm hg) were seen in rats with heart failure. Rats treated with sacubitril combined with aliskiren or ramipril showed a statistically significant reduction of NT-proBNP, MMP9, troponin serum urea, and serum creatinine. Sacubitril-aliskiren or sacubitril-ramipril administration produced a significant increase in renin plasma level, total solute excretion, urine flow, and glomerular filtration rate. Sacubitril in combination with aliskiren or with ramipril effectively reduced plasma cardiac biomarkers, such as CK-MB, MMP9, and NT-proBNP, in rats with heart failure. Both combinations showed significant remediation of renal function through increasing GFR, urine flow, and total solute excretion, as well as reducing plasma level of renin. Net results revealed that the sacubitril-aliskiren combination has similar remediating effects on neurohumoral changes compared to the sacubitril-ramipril combination.

    更新日期:2019-11-28
  • Nature and prevalence of adverse drug reaction of antiretroviral medications in Halibet National Referral Hospital: a retrospective study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-06
    Lidya Hagos; Siyoma Fessehaye; Indermeet Singh Anand

    Monitoring the safety of antiretroviral therapy (ART) remains a challenge in resource-constrained countries such as Eritrea due to their serious adverse drug reactions (ADRs). This study was aimed at assessing the prevalence, nature, seriousness and possible risk factors of ART associated ADRs in Halibet National Referral Hospital in Eritrea. A three month retrospective, longitudinal, descriptive study of patients treated with ART between September 2005 and December 2016 was conducted in Halibet National Referral Hospital. Demographic characteristics, treatment details, reaction and outcome details, laboratory investigations and other information was abstracted manually from patients’ clinical cards. Statistical analysis was conducted using both univariate and multivariate analysis and statistical significance was tested using 95% confidence intervals and/or p-value. A P-value < 0.05 was regarded as being statistically significant. Of the 309 patients screened, 62.8% encountered at least one ADR and 29.8% of the reactions were serious with similar male to female ratio. Gastrointestinal symptoms were the most common ADR and were associated mostly with Atripla followed by AZT + 3TC + NVP drug combinations, but lipodystrophy followed by peripheral neuropathy which were both commonly associated with Stavudine and anemia associated with Zidovudine were the most serious. Patients with CD4 count below 200 were more likely to develop ADRs (p = 0.000). ADRs associated with ART drugs in Halibet hospital were found to be highly prevalent. Furthermore, CD4 count below 200, was identified as a major risk factor that predisposes patients to ADRs. This is burdensome to resource constrained countries such as Eritrea who have limited drug options and high HIV prevalence, therefore these findings will help patients and healthcare professionals understand the nature as well as seriousness of these ADRs and identify the risks involved with ART medications which can help minimize ART associated ADRs early on.

    更新日期:2019-11-28
  • A study on combination of daptomycin with selected antimicrobial agents: in vitro synergistic effect of MIC value of 1 mg/L against MRSA strains
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-06
    Yi-Chien Lee; Pao-Yu Chen; Jann-Tay Wang; Shan-Chwen Chang

    Daptomycin is an important drug used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. A high dose of daptomycin is indicated for an MRSA infection with a minimum inhibitory concentration (MIC) of 1 mg/L for daptomycin. Combination therapies with daptomycin and other antimicrobial agents, including fosfomycin, display in vitro synergism potentially. This study was conducted to investigate the in vitro synergistic effect of daptomycin-based combination therapy against MRSA strains with high daptomycin MIC. The synergistic effects of daptomycin in combination with fosfomycin, gentamicin, linezolid, oxacillin, or rifampicin against MRSA with an MIC of 1 mg/L for daptomycin were measured using the microbroth checkerboard assay in vitro. A total of 100 MRSA isolates was tested. The synergistic interactions of the drugs were evaluated using the fractional inhibitory concentration index. The MIC values revealed that all isolates (100%) were found to be susceptible to linezolid, 85% to fosfomycin, 8% to gentamicin, 69% to rifampicin, and no isolate was susceptible to oxacillin. The in vitro synergism rates of daptomycin in combination with fosfomycin, oxacillin, gentamicin, linezolid, and rifampicin were 37, 11, 5, 3, and 1%, respectively. The combination of daptomycin plus fosfomycin may be an effective therapeutic option for MRSA infection.

    更新日期:2019-11-28
  • Abatacept induced granulomatous hepatitis with a sarcoidosis- like reaction: a blinded trial in mice
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-07
    Sultan M. Almogairen

    Abatacept is increasingly used for rheumatoid arthritis (RA) and juvenile idiophathic arthritis (JIA) treatment. However little is known about the risk of hepatotoxicity. The aim of this study was to determine whether the inhibition of the T cell CD28 receptor by abatacept results in acute hepatitis in BALB/c mice. Twenty BALB/c mice were studied. Ten mice received subcutaneous (SC) injection of abatacept (0.25mg per 25g body weight per 0.03 ml normal saline) at 0, 2, 4 and 8 weeks. For the control group, 10 mice received a SC injection of normal saline (NS) (0.03 ml). At the 10th week post injection, the mice were sacrificed, and histopathological studies were conducted. Of the abatacept-treated group, 3/10 mice died. Liver histology for the abatacept-treated group showed that 6/7 displayed histopathological changes in the lobular cellular infiltrates of eosinophils, lymphocytes and histiocytes, in addition to granuloma formation. In contrast, only minimal inflammation was observed in 3/10 mice in the control group (p=0.036). Abatacept may play a role in inducing granulomatous hepatitis with a sarcoidosis-like reaction. Additional data including transaminases, antinuclear antibodies (ANA), Antimitochondrial antibodies (AMA) and other auto antibodies should be tested.

    更新日期:2019-11-28
  • Evaluation of prophylactic dosages of Enoxaparin in non-surgical elderly patients with renal impairment
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-07
    Nibal Chamoun; Hady Ghanem; Ahmad Hachem; Essa Hariri; Christelle Lteif; Hanine Mansour; Hani Dimassi; Richard Zalloum; Georges Ghanem

    Thromboprophylaxis dosing strategies using enoxaparin in elderly patients with renal disease are limited, while dose adjustments or monitoring of anti-Xa levels are recommended. We sought to evaluate the efficacy and safety of enoxaparin 20 mg versus 30 mg subcutaneously daily by comparing anti-Xa levels, thrombosis and bleeding. We conducted a prospective, single-blinded, single-center randomized clinical trial including non-surgical patients, 70 years of age or older, with renal disease requiring thromboprophylaxis. Patients were randomized to receive either 20 mg or 30 mg of enoxaparin. The primary endpoint was peak anti-Xa levels on day 3. Secondary endpoints included trough anti-Xa levels on day 3, achievement of within range prophylactic target peak anti-Xa levels and the occurrence of hemorrhage, thrombosis, thrombocytopenia or hyperkalemia during hospitalization. Thirty-two patients were recruited and sixteen patients were randomized to each arm. Mean peak anti-Xa level was significantly higher in 30 mg arm (n = 13) compared to the 20 mg arm (n = 11) 0.26 ± 0.11, 95%CI (0.18–0.34), versus 0.14 ± 0.09, 95CI (0.08–0.19) UI/ml, respectively; p = 0.004. Mean trough anti-Xa level was higher in 30 mg arm (n = 10) compared to the 20 mg arm (n = 16), 0.06 ± 0.03, 95CI (0.04–0.08) versus 0.03 ± 0.03, 95CI (0.01–0.05) UI/ml, respectively; p = 0.044. Bleeding events reported in the 30 mg arm were one retroperitoneal bleed requiring multiple transfusions, and in the 20 mg arm one hematuria. No thrombotic events were reported. Peak anti-Xa levels provided by enoxaparin 20 mg were lower than the desired range for thromboprophylaxis in comparison to enoxaparin 30 mg. The trial was retrospectively registered on ClinicalTrials.gov identifier: NCT03158792 . Registered: May 18, 2017.

    更新日期:2019-11-28
  • Near fatal intoxication by nicotine and propylene glycol injection: a case report of an e-liquid poisoning
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-10
    Mhedi Belkoniene; Jennifer Socquet; Denise Njemba-Freiburghaus; Cyril Pellaton

    Concern about intoxication by e-liquid is growing as calls to poison control centers have increased since their introduction. Only three cases of intoxication by injection have been reported worldwide. Our case is unique because of the precise follow-up of a patient who survived a lethal dose of self-injected e-liquid, without other co-intoxication. A 51-year-old male presented to the Emergency Department after injecting himself intravenously (IV) in the forearm with 10 mL of e-liquid (1000 mg of nicotine diluted in propylene glycol). An agitation phase was followed by coma and bradypnoea requiring mechanical ventilation. The patient developed a transitory neurological impairment with the appearance of tetraparesis, gaze palsy and myoclonus due to nicotinic syndrome. The arterial blood gas (ABG) analysis confirmed uncompensated lactic acidosis with an elevated anion gap, which is an expected effect of propylene glycol. The toxicology screen indicated the presence of nicotine and cotinine in the blood and excluded the presence of concomitant intoxication. The patient recovered without sequelae. Even a small quantity of intravenous (IV) e-liquid can lead to an acute intoxication and fatal outcomes due to the toxic effects of nicotine. This case might help emergency doctors cope with acute intoxication by injection of e-liquid and increase their comprehension of the two main substances, nicotine and propylene glycol with overview of their pharmacodynamics and kinetic effects.

    更新日期:2019-11-28
  • One-year outcome of combination therapy with intravitreal aflibercept and photodynamic therapy for polypoidal choroidal vasculopathy
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-14
    Hsin-Yu Weng; Tzu-Lun Huang; Pei-Yao Chang; Jia-Kang Wang

    To investigate the one-year visual and anatomical outcomes of combination therapy with intravitreal aflibercept (IVA) and photodynamic therapy (PDT) for treating polypoidal choroidal vasculopathy (PCV). This was a retrospective case-series study, including 30 eyes from 30 patients with treatment-naïve PCV treated by combination therapy with IVA and PDT. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), complete polyp regression rate, and dry macula rate were recorded every 3 months during 12-month follow-up. Clinical factors associated with final visual outcome and retreatment were investigated. The mean LogMAR BCVA was significantly improved from 0.73 ± 0.65 at baseline to 0.51 ± 0.60 (p = 0.01), and the mean CRT was also significantly improved from 339 ± 96 μm at baseline to 244 ± 43 μm at 12-month follow-up (p < 0.001). Complete regression of polypoidal lesions was 76.7%, and dry macula rate was 100% at 12 months. Better final BCVA was associated with younger age and better baseline BCVA (p = 0.02 and p < 0 001). The patients without complete polyp regression at 3-month follow-up were associated with retreatment (p = 0.03). In this study, combination therapy with IVA and PDT had significant visual and anatomical improvements to PCV patients during one-year follow-up. Better baseline BCVA and younger age were found to be associated with better visual outcome.

    更新日期:2019-11-28
  • Study of the principles in the first phase of experimental pharmacology: the basic step with assumption hypothesis
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-21
    Yilkal Tariku Belay

    Experimental pharmacology deals with effects of various test substances studied on different animal species which is aimed at finding out safe therapeutic agent suitable for public health as well as mechanism and site of action of a test substance. It is the basic step in the discovery of new drugs or studying the pharmacological actions of already developed one using both preclinical and clinical study designs in a stepwise phase of investigations. However, the investigations in the first phase of experimental pharmacology are usually concluded with assumption hypothesis without any adequate validation of the scientific evidence. Single dose acute toxicology had been conducted on Balb c mice with three different level of doses prepared from each of three different test chemicals (Dichlorvos, Chlorpyrifos and Cypermethrin) with known median lethal dose (LD50) to define the fundamental principles, cause of toxicity and investigation timeframe in the first phase of experimental pharmacology. The methods used for data collection were: procurement of test chemicals, investigation of single dose acute toxicity on Balb c mice and quantitative immunoglobulins test. Data was thematically compiled for validation of the findings from each of the sources. The result showed that the dose had never limited the toxic property of tested chemicals but the magnitude of adverse effect and length of time at which adverse effect was manifested on treated Balb c mice. The toxicity of tested chemicals was however limited by the toxic reaction rate of a dose in the biological process of exposed Balb c mice. The toxic effect of tested chemicals became magnified within a short period of time when large amount administered orally. It also remained after a long period of time when small amount administered in the same route. Adequate investigation time for acute toxicity study was therefore essential for comprehensive analysis of pharmacological property of tested chemicals at different level of doses.

    更新日期:2019-11-28
  • Nephrotoxicity and ototoxic symptoms of injectable second-line anti-tubercular drugs among patients treated for MDR-TB in Ethiopia: a retrospective cohort study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-23
    Workineh Shibeshi; Anandi N. Sheth; Addisu Admasu; Alemseged Beyene Berha; Zenebe Negash; Getnet Yimer

    Nephrotoxicity and ototoxicity are clinically significant dose-related adverse effects associated with second-line anti-tubercular injectables drugs (aminoglycosides and capreomycin) used during intensive phase of treatment of multi-drug resistant tuberculosis (MDR-TB) patients. Data are scarce on injectable-induced nephrotoxicity and ototoxicity in Ethiopian MDR-TB patients. The aim of this study was to assess the prevalence, management of nephrotoxicity and ototoxic symptoms and treatment outcomes of patients treated for MDR-TB with injectable-based regimens. This was retrospective cohort study based on review of medical records of about 900 patients on MDR-TB treatment from January 2010 to December 2015 at two large TB referral hospitals in Addis Ababa, Ethiopia. Nephrotoxicity in study participants was screened using baseline and monthly measurement of serum creatinine and clinical diagnosis and patient reports. Overall, 473 (54.2%) of participants were male. Children accounted for 47 (5.5%) of cases and the mean age of participants was 32 ± 12.6 years with range of 2–75 years. The majority (n = 788, 84.6%) of participants had past history of TB. The most commonly used injectable anti-TB drug was capreomycin (n = 789, 84.7%), while kanamycin and amikacin were also used. There was a statistically significant increment (p<0.05) in the mean serum creatinine values from baseline throughout intensive phase of treatment with a 10–18% prevalence of nephrotoxicity. Based on clinical criteria, nephrotoxicity was detected in 62 (6.7%) and ototoxic symptoms were detected in 42 (4.8%) participants. Nephrotoxicity and ototoxic symptoms were clinically managed by modification of treatment regimens including dose and frequency of drug administration. Nephrotoxicity and ototoxic symptoms were significant problems among patients on follow-up for MDR-TB treatment. Based on laboratory criteria (serum creatinine), nephrotoxicity remained significant adverse events throughout intensive phase of treatment, indicating close monitoring of patients for successful outcome is mandatory until countries adopt the recent injectable-free WHO guideline and under specific conditions.

    更新日期:2019-11-28
  • Dexamethasone suppresses the differentiation of stem Leydig cells in rats in vitro
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-27
    Jingwei Zhang; Guanghui Hu; Bisheng Huang; Dong Zhuo; Yujie Xu; Huitao Li; Xiangcheng Zhan; Ren-Shan Ge; Yunfei Xu

    It is an established fact that excess of glucocorticoids could cause the harmful effects, such as suppression on the male reproduction. Although glucocorticoids pharmacologically inhibit the Leydig cell function, their roles in Leydig cell development are unclear. Therefore, the present study was designed to investigate effects of synthetic glucocorticoid dexamethasone (DEX) on rat stem Leydig cell proliferation and differentiation. Male Sprague-Dawley rats received a single intraperitoneal injection of 75 mg/kg EDS to eliminate Leydig cells and an in vitro culture system of the seminiferous tubules was established from Leydig cell-depleted testis. Using basal medium and Leydig cell differentiation-inducing medium (LIM) in the culture system, we examined the effects of DEX (0–100 nM) on the proliferation and differentiation of the stem Leydig cells in vitro, respectively. Results showed that LIM is a good agent to induce stem Leydig cell differentiation into Leydig cells that produce testosterone in vitro. DEX inhibited the differentiation of stem Leydig cells by reducing the expression levels of Cyp17a1 and Scarb1 and that NR3C1 antagonist RU38486 reversed the DEX-mediated effects. However, DEX are not involved with the proliferation of stem Leydig cells. DEX suppressed the differentiation of rat Leydig cells in vitro and glucocorticoid-induced effects acted through NR3C1. This suppression partially targets on Cyp17a1 and Scarb1 gene expression.

    更新日期:2019-11-28
  • Epinecidin-1, a highly potent marine antimicrobial peptide with anticancer and immunomodulatory activities
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-28
    Alireza Neshani; Hosna Zare; Mohammad Reza Akbari Eidgahi; Azad Khaledi; Kiarash Ghazvini

    Antibiotic-resistant pathogens are an emerging threat in this century. Epinecidin-1 is a multi-functional Antimicrobial Peptide (AMP) produced by Orange-spotted grouper (Epinephelus coioides) has been shown to have extensive potentials as an alternative for current antibiotics. Due to the huge costs for the study and the production of a new drug, if an antimicrobial peptide has other beneficial functions in addition to antimicrobial activities, it would be preferred. In this study, properties and applications of Epinecidin-1 were investigated and addressed comprehensively. To achieve this, the Google Scholar search engine and three databases of PubMed, Scopus, and Web of Science were used. Epinecidin-1 is a cationic AMP with an alpha-helical structure. Seven functional usages of this peptide have been reported in the literature including antibacterial, antifungal, antiviral, antiprotozoal, anticancer, immunomodulatory, and wound healing properties. Moreover, this peptide has high potential to be used as an active ingredient in cleaning solutions as well as application in vaccine production. Due to significant antimicrobial activities tested on bacteria such as Staphylococcus aureus and Helicobacter pylori and also wound healing properties, Epi-1 has high potential to be considered as an important candidate for the production of new drugs and treatment of various infections including diabetic foot ulcer and peptic ulcer. Moreover, adjuvant-like properties of Epi-1 make it a suitable candidate for the studies related to an adjuvant. Other attractive properties such as anticancer effects have also been reported for this peptide which encourages further studies on this peptide.

    更新日期:2019-11-28
  • Assessment of effect modification of statins on new-onset diabetes based on various medical backgrounds: a retrospective cohort study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-28
    Keiko Yamazaki; Yasuo Takahashi; Kotoe Teduka; Tomohiro Nakayama; Yayoi Nishida; Satoshi Asai

    The aim of this study was to investigate the association between statin use and new-onset diabetes in clinical settings and to assess its effect modification (heterogeneity) among patients with various medical histories and current medications. In a total of 12,177 Japanese patients without diabetes, from December 2004 to November 2012, we identified 500 statin users and 500 matched non-users using propensity-score matching. Patients were followed until December 2017. We estimated the hazard ratios of new-onset diabetes associated with statin use. We also tested the heterogeneity of the treatment effect by evaluating subgroup interactions in subgroups according to sex, age, medical history, and current medication. New-onset diabetes had occurred in 71 patients (13.6%) with statin use and 43 patients (8.3%) with non-use at 5 years (hazard ratio, 1.66; 95% confidence interval [CI], 1.11 to 2.48; P = 0.0143), and in 78 patients (15.6%) with statin use and 48 patients (9.6%) with non-use at 10 years (hazard ratio, 1.61; 95% CI, 1.10 to 2.37; P = 0.0141). There were no significant treatment-by-subgroup interactions in all subgroups defined according to sex, age, medical history, and current medication. In patients with various clinical backgrounds, those who received statin therapy had a higher risk of new-onset diabetes at 5 and 10 years than those who did not receive it. Effect modification of statins on new-onset diabetes was not found in patient populations defined according to various comorbid diseases or concomitant drugs.

    更新日期:2019-11-28
  • Microbial epidemiology and antimicrobial resistance patterns of wound infection in Ethiopia: a meta-analysis of laboratory-based cross-sectional studies
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-30
    Mekonnen Sisay; Teshager Worku; Dumessa Edessa

    Wound infections are responsible for significant human morbidity and mortality worldwide. Specifically, surgical site infections are the third most commonly reported nosocomial infections accounting approximately a quarter of such infections. This systematic review and meta-analysis is, therefore, aimed to determine microbial profiles cultured from wound samples and their antimicrobial resistance patterns in Ethiopia. Literature search was carried out through visiting electronic databases and indexing services including PubMed, MEDLINE, EMBASE, CINAHL, and Google Scholar. Original records, available online from 2000 to 2018, addressing the research question and written in English were identified and screened. The relevant data were extracted from included studies using a format prepared in Microsoft Excel and exported to STATA 15.0 software for analyses of outcome measures and subgrouping. Der-Simonian-Laird’s random effects model was applied for pooled estimation of outcome measures at 95% confidence level. Comprehensive meta-analysis version-3 software was used for assessing publication bias across studies. The study protocol is registered on PROSPERO with reference number ID: CRD42019117638. A total of 21 studies with 4284 wound samples, 3012 positive wound cultures and 3598 bacterial isolates were included for systematic review and meta-analysis. The pooled culture positivity was found to be 70.0% (95% CI: 61, 79%). Regarding the bacterial isolates recovered, the pooled prevalence of S. aureus was 36% (95% CI: 29, 42%), from which 49% were methicillin resistant strains. The pooled estimate of E. coli isolates was about 13% (95% CI: 10, 16%) followed by P. aeruginosa, 9% (95% CI: 6, 12%), K. pneumoniae, 9% (95% CI: 6, 11%) and P. mirabilis, 8% (95% CI: 5, 11%). Compared to other antimicrobials, S. aureus has showed lower estimates of resistance against ciprofloxacin, 12% (95% CI: 8, 16%) and gentamicin, 13% (95% CI: 8, 18%). E. coli isolates exhibited the highest point estimate of resistance towards ampicillin (P = 84%; 95% CI: 76, 91%). Gentamicin and ciprofloxacin showed relatively lower estimates of resistance with pooled prevalence being 24% (95% CI: 16, 33%) and 27% (95% CI: 16, 37%), respectively. Likewise, P. aeruginosa showed the lowest pooled estimates of resistance against ciprofloxacin (P = 16%; 95% CI: 9, 24%). Generally, the wound culture positivity was found very high indicating the likelihood of poly-microbial contamination. S. aureus is by far the most common bacterial isolate recovered from wound infection. The high estimate of resistance was observed among β-lactam antibiotics in all bacterial isolates. Ciprofloxacin and gentamicin were relatively effective in treating wound infections with poly-microbial etiology.

    更新日期:2019-11-28
  • Countrywide prevalence of critical drug interactions in Hungarian outpatients: a retrospective analysis of pharmacy dispensing data
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-05-31
    Anna Somogyi-Végh; Zsófia Ludányi; Ábel Erdős; Lajos Botz

    Drug-drug interactions (DDIs) present a significant source of adverse drug reactions. Despite being one of the commonly cited risks to patient safety, prevention of DDIs still poses a challenge to healthcare systems. The prevalence of DDIs can be used as a quality indicator for the safety of prescribing. With the analysis of drug utilization databases, real-world data on critical DDIs can be obtained. The aim of this study was to establish a list of critical DDIs and estimate their prevalence in the Hungarian outpatient population. Since there is no conclusive and generally accepted repository of high-risk DDIs, a systematic search of the literature for consensus-based lists was performed. Based on these results and their analysis with 5 interaction compendia, we propose a simple methodology to identify critical combinations. Present study focused on DDIs which are (1) of high clinical importance thus being most likely to cause significant harm if not detected, (2) well-supported by available evidence and (3) affect drugs which are routinely dispensed in the community pharmacy setting. A retrospective analysis of prescriptions filled between 2013 and 2016 was performed. The source of drug utilization data was the IQVIA’s national prescription fill database. The number of interacting drug pairs dispensed at the same time to the same patient was established. After excluding drugs with low dispensing rates, the analysis covered 39 DDIs. The distribution of risk categories of the analysed DDIs was inconsistent among different drug interaction compendia. The total number of prescriptions filled varied between 173924449 and 176368468 per year. The prevalence of the selected potential DDIs ranged from 0.00 to 355.89 per 100000 prescriptions per year. There was significant variation between how the number of cases had changed for each DDI throughout the study period, no general tendency could have been described. There were 1.8 million cases of co-dispensing each year, where prescribers’ and community pharmacists’ role in recognizing and managing potentially serious interactions was or would have been critical. The method presented to identify high-risk DDIs can serve as a starting point for the much-needed improvement of routine interaction screening.

    更新日期:2019-11-28
  • Safety and effectiveness of low-dose amikacin in nontuberculous mycobacterial pulmonary disease treated in Toronto, Canada
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-06-03
    Maria Luisa Aznar; Theodore K. Marras; Ahmed Said Elshal; Mahtab Mehrabi; Sarah K. Brode

    Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data supporting the low-dose approach are limited. The purpose of this study was to describe the safety and efficacy of the use of a low-dose of intravenous amikacin in a cohort of patients with NTM PD. We retrospectively reviewed all patients with NTM PD who received amikacin at our institution between July 1, 2003 and February 28, 2017. Demographics, clinical, microbiological and radiological data, indication and dose of amikacin, and adverse drug effects were recorded. A total of 107 patients received a regimen containing amikacin for a median (IQR) of 7 (4–11) months. Seventy (65.4%) were female and the mean age (SD) was 58.3 (14.9) years. Amikacin was started at a median dose of 9.9 (2.5) mg/kg/day. Ototoxicity was observed in 30/77 (39%) patients and it was related to female sex (OR 4.96, 95%CI 1.24–19.87), and total dose of amikacin per bodyweight (OR 1.62, 95%CI 1.08–2.43). Patients of East Asian ethnicity were less likely to develop ototoxicity (0.24, 95%CI 0.06–0.95). Out of 96 patients who received amikacin for more than 3 months, 65 (67.7%) experienced symptom improvement and 30/62 (49.2%) converted their sputum to culture negative within a year. Patients with NTM PD treated with low-dose intravenous amikacin frequently developed ototoxicity, which was associated with female sex, and total dose of amikacin per bodyweight. Physicians should carefully consider dose, treatment duration, and long term prognosis in balancing risks and benefits of intravenous amikacin in NTM PD.

    更新日期:2019-11-28
  • Single and simultaneous effects of acrylamide and ethanol on bone microstructure of mice after one remodeling cycle
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-01
    Anna Sarocka; Veronika Kovacova; Radoslav Omelka; Birgit Grosskopf; Edyta Kapusta; Zofia Goc; Grzegorz Formicki; Monika Martiniakova

    This study aimed to examine femoral bone microstructure of mice after single and simultaneous administration to acrylamide and ethanol since both substances are often consumed separately and/or together by humans. Interactive effects of these toxins were analysed after one remodeling cycle. Twenty clinically healthy adult mice were randomly divided into four groups following 2 weeks administration of toxins: A group - mice were fed with acrylamide (40 mg/kg bw); E group - mice were ethanol-fed (15% ethanol); AE group - mice were simultaneously fed with both toxins, and a C group – control (without acrylamide and/or ethanol supplementation). Generally, 2D and 3D imaging methods were used to determine cortical and trabecular bone tissues microstructure. Biochemical analyses of plasma parameters were also realized using commercially available ELISA tests and spectrophotometrically. Single and simultaneous exposure to acrylamide and ethanol affected only cortical bone microstructure. No significant changes in trabecular bone morphometry were detected among all groups. In mice from the A group, increased endocortical remodeling associated with a higher level of serum calcium and vasoconstriction of primary osteon’s vascular canals (POVC) were identified. On the contrary, increased cortical porosity consistent with a decreased relative bone volume, bone mineral density (BMD) and lower levels of alkaline phosphatase (ALP), glutathione (GSH), calcium in plasma and also with vasodilation of POVC were observed in the E group. In the AE group, the highest density of secondary osteons associated with a lower BMD and decreased levels of ALP, GSH were documented. The parameters of POVC and Haversian canals approximated to the C group. In addition, single and simultaneous exposure to both toxins caused liver disease consistent with a higher values of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in plasma of all experimental groups. Single administration to acrylamide and ethanol had negative effects on cortical bone structure of mice after one remodeling cycle. However, we identified possible antagonistic impact of these toxins on the structure of the cortical bone.

    更新日期:2019-11-28
  • Acute versus chronic methotrexate poisoning; a cross-sectional study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-03
    Arman Ahmadzadeh; Nasim Zamani; Hossein Hassanian-Moghaddam; Seyed Kaveh Hadeiy; Parinaz Parhizgar

    Data is limited on comparison of acute and chronic methotrexate (MTX) poisoning. Methotrexate is an anti-folate drug that may be prescribed in some malignant or chronic inflammatory conditions. The aim of the current study was to compare signs and symptoms, complications, treatment and final outcome of acute and chronic MTX toxicity. In a retrospective study in a referral center between March 2010 and March 2018, all patients who had been referred with the history of MTX poisoning and hospitalized due to acute or chronic poisoning were evaluated and compared. Of the total 27 patients admitted during the study period, 13 had referred with acute (group 1; consumption of MTX for less than 7 days) and 14 had referred with chronic toxicity (group 2; consumption of MTX for more than 7 days). Mean age was significantly higher in the second group (P < 0.001). Median total dose of MTX was similar between the groups (P = 0.90). Mucosal ulcers and skin lesions (P < 0.001 and 0.02, respectively) were the only symptoms significantly different between the two groups. Leukopenia (P < 0.001), thrombocytopenia (P < 0.001), and anemia (P = 0.04) were significantly more common in the second group. Blood urea nitrogen and creatinine were also significantly higher in the second group of the patients (P < 0.001 and P = 0.048). Median leucovorin administered dose was 200 mg [14, 480] versus 150 mg [75, 187] (P = 0.69) in groups 1 and 2, respectively. Chronic MTX poisoning is more serious than acute toxicity and accompanies higher dermatologic, hematologic, and hepatic complications necessitating more aggressive treatments including administration of higher doses of leucovorin or bone marrow stimulants such as G-CSF. This may be attributable to the underlying diseases and features (including older ages) which predispose these patients to complications.

    更新日期:2019-11-28
  • The effects of thiamine pyrophosphate on ethanol induced optic nerve damage
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-05
    Turgay Ucak; Yucel Karakurt; Gamze Tasli; Ferda Keskin Cimen; Erel Icel; Nezahat Kurt; Ibrahim Ahiskali; Halis Süleyman

    We aimed to determine the protective effects of thiamine pyrophosphate on ethanol induced optic neuropathy in an experimental model. The rats were assigned into 4 groups, with 6 rats in each group as follows: healthy controls (HC group), only ethanol administered group (EtOH group), ethanol + thiamine pyrophosphate (20 mg/kg) administered group (TEt-20 group), and only thiamine pyrophosphate (20 mg/kg) (TPG group) administered group. To the rats in TEt-20 and TPG groups, 20 mg/kg thiamine pyrophosphate was administered via intraperitoneal route. To the rats in HC and EtOH groups, the same volume (0.5 ml) of distilled water as solvent was applied in the same manner. To the rats in TEt-20 and EtOH groups, one hour after application of thiamine pyrophosphate or distilled water, 32% ethanol with a dose of 5 g/kg was administered via oral gavage. This procedure was repeated once a day for 6 weeks. From the blood samples and tissues obtained from the rats, Malondialdehyde (MDA), reduced glutathione (GSH), interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) levels were studied. Histopathological evaluations were performed to the optic nerve tissue. Serum and tissue IL-1β, TNF-α and MDA levels were the highest in EtOH group which were significantly lower in thiamine pyrophosphate administered group (TEt-20 group) (p: 0.001). Serum and tissue reduced GSH levels were the lowest in EtOH group which were also significantly higher in TEt-20 group (p:0.001). In histopathological evaluations, in EtOH group there was obvious destruction and edema with hemorrhage and dilated blood vessels which were not present in any other groups. There was an apparent destruction in ethanol administered group in histopathological analyses with an augmented level of oxidative stress markers and all those alterations were prevented with concomitant thiamine pyrophosphate administration. These protective effects of thiamine pyrophosphate are extremely important in chronic ethanol consumption. Clinical studies are warranted to define the exact role of thiamine pyrophosphate in prevention of ethanol induced optic neuropathy.

    更新日期:2019-11-28
  • Development of a mortality score to assess risk of adverse drug reactions among hospitalized patients with moderate to severe chronic kidney disease
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-08
    Monica Danial; Mohamed Azmi Hassali; Ong Loke Meng; Yoon Chee Kin; Amer Hayat Khan

    Chronic kidney disease (CKD) is a significant health burden that increases the risk of adverse events. Currently, there is no validated models to predict risk of mortality among CKD patients experienced adverse drug reactions (ADRs) during hospitalization. This study aimed to develop a mortality risk prediction model among hospitalized CKD patients whom experienced ADRs. Patients data with CKD stages 3–5 admitted at various wards were included in the model development. The data collected included demographic characteristics, comorbid conditions, laboratory tests and types of medicines taken. Sequential series of logistic regression models using mortality as the dependent variable were developed. Bootstrapping method was used to evaluate the model’s internal validation. Variables odd ratio (OR) of the best model were used to calculate the predictive capacity of the risk scores using the area under the curve (AUC). The best prediction model included comorbidities heart disease, dyslipidaemia and electrolyte imbalance; psychotic agents; creatinine kinase; number of total medication use; and conservative management (Hosmer and Lemeshow test =0.643). Model performance was relatively modest (R square = 0.399) and AUC which determines the risk score’s ability to predict mortality associated with ADRs was 0.789 (95% CI, 0.700–0.878). Creatinine kinase, followed by psychotic agents and electrolyte disorder, was most strongly associated with mortality after ADRs during hospitalization. This model correctly predicts 71.4% of all mortality pertaining to ADRs (sensitivity) and with specificity of 77.3%. Mortality prediction model among hospitalized stages 3 to 5 CKD patients experienced ADR was developed in this study. This prediction model adds new knowledge to the healthcare system despite its modest performance coupled with its high sensitivity and specificity. This tool is clinically useful and effective in identifying potential CKD patients at high risk of ADR-related mortality during hospitalization using routinely performed clinical data.

    更新日期:2019-11-28
  • Identification of undecylenic acid as EAG channel inhibitor using surface plasmon resonance-based screen of KCNH channels
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-17
    Ze-Jun Wang; Purushottam B. Tiwari; Aykut Üren; Tinatin I. Brelidze

    KCNH family of potassium channels is responsible for diverse physiological functions ranging from the regulation of neuronal excitability and cardiac contraction to the regulation of cancer progression. KCNH channels contain a Per-Arn-Sim (PAS) domain in their N-terminal and cyclic nucleotide-binding homology (CNBH) domain in their C-terminal regions. These intracellular domains shape the function of KCNH channels and are important targets for drug development. Here we describe a surface plasmon resonance (SPR)-based screening method aimed in identifying small molecule binders of PAS and CNBH domains for three KCNH channel subfamilies: ether-à-go-go (EAG), EAG-related gene (ERG), and EAG-like K+ (ELK). The method involves purification of the PAS and CNBH domains, immobilization of the purified domains on the SPR senor chip and screening small molecules in a chemical library for binding to the immobilized domains using changes in the SPR response as a reporter of the binding. The advantages of this method include low quantity of purified PAS and CNBH domains necessary for the implementation of the screen, direct assessment of the small molecule binding to the PAS and CNBH domains and easiness of assessing KCNH subfamily specificity of the small molecule binders. Using the SPR-based method we screened the Spectrum Collection Library of 2560 compounds against the PAS and CNBH domains of the three KCNH channel subfamilies and identified a pool of small molecules that bind to the PAS or CNBH domains. To further evaluate the effectiveness of the screen we tested the functional effect of one of the identified mEAG PAS domain specific small molecule binders on currents recorded from EAG channels. Undecylenic acid inhibited currents recorded from EAG channels in a concentration-dependent manner with IC50 of ~ 1 μM. Our results show that the SPR-based method is well suited for identifying small molecule binders of KCNH channels and can facilitate drug discovery for other ion channels as well.

    更新日期:2019-11-28
  • Influence of N-acetyl-L-cysteine against bisphenol a on the maturation of mouse oocytes and embryo development: in vitro study
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-22
    Qian Li; Zhenjun Zhao

    Bisphenol A (BPA), an endocrine disruptor, is a widely used chemical that has adverse effects on animal development and reproduction. The current research aimed to evaluate the effect of BPA on the in vitro maturation (IVM) and subsequent embryo development of mouse oocytes following in vitro fertilization (IVF). IVM was performed in the presence of different concentrations (0, 20, 50, or 100 μg/mL) of BPA. Nuclear maturation, IVF efficiency and embryonic development were determined. The levels of reactive oxygen species (ROS) and glutathione (GSH) in the BPA (50 μg/mL) group were evaluated. We explored the ability of N-acetyl-L-cysteine (NAC) in the IVM medium to rescue the BPA-induced damage by examining changes in nuclear maturation, IVF rate, blastocyst formation, ROS levels and GSH content. Compared with the control, BPA (50 μg/mL) supplementation during oocyte IVM significantly inhibited nuclear maturation and decreased fertilization and blastocyst formation rates. In addition, BPA exposure increased ROS levels and decreased GSH content in oocytes. The addition of NAC weakened the BPA-induced suppression of nuclear maturation, relieved the BPA-induced downregulation of the fertilization and blastocyst formation rates, and mitigated the increased ROS levels and decreased GSH content. BPA affects mouse oocyte maturation and subsequent early embryonic developmental competence following IVF by increasing intracytoplasmic oxidative stress in mature oocytes. NAC can reduce these harmful effects to a certain extent.

    更新日期:2019-11-28
  • Relationship between drug application and mortality rate in Chinese older coronary artery disease/chronic heart failure patients with and without low glomerular filtration rate
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-26
    Shihui Fu; Ping Ping; Ping Ye; Leiming Luo

    This analysis was designed to investigate the relationship between drug application and mortality rate in Chinese older coronary artery disease (CAD)/chronic heart failure (CHF) patients with and without low glomerular filtration rate (GFR). All 1050 Chinese hospitalized patients with diagnosed CAD were included in this analysis, and Cox Regression was used to analyze the relationship between drug application and mortality rate after multivariate adjustment. Low GFR was defined as GFR < 60 ml/min/1.73m2. There were 372 patients (35.4%) with low GFR in patients with CAD (1050 patients), and 168 patients (51.4%) in patients with CHF (327 patients). In CAD patients without low GFR, clopidogrel [P = 0.028, odds ratio (OR): 0.620, 95% confidence interval (CI): 0.404–0.951] rather than aspirin (P = 0.173) was significantly associated with lower mortality rate. Statins (P < 0.001, OR: 0.287, 95% CI: 0.180–0.456) were significantly associated with lower mortality rate. In CAD patients with low GFR, aspirin, clopidogrel and statins had no significant relationship with mortality rate (P > 0.05 for all). In CHF patients without low GFR, statins were significantly associated with lower mortality rate (P < 0.001, OR: 0.220, 95% CI: 0.098–0.490). In CHF patients with low GFR, statins had no significant relationship with mortality rate (P > 0.05 for all). Clopidogrel but not aspirin was beneficial in Chinese older CAD patients without low GFR rather than those with low GFR, and statins benefited for Chinese older CAD/CHF patients without low GFR rather than those with low GFR. These discoveries might offer some help for the therapy of Chinese older patients with cardiovascular/renal diseases.

    更新日期:2019-11-28
  • Potential drug-drug interactions among pneumonia patients: do these matter in clinical perspectives?
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-26
    Sidra Noor; Mohammad Ismail; Zahid Ali

    Pneumonia patients are usually hospitalized due to severe nature of the disease or for the management of comorbid illnesses or associated symptoms. Such patients are prescribed with multiple medications which increase the likelihood of potential drug-drug interactions (pDDIs). Therefore, in this study the prevalence, levels (severity and documentation), predictors (risk factors), and clinical relevance of pDDIs among inpatients diagnosed with pneumonia have been investigated. Clinical records of 431 hospitalized patients with pneumonia were checked for pDDIs using drug interactions screening software (Micromedex-DrugReax). Odds-ratios for predictors were calculated using logistic regression analysis. Clinical relevance of pDDIs was assessed by evaluation of patients’ clinical profiles for potential adverse outcomes of the most frequent pDDIs. Abnormal patients’ signs/symptoms and laboratory investigations indicating adverse outcomes of interactions were reported. Of total 431 profiles, pDDIs were reported in 73.1%. Almost half of the profiles were having major-pDDIs (53.8%). Total number of pDDIs were 1318, of which 606 were moderate- and 572 were major-pDDIs. Patient’s profiles identified with the most frequent interactions were presented with signs, symptoms, and abnormalities in labs indicating decrease therapeutic response, electrolyte abnormalities, hypoglycemia, bleeding, hepatotoxicity, and hypertension. These adverse events were more prevalent in patients taking higher doses of the interacting drugs as compared to lower doses. Logistic regression analysis revealed significant association for major-pDDIs with 6–10 prescribed medicines (OR = 26.1; p = 0.002), > 10 prescribed medicines (OR = 144; p < 0.001), and tuberculosis (OR = 8.2; p = 0.004). PDDIs are highly prevalent in patients with pneumonia. Most frequent and clinically important pDDIs need particular attention. Polypharmacy and tuberculosis increase the risk of pDDIs. Identifying patients more at risk to pDDIs and careful monitoring of pertinent signs/symptoms and laboratory investigations are important measures to reduce pDDIs and their related adverse consequences.

    更新日期:2019-11-28
  • Povidone-iodine ear wash and oral cotrimoxazole for chronic suppurative otitis media in Australian aboriginal children: study protocol for factorial design randomised controlled trial
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-07-27
    Christine Wigger; Amanda Jane Leach; Jemima Beissbarth; Victor Oguoma; Ruth Lennox; Sandra Nelson; Hemi Patel; Mark Chatfield; Kathy Currie; Harvey Coates; Keith Edwards; Heidi Smith-Vaughan; Kim Hare; Paul Torzillo; Steven Tong; Peter Morris

    Chronic suppurative otitis media (CSOM) is a significant health issue affecting Aboriginal Australians. Long-term hearing loss can cause communication problems, educational disadvantage, and social isolation. Current standard treatment for CSOM in our region is twice daily dry mopping of the pus from the ear canal followed by instillation of ciprofloxacin antibiotic ear drops for up to 16 weeks, or until the discharge resolves for a period of 3 days. The treatment is long, laborious and fails to resolve ear discharge in 70% of cases in remote communities. Bacterial pathogens also persist. Povidone-iodine ear wash is the preferred method of clearing ear discharge in Western Australia. However, evidence of its effectiveness is lacking. In systematic reviews, topical antibiotics (ciprofloxacin) have been shown to be more effective than oral antibiotics or topical antiseptics. Currently, it is unclear whether there are any benefits of combining these treatments. This protocol describes a 2 × 2 factorial randomised controlled trial of two different interventions (povidone-iodine ear wash and oral cotrimoxazole), given as adjunctive therapy to standard treatment for CSOM. 280 children, between 2 months and 17 years of age, Indigenous or non-Indigenous, living in participating Northern Territory (NT) communities are randomised to standard treatment (dry mopping and ciprofloxacin drops) plus one of two topical treatments (dilute povidone-iodine ear wash or no wash) and one of two oral medication treatments (16 weeks of cotrimoxazole or placebo). Current treatment of CSOM in our region shows that eradication of bacterial pathogens from the middle ear space and dry ears is often not achieved. This trial will evaluate the efficacy of adjunctive treatments of antiseptic ear washes and oral antibiotics. Clinical, microbiological and hearing outcomes will be reported. This trial (ACTRN12614000234617) was registered with ANZCTR on 05 April 2014.

    更新日期:2019-11-28
  • Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-05
    Ibrahim M. Shokry; Connor J. Shields; John J. Callanan; Zhiyuan Ma; Rui Tao

    MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.

    更新日期:2019-11-28
  • Behavioral and steroidogenic pharmacology of phenyl ring substituted etomidate analogs in rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-05
    Megan McGrath; Alissa Hofmann; Douglas E. Raines

    Cushing’s syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABAA receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABAA receptor modulatory activities. In the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg− 1 min− 1) of either etomidate or an etomidate analog. All rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80–84% and 68–94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations. Our studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.

    更新日期:2019-11-28
  • Analysis of severe adverse effects following community-based ivermectin treatment in the Democratic Republic of Congo
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-16
    Jean-Claude Makenga Bof; Daniel Muteba; Paul Mansiangi; Félicien Ilunga-Ilunga; Yves Coppieters

    The progress of mass, community-directed, treatment with ivermectin (CDTI) for onchocerciasis control was disrupted by severe adverse effects (SAE) in the Democratic Republic of Congo (DRC). The study aimed at determining the frequency of post-CDTI SAE as well as factors associated with the occurrence of SAE. Our retrospective study relied on SAE collection cards, as archived by the DRC Ministry of Health, and compiled for people who benefited from ivermectin treatment then further developed SAE. The study included 945 post-CDTI SAE recorded in DRC between 2003 and 2017. These cases occurred in 15 projects out of 22 projects implemented in the country. All cards were reviewed and analysed. Between the years 2003 and 2017, the total average population treated was around 15,552,588 among which 945 cases of SAE were registered in DR Congo, i.e. 6 cases of SAE for 100,000 persons treated per year. 55 deaths related to post-CDTI SAE were recorded, which represents 5.8% of all cases of SAE. Non-neurological SAE were dominated by severe headaches (74.8%), myalgia (64.0%) and arthralgia (62.7%). Neurological SAE were mainly coma (94.1%), motor deficit (75.4%) and palpebral subconjunctival haemorrhages (38.8%). Factors associated with the occurrence of SAE were: male, age over 18 years old, alcohol consumption, hemp intake and the presence of loiasis. The study also highlighted weaknesses of the National Program for Onchocerciasis Control (NPOC) in terms of awareness campaigns among the population. Co-endemicity of loiasis and onchocerciasis is one of the key factors responsible for the occurrence of SAE following ivermectin treatment. Mobilization of resources necessary to the appropriate management of SAE and awareness of populations are essential to achieve onchocerciasis control in DRC.

    更新日期:2019-11-28
  • Tigecycline-induced sustained severe hypoglycemia: a case report
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-19
    Yixin Chen; Lin Li; Nan Zhang; Hong Li

    Tigecycline, the first glycylcycline-class drug, is a broad-spectrum antibiotic with activity against multi-drug resistant (MDR) organisms. We describe a case of sustained and severe hypoglycemia in a patient treated with tigecycline for pneumonia due to MDR Klebsiella pneumoniae. A 74-year-old man was admitted for treatment of pneumonia. At admission he had prediabetes. In the hospital he developed renal failure. On day 3, the patient experienced severe shortness of breath. He was intubated and transferred to the intensive care unit (ICU) for ventilator support. In the ICU the antibiotic regimen was cefoperazone and sulbactam (1 g every 12 h). Continuous Renal Replacement Therapy was started on that day. Test for anti-neutrophil cytoplasmic antibodies (ANCA) was positive, and so the nephrologist and rheumatologist agreed on a diagnosis of ANCA-associated vasculitis, with renal and pulmonary involvement and acute renal failure. Plasmapheresis, and high-dose methylprednisolone treatment were started on day 6, and there was obvious improvement in the patient’s condition. The steroid regimen was gradually tapered to oral prednisone (35 mg every day) on day 19. Afterwards, the patient’s pneumonia worsened. Sputum culture showed Klebsiella pneumoniae sensitive to only tigecycline. Tigecycline treatment (100 mg every 12 h) was administered on day 20. Hypoglycemia started about 37 h after the first dose of tigecycline. Infusion of 50% glucose through the femoral vein was required for over 20 h to maintain normal blood glucose concentrations. Tigecycline was stopped, but the hypoglycemia resolved only after a further 34 h. The insulin and C-peptide levels were found to be markedly elevated during the hypoglycemia. The Naranjo scale score of 7 indicated that the likelihood of tigecycline causing severe hypoglycemia was “probable.” This is the first report of sustained severe hypoglycemia due to tigecycline. Oversecretion of insulin appears to have been the cause of the hypoglycemia in our patient. The mechanism needs to be investigated.

    更新日期:2019-11-28
  • Efficacy of a topical gabapentin gel in a cisplatin paradigm of chemotherapy-induced peripheral neuropathy
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-28
    Muhammad Shahid; Fazal Subhan; Nisar Ahmad; Robert D. E. Sewell

    Chemotherapy induced peripheral neuropathy (CIPN) has been attributed to chemotherapeutic agents such as cisplatin which adversely affect disease outcome leading to increased cancer related morbidity. The clinical efficacy of systemic gabapentin in neuropathic pain management is limited by central side-effects in addition to a scarceness of conclusive evidence of its efficacy in CIPN management. The topical route therefore may provide a relatively safe alternative for neuropathic pain treatment in general and CIPN in particular. Cisplatin induced neuropathic nociception was established in rats after a single weekly cisplatin injection (3.0 mg/kg, intraperitoneally) for 4 weeks. The evoked neuropathic sensation of allodynia was assessed by plantar application of von Frey monofilaments as the paw withdrawal threshold (PWT), whereas the expression of heat-hypoalgesia was determined on a hot-plate as paw withdrawal latency (PWL). Gabapentin gel (10% w/w) was applied three-times daily on the hind paws while in a concurrent systemic study, gabapentin was administered daily (75 mg/kg, intraperitoneally) for 4 weeks. To assess any evidence of neurological adverse symptoms of cisplatin and the central side-effect propensity of systemic or topical gabapentin, evaluation of motor coordination (rotarod test) and gait (footprint analysis) were performed. Cisplatin invoked a progressive development of neuropathic hind paw allodynia (decreased PWT, days 7–28) and heat hypoalgesia (increased PWL, days 21–28). Topical gabapentin significantly delayed the expression of both allodynia on protocol days 21 and 28 and heat-hypoalgesia (day 28). Systemic gabapentin displayed a comparative anti-neuropathic predisposition through a sustained suppression of tactile allodynia on days 14 and 21–28 as well as thermal hypoalgesia (days 21 and 28). Systemic gabapentin also impaired motor coordination and gait thus affirming its clinically documented central side effects, but these outcomes were not evident after topical treatment. Both topical and systemic gabapentin exhibit a propensity to attenuate CIPN in a cisplatin paradigm. Gabapentin applied topically may therefore provide an adjunctive or alternative route for CIPN management upon cessation of systemic medications due to intolerable side-effects.

    更新日期:2019-11-28
  • Use of long acting injectable aripiprazole before and through pregnancy in bipolar disorder: a case report
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-28
    Isabel Ballester-Gracia; Miriam Pérez-Almarcha; Ana Galvez-Llompart; Miguel Hernandez-Viadel

    Long-acting injectable (LAI) antipsychotics for psychotic disorders provide advantages in treatment compliance, but data on their use in pregnancy are very limited. We present a clinical case of aripiprazole LAI use in pregnancy. A 43-year-old woman diagnosed with bipolar disorder, with several relapses due to treatment interruption while trying to conceive. Finally, aripiprazole LAI treatment was planned by mutual agreement between doctor and the patient, who took aripiprazole LAI before and during pregnancy. She gave birth at 40 weeks to a 3500 g baby girl with no congenital malformations, who was healthy at 5 months after delivery. As far as we know, this is the first case report on aripiprazole LAI use during pregnancy. Although we exercise caution in drawing conclusions from a single case, and each case should be weighed up individually, aripiprazole LAI could be a therapeutic option in similar circumstances.

    更新日期:2019-11-28
  • Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-29
    Andrea Huppertz; Caspar Grond-Ginsbach; Chris Dumschat; Kathrin I. Foerster; Jürgen Burhenne; Johanna Weiss; David Czock; Jan C. Purrucker; Timolaos Rizos; Walter E. Haefeli

    Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91–321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41–230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249–463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5–1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.

    更新日期:2019-11-28
  • Effect of green tea on the gastrointestinal absorption of amoxicillin in rats
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-08-30
    Tivadar Kiss; Zoltán Timár; Andrea Szabó; Anita Lukács; Viktória Velky; Gábor Oszlánczi; Edina Horváth; István Takács; István Zupkó; Dezső Csupor

    The investigation of food-drug and plant-drug interactions has become increasingly important. In case of antibiotics, it is essential to achieve and maintain a plasma concentration sufficient for the antimicrobial action. Although, on theoretical basis, the interaction of polyphenols and antibiotics may be hypothesized, experimental data are lacking to assess its clinical relevance. The aim of our study was to assess the interaction between one of the most widely used antibiotics, amoxicillin, and green tea, the most frequently consumed drink with high polyphenol content. The effects of green tea on the plasma level of amoxicillin was studied in an in vivo experiment in rats. The plasma level of amoxicillin was monitored by LC-MS/MS for 240 min after oral administration. The polyphenol content of green tea was determined by the Folin-Ciocalteu method. The peak plasma concentration of amoxicillin significantly decreased upon its co-administration with green tea, although the AUC0–240 of the antibiotic did not decrease significantly in the group treated with amoxicillin suspended in green tea. Our results suggest a potentially relevant interaction between green tea and amoxicillin, worth being further studied in humans.

    更新日期:2019-11-28
  • Adverse drug reactions due to opioid analgesic use in New South Wales, Australia: a spatial-temporal analysis
    BMC Pharmacol. Toxicol. (IF 2.103) Pub Date : 2019-09-05
    Wei Du; Shanley Chong; Andrew J. McLachlan; Lan Luo; Nicholas Glasgow; Danijela Gnjidic

    Pharmaceutical opioid analgesic use continues to rise and is associated with potentially preventable harm including hospitalisation for adverse drug reactions (ADRs). Spatial detection of opioid-related ADRs can inform future intervention strategies. We aimed to investigate the geographical disparity in hospitalised ADRs related to opioid analgesic use, and to evaluate the difference in patient characteristics between areas inside and outside the geographic clusters. We used the all-inclusive Admitted Patient Dataset for an Australian state (New South Wales, NSW) to identify patients admitted for opioid-related ADRs over a 10-year period (July 2004 to June 2014). A space-time analysis was conducted using Kulldroff’s scan statistics to identify statistically significant spatial clusters over time. Relative risk (RR) was computed with p-value based on Monte Carlo Simulation. Chi-square test was used to compare proportional difference in patient clustering. During the study period, we identified four statistically significant geographic clusters (RRs: 1.63–2.17) during 2004–08; and seven clusters (RRs: 1.23–1.69) during the period 2009–14. While identified high-risk clusters primarily covered areas with easier access to health services, those associated with socioeconomically disadvantaged areas and individuals with mental health disorders experienced more unmet healthcare needs for opioid analgesic safety than those from the rest of the State. Older people (≥65 years and over) accounted for 62.7% of the total study population and were more susceptible to opioid-related ADRs than younger people,. In the first five-year period the clusters included a greater proportion of people with cancer in contrast to the second five-year period in which there was a lesser proportion of people with cancer. These results suggest that there is significant spatial-temporal variation in opioid-related ADRs and future interventions should target vulnerable populations and high-risk geographical areas to improve safer use of pharmaceutical opioid analgesics.

    更新日期:2019-11-28
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