Safety of an injection with a mixture of extracts from <Emphasis Type="Italic">Herba Artemisiae annuae</Emphasis>, <Emphasis Type="Italic">Fructus Gardeniae</Emphasis> and <Emphasis Type="Italic">Flos Lonicerae</Emphasis>

Objective This study aimed to evaluate the safety for an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae and to determine the risk factors that may affect its adverse drug reactions. Methods A drug-oriented prospective observational study was performed. Physicians filled in clinical observation forms with detailed information of the patients including general information, drug information, therapeutic effects and adverse drug events. The adverse drug reaction factors were analyzed by both mono-factor and multiple-factor logistic regression methods. Results From April to July 2007, we collected 12,427 observation forms from 46 hospitals in Jiangsu Province of China. Among the 11,707 observation forms we analyzed, 8,074 patients were children younger than 14 years old (69%). Among 51 reported adverse drug events, 45 cases were adverse drug reactions. The total adverse drug reaction incidence of the injection was 0.38%. While most adverse drug reactions were previously known (e.g., rash, pruritus, vomiting and diarrhea), we observed three new ADR symptoms: shiver, phlebitis and anhelation. All the adverse drug reactions were controlled very well through the follow-up therapy, and none of them was life threatening. The mono-factor analysis showed that adverse drug reactions of the injection were significantly correlated with total medication dose (P = 0.0049) and combination medication (P = 0.0143), especially with antimicrobial drugs (P = 0.0079) and macrolides (P = 0.0017). The multiple factor analysis confirmed these results: medication dosage and combination medication had a crucial impact on adverse drug reactions of the injection; the risk was increased by 24.8% (the estimated value of relative risk was 1.248, 95% confidence interval: 1.054–1.479) and 89% (1.890, 1.001–3.566), respectively. Conclusion The total adverse drug reaction incidence of the injection was 0.38% and lower than we expected. Moreover, we observed three new adverse drug reactions, none of which was severe.     

Attenuation of the effects of <Emphasis Type="Italic">d</Emphasis>-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion

Rationale  Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D₂-like dopamine receptor agonist quinpirole, and the D₁-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D₁-like and 5-HT_2A receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway. Objective  The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. Materials and methods  Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T ₅₀, time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg⁻¹ i.p.), quinpirole (0.08 mg kg⁻¹ i.p.), and SKF-81297 (0.4 mg kg⁻¹ s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Results  Quinpirole and SKF-81297 reduced T ₅₀ in both groups; d-amphetamine reduced T ₅₀ only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. Conclusions   d-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT_2A receptors, may play a ‘permissive’ role in dopamine release.

替加环素联合舒巴坦制剂治疗鲍曼不动杆菌感染的meta分析

目的 系统评价替加环素联合舒巴坦制剂治疗多重耐药/泛耐药鲍曼不动杆菌感染的疗效。方法 系统检索CNKI、Wangfang Data、CBM、PubMed、The Cochrane Library、Web of science、Embase,检索时间为建库至2018年7月1日,检索方式为主题词结合自由词检索,语种不限,由2名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.3软件进行meta分析。结果 检索到相关文献共1 062篇,按纳入及排除标准从中选择符合标准的46篇文献。Meta分析结果显示,替加环素联合舒巴坦制剂对比单用替加环素或单用舒巴坦制剂在总的有效率和细菌清除率方面有一定优势[OR=3.90,95%CI（3.25,4.68）,P<0.000 01],[OR=3.29,95%CI（2.76,3.92）,P<0.000 01];在不良反应方面,联合用药不会增加其发生率[OR=0.87,95%CI（0.67,1.14）,P=0.31]。亚组分析显示,联用舒巴坦制剂可降低替加环素的不良反应发生率[OR=0.51,95%CI（0.28,0.93）,P=0.03]。结论 替加环素联合舒巴坦制剂治疗多重耐药/泛耐药鲍曼不动杆菌感染优于单用替加环素或单用舒巴坦制剂。     

Botanical origin of Indian celery seed (fruit)

In the course of our study on the traditional medicines and foodstuffs used in Pakistan, we investigated the origin of Indian celery by using the analysis of the internal transcribed spacer (ITS) sequence of nuclear rDNA and a phytochemical approach. We found that the source plant of the Indian celery containing coumarin derivatives such as seselin (1), bergapten (2) and isopimpinellin (3) was not common celery, Apium graveolens. Our results suggest the source plant is Seseli diffusum even though Indian workers reported that A. graveolens seeds contain the aforementioned compounds. In addition, a market survey of the Indian celery in Pakistan and related countries revealed that the Indian celery seeds in Pakistani markets are mainly composed of three species which have been confused in rural markets. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

制川乌配方颗粒与标准煎剂对二甲苯致小鼠耳肿胀抑制作用的比较研究

目的 对制川乌配方颗粒与标准煎剂抗炎药效等效性进行研究。方法 应用二甲苯致小鼠耳肿胀法比较制川乌标准煎剂及配方颗粒对其抑制作用。结果 在抗炎药效等效性研究中,在小鼠耳廓肿胀抑制率22.51%～38.65%共同效应范围内,1/2、1、2倍临床等效剂量（195.00、390.00、780.00 mg/kg）制川乌标准煎剂等效于0.07、0.20、0.46倍临床等效剂量（27.36、77.67、178.29 mg/kg）制川乌配方颗粒所产生的抗炎效应,制川乌配方颗粒等效剂量DEE_{制川乌配方颗粒}=-22.950＋0.258× DEE_{制川乌标准煎剂}（R²=0.958,r=0.979,P<0.01）,回归系数b₀=-22.950,95% CI为（4.549,41.351）,与总体均值0相比,差异有显著性（P<0.05）,常数项b₁=0.258,95% CI为（-0.218,0.299）,与总体均值1相比,差异有显著性（P<0.05）。制川乌配方颗粒与制川乌标准煎剂药剂量在1/8～1倍临床等效应剂量范围内（48.75～390.00 mg/kg）具有可比性,制川乌配方颗粒的等剂量效应EED_{制川乌配方颗粒}=2.963＋1.573×EED_{制川乌标准煎剂}（R²=0.923,r=0.961,P<0.01）,回归系数b₀=2.963,95% CI为（-5.373,11.300）,与总体0比较差异有显著性（P<0.05）,常数项b₁=1.573,95% CI为（1.230,1.915）,与总体均值1相比差异有显著性（P<0.05）。结论 在抗炎方面制川乌配方颗粒和制川乌标准煎剂的等效应剂量不具有等效性,制川乌配方颗粒等效应剂量较制川乌标准煎剂小。在抗炎方面制川乌配方颗粒和制川乌标准煎剂的等剂量效应不具有等效性,制川乌配方颗粒等剂量效应较制川乌标准煎剂大。     

Biochemical and functional properties of a thrombin-like enzyme isolated from Bothrops pauloensis snake venom

In the present study, a thrombin-like enzyme named BpSP-I was isolated from Bothrops pauloensis snake venom and its biochemical, enzymatic and pharmacological characteristics were determined. BpSP-I is a glycoprotein that contains both N-linked carbohydrates and sialic acid in its structure, with M_r = 34,000 under reducing conditions and pI  6.4. The N-terminal sequence of the enzyme (VIGGDECDINEHPFL) showed high similarity with other thrombin-like enzymes from snake venoms. BpSP-I showed high clotting activity upon bovine and human plasma and was inhibited by PMSF, benzamidine and leupeptin. Moreover, this enzyme showed stability when examined at different temperatures (−70 to 37 °C), pH values (3–9) or in the presence of divalent metal ions (Ca²⁺, Mg²⁺, Zn²⁺ and Mn²⁺). BpSP-I showed high catalytic activity upon substrates, such as fibrinogen, TAME, S-2238 and S-2288. It also showed kallikrein-like activity, but was unable to act upon factor Xa and plasmin substrates. Indeed, the enzyme did not induce hemorrhage, myotoxicity or edema. Taken together, our data showed that BpSP-I is in fact a thrombin-like enzyme isoform isolated from Bothrops pauloensis snake venom.     

Temporal trends, risk factors and outcomes in albicans and non-albicans candidaemia: an international epidemiological study in four multidisciplinary intensive care units

This multicentre study (i) evaluated geographic and temporal changes in candidaemia ecology in the critically ill, (ii) identified risk factors associated with non-albicans candidaemia and (iii) examined the association of Candida ecology with mortality. A retrospective cohort study of patients who developed candidaemia in four general Intensive Care Units located in Australia, Greece, Belgium and Brazil was performed. Two hundred Candida organisms were identified by positive blood culture in 189 patients, including 112 Candida albicans (56.0%), 38 Candida glabrata (19.0%), 21 Candida parapsilosis (10.5%), 18 Candida tropicalis (9.0%), 6 Candida krusei (3.0%), 1 Candida famata (0.5%), 1 Candida zeylanoides (0.5%) and 3 non-differentiated Candida spp. (1.5%). No trend towards increased non-albicans species over the study period (P = 0.68) or by geographic area (P = 0.35) was demonstrated. Independent risk factors for non-albicans candidaemia included: female gender [odds ratio (OR) 2.09, 95% confidence interval (CI) 1.13–3.86] and increased central venous catheter days (OR 1.16 per 5-day interval, 95% CI 1.05–1.28). Mortality in the non-albicans group was non-significantly higher than in the albicans group (65% vs. 53%; P = 0.10). This study is unique in that a large number of intensive care candidaemias in four geographically diverse units have been studied.     

The botanical origin of kratom (<Emphasis Type="Italic">Mitragyna speciosa</Emphasis>; Rubiaceae) available as abused drugs in the Japanese markets

Kratom is the leaves of Mitragyna speciosa (Rubiaceae). Recently, kratom has been sold in street shops or on the Internet in Japan for the purpose of abuse due to its opium-like effects. In this study, we investigated the botanical origin of the commercial kratom products using the internal transcribed spacer (ITS) sequence analysis of rDNA in preparation for future regulation of this product. In addition, a previously reported method to authenticate the plant, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to the same products in order to estimate the method’s accuracy and utility. The ITS sequence analysis of the commercial kratoms revealed that most of them were derived from M. speciosa or closely related plants, while the others were made from the same tribe plant as M. speciosa. The reported PCR-RFLP method could clearly distinguish kratoms from the other psychoactive plants available in the Japanese markets and also from related plants. The authentication method is considered to be useful for the practical regulation of the plant due to its wide range of application, high accuracy and simplicity. Electronic supplementary material  The online version of this article () contains supplementary material, which is available to authorized users.

Identification of Novel Specific and General Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp,BCRP and MRP2 Among Registered Drugs

Purpose  To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs. Methods  Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics. Results  Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set. Conclusions  The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

头孢他啶/阿维巴坦治疗碳青霉烯类耐药肠杆菌感染疗效和安全性的Meta分析

目的 系统评价头孢他啶/阿维巴坦(ceftazidime/avibactam,CAZ/AVI)治疗耐碳青霉烯类肠杆菌/肺炎克雷伯菌(CRE/CRKP)感染的疗效和安全性,以期为临床治疗提供循证依据.方法 计算机检索PubMed、Embase、The Cochrane Library、CBM、CNKI、VIP电子数据库,...     

Effects of MDMA on sociability and neural response to social threat and social reward

Rationale  There has been controversy over the abuse potential of methylphenidate (MPH) in the context of treatment for attention deficit hyperactivity disorder (ADHD). Objective  The objective of this study was to compare the reinforcing and subjective effects of oral MPH in adults with and without ADHD. Materials and methods  Following screening, 33 adults (n = 16 with ADHD; n = 17 free from psychiatric diagnoses) completed four pairs of experimental sessions, each of which included a sampling session and a self-administration session. During sampling sessions, subjects received in randomized order 0 (placebo), 20, 40, and 60 mg MPH. During self-administration sessions, subjects completed a progressive ratio (PR) task to earn portions of the dose received on the corresponding sampling session. Subjective effects were recorded throughout all sessions. The main outcome measure for the study was the number of ratios completed on the PR task. Secondary measures included peak subjective effects and area-under-the-curve values for subjective effects. Results  Compared to the control group, the ADHD group completed more ratios on the PR task. Both groups showed robust effects of methylphenidate on subjective endpoints. Main effects of group were noted on subjective effects involving concentration and arousal. Conclusions  Compared to placebo, MPH produced reinforcing effects only for the ADHD group and not for the control group. Increases in stimulant-related subjective effects in non-ADHD subjects were not associated with drug reinforcement.

Antioxidant activities, metal contents, total phenolics and flavonoids of seven Morchella species

Seven Morchella species were analyzed for their antioxidant activities in different test systems namely β-carotene/linoleic acid, DPPH, reducing power, chelating effect and scavenging effect (%) on the stable ABTS⁺, in addition to their heavy metals, total phenolic and flavonoid contents. In β-carotene/linoleic acid system, the most active mushrooms were M. esculenta var. umbrina and M. angusticeps. In the case of DPPH, methanol extract of M. conica showed high antioxidant activity. The reducing power of the methanol extracts of mushrooms increased with concentration. Chelating capacity of the extracts was also increased with the concentration. On the other hand, in 40 μg ml⁻¹ concentration, methanol extract of M. conica, exhibited the highest radical scavenging activity (78.66 ± 2.07%) when reacted with the ABTS⁺ radical. Amounts of seven elements (Cu, Mn, Co, Zn, Fe, Ca, and Mg) and five heavy metals (Ni, Pb, Cd, Cr, and Al) were also determined in all species. M. conica was found to have the highest phenolic content among the samples. Flavonoid content of M. rotunda was also found superior (0.59 ± 0.01 μg QEs/mg extract).     

Effects of Tityus serrulatus scorpion venom on lung mechanics and inflammation in mice

The present study evaluated the effects of an intramuscular injection of Tityus serrulatus venom (TsV) (0.67 μg/g) on lung mechanics and lung inflammation at 15, 30, 60 and 180 min after inoculation. TsV inoculation resulted in increased lung elastance when compared with the control group (p < 0.001); these values were significantly higher at 60 min than at 15 and 180 min (p < 0.05). Resistive pressure (ΔP₁) values decreased significantly at 30, 60 and 180 min after TsV injection (p < 0.001). TsV inoculation resulted in increased lung inflammation, characterised by an increased density of mononuclear cells at 15, 30, 60 and 180 min after TsV injection when compared with the control group (p < 0.001). TsV inoculation also resulted in an increased pulmonary density of polymorphonuclear cells at 15, 30 and 60 min following injection when compared to the control group (p < 0.001). In conclusion, T. serrulatus venom leads to acute lung injury, characterised by altered lung mechanics and increased pulmonary inflammation.     

Detection of lfrA and tap efflux pump genes among clinical isolates of non-pigmented rapidly growing mycobacteria

This study was performed to detect LfrA and Tap efflux pumps among clinical isolates of non-pigmented rapidly growing mycobacteria (NPRGM). Gene detection was performed using polymerase chain reaction (PCR) with specific primers designed for each gene. Susceptibility of the strains to doxycycline, tigecycline and ciprofloxacin was analysed using the broth microdilution reference technique. In total, 166 clinical isolates were included in the study. The lfrA gene was detected in four strains (2.4%), comprising two strains of Mycobacterium chelonae (6.7% of this species), one Mycobacterium fortuitum (1.1%) and one Mycobacterium mucogenicum (14.3%). The tap gene was detected in 109 strains (65.7%), comprising 3 Mycobacterium abscessus (33.3%), 12 M. chelonae (40%), 75 M. fortuitum (84.3%), 2 Mycobacterium mageritense (40%), 15 Mycobacterium peregrinum (68.2%), 1 Mycobacterium alvei and 1 Mycobacterium porcinum; no strains of M. mucogenicum were tap-positive. No differences between tap-positive and -negative strains were observed for resistance to doxycycline (Fisher's exact test, P = 0.055). lfrA is rare among clinical isolates of NPRGM, whilst tap is found more commonly. No correlation was detected between the presence of the efflux pumps and resistance to quinolones or tetracyclines.     

Safety assessment of Lactobacillus brevis KB290 as a probiotic strain

Lactobacillus brevis KB290 (KB290), a plant-derived probiotic lactic acid bacterium, reportedly improves gut health and stimulates immune function. Here we extensively investigated the geno-, acute, subacute, and subchronic toxicity of KB290 and its bacterial translocation potential. KB290 was non-mutagenic in the bacterial reverse mutation assay by the preincubation method. In the single oral dose toxicity test, KB290 at 10⁹ cfu/ml was nontoxic at maximum capacity (20 ml/kg). When 10⁸, 10⁹, or 10¹⁰ cfu/kg was administered daily to rats by gavage for 2 weeks (subacute assay), we observed no clear treatment-related effect and no evidence of bacterial translocation from the gastrointestinal tract. When it was administered for 13 weeks (subchronic assay), we again observed no clear treatment-related effect and no significant toxicological effect. Based on those results, we consider 10¹⁰ cfu/kg per day, the highest dose tested, to be the no observed adverse effect level (NOAEL). These results suggest that KB290 is safe for human consumption.     

Potential analgesic and anti-inflammatory activities of Panax ginseng head butanolic fraction in animals

The present study reports the potential anti-rheumatoid activity of Panax ginseng head part. P. ginseng-head part BuOH fraction (PGHB) was safe in acute toxicity (LD₅₀ > 5000 mg/kg) and inhibited the partially acetic acid-induced writhes (approximately 32%, P < 0.05) in mice. PGHB (500 mg/kg) inhibited the acetic acid-induced extravasation of Evan’s blue dye in mice by approximately 20.6% (P < 0.05), and was similar to the suppressive effect of ibuprofen (27.7%) as a positive control drug. Also, PGHB reduced the carrageenan-induced paw edema at 3 h after oral administration, and suppressed the production of serum IL-6 in CIA mice. This suggests that PGHB has potential analgesic and anti-inflammatory activities, and will be the supporting evidence for the potential anti-rheumatoid activity of Korean P. ginseng-head.     

益生菌四联对比铋剂四联疗法补救根除幽门螺杆菌感染的Meta分析

目的 系统评价益生菌四联疗法（PQT）对比铋剂四联疗法（BQT）补救根除幽门螺杆菌（Helicobacter pylori,Hp）感染的疗效和安全性。方法 检索关于PQT对比BQT补救根除Hp感染的临床试验,检索时限均为建库至2016年10月。由2名评价员,根据纳入与排除标准筛选文献、提取资料,依据改良Jadad量表评价纳入研究的方法学质量,采用RevMan 5.3软件进行meta分析。结果 最终纳入9个临床试验,共875例患者,结果显示：补救治疗中PQT的Hp根除率高于BQT,但差异无统计学意义（RR=1.03,95% CI：0.97~1.10,P=0.36）;按PP分析,PQT与BQT的Hp根除率相当,但差异无统计学意义（RR=1.00,95% CI：0.94~1.07,P=0.90）。PQT的不良反应发生率明显低于BQT,且差异有统计学意义（RR=0.31,95% CI：0.23~0.41,P<0.000 01）。结论 与BQT相比,补救治疗中PQT的不良反应发生率更低,但Hp的根除率无差异,该结论有待大样本高质量的研究验证。