Lipo-PGE1 treatment of the neonate with critical congenital heart disease and ductus-arteriosus dependent circulation

The effects of lipo-PGE₁ and the conventional PGE₁ were compared in the treatment of neonates with critical congenital heart disease and ductus-arteriosus-dependent circulation. Lipo-PGE₁ is effective in a smaller dose, with a one-tenth dose of lipo-PGE₁ being equivalent to conventional PGE₁. Lipo-PGE₁ has less side effects such as apnea and diarrhea. Lipo-PGE₁ shows persistence of effect for several days' duration after cessation of continuous administration. Because of these features, lipo-PGE₁ is the first choice for treatment of neonates with pulmonary atresia and complete transposition of the great arteries. For treatment of neonates with interruption or coarctation of the aorta and hypoplastic left heart, conventional PGE₁ in large doses is indicated rather than lipo-PGE₁.     

New lipo-PGE1 using a stable prodrug of prostaglandin E1 (PGE1)

Lipo-PGE₁ is an excellent drug delivery system (DOS) of PGE₁ widely used in Japan since 1988 for the treatment of various vascular diseases. However, this preparation has two major disadvantages. One is PGE₁ chemical instability in the lipid microspheres (LM) and the other is PGE₁ rapid leakage from the LM in the blood, leading to a decrease in the targeting of this drug. Δ⁸-9-O-butyryl prostaglandin F₁ butylester (AS013) was readily hydrolyzed to PGE₁ in human serum. AS013 was stable as an LM preparation and more effectively retained in the LM after incubation with human blood or serum when compared to PGE₁. These results suggested that lipo-AS013 would be a far superior PGE₁ LM preparation than lipo-PGE₁, for clinical use.     

A preclinical assessment of the effect of lipo-PGE1 on thrombus formation and thrombus disaggregation

Prostaglandin E₁ incorporated in lipid microspheres (lipo-PGE₁) was evaluated as an inhibitor of ADP-induced thrombus growth and as a thrombus disaggregating agent following vascular damage in the microcirculation of the hamster cheek pouch. The lipo-preparation was shown to be significantly more active and longer acting than PGE₁ as an inhibitor of ADP-induced thrombus formation. In the vascular damage model, Lipo-PGE₁ was very efficacious as a thrombus-disaggregating agent and was significantly more effective when administered after, rather than before, vascular damage and thrombus induction. The data suggested that the lipo-preparation might be targeted to the site of damage.     

A study of the interaction between recombinant bactericidal permeability increasing protein (rBPI(23)) and gentamicin

rBPI₂₃ is a recombinant protein based upon the N-terminal sequence of bactericidal permeability increasing protein (BPI), a protein present in the granules of polymorphonuclear leukocytes. BPI has antibacterial activity against Gram-negative organisms and potent endotoxin neutralising properties. rBPI₂₃ has been developed as a potential agent for use in Gram-negative sepsis and has completed phase 1 clinical trials. In this study a broth microdilution chequerboard method has been used to investigate the interaction between rBPI₂₃ and gentamicin, an antibiotic used in a similar clinical setting. Using organisms with a range of inherent susceptibilities to rBPI₂₃, additive or synergistic effects were seen which tended to be proportional to the sensitivity to rBPI₂₃ alone.     

Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback

The concept that NK₁ receptors are located pre-junctionally on substance P (SP)-containing nerves, acting as autoreceptors to inhibit SP release, has been suggested, but remains a controversial issue. To further investigate the existence of this receptor on central and peripheral terminals of primary afferent fibres, NK₁ receptor knockout mice and an NK₁ receptor antagonist were used in nerve-attached tissue preparations. These were the isolated dorsal horn of the spinal cord with dorsal roots attached, and the hairy skin of the hind paw with attached saphenous nerve. The results reveal that in the dorsal horn preparation, basal release of SP is significantly higher in NK₁^−/− mice than NK₁^+/+ mice (P<0.05, n=7 mice/strain). However, a difference in SP release evoked in the dorsal horn by electrical stimulation of the dorsal roots or capsaicin application was not observed. In contrast, antidromic electrical stimulation of the saphenous nerve caused a substantially greater release of SP in the skin of NK₁^−/− mice than in NK₁^+/+ mice (P<0.05, n=5 to 6 mice/strain). These results provide evidence for the existence of NK₁ autoreceptors on sensory nerves in skin, which may be relevant to the modulation of their peripheral pathophysiological effector functions.     

The role of the phosphatidyinositol-linked D1 dopamine receptor in the pharmacology of SKF83959

SKF83959, previously described as an antagonist of the D₁ dopamine receptor, has been shown to be a potent anti-parkinsonian agent. However, its mechanism of action is unknown. The present communication was designed to study the mechanism by which SKF83959 exerts its pharmacological effects. SKF83959 induced contralateral rotations in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease (PD). The rotations were completely blocked by the D₁ dopamine receptor antagonist, SCH23390. The response was not affected by the serotonin receptor antagonist, mesulergine and was transiently attenuated by ₁ adrenergic or D₂ dopamine receptor antagonists, prazosin or spiperone, respectively. Injection of 0.5 and 1 mg/kg SKF83959 elicited significant elevations in IP₃ accumulation in lesioned as compared to intact striata. This effect was blocked by SCH23390 at a dose that completely obviated the rotational response to SKF83959, suggesting that activation of the PI-linked D₁ dopamine receptor and the PLC/IP₃ pathway may be the underlying mechanism for the rotational activity induced by SKF83959. The present data provide the first evidence that the PI-linked D₁ dopamine receptor plays a role in regulating motor activity in striatum and that modulation of the D₁ dopamine receptor/PLC/IP₃ pathway may be a novel target in the discovery of drugs for the treatment of Parkinson's disease.     

Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists

The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin NK₁ receptor during the past decade represents an important opportunity to exploit these molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress. Recent clinical trials have confirmed the efficacy of NK₁ receptor antagonists to alleviate depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to appropriate patient populations, are necessary to define the therapeutic potential of novel neurotransmitter ligands.     

Effects of picotamide, an antiplatelet agent, on cardiovascular events in 438 claudicant patients with diabetes: a retrospective analysis of the ADEP study

Picotamide is an antiplatelet drug which inhibits thromboxane A₂ (TxA₂) synthase and antagonizes TxA₂ receptors. In the ADEP (Atherosclerotic Disease Evolution by Picotamide) trial, 2304 patients with peripheral obstructive arterial disease (POAD) were studied in a double-blind, placebo-controlled, 18-month, multicentre trial. In this study, 151 events (13.1%) occurred on placebo and 122 (10.6%) on picotamide (900  mg day⁻¹). The relative risk reduction was 19%, ( P =0.056). This paper reports a post-hoc analysis in a subgroup of 438 diabetic patients (picotamide=230; placebo=208). There were 32 vascular events on placebo (15%) and 18 on picotamide (8%) (relative risk reduction: 48%; 95% CI=26, 76; P =0.022). The results of this retrospective analysis suggest that a prospective study to investigate events in claudicant patients with diabetes mellitus is warranted.     

金合欢素对雌激素致癌代谢产物生成的抑制作用

目的：揭示金合欢素预防雌激素依赖性肿瘤发生的一种机制。方法：通过建立体外代谢模型,采用高效液相色谱-电化学检测器法,分析金合欢素对雌二醇经人细胞色素酶CYP1B1亚酶途径代谢生成致癌产物4-羟基雌二醇的抑制作用。结果：金合欢素对以雌二醇为底物的CYP1B1酶活性的半抑制浓度为（1.43±0.27）μmol·L^-1,具有较强的抑制雌激素致癌代谢产物生成的活性。结论：金合欢素可以有效地抑制人CYP1B1酶的活性,阻碍雌激素致癌代谢产物的生成,从而预防肿瘤的发生。     

Effects of Zhenyuan capsule on the pharmacokinetics comparison of simvastatin and its active metabolites in rats

The total ginsenosides of ginseng fruit are the main constituents of Zhenyuan capsule, which is mainly used for the treatment of cardiovascular diseases. It has been reported that ginsenoside can affect the activity of CYP450 enzymes. Zhenyuan capsule and simvastatin may interact with each other through CYP3A4 mediation, then affect the efficacy and even produce adverse reactions. However, no studies have investigated the effects of Zhenyuan capsule on the pharmacokinetics of simvastatin and its active metabolites. In this study, liquid chromatography–electrospray ionization–mass spectrometry (LC-MS/MS) was used to detect the pharmacokinetics of simvastatin and its active metabolites-simvastatin acid with or without Zhenyuan capsule in rats. Compared with the simvastatin alone, the pharmacokinetic parameters of simvastatin and simvastatin acid were significantly different in AUC_0–24 and AUC_0–∞, and they were decreased in varying degrees (P<0.05). It appeared that the Zhenyuan capsule might increase the activity of CYP3A4 to some extent.     

噻托溴铵联合N-乙酰半胱氨酸治疗慢性阻塞性肺疾病的临床效果

目的观察噻托溴铵联合N-乙酰半胱氨酸治疗慢性阻塞性肺疾病的临床效果。方法选取2019年1-10月江苏省张家港市第一人民医院收治的慢性阻塞性肺疾病患者58例采用随机数字表法分为观察组和对照组各29例。对照组接受噻托溴铵治疗,观察组接受噻托溴铵联合N-Z酰半胱氨酸治疗,2组均开展呼吸训练。比较2组临床疗效,治疗前后血气状况[动脉血氧分压(PaO₂)、血氧饱和度(SpO₂)、动脉血二氧化碳分压(PaCO₂)]、肺功能[1 s用力呼气容积(FEV₁)、FEV₁/用力肺活量(FVC)、FEV₁占预计值的百分比]不良反应。结果治疗后,2组PaO₂、SpO₂均升高PaCO₂均下降且观察组改善幅度大于对照组(P<0.01);治疗后2组FEV₁、FEV₁/FVC、FEV₁占预计值的百分比均升高且观察组高于对照组(P<0.05);观察组不良反应总发生率为17.24%,对照组不良反应总发生率为13.79%2组比较差异无统计学意义(χ²=0.132,P=0.717)。结论噻托溴铵联合N-乙酰半胱氨酸治疗慢性阻塞性肺疾病可更明显改善患者血气状况与肺功能且治疗安全性高,值得推广。     

Pharmacological studies in vivo with ICI 169,369, a chemically novel 5-HT2/5-HT1C receptor antagonist

ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) has been tested in vivo for its potency and selectivity as an antagonist at 5-HT₂ and 5-HT_1C receptors. It caused a 50% inhibition of 5-HTP-induced head twitches in mice and fenfluramine-induced hyperthermia in the rat at approximately 1 mg/kg following parenteral administration. Results showed that ICI 169,369 had good oral bioavailability, since in the fenfluramine test the oral and s.c. ID₅₀ values were similar. ICI 169,369 was a selective antagonist of 5-HT-induced bronhoconstriction in the guinea-pig and 5-HT-induced pressor effects in the anaesthetised dog. In a series of other test in vivo the compound was shown to be devoid of significant activity at ₂- and ₂-adrenoceptors, dopamine (D₂), muscarinic (M₁) and histamine (H₁) receptors at 30–100 times its ID₅₀ values used in the 5-HT tests. Thus, ICI 169, 369 is a selective, orally active 5-HT₂/5-HT_1C antagonist that should prove useful in the analysis of the role of 5-HT in physiological and pathological states.     

Chemical comparison of Semen Euphorbiae and Semen Euphorbiae Pulveratum by UPLC-Q-TOF/MS coupled with multivariate statistical techniques

In the present study, we aimed to assess the chemical composition changes of Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP) by UPLC-Q-TOF/MS and multivariate statistical methods. The UPLC-Q-TOF/MS method and SIMCA-P software were used to analyze the changes of chemical components of SE and SEP based on PCA and PLS-DA multivariate statistical methods. A “component-target-disease” network model was constructed by Intelligent Platform for Life Sciences of traditional Chinese medicine (TCM) to predict potential related diseases. The differences of chemical composition were significant between SE and SEP. Under positive ion mode, the amounts of Euphorbia factor L₂, L₃, L_7a, L₈, L₉ and lathyrol were obviously decreased after processing. Under negative ion mode, the amounts of aesculetin, bisaesculetin, ingenol and cetylic acid were increasedobviously, while Euphorbia factor L₁, L₄ and L₅ were decreased obviously after processing, and the components of euphobiasteroid, aesculetin, lathyrol and linoleic acid among the 14 differentiated compounds were closely related to the SE-related diseases through the “component-target-disease” network model. UPLC-Q-TOF/MS technology in combination with multivariate statisticalmethods had certain advantages in studying the complex changes of chemical composition before and after manufacturing pulveratumof SE. It provided a basis for clarifying the toxicity-attenuated mechanisms of SE manufacturing pulveratum, and laid the foundation for its further development and utilization.     

维生素治疗和诊断性监测的临床应用

目的:采用电化学方法测定人血清九种维生素浓度,为维生素相关性疾病的诊断和治疗提供依据。方法:于2013年3月至2014年11月,采集新生儿和婴幼儿、孕妇、老年、消耗性疾病等患者肘静脉血,经处理取适量血清与样本处理液震荡混匀,采用LK3000V维生素检测仪测定各维生素血清浓度。结果:2 050例维生素A、D、E,1 894例维生素B₁和维生素C,1 857例维生素B₂和维生素B₆,2 028例维生素B₉、B₁2的检测结果有助于发现维生素血浓度异常个体,可作为维生素相关性疾病诊断和治疗的依据。结论:该方法灵敏、准确、快速、重复性好,可用于人体血清维生素浓度常规检测以及维生素相关性疾病的诊断和治疗。     

应用非线性混合效应模型法考察儿童疾病因素对环孢素药动学的影响

目的:考察疾病因素对于环孢素A(CsA)在儿童体内药动学的影响,促进个体化用药。方法:收集150例包括再生障碍性贫血(AA)、嗜血细胞综合征(HPS)和难治性肾病综合征(RNS)不同病种患儿的CsA血药浓度数据和临床资料。采用非线性混合效应模型法考察疾病种类因素对于CsA药动学的影响。采用Bayesian最大后验概率法获取并比较CsA在不同病种患者中药动学参数的差异。用拟合优度(goodness-of-fit)、自举法(bootstrap)、直观预测检验法(VPC)、正态化预测分布误差(NPDE)对最终模型的预测性能进行验证。结果:最终模型药动学参数的群体典型值分别为:吸收速率常数(k_a)1.22 h^-1,吸收时滞时间(T_lag)0.45 h,表观分布容积(V_d)218.18 L,口服清除率(CL)14.45 L·h^-1。拟合优度、自举验证、VPC和NPDE结果表明最终模型稳定,预测结果可靠。模型结构显示只有患者的体质量和AST值是影响CsA清除率的显著性因素。CsA在AA、HPS和RNS患者中的药动学参数差异无显著性(P>0.05)。结论:本研究成功获取了CsA在儿童AA、HPS和RNS患者中的药动学参数,上述疾病因素不会显著影响CsA在儿童体内的药动学过程。     

Levels of fumonisin B1 in corn naturally contaminated with aflatoxins

Aflatoxins and fumonisin B₁ are hepatotoxic and carcinogenic metabolites produced by Aspergillus flavus and Fusarium moniliforme, respectively. These fungi are common natural contaminants of corn, and both aflatoxins and fumonisin B₁ have been implicated as aetiological agents in animal and human diseases. To determine whether these mycotoxins co-exist on corn under natural conditions, 28 samples from the 1991 Georgia (USA) corn crop were assayed for (total) aflatoxin and fumonisin B₁. 27 samples were positive for aflatoxin, 24 samples were positive for fumonisin B₁, and 23 samples had detectable levels of both. In the positive samples, the mean aflatoxin concentration was 73 ppb (SD = 86), and the average fumonisin B₁ concentration was 0.87 ppm (SD = 0.65). A correlation between aflatoxin and fumonisin B₁ concentrations was not evident. None the less, these results demonstrate that exposure to both mycotoxins can occur simultaneously by consumption of co-contaminated corn.     

Lipid microspheres as drug carriers: a pharmaceutical point of view

The lipid microsphere (LM) formulation (Lipo-PGE₁) of prostaglandin E₁ (PGE₁) is an excellent pharmaceutical with a high degree of clinical efficacy. This review describes, from the pharmaceutical point of view, an attempt to clarify the physicochemical properties of LM for injection. Almost all PGE₁ was retained in the LM particles in Lipo-PGE₁, and was present at the oil-water interface. The high retentivity of PGE₁ in the LM particles was clarified when the mixture of Lipo-PGE₁ and transfusion was used in the clinical treatments. The evaluation of emulsion stability is most important to formulate LM. We established a method to evaluate the emulsion stability by considering flocculation and coalescence separately. This method is useful for predicting the stability of LM.     

无创正压通气联合洛贝林治疗COPD合并呼吸衰竭的疗效观察

目的　观察无创正压通气（NPPV）联合洛贝林对慢性阻塞性肺疾病（COPD）合并呼吸衰竭患者的疗效。方法　选择2020年1月至2021年10月期间南方医科大学第七附属医院收治的COPD合并呼吸衰竭患者82例,并简单随机分为两组,各41例。对照组男25例、女16例,年龄（69.12±7.53）岁,给予洛贝林治疗;观察组男24例、女17例,年龄（68.96±7.31）岁,在对照组基础上联合NPPV治疗。比较两组患者血气指标、肺功能指标及临床疗效。计量资料采用t检验,计数资料采用χ²检验。结果　治疗1周后,观察组总有效率为97.56%（40/41）,明显高于对照组80.49%（33/41）,差异有统计学意义（χ²=6.116,P=0.002）。治疗1周后,观察组动脉血氧分压（PaO₂）、氧合指数（PaO₂/FiO₂）分别为（70.35±10.79）mmHg（1 mmHg=0.133 kPa）、（371.14±49.86）mmHg,均明显高于对照组［（61.87±10.77）mmHg、（336.07±47.82）mmHg］,动脉血二氧化碳分压（PaCO₂）为（49.15±8.27）mmHg,显著低于对照组［（56.03±8.69）mmHg］,差异均有统计学意义（均P<0.05）。治疗1周后,观察组第1秒用力呼气容积（FEV₁）、肺活量（FVC）、最高呼气峰流速（PEF）分别为（1.66±0.40）L、（2.63±0.46）L、（2.87±0.59）L/s,均明显高于对照组［（1.37±0.29）L、（2.31±0.40）L、（2.39±0.54）L/s］,差异均有统计学意义（均P<0.05）。两组治疗过程中未出现明显不良反应。结论　NPPV联合洛贝林治疗COPD合并呼吸衰竭患者能够显著提高临床疗效,安全可靠,有效改善患者血气及肺功能指标,大大促进了患者早日恢复。     

Characterization of 5-hydroxytryptamine-induced depolarizations in rat isolated vagus nerve

An additional component of the depolarization induced by 5-hydroxytryptamine (5-HT) in the rat isolated vagus nerve has recently been attributed to activation of 5-HT₄ receptors. To confirm and extend this finding, extracellular recordings of D.C. potentials were made using the ‘grease-gap’ technique during continuous superfusion of the isolated nerve. Beginning at 1 nM, 5-HT induced small depolarizations that displayed a slow onset. At concentrations 1 μM, large depolarizations with rapid onset were elicited. In the presence of the 5-HT₃ receptor antagonists, granisetron or ondansetron, 5-HT responses were diminished and exhibited an increased latency to peak. These small, slow depolarizations were not reduced by 5-HT₁ or 5-HT₂ receptor antagonists, but were potently inhibited by the 5-HT₄ receptor antagonist GR 113808 (pA₂ = 9.3), and mimicked by 5-methoxytryptamine (pEC₅₀ = 5.3). 5-HT₄-mediated responses were larger at 37°C than at 31°C, but also showed marked diminution with repeated 5-HT applications at concentrations greater than 1 μM. Conversely, 5-HT₃ receptor responses were potentiated at lower temperatures (31°C). Consistent with the reported positive coupling of 5-HT₄ receptors to adenylyl cyclase, forskolin and 8-Br-cAMP produced slowly developing depolarizations which were qualitatively similar to 5-HT₄ receptor activation. Pre-depolarization of nerves with 10 μM forskolin or 300 μM 8-Br-cAMP diminished the effect of 5-HT₄ receptors. This study has confirmed the presence of 5-HT₄ receptors on the vagus nerve of the rat and defined some conditions that optimize their pharmacological isolation. The rat isolated vagus nerve constitutes a simple and robust preparation for studying 5-HT₄ receptors in the peripheral nervous system.     

Potassium channels and pain: present realities and future opportunities

Four families of potassium channels with different structures, functional characteristics and pharmacological sensitivity, are distinguished in neurons: voltage-gated (K_v), calcium-activated (K_Ca), inward rectifier (K_ir) and two-pore (K_2P) K⁺ channels. During the last 15 years, numerous studies have demonstrated that the opening of some of these K⁺ channels plays an important role in the antinociception induced by agonists of many G-protein-coupled receptors (₂-adrenoceptors, opioid, GABA_B, muscarinic M₂, adenosine A₁, serotonin 5-HT_1A and cannabinoid receptors), as well as by other antinociceptive drugs (nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants, etc.) and natural products. Several specific types of K⁺ channels are involved in antinociception. The most widely studied are the ATP-sensitive K⁺ channels (K_ATP), members of the K_ir family, which participate in the antinociception induced by many drugs that activate them in both the central and the peripheral nervous system. The opening of G-protein-regulated inwardly rectifying K⁺ channels (GIRK or K_ir3), K_v1.1 and two types of K_Ca channels, the small- and large-conductance calcium-activated K⁺ channels (SK and BK channels, respectively), also play a role in the antinociceptive effect of different drugs and natural products. Recently, drugs that open K⁺ channels by direct activation (such as openers of neuronal K_v7 and K_ATP channels) have been shown to produce antinociception in models of acute and chronic pain, which suggests that other neuronal K⁺ channels (e.g. K_v1.4 channels) may represent an interesting target for the development of new K⁺ channel openers with antinociceptive effects.