氯霉素片质量的热分析法检验

目的研究氯霉素片剂的热特征。方法应用热重法(TG)、微分热重法(DTG)、差热分析法(DTA)进行热图谱扫描及热特征分析。结果根据氯霉素片的热性能进行定性、定量分析。结论热分析法可作为鉴定氯霉素片质量优劣的一种简便,直观可比,用量少,灵敏度高的检验方法。     

差示扫描量热法(DSC)研究阿莫西林的热谱表征

目的:研究阿莫西林的热特征.方法:采用差示扫描量热法(DSC)、微分热重法(DTG)和热重法(TG)3种方法分析,根据阿莫西林的热特征曲线进行了定性、定量分析,并计算具有特征热分解动力学参数--表观失重活化能(E).结果:阿莫西林的表观失重活化能E2=101.35kJ·mol-1;E3=128.11kJ·mol-1.结论:本方法可作为阿莫西林质量检测的一种快速、简便方法.     

中药材沉香的鉴别分析

目的探讨中药材沉香的鉴别方法。方法从药材性状、薄层分析等方面对沉香及其几种常见伪品进行比较分析。结果沉香一般以色黑、质坚硬、油性足、香气浓而持久、能沉水者为佳。在其薄层色谱中,均可在其相同位置显现明显的桃红色斑点,颜色持久不褪,不含或含少量树脂的沉香微分热重曲线为单峰,而且含量越少,峰越陡,随着树脂含量的增加,而形成肩峰至双峰,且后峰顶温度向高温偏移。结论一般可从药材的性状及显微特点、薄层色谱分析和微分热重法对沉香及其伪品进行鉴别。     

盐酸环丙沙星的热稳定性和热分解反应动力学研究

目的:用热分析法分析盐酸环丙沙星的热分解过程及机制。方法:以Al2O3为参比物,在氮气条件下采用差示扫描量热法、热重法和微分热重法分析样品,根据热重曲线数据计算出其特征热分解反应表观活化能(E)、指前因子(A)、反应级数n和pk值。结果:E=101.18kJ.mol-1、lnA=26.96s-、n=1、pk=7.01,常温下药品贮存期为2年。结论:用热分析法研究盐酸环丙沙星等固体药物的热分解过程方法简便,结果可靠。     

热分析法在医药品研究方面的应用

热分析法包括热重法、差示扫描量热法及其它。本文对热重法及差示扫描量热法在药物分析中的应用作一概述。     

热重法用于测定无机化合物和有机酸盐类药物的结晶水

采用热重法测定无机化合物和有机酸盐类药物的结晶水，该方法快速，简便，对大多数药物均适用。     

热分析法检验安乃近片

目的：研究安乃近片剂的热特征。方法：应用DTA、TG、DTG方法进行分析。结果：根据安乃近片的热性能进行定性、定量分析。结论：热分析法可作为鉴别安乃近片剂质量优劣的一种快速、简便的检验方法。     

人工结香沉香质量评价体系的研究

目的：探讨建立人工结香沉香的质量评价体系及结香作用机制的初探。方法：采用“小孔滴注法”真菌诱导结香的方式,选取不同产地白木香树,按照2010年《中国药典》中对沉香药材性状描述、显微鉴别、薄层鉴别、醇溶性浸出物含量方法,建立切实可行的沉香质量评价标准。结果：苄基丙酮是沉香样品中的化学成分,不同批次人工结香沉香药材性状、显微特征、薄层色谱与对照药材相同,醇溶性浸出物含量在12.07%～25.00%之间。结论：不同批次的人工结香沉香药材质量符合药典的规定,苄基丙酮成为结香的标志进行含量测定评价沉香药材质量具有科学价值。     

中药沉香品种鉴定及探讨鉴别方法

目的对沉香品种的鉴定和鉴别方式进行探讨及分析。方法对沉香正品及赝品样本分别进行理化分析、薄层色谱和紫外光吸收图谱分析,对实验数据进行记录及比对。结果通过波长范围为200~300nm的紫外线对样本的吸光度进行测试,正品中药沉香的紫外光吸收图谱显示,其最大吸收峰值在222nm左右。结论采用薄层色谱和紫外光吸收图谱对中药沉香进行鉴别和鉴定,具有简单使用、准确高效等有点,因此值得推广使用。     

正品沉香与伪制沉香的鉴别

目的：为识别伪制沉香提供方法。方法：对正品沉香、伪制沉香进行性状、薄层色谱、紫外色谱及浸出物的鉴别、比较。结果：伪品与正品沉香存在较大差异，特别是伪制沉香经醇流物处理后其浸出物含量远高于15％。结论：建议在《中国药典》鉴别项中增加薄层色谱鉴别。     

国产沉香资源开发利用及化学成分研究进展

沉香为白木香Aquilaria sinensis(Lour.)Gilg含树脂的木材,是逾百种中成药的主要组方原料,用于治疗消化、呼吸、心脑血管、风湿等科的疾病。沉香药材主含挥发性(倍半萜类化合物)、2-(2-苯乙基)色酮类等成分;白木香叶具抗肿瘤和清除自由基活性;果皮具抗肿瘤活性;种子主含棕榈酸和油酸等脂肪酸,具有一定的抗耐甲氧西林金黄色葡萄球菌(MRSA)活性。沉香药材及白木香其他部位均具有非常高的药用开发价值。本文查阅了近15年国内外有关国产沉香药材的研究文献资料,对国产沉香药材资源开发利用、化学成分及药理活性研究作系统的归纳总结,为其新药开发及资源的综合开发利用提供参考。     

Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment

Purpose

Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.

Methods

This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.

Results

DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.

Conclusions

The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.     

Labeling by [3H]1,3-di(2-tolyl)guanidine of two high affinity binding sites in guinea pig brain: evidence for allosteric regulation by calcium channel antagonists and pseudoallosteric modulation by sigma ligands.

Equilibrium binding studies with the sigma receptor ligand [3H]1,3-di(2-tolyl)guanidine ([3H]DTG) demonstrated two high affinity binding sites in membranes prepared from guinea pig brain. The apparent Kd values of DTG for sites 1 and 2 were 11.9 and 37.6 nM, respectively. The corresponding Bmax values were 1045 and 1423 fmol/mg of protein. Site 1 had high affinity for (+)-pentazocine, haloperidol, (R)-(+)-PPP, carbepentane, and other sigma ligands, suggesting a similarity with the dextromethorphan/sigma 1 binding site described by Musacchio et al. [Life Sci. 45:1721-1732 (1989)]. Site 2 had high affinity for DTG and haloperidol (Ki = 36.1 nM) and low affinity for most other sigma ligands. Kinetic experiments demonstrated that [3H]DTG dissociated in a biphasic manner from both site 1 and site 2. DTG and haloperidol increased the dissociation rate of [3H]DTG from site 1 and site 2, demonstrating the presence of pseudoallosteric interactions. Inorganic calcium channel blockers such as Cd2+ selectively increased the dissociation rate of [3H]DTG from site 2, suggesting an association of this binding site with calcium channels.     

Multivalent cation and polycation polymer preparations influence pharmacokinetics of dolutegravir via chelation-type drug interactions

Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH)₃, LaCO₃, and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH)₃ (150 or 300 mg/kg), LaCO₃ (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH)₃, LaCO₃, Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH)₃, LaCO₃, Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG.     

Interaction of 1,3-di(2-[5-3H]tolyl) guanidine with sigma 2 binding sites in rat heart membrane preparations.

Membrane preparations of rat hearts displayed specific binding activity for the prototypic sigma (sigma) receptor ligand, 1,3-di(2-[5-3H]tolyl) guanidine [( 3H]DTG), but not for the phencyclidine (PCP) receptor ligand, [3H]MK-801. Scatchard plot analysis of [3H]DTG binding revealed the presence of one high affinity saturable binding site with a KD of 8.7 nM and a Bmax of 100 pmol/g protein. The drug specificity profile of the receptor correlated with that of the sigma receptor with the following order of potency: DTG greater than haloperidol greater than (-)-pentazocine greater than (-)-butaclamol greater than (+)-butaclamol greater than (-) SKF-10047 greater than (+)pentazocine greater than PCP greater than TCP greater than MK-801 greater than (+)SKF-10047. [3H]DTG binding was sensitive to the Ca2+ channel blocker, verapamil (Ki 202 nM) but not to the K+ channel blocker, 4-aminopyridine. The reverse stereoselectivity of [3H]DTG binding for (-)-SKF-10047 and (-)-pentazocine (Ki of 1289 and 140 nM as compared with 17,582 and 2190 nM for (+)-SKF-10047 and (+)-pentazocine, respectively) indicated that the heart contains sigma receptors with characteristics of the sigma 2 subtype.     

Abacavir + dolutegravir + lamivudine for the treatment of HIV

Introduction: Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients.

Areas covered: In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies.

Expert opinion: Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration.

In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.     

Selective reduction of N-methyl-D-aspartate-evoked responses by 1,3-di(2-tolyl)guanidine in mouse and rat cultured hippocampal pyramidal neurones.

1. The effects of 1,3-di(2-tolyl)guanidine (DTG) were examined on the responses of cultured hippocampal neurones to the excitatory amino acid analogues N-methyl-D-aspartate (NMDA), kainate, quisqualate and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). 2. In rat hippocampal neurones loaded with the Ca(2+)-sensitive dye Fura-2, DTG (10-100 microM) produced a concentration-dependent depression of the NMDA-evoked rises in intracellular free calcium ([Ca2+]i), an effect that was not modified by changes in the extracellular glycine concentration. DTG (at 50 and 100 microM) also attenuated, although to a lesser extent, the rises in [Ca2+]i evoked by naturally-derived quisqualate. In contrast, 50 and 100 microM DTG did not depress responses evoked by kainate, AMPA and synthetic, glutamate-free (+)-quisqualate although on occasions DTG enhanced kainate- and AMPA-evoked rises in [Ca2+]i. 3. DTG attenuated NMDA-evoked currents recorded from mouse hippocampal neurones under whole-cell voltage-clamp with an IC50 (mean +/- s.e. mean) of 37 +/- 5 microM at a holding potential of -60 mV. The DTG block of NMDA-evoked responses was not competitive in nature and was not dependent on the extracellular glycine or spermine concentration. The block did, however, exhibit both voltage-, and use-, dependency. The steady-state current evoked by naturally-derived quisqualate was also attenuated by DTG whereas those evoked by kainate and AMPA were not. 4. We conclude that DTG, applied at micromolar concentrations, is a selective NMDA antagonist in cultured hippocampal neurones, the block exhibiting both Mg(2+)- and phencyclidine-like characteristics. Given the nanomolar affinity of DTG for sigma binding sites it is unlikely that the antagonism observed here is mediated by sigma-receptors, but the data emphasize the potential danger of ascribing the functional consequences of DTG administration solely to sigma receptor-mediated events.     

The effects of sigma ligands and of neuropeptide Y on N-methyl-D-aspartate-induced neuronal activation of CA3 dorsal hippocampus neurones are differentially affected by pertussin toxin.

1. The in vivo effects of the high affinity sigma ligands 1,3-di(2-tolyl)guanidine (DTG), (+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-ylamine hydrochloride (JO-1784), (+)-pentazocine and haloperidol, as well as of those of neuropeptide Y (NPY), on N-methyl-D-aspartate (NMDA)- and quisqualate (Quis)-induced neuronal activations of CA3 pyramidal neurones were assessed, using extracellular unitary recording, in control rats and in rats pretreated with a local injection of pertussis toxin (PTX), to evaluate the possible involvement of Gi/o proteins in mediating the potentiation of the neuronal response to NMDA by the activation of sigma receptors in the dorsal hippocampus. 2. Microiontophoretic applications as well as intravenous injections of (+)-pentazocine potentiated selectively the NMDA response in control rats as well as in PTX-pretreated animals. In contrast, the PTX pretreatment abolished the potentiation of the NMDA response by DTG, JO-1784 and NPY. Moreover, microiontophoretic applications of DTG induced a reduction of NMDA-induced neuronal activation. Neither in control nor in PTX-treated rats, did the sigma ligands and NPY have any effect on Quis-induced neuronal response. 3. In PTX-treated rats, the potentiation of the NMDA response induced by (+)-pentazocine was suppressed by haloperidol, whereas the reduction of the NMDA response by DTG was not affected by haloperidol. 4. This study provides the first in vivo functional evidence that sigma ligands and NPY modulate the NMDA response by acting on distinct receptors, differentiated by their PTX sensitivity.