Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide,a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Background and Purpose

α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).

Experimental Approach

The attentional set‐shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro‐cognitive activity of each ligand [i.e., PAM‐2 (0.5, 1.0, and 2.0 mg·kg⁻¹), DMXBA and A‐582941 (0.3 and 1.0 mg·kg⁻¹)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM‐2 (0.5 mg·kg⁻¹) was co‐injected with inactive doses of either agonist ‐ DMXBA: 0.1 (NORT); 0.3 mg·kg⁻¹ (ASST) or A‐582941: 0.1 mg·kg⁻¹.

Key Results

PAM‐2, DMXBA, and A‐582941 improved cognition in a MLA‐dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co‐injection of inactive doses of PAM‐2 and DMXBA or A‐582941 also improved cognition, suggesting drug interactions. Moreover, PAM‐2 reversed the scopolamine‐induced NORT deficit. The electrophysiological results also support the view that PAM‐2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC₅₀ = 34 ± 3 μM and E_max = 225 ± 5 %.

Conclusions and Implications

Our results support the view that α7 nAChRs are involved in cognition processes and that PAM‐2 is a novel promising candidate for the treatment of cognitive disorders.

Abbreviations

α7 nAChR

nicotinic acetylcholine receptor with α7 subunit

AD

Alzheimer''s disease

apparent EC₅₀

enhancement potency

ASST

attentional set‐shifting task

CD

compound discrimination

DI

discrimination index

E

exploration time

ED

extra‐dimensional

E_max

ligand efficacy

ID

intra‐dimensional

ITI

inter‐trial interval

MLA

methyllycaconitine

NORT

novel object recognition task

n_H

Hill coefficient

PAM

positive allosteric modulator

PAM‐2

3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide

Rev

reversal of discrimination

SD

simple discrimination

T1

familiarisation trial

T2

retention trial

     

Intravesical delivery of 5‐aminolevulinic acid from water‐in‐oil nano/submicron‐emulsion systems

The present work reports on the development of water‐in‐oil (w/o) emulsions for the intravesical administration of 5‐aminolevulinic acid (ALA). The physicochemical properties of droplet size, zeta potential, and viscosity of the emulsions are characterized and the ability of the emulsions to release ALA following in vitro application is tested. The delivery systems are administered intravesically for 1 and 3 h in rats to examine the drug accumulation in bladder tissue. The mean size and zeta potential of the emulsions are 50–200 nm and ?3 to ?14 mV, respectively. The loading of ALA into the emulsions resulted in a slower and sustained release. The release extent was found to be inversely related to the droplet size of the emulsions. The emulsions did not increase the drug permeation into tissues during short exposure duration (1 h). When the dwell time was extended to 3 h, the systems showed a 2.7‐fold increase in the ALA concentration in the bladder wall. Images of confocal laser scanning microscopy demonstrated a higher and deeper fluorescence signal, with emulsion administration, as compared to the aqueous control. Intravesical emulsion delivery provides a significant advantage for drugs targeting bladder tissues. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2375–2385, 2010     

Texture Optimization of Water‐in‐Oil Emulsions

The aim of this research is to demonstrate the effect of variations in certain parameters of the oily phase (OP) in water‐in‐oil (W/O) emulsions on rheological and texture properties of finished products. The formulated emulsions were selected according to an optimal experimental procedure. The applied variations were nature of the OP, its volume fraction, the hydrophilic‐lipophilic balance (HLB) value, and the surfactant proportion. Results are presented for the followed tests carried out on the emulsions: texture analysis, rheology, and particle size analysis. The oils used in the study were sweet almond oil, liquid paraffin, maize oil, cyclomethicone, dimethicone, and wheat germ oil. The resulting data demonstrate a notable influence of the volume fraction oil on hardness, viscosity, adhesiveness, and cohesiveness of W/O emulsions. Emulsion hardness and viscosity increased as the OP percentage increased; this effect being even more pronounced for the vegetable oils. In contrast, emulsion adhesiveness and cohesiveness decreased as the volume fraction oil increased. The HLB value of the surfactant mixture of the emulsion also influenced hardness, adhesiveness, and elasticity, increasing or decreasing as HLB value did.     

Differences in perimenstrual symptoms between cocaine‐abusing and non‐cocaine‐abusing women

Cocaine abuse among women has become a major health problem in the United States, yet there is little information in the literature concerning the effects of this form of substance abuse on a woman's reproductive system. This study of 65 women in residential treatment for cocaine abuse and 65 non‐cocaine‐abusing women was undertaken to determine if there are differences in frequency or severity of perimenstrual symptoms between these two groups of women. Data were collected by questionnaire and included demographics, a substance use history, and the Menstrual Distress Questionnaire developed by Moos. Findings suggested that there are statistically significant differences in frequency and severity of perimenstrual symptoms between the two groups of women.     

A comparison of medical symptoms reported by cocaine‐, opiate‐, and alcohol‐dependent patients

Substance abuse is frequently associated with adverse medical consequences. The differences in medical symptoms reported by 101 alcohol‐, 113 cocaine‐, and 107 opiate‐dependent individuals receiving outpatient treatment were studied using a 134‐item questionnaire (MILCOM). Data analysis revealed interesting and unexpected findings, with cocaine patients reporting the fewest total symptoms among the three groups. Moreover, cocaine patients reported significantly fewer CNS and musculo‐skeletal symptoms compared to both alcohol and opiate patients and significantly fewer GI and urinary symptoms than the alcohol but not the opiate patients. In addition, there were sex‐ and race‐related differences in the pattern of symptoms reported. Women reported significantly more CVS, mood, nose/throat, CNS, skin, and GI symptoms than men. Similarly, Caucasians reported significantly more mood, CNS, nose/throat, head/neck, musculoskeletal, and GI symptoms than African‐Americans. The study highlights the influence of drug of choice, gender, and race on medical needs of substance‐abusing persons.     

High‐throughput screening assays for SARS‐CoV‐2 drug development: Current status and future directions

In response to the ongoing coronavirus disease 2019 (COVID-19) pandemic, a panel of assays has been developed and applied to screen collections of approved and investigational drugs for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity in a quantitative high-throughput screening (qHTS) format. In this review, we applied data-driven approaches to evaluate the ability of each assay to identify potential anti-SARS-CoV-2 leads. Multitarget assays were found to show advantages in terms of accuracy and efficiency over single-target assays, whereas target-specific assays were more suitable for investigating compound mechanisms of action. Moreover, strict filtering with counter screens might be more detrimental than beneficial in identifying true positives. Thus, developing novel HTS assays acting simultaneously against multiple targets in the SARS-CoV-2 life cycle will benefit anti-COVID-19 drug discovery.     

Antisense‐mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first‐in‐human randomized,placebo‐controlled trial

AimsLDL‐receptor expression is inhibited by the protease proprotein convertase subtilisin/kexin type 9 (PCSK9), which is considered a pharmacological target to reduce LDL‐C concentrations in hypercholesterolaemic patients. We performed a first‐in‐human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9.MethodsIn this randomized, placebo‐controlled trial, 24 healthy volunteers received three weekly subcutaneous administrations of SPC5001 (0.5, 1.5 or 5 mg kg^–1) or placebo (SPC5001 : placebo ratio 6 : 2). End points were safety/tolerability, pharmacokinetics and efficacy of SPC5001.ResultsSPC5001 plasma exposure (AUC(0,24 h)) increased more than dose‐proportionally. At 5 mg kg^–1, SPC5001 decreased target protein PCSK9 (day 15 to day 35: −49% vs. placebo, P < 0.0001), resulting in a reduction in LDL‐C concentrations (maximal estimated difference at day 28 compared with placebo −0.72 mmol l^–1, 95% confidence interval − 1.24, −0.16 mmol l^–1; P < 0.01). SPC5001 treatment (5 mg kg^–1) also decreased ApoB (P = 0.04) and increased ApoA1 (P = 0.05). SPC5001 administration dose‐dependently induced mild to moderate injection site reactions in 44% of the subjects, and transient increases in serum creatinine of ≥20 μmol l^–1 (15%) over baseline with signs of renal tubular toxicity in four out of six subjects at the highest dose level. One subject developed biopsy‐proven acute tubular necrosis.ConclusionsSPC5001 treatment dose‐dependently inhibited PCSK9 and decreased LDL‐C concentrations, demonstrating human proof‐of‐pharmacology. However, SPC5001 caused mild to moderate injection site reactions and renal tubular toxicity, and clinical development of SPC5001 was terminated. Our findings underline the need for better understanding of the molecular mechanisms behind the side effects of compounds such as SPC5001, and for sensitive and relevant renal toxicity monitoring in future oligonucleotide studies.     

Novel Starch‐Based PVA Thermoplastic Capsules for Hydrophilic Lipid‐Based Formulations

For decades, gelatin has been used in the rotary die process as a shell‐forming material of soft capsules because of its unique physicochemical properties. However, with respect to the encapsulation of comparatively hydrophilic lipid‐based formulations, gelatin has one considerable drawback: Immediately after production, the capsule shell contains a large amount of water (up to 35%). There is the potential for water to migrate from the capsule shell into the formulation, which will lead to a decrease in drug solubility and, in turn, the potential for drug crystallization. The present study introduces a novel capsule material that was obtained from extrusion. The starch‐based polyvinyl alcohol thermoplastic capsules (S‐PVA‐C) mainly comprised a blend of starch and PVA. Gelatin and the novel material were used to encapsulate a hydrophilic lipid‐based system of fenofibrate. Considerable water migration was observed from the soft gelatin shell to the hydrophilic formulation during drying and drug crystallization resulted in soft gelatin capsules. In contrast, S‐PVA‐C displayed no substantial water exchange or drug crystallization upon storage. The thermoplastic capsule material further exhibited more surface roughness and higher resistance to mechanical deformation compared with gelatin. In conclusion, S‐PVA‐C provided a robust drug product following encapsulation of a rather hydrophilic lipid‐based formulation.     

Meningeal blood flow is controlled by H2S‐NO crosstalk activating a HNO‐TRPA1‐CGRP signalling pathway

Background and Purpose

Meningeal blood flow is controlled by CGRP released from trigeminal afferents and NO mainly produced in arterial endothelium. The vasodilator effect of NO may be due to the NO–derived compound, nitroxyl (HNO), generated through reaction with endogenous H₂S. We investigated the involvement of HNO in CGRP release and meningeal blood flow.

Experimental Approach

Blood flow in exposed dura mater of rats was recorded by laser Doppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an elisa. NO and H₂S were localized histochemically with specific sensors.

Key Results

Topical administration of the NO donor diethylamine‐NONOate increased meningeal blood flow by 30%. Pretreatment with oxamic acid, an inhibitor of H₂S synthesis, reduced this effect. Administration of Na₂S increased blood flow by 20%, an effect abolished by the CGRP receptor antagonist CGRP _8‐37 or the TRPA1 channel antagonist HC030031 and reduced when endogenous NO synthesis was blocked. Na₂S dose‐dependently increased CGRP release two‐ to threefold. Co‐administration of diethylamine‐NONOate facilitated CGRP release, while inhibition of endogenous NO or H₂S synthesis lowered basal CGRP release. NO and H₂S were mainly localized in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after treatment with L‐NMMA and oxamic acid.

Conclusions and Implications

NO and H₂S cooperatively increased meningeal blood flow by forming HNO, which activated TRPA1 cation channels in trigeminal fibres, inducing CGRP release. This HNO‐TRPA1‐CGRP signalling pathway may be relevant to the pathophysiology of headaches.

Abbreviations

CBS

cystathionine β‐synthase

CSE

cystathionine γ‐lyase

Cy3

cyanine dye 3

DAF

4‐amino‐5‐methylamino‐2′,7′‐difluoresceine diacetate

HNO

nitroxyl

iNOS

inducible NOS

L‐NMMA

L‐NG‐monomethylarginine acetate

MMA

middle meningeal artery

MST

mercaptopyruvate sulfurtransferase

nNOS

neuronal NOS

NONOate

diethylamine‐NONOate, DEANONOate

ODQ

1H‐[1,2,4]oxadiazole[4,3‐a]quinoxalin‐1‐one

sGC

soluble GC

SIF

synthetic interstitial fluid

TRPA1

transient receptor potential ankyrin 1 channel

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Pharmacodynamics,pharmacokinetics and safety of GSK2190915, a novel oral anti‐inflammatory 5‐lipoxygenase‐activating protein inhibitor

Aim

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.

Method

Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose‐escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity.

Results

There was no clear difference in adverse events between placebo and active drug‐treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose‐related manner and mean half‐life values ranged from 16–34 h. Dose‐dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nm and 89 nm in the Western European and Japanese studies, respectively.

Conclusion

GSK2190915 is well‐tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post‐dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.     

Bcl‐2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT‐737, ABT‐263 and ABT‐199 by impeding direct binding

Background and Purpose

Although the ongoing clinical trials of ABT‐263 and ABT‐199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.

Experimental Approach

The LD₅₀ values of ABT‐737, ABT‐263 and ABT‐199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl‐2 family proteins, including phosphorylated Bcl‐2 (pBcl‐2) and their interactions were measured by immunoblotting and co‐immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.

Key Results

The ratio of (Mcl‐1 + pBcl‐2) to Bcl‐2 expression provided the most significant predictive marker for the cytotoxic potential of ABT‐737, ABT‐263 and ABT‐199 in the panel of CLL samples. Mechanistically, pBcl‐2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl‐2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100–300‐fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl‐2 (T69E, S70E and S87E; EEE‐Bcl‐2). BH3 peptides exhibited different rank orders of binding affinities to full‐length WT‐Bcl‐2 and full‐length EEE‐Bcl‐2.

Conclusions and Implications

Our study suggested that a structural alteration in the BH3‐binding groove was induced by phosphorylation of Bcl‐2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl‐2 kinase inhibitors with the ABT compounds.

Abbreviations

CLL

chronic lymphocytic leukaemia

ITC

isothermal titration calorimetry

MOMP

mitochondrial outer membrane permeabilization

     

Inhibition of Agitation‐Induced Aggregation of an IgG‐Antibody by Hydroxypropyl‐β‐Cyclodextrin

In order to provide an alternative to nonionic surfactants as excipients for protein formulations, cyclodextrin‐derivatives (CDs) were examined for their potential to inhibit agitation‐induced aggregation of an IgG in aqueous solution. Loss of monomeric protein and protein aggregation were monitored throughout the agitation experiments by size exclusion chromatography. Hydroxypropyl‐β‐cyclodextrin (HPβCD) completely suppressed IgG‐aggregation at a remarkably low concentration (2.5 mM) and in contrast to other CDs it also did not negatively affect IgG‐stability during storage in nonagitated solution. Further agitation experiments demonstrated the superiority of HPβCD to other common excipients in protein formulation, such as sugars and sugar alcohols or polysorbate 80 in low concentrations. Spectroscopic (fluorescence spectroscopy and Fourier transform infrared spectroscopy), thermodynamic (microcalorimetry), and physical investigations (surface tension measurements) were carried out to elucidate the mechanism of stabilization of the IgG. In contrast to other studies with HPβCD, protein stabilization could not be attributed to direct interaction between hydrophobic amino acids on the IgG and this excipient. Competition with the protein for the air–water interface appears to be the dominating mechanism of stabilization. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1193–1206, 2010     

Protective effect of 23‐hydroxybetulinic acid on doxorubicin‐induced cardiotoxicity: a correlation with the inhibition of carbonyl reductase‐mediated metabolism

Background and Purpose

The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. 23‐Hydroxybetulinic acid (23‐HBA), isolated from P ulsatilla chinensis, enhances the anticancer effect of doxorubicin while simultaneously reducing its cardiac toxicity, but does not affect the concentration of doxorubicin in the plasma and heart. As the metabolite doxorubicinol is more potent than doxorubicin at inducing cardiac toxicity, in the present study we aimed to clarify the role of doxorubicinol in the protective effect of 23‐HBA.

Experimental Approach

Doxorubicin was administered to mice for two weeks in the presence or absence of 23‐HBA. The heart pathology, function, myocardial enzymes and accumulation of doxorubicin and doxorubicinol were then analysed. A cellular pharmacokinetic study of doxorubicin and doxorubicinol, carbonyl reductase 1 (CBR1) interference and molecular docking was performed in vitro.

Key Results

23‐HBA alleviated the doxorubicin‐induced cardiotoxicity in mice, and this was accompanied by inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts. In H9c2 cells, the protective effect of 23‐HBA was shown to be closely associated with a decreased rate and extent of accumulation of doxorubicinol in mitochondria and nuclei. siRNA and docking analysis demonstrated that CBR1 has a crucial role in doxorubicin‐mediated cardiotoxicity and 23‐HBA inhibits this metabolic pathway.

Conclusions and Implications

Inhibition of CBR‐mediated doxorubicin metabolism might be one of the protective mechanisms of 23‐HBA against doxorubicin‐induced cardiotoxicity. The present study provides a new research strategy guided by pharmacokinetic theory to elucidate the mechanism of drugs with unknown targets.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

23‐HBA

23‐hydroxybetulinic acid

AST

aspartate aminotransferase

CBR1

carbonyl reductase 1

CMC

carboxymethyl cellulose

CK

creatine kinase

CK‐MD

creatine kinase isoenzyme

EF

ejection fraction

FS

fractional shortening

i.g

intragastrically

LV

left ventricle

MDR

multidrug resistance

TCM

traditional Chinese medicine

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Protective Effect of N‐Acetylcysteine Against Arsenic‐Induced Depletion In Vivo of Carbohydrate

N‐acetylcysteine (NAC), a synthetic aminothiol, possesses antioxidative and cytoprotective properties. The present study evaluates the effect of NAC supplementation on arsenic‐induced depletion in vivo of carbohydrates. Arsenic (as sodium arsenite) treatment (i.p.) of male Wistar rats (120–140 g b.w.) at a dose of 5.55 mg/kg body weight (35% of LD₅₀) per day for a period of 30 days produced a significant decrease in blood glucose level (hypoglycemia) and a fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver increased while that of kidney decreased after arsenic treatment. Arsenic also enhanced the liver lactate dehydrogenase activity whereas glucose 6‐phosphatase activity in both liver and kidney decreased significantly following arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except the glutamate–pyruvate transaminase activity that was reduced in kidney after arsenic treatment. Oral administration of NAC (163.2 mg/kg/day) for last 7 days of treatment prevented the arsenic‐induced hypoglycemia and glycogenolytic effects to an appreciable extent. There was also recovery of liver pyruvic acid as well as liver and kidney free amino acid nitrogen content after NAC supplementation. Arsenic‐induced alteration of glucose 6‐phosphatase activity in both liver and kidney was also counteracted by NAC. It is suggested that carbohydrate depletion in vivo due to exposure to arsenic can be counteracted by NAC supplementation.     

Can Controlled Ice Nucleation Improve Freeze‐Drying of Highly‐Concentrated Protein Formulations?

The aim of this study was to investigate if controlled ice nucleation with our previouly published method is applicable to highly‐concentrated protein formulations of bovine serum albumin (100 mg/ml and 193.9 mg/ml) and a monoclonal antibody (161.2 mg/ml) and if positive effects on primary drying time as well as reconstitution times can be achieved. We observed that for both proteins, ice nucleation at a product temperature of ?5 °C significantly reduced primary drying time. Furthermore, reconstitution times of the lyophilized cakes could be shortened, especially for the monoclonal antibody formulation with a reconstitution time of 5 minutes instead of 15 minutes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3915–3919, 2013     

Cryptotanshinone,an orally bioactive herbal compound from Danshen,attenuates atherosclerosis in apolipoprotein E‐deficient mice: role of lectin‐like oxidized LDL receptor‐1 (LOX‐1)

Background and Purpose

Cryptotanshinone (CTS) is a major bioactive diterpenoid isolated from Danshen, an eminent medicinal herb that is used to treat cardiovascular disorders in Asian medicine. However, it is not known whether CTS can prevent experimental atherosclerosis. The present study was designed to investigate the protective effects of CTS on atherosclerosis and its molecular mechanisms of action.

Experimental Approach

Apolipoprotein E‐deficient (ApoE ^−/−) mice, fed an atherogenic diet, were dosed daily with CTS (15, 45 mg kg⁻¹ day⁻¹) by oral gavage. In vitro studies were carried out in oxidized LDL (oxLDL)‐stimulated HUVECs treated with or without CTS.

Key Results

CTS significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in ApoE ^−/− mice by inhibiting the expression of lectin‐like oxLDL receptor‐1 (LOX‐1) and MMP‐9, as well as inhibiting reactive oxygen species (ROS) generation and NF‐κB activation. CTS treatment significantly decreased the levels of serum pro‐inflammatory mediators without altering the serum lipid profile. In vitro, CTS decreased oxLDL‐induced LOX‐1 mRNA and protein expression and, thereby, inhibited LOX‐1‐mediated adhesion of monocytes to HUVECs, by reducing the expression of adhesion molecules (intracellular adhesion molecule 1 and vascular cellular adhesion molecule 1). Furthermore, CTS inhibited NADPH oxidase subunit 4 (NOX4)‐mediated ROS generation and consequent activation of NF‐κB in HUVECs.

Conclusions and Implications

CTS was shown to have anti‐atherosclerotic activity, which was mediated through inhibition of the LOX‐1‐mediated signalling pathway. This suggests that CTS is a vasculoprotective drug that has potential therapeutic value for the clinical treatment of atherosclerotic cardiovascular diseases.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ApoE^−/−

apolipoprotein E deficient

CD36

cluster of differentiation 36

CTS

cryptotanshinone

HCD

high cholesterol diet

ICAM‐1

intracellular adhesion molecule 1

LOX‐1

lectin‐like oxidized low‐density lipoprotein receptor‐1

NOX4

NADPH oxidase subunit 4

oxLDL

oxidized low‐density lipoprotein

ROS

reactive oxygen species

SMCs

smooth muscle cells

SR‐A

scavenger receptor‐A

VCAM‐1

vascular cellular adhesion molecule 1

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Dose‐dependent plasma clearance of MK‐826, a carbapenem antibiotic,arising from concentration‐dependent plasma protein binding in rats and monkeys

After intravenous administration of MK‐826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmaco‐kinetics in rats and monkeys. In both species, time‐averaged plasma clearance (based on total concentrations) increased about 5‐fold over the 10‐ to 180‐mg/kg dose range. MK‐826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK‐826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.