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1.
《Pharmaceutical development and technology》2013,18(2):125-134
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. 相似文献
2.
Jia‐You Fang Pao‐Chu Wu Chia‐Lang Fang Chao‐Huang Chen 《Journal of pharmaceutical sciences》2010,99(5):2375-2385
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 相似文献
3.
Tim Serno John F. Carpenter Theodore W. Randolph Gerhard Winter 《Journal of pharmaceutical sciences》2010,99(3):1193-1206
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 相似文献
4.
《Drug and chemical toxicology》2013,36(2):179-189
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. 相似文献
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Ashwin A. Patkar M.D. Robert C. Sterling Ph.D. Edward Gottheil M.D. Ph.D. Stephen P. Weinstein Ph.D. 《Substance Abuse》2013,34(4):227-235
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. 相似文献
8.
Fang Zhou Gang Hao Jingwei Zhang Yuanting Zheng Xiaolan Wu Kun Hao Fang Niu Dan Luo Yuan Sun Liang Wu Wencai Ye Guangji Wang 《British journal of pharmacology》2015,172(23):5690-5703
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-23Abbreviations
- 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
TARGETS |
---|
Aspartate aminotransferase (AST) |
Carbonyl reductase 1 (CBR1) |
Caspase‐3 |
LIGANDS | |
---|---|
Azithromycin | Doxorubicin |
Camptothecin | EGCG |
Dexrazoxane |
9.
F. Eggelmeijer 《Pharmacy World & Science》1998,20(5):193-197
Glucocorticoidinduced osteoporosis is a common clinical problem. This review briefly summarizes the pathogenesis of this disorder. All relevant studies on the prevention and treatment of glucocorticoidinduced osteoporosis are discussed more in detail. As the results of these studies are inconclusive, a proposal for a practical approach of the individual patient is formulated. 相似文献
10.
Neuropsychiatric side effects of interferon‐alfa therapy 总被引:1,自引:0,他引:1
A.R. Van Gool W.H.J. Kruit G. Stoter F.K. Engels A.M.M. Eggermont 《Pharmacy World & Science》2003,25(1):11-20
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《Journal of pharmaceutical sciences》1999,88(1):52-57
β‐1‐O‐ (NAG) and 2‐O‐glucuronides (2‐isomer) of (S)‐naproxen (NA) were prepared to determine which positional isomer‐(s) of the acyl glucuronide of NA is responsible for forming covalent adducts with human serum albumin (HSA). Their comparative stability and covalent binding adduct formation with HSA were investigated at pH 7.4 and at 37 °C. NA and its acyl glucuronides were simultaneously determined by HPLC. Three positional isomers were formed successively after incubation of NAG in the buffer only. However, when NAG was incubated with HSA (30 mg/mL), isomers other than the 2‐isomer were formed in little or negligible quantities. In HSA solution, NAG (kd = 2.08 ± 0.08 h−1) was four times less stable than 2‐isomer (kd = 0.51 ± 0.02 h−1). NAG was degraded by hydrolysis (khyd = 1.01 ± 0.10 h−1) and isomerization (kiso = 1.07 ± 0.07 h−1) to the same extent; however, hydrolysis was predominant for the 2‐isomer (kd = 0.51 ± 0.02 h−1). The incubation of both NAG and 2‐isomer with HSA led to the formation of a covalent adduct; however, the adduct formation from the 2‐isomer proceeded more slowly than that from NAG. The present results suggest that the covalent binding of NA to HSA via its acyl glucuronides proceeds through both transacylation (direct nucleophilic displacement) and glycation mechanisms; NAG rapidly forms an adduct that may be unstable, and the protein adduct from the 2‐O‐acyl glucuronide is as important for the covalent binding as those from the 1‐O‐acyl glucuronides. 相似文献
13.
Raimund Geidobler Ilona Konrad Gerhard Winter 《Journal of pharmaceutical sciences》2013,102(11):3915-3919
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 相似文献
14.
Koreyoshi Imamura Mayo Nomura Kazuhiro Tanaka Nobuhide Kataoka Jun Oshitani Hiroyuki Imanaka Kazuhiro Nakanishi 《Journal of pharmaceutical sciences》2010,99(3):1452-1463
An amorphous matrix comprised of sugar molecules is used as excipient and stabilizing agent for labile ingredients in the pharmaceutical industry. The amorphous sugar matrix is often compressed into a tablet form to reduce the volume and improve handling. Herein, the effect of compression on the crystallization behavior of an amorphous sucrose matrix was investigated. Amorphous sucrose samples were prepared by freeze‐drying and compressed under different conditions, followed by analyses by differential scanning calorimetry, isothermal crystallization tests, X‐ray powder diffractometry, Fourier transform infrared spectroscopy (FTIR), and gas pycnometry. The compressed sample had a lower crystallization temperature and a shorter induction period for isothermal crystallization, indicating that compression facilitates the formation of the critical nucleus of a sucrose crystal. Based on FTIR and molecular dynamics simulation results, the conformational distortion of sucrose molecules due to the compression appears to contribute to the increase in the free energy of the system, which leads to the facilitation of critical nucleus formation. An isothermal crystallization test indicated an increase in the growth rate of sucrose crystals by the compression. This can be attributed to the transformation of the microstructure from porous to nonporous, as the result of compression. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1452–1463, 2010 相似文献
15.
E. Zieliska J. Bodalski K. Mianowska W. Niewiarowski G. Rbowski J. Skrtkowicz M. Sekulska 《Pharmacy World & Science》1998,20(3):123-130
The pathogenesis of hypersensitivity to trimethoprimsulfamethoxazole (TMPSMX) is supposed to be associated with the slow acetylation phenotype. This pharmacogenetic defect is associated with the mutations of the arylamine Nacetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole in infants. The study was carried out in the group of 20 infants, aged 212 months (mean age 6.3 months) treated with Cotrimoxazole, administered at 100 mg/kg b.w./24 h doses. In seven children (35%) no adverse effects of the treatment have been observed, whereas in 13 (65%) children various adverse effects occurred as a result of the therapy, such as rash (4 children), granulocytopenia with anemization (5 children) or liver impairment (4 children). The acetylation phenotype of each child was determined on the basis of urine of Nacetyl isoniazid/isoniazid ratio, after ingestion of isoniazid as a model drug. Furthermore we used polymerase chain reaction (PCR) followed by the analysis of restriction fragments length polymorphism (RFLP) technique to identify the known mutant alleles of the NAT2 gene. It has been presumed that the genotype determining fast acetylation contains at least one of wildtype allele. No correlation has been found between the observed adverse effects of Cotrimoxazole and age, gender and acetylation phenotype. However, it has been demonstrated that the risk of adverse effects of Cotrimoxazole is considerably higher in children with mutations of the NAT2 encoding gene. The comparison of the results from PCRRFLP genotyping with phenotyping suggested that in infants, the NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to TMPSMX. 相似文献
16.
Man K S Lee Xiao‐Lei Moore Yi Fu Annas Al‐Sharea Dragana Dragoljevic Manuel A Fernandez‐Rojo Robert Parton Dmitri Sviridov Andrew J Murphy Jaye P F Chin‐Dusting 《British journal of pharmacology》2016,173(4):741-751
Background and Purpose
Monocyte‐derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High‐density lipoproteins (HDLs) have many cardio‐protective properties including potent anti‐inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur.Experimental Approach
Human blood monocytes were differentiated into macrophages in the presence or absence of HDL and were then induced to either an inflammatory macrophage (M1) or anti‐inflammatory macrophage (M2) phenotype using LPS and IFN‐γ or IL‐4, respectively.Key Results
HDL inhibited the induction of macrophages to an M1‐phenotype, as evidenced by a decrease in the expression of M1‐specific cell surface markers CD192 and CD64, as well as M1‐associated inflammatory genes TNF‐α, IL‐6 and MCP‐1 (CCL2). HDL also inhibited M1 function by reducing the production of ROS. In contrast, HDL had no effect on macrophage induction to the M2‐phenotype. Similarly, methyl‐β‐cyclodextrin, a non‐specific cholesterol acceptor also suppressed the induction of M1 suggesting that cholesterol efflux is important in this process. Furthermore, HDL decreased membrane caveolin‐1 in M1 macrophages. We confirmed that caveolin‐1 is required for HDL to inhibit M1 induction as bone marrow‐derived macrophages from caveolin‐1 knockout mice continued to polarize into M1‐phenotype despite the presence of HDL. Moreover, HDL decreased ERK1/2 and STAT3 phosphorylation in M1 macrophages.Conclusions and Implications
We concluded that HDL reduces the induction of macrophages to the inflammatory M1‐phenotype via redistribution of caveolin‐1, preventing the activation of ERK1/2 and STAT3.Linked Articles
This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4Abbreviations
- BMDMs
- bone marrow‐derived macrophages
- Cav‐1−/−
- caveolin‐1 knockout
- HDL
- high‐density lipoprotein
- MβCD
- methyl‐beta‐cyclodextrin
- M1
- inflammatory macrophage
- M2
- anti‐inflammatory macrophage
- WT
- wild‐type
17.
Gretchen Bain Christopher D. King Kevin Schaab Melissa Rewolinski Virginia Norris Claire Ambery Jane Bentley Masanori Yamada Angelina M. Santini Jeroen van de Wetering de Rooij Nicholas Stock Jasmine Zunic John H. Hutchinson Jilly F. Evans 《British journal of clinical pharmacology》2013,75(3):779-790
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. 相似文献18.
Štěpán Koudelka Josef Mašek Jiri Neuzil Jaroslav Turánek 《Journal of pharmaceutical sciences》2010,99(5):2434-2443
α‐Tocopheryl succinate (α‐TOS) is a semisynthetic analogue of α‐tocopherol with selective toxicity to the cancer cells and anticancer activity in vivo. Yet, no suitable formulation of α‐TOS for medical application has been reported. Various formulations, for example, solutions in organic solvents, oil emulsions and vesicules prepared by spontaneous vesiculation, polyethylene glycol conjugates and liposomes of various compositions have been tested. We developed and characterised a stable lyophilised liposome‐based α‐TOS formulation. α‐TOS (15 mol%) was incorporated into large oligolamellar vesicles (OLVs) composed of soy phosphatidylcholine (SPC) by the method of lipid film hydration followed by extrusion through polycarbonate filters. Stabilised liposomal formulation was prepared by lyophilisation in the presence of sucrose (molar ratio lipid/sucrose, 1:5). The size distribution of the liposomes (130–140 nm, polydispersity index 0.14) as well as the stable lipid and α‐TOS contents were preserved during storage in the lyophilised form at 2–8°C for at least 6 months. The data indicate good physical and chemical stability of the lyophilised preparation of α‐TOS liposomes that can be used in clinical medicine. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2434–2443, 2010 相似文献
19.
Wen‐Lin Cheng Pi‐Xiao Wang Tao Wang Yan Zhang Cheng Du Hongliang Li Yong Ji 《British journal of pharmacology》2015,172(23):5676-5689
Background and Purpose
Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.Experimental Approach
RGS5−/− apolipoprotein E (ApoE)−/− and ApoE −/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.Key Results
Atherosclerotic phenotypes were significantly accelerated in RGS5−/− ApoE −/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.Conclusions and Implications
RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.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-23Abbreviations
- ApoE
- apolipoprotein E
- CHD
- coronary heart disease
- H&E
- haematoxylin‐eosin
- ICAM‐1
- intercellular adhesion molecue‐1
- LDL
- low‐density lipoprotein
- MEK
- MAPK/ERK kinase
- RGS
- regulator of G‐protein signalling
- SMC
- smooth muscle cell
- VCAM‐1
- vascular cell adhesion molecule‐1
TARGETS |
---|
Enzymes |
Caspase 3 |
ERK1/2 |
JNK1/2 |
MEK 1 |
MEK 2 |
p38 (kinase) |
LIGANDS |
---|
ICAM‐1 |
IL‐10 |
IL‐1β |
IL‐6 |
RGS5 |
TNFα |
VCAM‐1 |
20.
Eveline P. van Poelgeest Michael R. Hodges Matthijs Moerland Yann Tessier Arthur A. Levin Robert Persson Marie W. Lindholm Kamille Dumong Erichsen Henrik ?rum Adam F. Cohen Jacobus Burggraaf 《British journal of clinical pharmacology》2015,80(6):1350-1361
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. 相似文献