Q95373565 Dotaz Zobrazit nápovědu
- MeSH
- mezinárodní spolupráce MeSH
- školy farmaceutické * MeSH
- Publikační typ
- zprávy MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- školy farmaceutické organizace a řízení MeSH
- studium farmacie vysokoškolské * MeSH
- Publikační typ
- rozhovory MeSH
This investigation deals with the affection of permeation of acetylsalicylic acid and paracetamol applied in the system propylene glycol-water 1:1 through full-thickness pig ear skin by alaptide that was applied in nanonized form as a potential chemical penetration enhancer. Alaptide, (S)-8-methyl-6,9- diazaspiro[4.5]decan-7,10-dione, is the original Czech compound. The application of nanonized alaptide significantly enhanced the permeation of both drugs through the skin. Enhancement ratios in the studied time interval 0.5-2.0 h varied from 1.11 to 17.70 for acetylsalicylic acid and from 6.83 to 19.83 for paracetamol.
- MeSH
- analýza rozptylu MeSH
- aplikace kožní * MeSH
- Aspirin * farmakokinetika MeSH
- časové faktory MeSH
- cyklické peptidy * farmakokinetika MeSH
- epidermis účinky léků MeSH
- farmaceutická chemie * MeSH
- hormon inhibující uvolňování MSH MeSH
- kožní absorpce účinky léků MeSH
- multivariační analýza MeSH
- nanočástice MeSH
- neuropeptidy farmakokinetika MeSH
- paracetamol * farmakokinetika MeSH
- permeabilita MeSH
- pomocné látky farmakokinetika chemická syntéza terapeutické užití MeSH
- prasata MeSH
- propylenglykol terapeutické užití MeSH
- suspenze farmakokinetika chemická syntéza MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25μM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.
- MeSH
- aplikace kožní MeSH
- hydrofobní a hydrofilní interakce MeSH
- kapronáty chemie farmakologie MeSH
- kožní absorpce účinky léků MeSH
- molekulární struktura MeSH
- nosiče léků chemie MeSH
- simulace molekulární dynamiky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Two newly synthesized short-acting agents 44Bu and 444 were observed to suppress the aconitine-induced arrhythmias and block the fast sodium current INa in the rat heart. No data about their effect on the electrocardiographic parameters are available. In this study, we explored the effect of both racemates and particular isomers of 44Bu and 444 on the QRS-complex width in vivo in rats and on INa in isolated rat ventricular myocytes. All variants of 44Bu and 444 (1.5 mg/kg) caused a significant QRS-widening reaching the peak effect at the 1st or 2nd min after their intravenous administration. 44Bu racemate widened the QRS-complex from 16.8 ± 0.4 to 26.3 ± 0.5 ms (by 57%), significantly more than R- (33%-widening) and S-isomer (36%-widening). 444 racemate widened the QRS-complex from 20.8 ± 1.0 to 34.1 ± 0.9 ms (by 64%), which was comparable to S-isomer (63%-widening), however, substantially more than R-isomer (40%-widening). Regarding the effect on INa, 44Bu caused a significantly deeper INa- block compared to 444 when applied at the same concentration of 3 μmol/l (~0.1 mg/kg). 44Bu racemate and R-isomer blocked INa similarly (91.7 ± 0.8 and 91.8 ± 1.6%-block, respectively) and significantly more than S-isomer (82.4 ± 2.3%-block). 444 R-isomer blocked INa less than racemate and S-isomer (by 31.7 ± 3.9% vs. 48.3 ± 4.7 and 50.2 ± 4.1%, respectively). We conclude that both racemates and particular isomers of 44Bu and 444 induce a QRS-widening and block INa in the rat heart, however, their effects notably differed. The relative widening of the QRS-complex after application of 44Bu did not conform to the level of INa-block observed in isolated cardiomyocytes which stresses the importance of in vivo experiments in the pre-clinical testing of new drugs.
- Klíčová slova
- rychlý proud sodíku, prodloužení QRS komplexu, 44Bu, 444,
- MeSH
- benzoáty * farmakologie chemie klasifikace MeSH
- blokátory sodíkových kanálů MeSH
- elektrokardiografie * MeSH
- potkani Wistar MeSH
- preklinické hodnocení léčiv MeSH
- srdeční arytmie farmakoterapie chemicky indukované MeSH
- srdeční elektrofyziologie MeSH
- srdeční komory * účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of substituted 6-aminohexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (logk) was determined. Hydrophobicities (logP/ClogP) of the studied compounds were also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio/DFT calculations of geometry. All the synthesized esters were tested for their in vitro transdermal penetration enhancer activity. The relationships between the lipophilicity and the chemical structure (SLR) of the studied compounds as well as the relationships between their chemical structure and transdermal penetration activity are mentioned.
- MeSH
- aplikace kožní MeSH
- kožní absorpce účinky léků MeSH
- kůže účinky léků metabolismus MeSH
- kyselina 6-aminokapronová chemie farmakologie MeSH
- lipidy chemie MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- nosiče léků chemie farmakologie MeSH
- permeabilita účinky léků MeSH
- prasata MeSH
- theofylin aplikace a dávkování farmakokinetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
