Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1R,2S-Mox (NRL001) has been also undergoing clinical testing to increase the canal resting pressure in patients with bowel incontinence. Here we show, that Mox hydrochloride acts as an inhibitor of base excision repair (BER). The effect is mediated by the inhibition of apurinic/apyrimidinic endonuclease APE1. We link this observation to our previous report showing the biologically relevant effect of Mox on BER - prevention of converting oxidative DNA base damage to double-stranded breaks. We demonstrate that its effect is weaker, but still significant when compared to a known BER inhibitor methoxyamine (MX). We further determined Mox's relative IC50 at 19 mmol L-1, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.
- MeSH
- adrenalin * MeSH
- adrenergní receptory MeSH
- endonukleasy MeSH
- lidé MeSH
- methoxamin MeSH
- oprava DNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Despite several shortcomings such as extreme hydrophobicity, low drug capacity, characteristic triphasic drug release pattern with a high burst effect, poly(lactic-co-glycolic acid derivatives are widely used in drug delivery. Most frequent attempts to improve their properties are blending with other polymers or synthesis of block copolymers. We introduce a new class of branched poly(lactic-co-glycolic acid) derivatives as promising biodegradable carriers for prolonged or targeted drug release systems, employed as thin adhesive films, solid dispersions, in situ forming implants or nanoparticles. A series of poly(lactic-co-glycolic acid) derivatives with lower molar mass and star or comb architecture were synthesized by a simple, catalyst free, direct melt polycondensation method not requiring purification of the obtained sterile product by precipitation. Branching monomers used were mannitol, pentaerythritol, dipentaerythritol, tripentaerythritol and polyacrylic acid. The products were characterized by molar mass averages, average branching ratio, rheological and thermal properties.
The original purpose of vaginally applied microbicides was to slow down the HIV epidemic among the population until an effective vaccination was developed. Nowadays, antiretrovirals applied in the form of gels or vaginal rings are considered most prominent in this field and are tested via vaginal or, rarely, rectal applications in numerous clinical studies (9 different antiretroviral drugs in 33 clinical studies, especially in Africa). Only tenofovir (1 % gel) and dapivirine (25 mg in vaginal ring) progressed into the phase III clinical testing. Their efficiency depended on the user´s strict adherence to the application regimen (for tenofovir 54 %, for dapivirine 61 % in participants over 25 years of age). Despite this, they are expected to be important and effective tools of preventive medicine in the near future. This review summarizes the results obtained during long-term clinical testing (2005-2018) of antiretroviral drugs against vaginal and rectal transmission of HIV infection.
- MeSH
- antikoncepční prostředky ženské virologie MeSH
- antiretrovirové látky terapeutické užití MeSH
- HIV infekce farmakoterapie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- rektum virologie MeSH
- vagina virologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The present study is designed to find out if sesquiterpenes, α-humulene (HUM), valencene (VAL), β-caryphyllene-oxide (CAO) and trans-nerolidol (NER), are able to improve the antiproliferative effect of classical cytostatic drugs, 5-fluorouracil (FU) and oxaliplatin (1,2-diaminocyclohexaneoxalato-platinum, OxPt), in colon cancer cell lines Caco-2 and SW-620. In addition, the possible mechanisms of sesquiterpene action are studied. The results show significant ability of HUM and especially of CAO to enhance the anti-proliferative effects of FU and OxPt in cancer cell lines Caco-2 and SW-620. On the other hand, VAL and NER are ineffective. The action of CAO could be partly based on its ability to disrupt the mitochondrial membrane potential and to activate initiator caspases, but other mechanisms are probably also involved. Based on these results, CAO seems to have the potential for combination therapy of colon cancers and deserves further study.
- MeSH
- Caco-2 buňky MeSH
- fluorouracil farmakologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- monocyklické seskviterpeny farmakologie MeSH
- nádorové buněčné linie MeSH
- nádory tračníku farmakoterapie MeSH
- oxaliplatin farmakologie MeSH
- polycyklické seskviterpeny farmakologie MeSH
- proliferace buněk účinky léků MeSH
- seskviterpeny farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In the present study, time-dependency of the induction effect of a selective inducer on the activity, protein and mRNA levels of cytochromes P450 1A1/2 (CYP1A1/2), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferases (GSTA), in primary culture of rat hepatocytes was tested and evaluated. To show the differences in responses of tested enzymes, the common aryl hydrocarbon receptor (AhR) ligand agonist, beta-naphthoflavone (BNF), was used. Induction of CYP1A1/2 by BNF was detected at all time intervals and at all levels (i.e., mRNA, protein, enzyme activity). Different responses of NQO1 and GSTA upon BNF treatment were observed. Our results demonstrate that the responses of different xenobiotic-metabolizing enzymes to the inducer vary in time and depend on the measured parameter. For these reasons, an induction study featuring only one-time interval treatment and/ or one parameter testing could produce misleading information.
- MeSH
- beta-naftoflavon metabolismus MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- cytochrom P-450 CYP1A2 metabolismus MeSH
- glutathiontransferasa metabolismus MeSH
- hepatocyty metabolismus MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- ligandy MeSH
- messenger RNA metabolismus MeSH
- NAD(P)H dehydrogenasa (chinon) metabolismus MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- xenobiotika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
This paper evaluates and compares the properties of directly compressible tabletting materials and matrix tablets containing a combination of α-lactose monohydrate and microcrystalline cellulose in the 3:1 ratio in a physical mixture and in a coprocessed dry binder. Tested parameters include flow properties, compressibility, compactibility and the rate of drug release from tablets. Compressibility is evaluated by means of the energy profile of the compression process. Compactibility is evaluated by means of the tensile strength of the tablets. Dissolution testing is done using the rotating basket method. Dissolution profiles are evaluated by non-linear regression analysis. Total energy of compression and plasticity values were higher in tabletting materials with the coprocessed dry binder. Increasing additions of polyvinyl alcohol decreased the values of total energy of compression, plasticity, tensile strength of tablets and drug release rate. Dissolution behaviour of tablets, which contained the physical mixture or coprocessed dry binder and the same amount of polyvinyl alcohol, was comparable.
- MeSH
- celulosa chemie MeSH
- chemie farmaceutická metody MeSH
- farmaceutická technologie metody MeSH
- kyselina salicylová aplikace a dávkování chemie MeSH
- laktosa chemie MeSH
- nelineární dynamika MeSH
- pevnost v tahu MeSH
- polyvinylalkohol chemie MeSH
- pomocné látky chemie MeSH
- rozpustnost MeSH
- tablety MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The paper evaluates and compares the compressibility and compactibility of directly compressible tableting materials for the preparation of hydrophilic gel matrix tablets containing tramadol hydrochloride and the coprocessed dry binders Prosolv® SMCC 90 and Disintequik™ MCC 25. The selected types of hypromellose are Methocel™ Premium K4M and Methocel™ Premium K100M in 30 and 50 % concentrations, the lubricant being magnesium stearate in a 1 % concentration. Compressibility is evaluated by means of the energy profile of compression process and compactibility by the tensile strength of tablets. The values of total energy of compression and plasticity were higher in the tableting materials containing Prosolv® SMCC 90 than in those containing Disintequik™ MCC 25. Tramadol slightly decreased the values of total energy of compression and plasticity. Tableting materials containing Prosolv® SMCC 90 yielded stronger tablets. Tramadol decreased the strength of tablets from both coprocessed dry binders.
- MeSH
- celulosa chemie MeSH
- deriváty hypromelózy chemie MeSH
- gely MeSH
- hydrofobní a hydrofilní interakce MeSH
- kyseliny stearové chemie MeSH
- mechanické jevy MeSH
- opioidní analgetika chemie MeSH
- pevnost v tahu MeSH
- pevnost v tlaku MeSH
- pomocné látky chemie MeSH
- přenos energie MeSH
- příprava léků * MeSH
- pružnost MeSH
- tablety MeSH
- tramadol chemie MeSH
- viskozita MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
Patients tend to prevent hypoglycemia by excessive saccharide intake leading to poorer glycemic control with potentially fatal consequences. This problem could be resolved by means of pellets with glucose release delayed by 120-360 min as a compensation of the antidiabetic drug peak effect. No glucose is released before; hence there is no risk of hyperglycemia and secondary complications. The pellets contain glucose in combination with an osmotically active ingredient and are coated with an ethylcellulose dispersion, which forms an insoluble semipermeable membrane and ensures delayed release. The release of glucose was assessed using dissolution and high-performance liquid chromatography. Dissolution profiles indicated the possibility of achieving the requested lag time using a combination of adequate compositions and coating concentrations. Lag times of 60, 240 and 360 min were achieved. The sample containing carboxymethyl starch was found to be most suitable for the intent of this work.
- MeSH
- celulosa analogy a deriváty chemie MeSH
- glukosa aplikace a dávkování chemie MeSH
- hypoglykemie krev prevence a kontrola MeSH
- kinetika MeSH
- krevní glukóza metabolismus účinky léků MeSH
- léky s prodlouženým účinkem MeSH
- lidé MeSH
- membrány umělé MeSH
- pomocné látky chemie MeSH
- povrchové vlastnosti MeSH
- příprava léků MeSH
- rozpustnost MeSH
- škrob chemie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
