Neurosteroids are endogenous steroidal compounds that can modulate neuronal receptors. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that are of particular interest, as they participate in synaptic transmission and are implicated in various processes, such as learning, memory, or long-term neuronal potentiation. Positive allosteric modulators that increase the activity of NMDARs may provide a therapeutic aid for patients suffering from neuropsychiatric disorders where NMDAR hypofunction is thought to be involved, such as intellectual disability, autism spectrum disorder, or schizophrenia. We recently described a new class of pregn-5-ene and androst-5-ene 3beta-dicarboxylic acid hemiesters (2-24) as potent positive modulators of NMDARs. Considering the recommended guidelines for the early stage development of new, potent compounds, we conducted an in vitro safety assessment and plasma stability screening to evaluate their druglikeness. First, compounds were screened for their hepatotoxicity and mitochondrial toxicity in a HepG2 cell line. Second, toxicity in primary rat postnatal neurons was estimated. Next, the ability of compounds 2-24 to cross a Caco-2 monolayer was also studied. Finally, rat and human plasma stability screening revealed an unforeseen high stability of the C-3 hemiester moiety. In summary, by using potency/efficacy towards NMDARs data along with toxicity profile, Caco-2 permeability and plasma stability, compounds 14 and 15 were selected for further in vivo animal studies.
- MeSH
- androstenoly chemie farmakologie krev MeSH
- buňky Hep G2 MeSH
- cholesterol chemie farmakologie krev MeSH
- estery chemie farmakologie krev MeSH
- kyseliny dikarboxylové chemie farmakologie krev MeSH
- lidé MeSH
- poruchy autistického spektra farmakoterapie metabolismus MeSH
- stabilita léku MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
Neurosteroids are endogenous steroidal compounds that can modulate neuronal receptors. N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that are of particular interest, as they participate in synaptic transmission and are implicated in various processes, such as learning, memory, or long-term neuronal potentiation. Positive allosteric modulators that increase the activity of NMDARs may provide a therapeutic aid for patients suffering from neuropsychiatric disorders where NMDAR hypofunction is thought to be involved, such as intellectual disability, autism spectrum disorder, or schizophrenia. We recently described a new class of pregn-5-ene and androst-5-ene 3β-dicarboxylic acid hemiesters (2-24) as potent positive modulators of NMDARs. Considering the recommended guidelines for the early stage development of new, potent compounds, we conducted an in vitro safety assessment and plasma stability screening to evaluate their druglikeness. First, compounds were screened for their hepatotoxicity and mitochondrial toxicity in a HepG2 cell line. Second, toxicity in primary rat postnatal neurons was estimated. Next, the ability of compounds 2-24 to cross a Caco-2 monolayer was also studied. Finally, rat and human plasma stability screening revealed an unforeseen high stability of the C-3 hemiester moiety. In summary, by using potency/efficacy towards NMDARs data along with toxicity profile, Caco-2 permeability and plasma stability, compounds 14 and 15 were selected for further in vivo animal studies.
- MeSH
- androstenoly krev chemie farmakologie MeSH
- buňky Hep G2 MeSH
- cholesterol krev chemie farmakologie MeSH
- estery krev chemie farmakologie MeSH
- krysa rodu rattus MeSH
- kyseliny dikarboxylové krev chemie farmakologie MeSH
- lidé MeSH
- mentální retardace farmakoterapie metabolismus MeSH
- mitochondrie účinky léků metabolismus MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- neurony účinky léků metabolismus MeSH
- neuroprotektivní látky krev chemie farmakologie MeSH
- poruchy autistického spektra farmakoterapie metabolismus MeSH
- potkani Wistar MeSH
- pregnenolon analogy a deriváty krev farmakologie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- schizofrenie farmakoterapie metabolismus MeSH
- stabilita léku MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- kyselina bempedoová,
- MeSH
- hypolipidemika MeSH
- kyseliny dikarboxylové farmakologie chemie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- zprávy MeSH
- MeSH
- acne vulgaris * etiologie farmakoterapie klasifikace terapie MeSH
- antibakteriální látky MeSH
- dospělí MeSH
- hormonální substituční terapie MeSH
- kyseliny dikarboxylové farmakologie terapeutické užití MeSH
- lidé MeSH
- retinoidy farmakologie terapeutické užití MeSH
- tetracykliny farmakologie terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
Akné je chronické neinfekční zánětlivé onemocnění. S lehčími projevy akné pacienti často vyhledávají, jako jednu z prvních voleb, personál lékárny. Text proto shrnuje volně prodejné registrované přípravky, jejich použití i nežádoucí účinky. Uvádí také možnost doplňkové léčby.
Acne is a chronical non-infectious inflammatory disease. Patients visit pharmacy with mild acne very often. This article summarises common use and side effects of over-the-counter products. The text also describes possibilities of additional therapy.
- Klíčová slova
- klasifikace rozacey, pulzní barvivový laser, intenzivní pulzní světlo, rhinofyma, katelicidin, kyselina azelaová,
- MeSH
- aplikace kožní MeSH
- aplikace orální MeSH
- chronická nemoc MeSH
- erytém MeSH
- klindamycin terapeutické užití MeSH
- kyseliny dikarboxylové farmakologie terapeutické užití MeSH
- laserová terapie s nízkou intenzitou světla MeSH
- lidé MeSH
- metronidazol aplikace a dávkování farmakologie terapeutické užití MeSH
- příznaky a symptomy MeSH
- progrese nemoci MeSH
- retinoidy škodlivé účinky terapeutické užití MeSH
- rinofyma chirurgie MeSH
- rizikové faktory MeSH
- rosacea klasifikace patofyziologie terapie MeSH
- sulfacetamid terapeutické užití MeSH
- teleangiektazie prevence a kontrola terapie MeSH
- tetracykliny aplikace a dávkování farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Pharmaceutical cocrystals are H-bonded multicomponent mixtures formed from a molecular or ionic substance and a cocrystal former, which are solids under ambient conditions. The cocrystals are the latest material investigated to enhance drug properties such as solubility, dissolution rate, stability, powder flow, and hygroscopicity. Very close to cocrystals are salts which can be distinguished by the localization of proton between an acid and base. Crystal engineering of cocrystals is based on the concept of supramolecular synthons. The major experimental techniques in cocrystal screening are cocrystallization in solution, solvent evaporation, melt crystallisation, dry cogrinding, solvent-assisted grinding and cryogrinding.
- MeSH
- butyráty farmakologie chemie MeSH
- chemické jevy MeSH
- chemie farmaceutická metody trendy MeSH
- farmaceutická technologie metody trendy MeSH
- farmaceutický průmysl metody trendy MeSH
- financování organizované MeSH
- itrakonazol MeSH
- karbamazepin chemie MeSH
- kofein farmakologie chemie MeSH
- krystalizace metody trendy využití MeSH
- kyseliny dikarboxylové farmakologie chemická syntéza chemie MeSH
- kyseliny mandlové farmakologie chemie MeSH
- lékové formy MeSH
- objevování léků MeSH
- paracetamol farmakologie chemie MeSH
- rozpouštědla farmakologie chemie MeSH
- sacharin farmakologie chemie MeSH
- soli farmakologie chemie MeSH
SUMMARY: Metabotropic glutamate receptors (mGluR) may represent a perspective target for anticonvulsant therapy but spectrum of their anticonvulsant effects is not sufficiently known. Our study was aimed at comparison of anticonvulsant actions of antagonists of mGluR1 and mGluR5 subtypes in immature rats. Seven-, 12-, 18- and 25-day-old animals were pretreated with mGluR1 antagonist AIDA (1-20mg/kg i.p.) or mGluR5 antagonist MTEP (5-40 mg/kg i.p.) 30 min before pentetrazol administration (100mg/kg s.c.). Two types of motor seizures were elicited: minimal, clonic seizures (mS) and generalized tonic-clonic seizures (GTCS). mS could be induced only in 18- and 25-day-old rats, and their incidence was decreased to 0-50% by nearly all doses of either drug in 18- but not in 25-day-old rats. GTCS were observed in all age groups; higher doses of both antagonists specifically suppressed the tonic phase in 7-, 12- and 18-day-old rats. The highest efficacy was found in 12-day-old rats; seizure severity was significantly decreased even by the 10-mg/kg dose of MTEP and the 2-mg/kg dose of AIDA in this age group. In addition, MTEP tended to suppress also the clonic phase in 7-day-old rats. Time course of action studied in 12-day-old animals demonstrated much longer action of MTEP (more than 4h) than of AIDA (less than 1h). Administration of AIDA but not MTEP resulted in a paradoxical shortening of latencies of seizures even at time intervals when the incidence of the tonic phase of GTCS was decreased. Both mGluR antagonists exhibit specific anticonvulsant action in rat pups during the first 3 postnatal weeks.
- MeSH
- analýza rozptylu MeSH
- antikonvulziva farmakologie terapeutické užití MeSH
- časové faktory MeSH
- epilepsie chemicky indukované prevence a kontrola MeSH
- financování organizované MeSH
- krysa rodu rattus MeSH
- kyseliny dikarboxylové farmakologie MeSH
- nemoci zvířat MeSH
- novorozená zvířata MeSH
- pentylentetrazol MeSH
- potkani Wistar MeSH
- pyridiny farmakologie MeSH
- reakční čas účinky léků MeSH
- receptory metabotropního glutamátu antagonisté a inhibitory metabolismus účinky léků MeSH
- stárnutí MeSH
- stupeň závažnosti nemoci MeSH
- thiazoly farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
