11 β

Preeclampsia is a serious medical problem affecting the mother and her child and influences their health not only during the pregnancy, but also many years after. Although preeclampsia is a subject of many research projects, the etiology of the condition remains unclear. One of the hypotheses related to the etiology of preeclampsia is the deficiency in placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), the enzyme which in normal pregnancy protects the fetus from the excess of maternal cortisol. The reduced activity of the enzyme was observed in placentas from pregnancies complicated with preeclampsia. That suggests the overexposure of the developing child to maternal cortisol, which in high levels exerts proapoptotic effects and reduces fetal growth. The fetal growth restriction due to the diminished placental 11β-HSD2 function may be supported by the fact that preeclampsia is often accompanied with fetal hypotrophy. The causes of the reduced function of 11β-HSD2 in placental tissue are still discussed. This paper summarizes the phenomena that may affect the activity of the enzyme at various steps on the way from the gene to the protein

Pacjent z podejrzeniem zespołu pozornego nadmiaru mineralokortykosteroidów — trudności diagnostyczne

Pozorny nadmiar mineralokortykosteroidów (AME) jest rzadką postacią dziedzicznego nadciśnienia tętniczego związaną z zaburzeniami w funkcjonowaniu dehydrogenazy 11β-hydroksysteroidowej 2. Diagnostyka tego schorzenia opiera się na ocenie fenotypu, na który składają się charakterystyczne objawy kliniczne, zaburzenia w gospodarce elektrolitowej oraz analiza profilu steroidowego (mineralo- i glikokortykosteroidowego). Ponadto wykonuje się genotypowanie mające na celu ustalenie występowania mutacji w genie HSD11B2. W niniejszej pracy przedstawiono trudności w diagnostyce AME na podstawie przypadku pacjenta, u którego ocena jedynie fenotypu mogłaby doprowadzić do błędnego rozpoznania

Glucocorticoids action in etiology of hypertension

Glikokortykosteroidy (GKS), z których kluczową rolę pełni kortyzol (F), odgrywają wiele istotnych funkcji metabolicznych, przede wszystkim w regulacji stężenia glukozy czy wpływie na przemiany białek i tłuszczy. Zwiększona sekrecja F lub jego nieprawidłowy metabolizm lub zwiększona wrażliwość tkanek na działanie GKS może prowadzić do powstawania zaburzeń metabolicznych i wielu chorób, między innymi nadciśnienia tętniczego. Kluczowym enzymem w metabolizmie F jest dehydrogenaza 11β-hydroksysteroidowa, która katalizuje wzajemne przekształcenie aktywnego biologicznie F i nieczynnego kortyzonu. Izoforma 2 tego enzymu odpowiada za ochronę receptora mineralokortykosteroidowego przed działaniem F. W przypadku defektu jej aktywności, między innymi w zespole pozornego nadmiaru mineralokortykosteroidów, dochodzi do pobudzenia MR przez F, zwiększenia objętości płynów w łożysku naczyniowym i w konsekwencji do nadciśnienia tętniczego. Innym potencjalnym mechanizmem hipertensyjnego działania GKS jest wpływ na syntezę tlenku azotu (NO). Obniżenie stężenia NO, głównego czynnika rozszerzającego naczynia krwionośne, zachodzi między innymi na drodze hamowania ekspresji izoformy 2 i 3 syntazy tlenku azotu, niekorzystnego wpływu na dostępność niezbędnego kofaktora oraz poprzez zmniejszenie poziomu substratu do syntezy NO. W pracy przedstawiono aktualne dane z piśmiennictwa dotyczące udziału GKS w patogenezie nadciśnienia tętniczego.Glucocorticoids (GKS), among which cortisol (F) is the most important factor, have various metabolic functions. They regulate glucose levels and influence proteins and lipids metabolism. Higher secretion of F, its changed metabolism or higher sensitivity of cells or tissues to F might be a source of metabolic disorders and many diseases, inter alia arterial hypertension. The key enzyme in F metabolism is 11b-hydroxysteroid dehydrogenase, which catalyzes the interconversion of F and inactive cortisone. The isoform 2 of that enzyme (11β-HSD2) is responsible for mineralocorticoid receptor’s protection from F. Disturbances in activity of 11β-HSD2, for example in apparent mineralocorticoid excess, lead to mineralocorticoid receptor activation by F, water retention and finally to hypertension. The influence of GKS on nitric oxide (NO) synthesis is another possible mechanism of hypertensive action of GKS. Decrease of NO levels may be an effect of inhibition of expression of nitric oxide synthase isoform 2 and 3, lack of enzyme co-factor or the substrate for NO synthesis. The paper summarises data considering GKS influence on pathomechanism of arterial hypertension. Arterial Hypertension 2010, vol. 14, no 3, pages 208-21

Pharmacokinetic Drug–Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug–drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

ABSTRACT Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into the CNS was studied in juvenile (JR) and young adult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S,S-EBDM, and S,S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREO was 0.14, 0.17, 0.10, and 0.07 and for unbound S,S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S,S-EBDM, respectively. Elimination rate constants of TREO and S,S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S,S-DEB were found in the studied samples. TREO and S,S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO-related CNS exposure than young adults