Chem. Listy 2022; 116: 101−109. doi: 10.54779/ chl20220101 vladimir.pliska@biol.ethz.ch, parizek@porodnice.cz Došlo 12. 10. 2021, přijato 1. 11. 2021.
Abstract: Licence agreements between the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague (IOCB), and the pharmaceutical company Ferring AB Malmö enabled the Swedish company to produce and commercialize worldwide a number of neurohypophyseal peptides designed at the IOCB. Several of them found therapeutic applications. dDAVP: 1-deamino-8-D-arginine-vasopressin was designed in one of the IOCB peptide laboratories (M. Zaoral and F. Šorm) in 1967. It displayed an extremely high antidiuretic activity (various tests indicate a 2- to 50-fold increase, as compared to arginine vasopressin) and a very low pressor activity. The peptide (covered by the U.S. Patent No. 3,497,491, 1970) has been used as a preferred drug in the substitution therapy of the central form of diabetes insipidus (Minirin®, today as Desmopressin INN). Besides, as later discovered (Mannucci et al. 1977), dDAVP increases the plasma concentration of the blood clottiing factor VIII. This fact extended its clinical use as haemostatics in cases of milder forms of haemophilia A, von Willebrand-Jürgens syndrome and some thrombocyte dysfunctions. Despite of the clinical success of dDAVP, a closer look reveals certain inadequacies in the presently available pharmacological data: several reports declare activity values and the prolongation effect (index of persistence) in very broad ranges. Triglycyl-8- -lysine-vasopressin (Terlipressin), a peptide with lysine vasopressin chain extended at the N-terminal by a triglycine residue, acts mainly as a prodrug (releasing lysine vasopressin after aminopeptidase splitting at the Na group). The analogue belongs to the so-called „synthetic hormonogens“; individual peptides carrying various acylating groups were synthesized in the midsixties at the IOCB and legally protected by U.S. Patent No. 3,558,590 (1968). It was a part of the licence agreements mentioned above. The activities of triglycyl-8-lysine-vasopressin (both antidiuretic and vasopressor) are about 100 times lower than those of lysine vasopressin, but its persistence is 5 times longer. As such, it is occasionally used in emergency medicine in cases of esophageal (and other gastroenteral) bleeding, traumatic or septic shock, in cirrhotic patients and patients with portal hypertension. Its use as an early abortion drug was discussed but not pursued. Carbetocin (deaminocarba1-2-O-methyltyrosin-oxytocin) was synthetized in the laboratory of Karel Jošt at the IOCB before 1971; its synthesis was covered by a Czechoslovak patent (CS-149,028 B1) in June 1973 (at that time, Czechoslovak patent law did not provide for the patentability of substances as such) and first published in a biophysical communication by Frič et al., 1974). As a part of the licence agreement, it was included in the production program of Ferring AB, but marketed later also by several other pharmaceutical companies due to an incomplete patent protection. The peptide is a moderately active uterotonic partial agonist and as such has been utilized in veterinary obstetrics for delivery induction in cows and (multiparous) pigs: its milder and better--controlled uterotonic action was found preferential as compared to oxytocin so far used for these purposes. In the last two decades, carbetocin has been commonly used also in the human obstetrics, especially to prevent the peri- and post-partum haemorrhage, from the maternal side the most frequent and most severe delivery complication. It became a life-saving drug in emergency obstetrics.
- Keywords
- carbetocin,
- MeSH
- Deamino Arginine Vasopressin administration & dosage history pharmacology therapeutic use MeSH
- Humans MeSH
- Pituitary Hormones, Posterior * history pharmacology classification MeSH
- Oxytocin antagonists & inhibitors history pharmacology MeSH
- Postpartum Hemorrhage drug therapy MeSH
- Terlipressin administration & dosage history pharmacology therapeutic use MeSH
- Oxytocics administration & dosage history pharmacology classification MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Geographicals
- Czech Republic MeSH
- Sweden MeSH
- MeSH
- Aspirin * pharmacokinetics pharmacology therapeutic use MeSH
- Diabetes Mellitus * drug therapy pathology MeSH
- Platelet Aggregation Inhibitors MeSH
- Diabetes Complications MeSH
- Humans MeSH
- Megakaryocytes pathology MeSH
- Blood Platelets pathology drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
Androgen deprivation therapy has long been the first-line treatment for hormone-sensitive prostate cancer (HSPC). After progression to castration-resistant prostate cancer (CRPC), androgen receptor pathway inhibitors (ARPIs) are commonly used. Recently, combined therapy with androgen deprivation and an ARPI has been recommended for metastatic HSPC patients. Novel markers are urgently needed for monitoring this disease and for making therapeutic decisions. Plasma samples were collected from 140 patients with either metastatic HSPC (n = 72) or CRPC (n = 68) before the start of ARPI therapy. Digital PCR was used to assess AR gene amplification, while the expression levels of miR-375 were measured by quantitative PCR. Sixteen other clinical markers were also evaluated, including prostate-specific antigen (PSA), chromogranin A (CGA), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), C-reactive protein (CRP), lymphocyte-to-monocyte ratio, and platelet count. A multivariate analysis, adjusted for age and metastatic dissemination, identified miR-375 expression and lymphocyte-to-monocyte ratio to be the independent negative predictors of ARPI therapy failure in CRPC patients. Regarding the HSPC patients, this article reports the primary finding of the independent negative predictive value of platelet count, CRP, and CGA for the failure of combined androgen deprivation therapy and ARPI.
- MeSH
- Receptors, Androgen genetics MeSH
- C-Reactive Protein * metabolism MeSH
- Chromogranin A * blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- MicroRNAs * genetics blood MeSH
- Biomarkers, Tumor blood MeSH
- Prostatic Neoplasms, Castration-Resistant * blood genetics pathology drug therapy diagnosis MeSH
- Treatment Failure MeSH
- Prognosis MeSH
- Prostate-Specific Antigen * blood MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Blood Platelets * metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
Diagnostika jaterních chorob sestává ze dvou kroků: určení příčiny jaterního poškození a stanovení jeho pokročilosti, čímž se myslí zejména vyloučení přítomnosti pokročilé jaterní fibrózy. Pro tyto účely nelze využít jednotlivé rutinní laboratorní parametry ani běžnou abdominální sonografii, která uspokojivou senzitivitu vykazuje až u velmi pokročilých strukturálních změn jater při cirhóze. Zlatým standardem v diagnostice jaterní fibrózy je v současné době hodnocení tuhosti jaterní tkáně pomocí jaterní elastografie. Její dostupnost je však v běžné praxi omezená, a proto tato metoda není vhodná ke screeningu rozsáhlých skupin pacientů, kteří jsou v riziku rozvoje či přítomnosti jaterní fibrózy (diabetici, pacienti s obezitou, metabolickým syndromem, nadměrnou konzumací alkoholu apod.). Z tohoto důvodu jsou do rutinní praxe zaváděny tzv. neinvazivní skórovací indexy využívající kombinaci většinou běžně dostupných klinických dat a laboratorních parametrů. Pravděpodobně nejvíce využívaným je index FIB‐4, jehož použití v rutinní praxi doporučují téměř všechny odborné organizace. Jeho stanovení je rychlé, nepřináší zvýšené náklady (kalkuluje se z rutinně dostupných dat: věk, hodnoty AST, ALT, trombocyty) a dokáže s uspokojivou přesností primárně vyloučit přítomnost pokročilé jaterní choroby. Jeho hlavní nevýhodou je relativně vyšší podíl falešně pozitivních výsledků, o čemž mj. pojednává také následující text.
Evaluation of liver disease consists of two steps in general: finding out why the liver is damaged and establishing the severity of its damage, especially ruling out an advanced liver cirrhosis. Neither routine laboratory parameters, nor a common abdominal utrasonography (achieving an acceptable sensitivity for very advanced structural cirrhotic changes only) are useful in this context. Liver elastography, quantifying the liver stiffness, represents a current gold standard in the evaluation of liver cirrhosis. Its availability, however, is limited in everyday clinical practice, making it unsuitable for screening of large patient groups at risk of this condition (diabetics, obese patients, metabolic syndrome sufferers, excessive alcohol users etc.). Thus, so called non‐invasive scoring systems are being introduced in clinical practice, using combinations of easily available clinical data and laboratory parameters. FIB‐4 is probably the most popular one, being recommended by virtually all expert organizations. The calculation of FIB‐4 is fast, cheap (using routine information such as age, AST and ALT levels, thrombocyte count) and capable of excluding an advanced liver disease with reasonable accuracy. Its main drawback consists of relatively high percentage of false positive results – a problem discussed in detail below.
BACKGROUND: Metabolic syndrome is a significant pro-inflammatory and pro-coagulant condition. The clinical association of adiponectin, a mainly antidiabetogenic molecule, and its interaction with platelets and platelet indices remains insufficiently investigated. OBJECTIVE: The aim of our study was to investigate the association of adiponectin with platelets and platelet indices in patients with metabolic syndrome. METHODS: The investigation was conducted as a cross-sectional study involving 113 subjects: 63 patients with the diagnosis of metabolic syndrome, and 50 healthy controls - with clear inclusion and exclusion criteria. The group of patients with metabolic syndrome was divided into two subgroups according to the platelet/high-density lipoprotein (HDL) ratio. RESULTS: The subgroup with a higher platelet/HDL ratio was prediabetic. In the same subgroup of patients, a positive correlation between the adiponectin and mean platelet volume (MPV) was seen, while linear regression (95% CI) confirmed the association. CONCLUSION: Considering that MPV is the index that indicates average platelet volume and activity, we believe this association with adiponectin can represent a protective compensatory response in patients with metabolic syndrome and prediabetes. Our results provide a basis for a more precise selection of patients in whom the future therapeutic application of recombinant adiponectin would be most effective.
- MeSH
- Adiponectin * blood MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Metabolic Syndrome * blood MeSH
- Cross-Sectional Studies MeSH
- Mean Platelet Volume * MeSH
- Case-Control Studies MeSH
- Blood Platelets metabolism pathology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Chelation is the rational treatment modality in metal overload conditions, but chelators are often non-selective and can, hence, cause an imbalance in the homeostasis of physiological metals including calcium and magnesium. The aim of this study was to develop an affordable, rapid but sensitive and precise method for determining the degree of chelation of calcium and magnesium ions and to employ this method for comparison on a panel of known metal chelators. Spectrophotometric method using o-cresolphthalein complexone (o-CC) was developed and its biological relevance was confirmed in human platelets by impedance aggregometry. The lowest detectable concentration of calcium and magnesium ions by o-CC was 2.5 μM and 2 μM, respectively. The indicator was stable for at least 110 days. Four and seven out of twenty-one chelators strongly chelated calcium and magnesium ions, respectively. Importantly, the chelation effect of clinically used chelators was not negligible. Structure-activity relationships for eight quinolin-8-ols showed improvements in chelation particularly in the cases of dihalogen substitution, and a negative linear relationship between pKa and magnesium chelation was observed. Calcium chelation led to inhibition of platelet aggregation in concentrations corresponding to the complex formation. A novel method for screening of efficacy and safety of calcium and magnesium ion chelation was developed and validated.
- MeSH
- Platelet Aggregation drug effects MeSH
- Chelating Agents * chemistry MeSH
- Magnesium * chemistry MeSH
- Humans MeSH
- Drug Evaluation, Preclinical methods MeSH
- Blood Platelets drug effects metabolism MeSH
- Calcium * analysis metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
- MeSH
- Acute Coronary Syndrome complications physiopathology MeSH
- Enzymes classification metabolism MeSH
- Epoprostenol physiology MeSH
- Intracranial Embolism and Thrombosis * complications physiopathology MeSH
- Arachidonic Acid metabolism MeSH
- Humans MeSH
- Fatty Acids * physiology metabolism MeSH
- Fatty Acids, Unsaturated physiology metabolism MeSH
- Blood Platelets enzymology physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND AND PURPOSE: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent capable of interacting with the lipid bilayer in a receptor-independent way. In this study, we investigated the influence of Ticagrelor on plasma membrane lipid order in platelets and if this modulates the potency of Ticagrelor at the P2Y12 receptor. EXPERIMENTAL APPROACH: We combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelet plasma membrane and large unilamellar vesicles was studied using the advanced fluorescent probe NR12S. Furthermore, the properties of model lipid bilayers in the presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose-response of platelets to Ticagrelor was studied. KEY RESULTS: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets, in a nontrivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to a lower IC50 value for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases its potency at the P2Y12 receptor, by increasing the order of the platelet plasma membrane. CONCLUSION AND IMPLICATIONS: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor-lipid microenvironment.
- MeSH
- Purinergic P2Y Receptor Antagonists pharmacology chemistry MeSH
- Cell Membrane * drug effects metabolism MeSH
- Humans MeSH
- Lipid Bilayers metabolism MeSH
- Membrane Lipids metabolism MeSH
- Receptors, Purinergic P2Y12 * metabolism drug effects MeSH
- Molecular Dynamics Simulation MeSH
- Ticagrelor * pharmacology chemistry MeSH
- Blood Platelets * drug effects metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Cíl: Vliv autoplazmy obohacené o krevní destičky na tloušťku endometria a citlivost receptorů na estrogen a progesteron. Materiál a metody: Do této prospektivní studie bylo zařazeno 200 pacientek. Účastnice studie byly rozděleny do dvou skupin. První, kontrolní skupina dostávala hormonální substituční terapii (HRT – hormone replacement therapy). Druhá, studijní skupina dostávala intrauterinní infuzi autoplazmy obohacené o krevní destičky (PRP – platelet-rich autoplasma). Devatenáctý den menstruačního cyklu bylo provedeno ultrazvukové vyšetření s cílem zhodnotit tloušťku endometria a dále imunohistochemická analýza k stanovení citlivosti receptorů pro estrogen a progesteron. Výsledky: Během studie jsme zjistili, že po podání autoplazmy obohacené o krevní destičky se zvýšila tloušťka endometria o 0,85 mm; průměrná tloušťka endometria ve skupině na terapii PRP byla 8,25 mm (8,25–8,61 mm) a ve skupině pacientek, které dostávaly pouze HRT, byla 7,40 mm (7,34–7,65 mm). Citlivost receptorů pro estrogen se v experimentální skupině zvýšila o 3,5, přičemž v této skupině dosáhla hodnoty 75,00 (71,43–74,22) a v kontrolní skupině 71,50 (67,05–70,85). Citlivost receptorů pro progesteron se zvýšila o 9,0, hodnota v této skupině byla 95,0 (91,4–93,8) a v kontrolní skupině 86,0 (83,47–86,27). Závěr: Díky působení destičkových faktorů má terapie PRP pozitivní vliv na endometrium, kdy zvyšuje jeho tloušťku a zlepšuje receptivitu. Je tedy možné vyvodit závěr, že tato metoda zřejmě nalezne velké praktické uplatnění při zlepšování výsledků programů asistované reprodukce.
Aim: The effect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone. Materials and methods: This prospective clinical study included 200 patients. The participants in the study were divided into two groups. The first control group received hormone replacement therapy (HRT). The second study group received an intrauterine infusion of platelet-rich autoplasma (PRP group). On the 19th day of the menstrual cycle, an ultrasound examination was performed to assess endometrial thickness, as well as an immunohistochemical analysis to determine receptor sensitivity to estrogen and progesterone. Results: In the course of the study, we found that the use of platelet-rich autoplasma increased the thickness of the endometrium by 0.85 mm; the average thickness of the endometrium in the group who received PRP therapy was 8.25 (8.25–8.61) mm; and in the group of patients who only received HRT, it was 7.40 (7.34–7.65) mm. The sensitivity of receptors to estrogen in the experimental group increased by 3.5, in the experimental group it was 75.00 (71.43–74.22), and in the control group it was 71.50 (67.05–70.85). The sensitivity of receptors to progesterone also increased by 9.0, in the experimental group it was 95.0 (91.4–93.8), and in the control group it was 86.0 (83.47–86.27). Conclusion: Due to the action of platelet factors, PRP therapy has a positive effect on the endometrium, increasing its thickness and improving its receptivity. Therefore, it can be concluded that this method can find great practical application to improve the outcomes of assisted reproductive technology programs.
- Keywords
- autoplazma,
- MeSH
- Adult MeSH
- Endometrium * anatomy & histology blood supply pathology MeSH
- Hormone Replacement Therapy methods MeSH
- Immunohistochemistry MeSH
- Humans MeSH
- Infusions, Parenteral * methods MeSH
- Prospective Studies MeSH
- Statistics as Topic MeSH
- Receptors, Steroid MeSH
- Blood Platelets MeSH
- Ultrasonography MeSH
- Organ Size MeSH
- Infertility, Female etiology therapy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Clinical Study MeSH
Zhodnotit prognostickou hodnotu skóre s použitím hodnot hemoglobinu, albuminu, lymfocytů a trombocytů (hemoglobin, albumin, lymphocyte, and platelet, HALP) u akutní plicní embolie (APE). Metody: Retrospektivně jsme vyhodnotili údaje pacientů ve věku 18 let a starších, u nichž CT angiografické vyšetření plic na oddělení urgentního příjmu v období mezi lednem 2019 a lednem 2023 prokázalo APE. Byly vyhodnoceny klinické a demografické údaje pacientů a následně vypočítán zjednodušený index závažnosti jejich plicní embolie. Skóre HALP se vypočítávalo z prvního krevního vzorku odebraného po přivezení pacienta na oddělení urgentního příjmu; přitom se používala rovnice HALP: hemoglobin × albumin × lymfocyty / trombocyty. Výsledky: U 277 pacientů s APE, zařazených do studie, dosáhla nemocniční mortalita hodnoty 19,1 %. Skóre HALP zemřelých pacientů bylo statisticky významně vyšší než skóre přeživších (p < 0,001). Mezní hodnota skóre HALP na křivce ROC pro nemocniční mortalitu byla 3,21 (senzitivita: 81,13 %; specificita: 84,37 %; plocha pod křivkou ROC: 0,879; 95% interval spolehlivosti [confidence interval, CI] 0,827–0,930; p < 0,001). Na základě těchto mezních hodnot byla provedena logistická regresní analýza a multivariační logistická analýza prokázala, že skóre HALP (poměr šancí: 0,24; 95% CI: 0,17–0,96) je nezávislým ukazatelem mortality. Závěr: Zjistili jsme, že skóre HALP, zahrnující čtyři hematologické parametry, může sloužit jako cenný biomarker v predikci nemocniční mortality.
To investigate the prognostic value of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score in acute pulmonary embolism (APE). Methods: We retrospectively evaluated patients aged 18 years and over who were diagnosed with APE by computed tomography pulmonary angiography at the emergency department (ED) between January 2019 and January 2023. The patients' clinical and demographic data were evaluated, and their simplified pulmonary embolism severity index values were calculated. The HALP score was obtained using the first blood sample measured after the patients were admitted to the ED. The HALP score was calculated according to the formula: HALP = hemoglobin × albumin × lymphocytes / platelets Results: The in-hospital mortality rate was 19.1% in 277 patients with APE included in the study. The HALP score of the patients who died was significantly lower than the HALP score of those who survived (p <0.001). The cut-off value of the HALP score on the receiver operating characteristic (ROC) curve for in-hospital mortality was 3.21 (sensitivity: 81.13%; specificity: 84.37%; area under the ROC curve [AUC]: 0.879, 95% confidence interval [CI]: 0.827-0.930, p <0.001). A logistic regression analysis was performed based on these cut-off values, and the multivariate logistic regression analysis revealed that the HALP score (odds ratio: 0.24, 95% CI: 0.17-0.96) was an independent indicator of mortality. Conclusion: Our findings showed that the HALP score, which comprises four hematological parameters, can be a valuable biomarker that can be used to predict in-hospital mortality.
