Značenje reakcija biotransformacija u pojavi idiosinkratskih reakcija lijekova

Osnovna podjela nuspojava na lijekove je na nuspojave tipa A koje nastaju kao posljedica pretjeranog farmakološkog učinka lijeka, te na nuspojave tipa B, odnosno idiosinkratske reakcije. Idiosinkratske reakcije su nepredvidive, odgođene u nastanku, niske učestalosti, ali velike smrtnosti. Čine 10% ukupnih nuspojava na lijekove i predstavljaju veliki problem s obzirom da su posljedice takvih reakcija često opasne po život, a sam mehanizam nastanka nije u potpunosti razjašnjen. Ispitivanja toksičnosti tijekom razvoja novih lijekova pokazala su se neučinkovita u predviđanju lijeka kandidata i njegove povezanosti s pojavom idiosinkratskih reakcija, što ponekad dovodi do povlačenja lijekova s tržišta ili stavljanja oznake upozorenja. Dosadašnja istraživanja pokazuju kako je biotransformacija lijekova u reaktivne metabolite često uzrokom nastanka idiosinkratskih reakcija, stoga postoji potreba za boljim razumijevanjem osnovnih mehanizama koji dovode do stvaranja reaktivnih metabolita. Idiosinkratske reakcije mogu zahvatiti bilo koji organ, no najčešće se manifestiraju na koži, jetri te koštanoj srži, a većina nastaje posredovanjem imunološkog sustava. Pregledom literature iz PubMed citatne baze primjenom ključnih riječi naziv lijeka i idiosinkratske reakcije, prikazani su karakteristični lijekovi i njihova biotransformacija u reaktivne metabolite prema mjestu nastanka idiosinkratske reakcije. Kako je malen broj prikladnih modela za ispitivanje mehanizama nastanka idiosinkratskih reakcija, prilikom razvoja novih lijekova potrebno je razviti strategije za predviđanje takvih reakcija. Moguće strategije su izbjegavanje funkcionalnih skupina koje su podložne biotransformaciji u reaktivne metabolite, praćenje kovalentnog vezanja potencijalnog lijeka za makromolekule ili glutation te pronalazak novih animalnih modela koji bi omogućili bolje razumijevanje mehanizma.Adverse drug reactions (ADR) are conventionally classified into two types – type A reactions that are result of enhanced pharmacological effect, and type B reactions or idiosyncratic drug reactions. Idiosyncratic drug reactions are unpredictable, delayed in onset, low frequency but high mortality. Representing 10% of total ADRs, they remain a big problem considering that the consequences of such reactions are often life-threatening, and the mechanisms are not fully understood. Toxicity testing has been ineffective in the prediction of drug candidates that could be associated with a relatively high incidence of idiosyncratic drug reactions, which sometimes leads to the withdrawal of some drugs from the market or “black box” warnings for others. Previous studies have shown that the biotransformation of drugs to reactive metabolites are often cause of idiosyncratic drug reaction, therefore there is a need for better understanding of the basic mechanisms involved in the formation of reactive metabolites. Idiosyncratic drug reactions can affect any organ, but skin, liver, and bone marrow are the most common targets and most idiosyncratic drug reactions appear to be immune mediated. A literature search of PubMed citation database using the keywords drug and idiosyncratic drug reactions was used in this review. The paucity of animal models makes mechanistic studies very difficult to proceed, so there is a need to develop some screening methods for the idiosyncratic drug reactions. Possible strategies are avoiding functional groups that are susceptible to biotransformation to reactive metabolites, screening of covalent binding to proteins or formation of gluthatione conjugates, and finding new animal models which would allow better understanding of the mechanism

Antithrombotic activity of flavonoids and polyphenols rich plant species

Cardiovascular diseases represent one of the most notable health problems of the modern civilization. Stroke and heart attack often lead to lethal outcome, and essential problem underneath being thrombus formation. Prophylactic approaches include acetylsalicylic acid and clopidogrel therapy on the level of primary hemostasis, i.e., primary clot formation. In the last five years, in the USA, health care expenses related to cardiovascular diseases have increased 50 %, to over 350 billion dollars. Thus, application of plant species and medicinal plants rich in polyphenols in prevention of thrombus formation are of interest. This is supported by the fact that the number of publications on antiaggregatory effect of polyphenols has doubled in the last decade. In this mini-review we focus on antiaggregatory effect of most abundant polyphenols – flavonoids, the effect of plant extracts rich in polyphenols (propolis, species Salvia sp., Calamintha nepeta L., Lavandula angustifolia Mill., Melissa officinalis L, Mentha x piperita L., Ocimum basilicum L., Origanum vulgare L., Rosmarinus officinalis L.) on platelet aggregation, association of chemical composition and antioxidant properties with the observed biological effect, and possible clinical significance of the published results

The Effect of Short-Toothed and Dalmatian Sage Extracts on Platelet Aggregation

Kadulja (Salvia sp.) je rod mediteranskih biljaka koji se koristi za aromatiziranje hrane. U ovom su radu ispitani ukupni udjel polifenola, antioksidacijska svojstva i antitrombocitni učinak kratkozupčaste kadulje (Salvia brachyodon Vandas), te su uspoređeni s najčešće korištenom vrstom kadulje (S. officinalis, tj. dalmatinska kadulja). Udjel ukupnih flavonoida iznosio je 0,08-0,23 %, a fenolnih kiselina 0,47-3,04 %. Antioksidacijska aktivnost kratkozupčaste kadulje, ispitana pomoću DPPH testa, bila je izraženija (29-36 mg/mL ekvivalenata galne kiseline) od aktivnosti dalmatinske kadulje. U funkcionalnom testu primarne hemostaze, ekstrakt kratkozupčaste kadulje nanomolarne koncentracije od 21 nM spriječio je agregaciju trombocita, čime je potvrđeno da se može upotrijebiti za prevenciju tromboze, i to kao funkcionalna hrana ili nadomjestak prehrani. Antitrombocitna aktivnost povezana je s antioksidacijskim kapacitetom (r=0,7014, p=0,0352), što upućuje na zaključak da na prevenciju agregacije ne utječe samo jedan spoj, već je to rezultat sinergističkog učinka polifenola. Dobiveni rezultati su preliminarni i zahtijevaju detaljnije ispitivanje moguće primjene navedenih biljnih vrsta u svrhu prevencije kardiovaskularnih bolesti i agregacije trombocita.Sage (Salvia sp.) is a genus of a native Mediterranean plant used for aromatization of foods. In this study, total polyphenolic profile, antioxidant properties and antiplatelet effect of short-toothed sage (Salvia brachyodon Vandas) are analyzed and compared to most commonly used Salvia species (S. officinalis, Dalmatian sage). Content of total flavonoids was 0.08-0.23 % and of phenolic acids 0.47-3.04 %. Antioxidant DPPH assay showed higher antioxidant capacity of S. brachyodon (29-36 mg/mL of gallic acid equivalents) than of S. officinalis. In functional test of primary haemostasis, extracts of S. brachyodon have prevented platelet aggregation in nanomolar concentration (21 nM), thus showing potential in prevention of thrombus formation as functional food or dietary supplement. Antiplatelet activity was related to antioxidant capacity (r=0.7014, p=0.0352) indicating that prevention of aggregation is not caused by an individual component, but it is rather a result of synergistic effect of polyphenols. The obtained results are preliminary and a more detailed study of the possibility of applying the investigated plant species as supplements for the prevention of the problem of cardiovascular system and platelet aggregation is needed

Značenje reakcija biotransformacija u pojavi idiosinkratskih reakcija lijekova

Idiosyncratic drug reactions (IDRs) are rare, dose independent adverse drug reactions. Although non-predictable they are not idiopathic and their causes can be rationalized. Drugs susceptible to IDRs usually undergo extensive metabolism. Most common cause of IDRs are reactive metabolites generated through drug biotransformation. In this paper an overview of drugs susceptible to IDRs is given, based on effected organs. IDRs on skin are illustrated with metabolism phenytoin and nevirapine. Hematological IDRs are exemplified with clozapine and felbamate. Hepatotoxicity related to IDRs is explained on valproic acid, troglitazone and ximelagatran. Among strategies on how to reduce occurrence of IDRs include avoidance of specific functional groups (toxicophores) present a viable option

The Effect of Short-Toothed and Dalmatian Sage Extracts on Platelet Aggregation

Sage (Salvia sp.) is a genus of a native Mediterranean plant used for aromatization of foods. In this study, total polyphenolic profile, antioxidant properties and antiplatelet effect of short-toothed sage (Salvia brachyodon Vandas) are analyzed and compared to most commonly used Salvia species (S. officinalis, Dalmatian sage). Content of total flavonoids was 0.08-0.23 % and of phenolic acids 0.47-3.04 %. Antioxidant DPPH assay showed higher antioxidant capacity of S. brachyodon (29-36 mg/mL of gallic acid equivalents) than of S. officinalis. In functional test of primary haemostasis, extracts of S. brachyodon have prevented platelet aggregation in nanomolar concentration (21 nM), thus showing potential in prevention of thrombus formation as functional food or dietary supplement. Antiplatelet activity was related to antioxidant capacity (r=0.7014, p=0.0352) indicating that prevention of aggregation is not caused by an individual component, but it is rather a result of synergistic effect of polyphenols. The obtained results are preliminary and a more detailed study of the possibility of applying the investigated plant species as supplements for the prevention of the problem of cardiovascular system and platelet aggregation is needed

Mogu li biljni pripravci propolisa i ginkga smanjiti hiperreaktivnost trombocita u bolesti COVID-19?

Propolis is flavonoid rich source that has shown numerous beneficial biological effects such as antibacterial, antiviral, antitumoral, antiaggregatory, and hepatoprotective. Ginkgo has been used as a dietary supplement for enhancement of cognitive functions. The aim of this study was assessment of the effect of propolis and ginkgo extracts on primary hemostasis and verify whether the use of a combination of propolis and ginkgo extracts in the prevention of cardiovascular diseases is justified. Commercially available extracts were assessed by impedance aggregometry on the whole blood samples of healthy subjects collected at the Croatian Institute of Transfusion Medicine. Two aggregation inducers were used: ADP (adenosine diphosphate, weak agonist of platelet aggregation) and TRAP (hexapeptide surrogate of thrombin, strong inducer of platelet aggregation). In an ADP induced aggregation assay, propolis showed an antiaggregatory effect at a concentration of 10 μM. In the same test, the antiplatelet effect of ginkgo extract was absent. In the hexapeptide-induced thrombin mimetic (TRAP) aggregation test, propolis showed an antiplatelet effect at a concentration of 20 μM as well as ginkgo extract. Combinations of propolis and ginkgo in a ratio of 1:25 and 1:50 showed an antiplatelet effect at 20 μM concentrations of extracts. Combination of propolis and ginkgo is justified from a pharmacodynamic aspect, as propolis and ginkgo have different mechanisms of action because they act on different signaling pathways of aggregation

Invasion of Caulerpa racemosa var. cilindrica (Caulerpales, Chlorophyta) in the Mediterranean Sea: an assessment of the spread

Peer reviewe

Invasion of Caulerpa racemosa var. cylindracea (Caulerpales, Chlorophyta) in the Mediterranean Sea: an assessment of the spread

Peer reviewe

Propolis ethanolic extracts reduce adenosine diphosphate induced platelet aggregation determined on whole blood

Abstract Background Propolis is a well-known bee product containing more than 2000 identified compounds. It has many beneficial effects on human health that include antibacterial, antiviral, anticancer and hepatoprotective justifying its use as a dietary supplement. Platelet aggregation plays crucial role in thrombus formation that can cause stroke or heart attacks. As cardiovascular diseases, including those caused by thrombus formation, are related to 50% of deaths of Western population, the objective of this study was to determine antiaggregatory activity of propolis on platelet aggregation on the whole blood samples. Methods Twenty one propolis samples from Southeast Europe were characterized by spectrophotometric methods to determine content of the total flavonoids and phenolic acids. High performance liquid chromatography coupled with diode array detection was used to identify and quantify individual polyphenols. Platelet aggregation was tested by impedance aggregometry on the whole blood samples of ten healthy volunteers. Results The mean content of total polyphenols was 136.14 mg/g and ranged from 59.23 to 277.39 mg/g. Content of total flavonoids ranged between 6.83 and 55.44 mg/g with the mean value of 19.28 mg/g. Percentage of total phenolic acids was in the range 8.79 to 45.67% (mean 26.63%). Minimal antiaggregatory concentration, representing the lowest concentration of propolis extract sample that can cause statistically significant reduction of aggregation, ranged from 5 μM to 10.4 mM. Samples of propolis with lower content of luteolin and higher content of pinocembrin-7-methyleter showed better antiplatelet activity i.e. lower values of minimal antiaggregatory concentration. Conclusions This is the first study that shows antiaggregatory potential of propolis ethanolic extracts on the whole blood samples in the low micromolar concentrations suggesting that propolis supplementation may influence platelet aggregation and consequently thrombus formation. Further in vivo studies are needed to confirm the beneficial effects in prevention of cardiovascular diseases