<p>Uprkos opšte prihvaćenom stavu da u trudnoći lekove treba izbegavati, veliki broj trudnica tokom trudnoće uzima lekove sa manje ili više opravdanja. Primena lekova u trudnoći zahteva dodatnu patnju, jer se mora voditi računa o zdravlju majke i zdravlju još nerođenog deteta. Većina lekova koji nalaze primenu u trudnoći, nisu ispitani u kontrolisanim studijama na trudnicama, već se njihov uticaj naljudski fetus, bazira na predpostavkama i kliničkim istraživanjima na životinjama. Odsustvo studija dovodi do toga da se trudnicama obično prepisuju lekovi u dozi za odrasle osobe, koje ne prate fiziološke promene u trudnoći. Tokom trudnoće u telu trudnica dolazi do promena u funkciji organa i organskih sistema, a zbog nastalih promena menja se i sudbina leka u organizmu. Sistemske bolesti trudnice poput hipertenzije i dijabetesa dovode do hemodinamskih promena i utiču na nastanak patoloških promena posteljice, što sve zajedno menja farmakokinetiku lekova i njihov transplacentrarni transport. Ukupno 75 trudnica je uključeno u studiju i podeljeno u tri grupe: zdrave trudnice-kontrolna grupa (n=31), trudnice sa hipertenzijom (n=30) i trudnice sa dijabetesom (n=14). Sve trudnice su u premedikaciji primile iste lekove koji su deo standardne kliničke procedure. Trudnice su primile jednu dozu diazepama intramuskularnom injekcijom (10mg/2ml), a intravenski su primile pojedinačne doze cefuroksima (1,5g), metoklopramida (10mg/2ml) i ranitidina (50mg/2ml). Od svakog para majka-dete ukupno je analizirano po 5 uzoraka. Uzorci krvi od majke uzimani su u tri vremenske tačke: nakon davanja leka, u momentu ekstrakcije deteta i nakon porođaja. Uzorci krvi deteta uzimani su nakon porođaja iz pupčane vene i arterije. Prikupljeni uzorci plazme analizirani su metodom tečne hromatografije visokih performansi (HPLC). Istraživanje je pokazalo da lekovi primenjeni u premedikaciji carskog reza prolaze transplacentarnu membranu i da se ni jedan od lekova primenjenih u studiji nije akumulirao u fetusu i nije imao neželjeno dejsvo na novorođenče. Cefuroksim, ranitidin i metoklopramid pokazali su nizak feto-maternalni transfer, dok je diazepam pokazao visok feto-maternalni transfer. Izmerene koncentracije cefuroksima u plazmi trudnica u momentu porođaja bile su ≥8 μg/ml, što je koncentracija veća od MIC za većinu patogena odgovornih za nastavak infekcija u akušerstvu. Koncentracije cefuroksima u fetalnoj plazmi bile su ≥4μg/ml što je veće od MIC koncentracija za veliki broj patogena. Gestacijska starost trudnoće nije uticala na obim prolaska cefuroksima kroz placentu, koji je prolazi uglavnom pasivnom difuzijom. Farmakokinetski parametri cefuroksima razlikovali su se kod hipertenzivnih i dijabetičnih trudnica, u odnosu kontrolnu grupu, ali ove bolesti nisu imale značajan uticaj na smanjenje terapijske efikasnosti cefuroksima. Farmakokinetika cefuroksima kod hipertenzivnih trudnica ukazala je na bržu eliminaciju cefuroksima iz krvi majke i na veću distribuciju leka u okolna tkiva. U dijabetičnoj grupi trudnica i novorođenčadi koncentracije cefuroksima su bile više u odnosu na druge ispitivane grupe, dok je feto-maternalni odnos bio niži, što ukazuje na postojanje strukturalne i funkcionalne pomenu posteljice u dijabetesu. Hipertenzija i dijabetes trudnica nisu imali uticaj na prodor ranitidina kroz placentu. Hipertenzija i dijabetes trudnica nisu uticali na većinu farmakokinetskih parametara ranitidina, mada je zabeleženo smanjenje volumena distribucije u ovim grupama trudnica, što bi moglo da ukazuje na njihovu hemodinamsku nestabilnost i povećanje slobodne frakcije ranitidina. Koncentracija metoklopramida bila veća u krvi majki u odnosu na krv fetusa. Transport metoklopramida iz fetusa ka majci bio je dominantniji, a naročito u hipertenzivnoj i dijabetičnoj grupi trudnica. Hipertenzija i dijabetes trudnica uticali su na zadržavanje metoklopramida u fetusu. Koncentracije dijazepama u majčinoj i fetalnoj krvi bile su više u kontrolnoj i hipertenzivnoj grupi trudnica. Hipertenzija i dijabetes trudnica povećavaju transfer diazepama kroz placentu, povećanjem koncentracije slobodnih masnih kiselina, steroidnih hormona, smanjenjem vezivnog kapaciteta potencijalna opasnost od neželjenog dejstva diazepama i njegovih metabolita na fetus i novorođenče. Ova doktorska studija ukazuju na potrebu obimnijih farmakokinetskih istraživanja kako na zdravim tako i na bolesnim trudnicama, koja će dati zaključke utvrđene na dokazima i pomoći u individualnom terapijskom pristupu svakoj trudnici.</p> / <p>In spite of the widespread opinion that drugs should be avoided in pregnancy, a great number of pregnant women take drugs with more or less justification. Administration of drugs in pregnancy requires additional attention because the health of both the mother and her unborn child must be protected. Majority of drugs administered in pregnancy have not been tested within the controlled studies performed on pregnant women, but their effect on the human foetus is based on assumptions and clinical trials performed on animals. This absence of studies results in the situation that pregnant women are usually prescribed drugs in a dose for adults, which does not take into account the physiological changes happening in pregnancy. During pregnancy, the pregnant woman’s body undergoes changes in the<br />functions of organs and organ systems. These changes further affect the destiny of a drug in the organism. In pregnant women, systemic diseases such as hypertension and diabetes mellitus lead to hemodynamic changes and cause pathological changes in placenta, thus changing the pharmacokinetics of drugs and their transplacental transport. The study sample consisted of 75 pregnant women, who were divided into three groups as follows: the control group included healthy pregnant women (n=31), a group of pregnant women with hypertension (n=30) and a group of those with diabetes mellitus (n=14). All of them were administered the same drugs as a part of standard clinical procedure in premedication. The pregnant women received a single dose of diazepam by intramuscular injection (10mg/ml), and individual doses of cefuroxime (1.5mg), metoclopramide (10mg/2ml) and ranitidine (50mg/2ml). Five samples taken from each mother-infant pair were analyzed. Blood samples were taken from the mother three times: after drug administration, at the moment of extraction of baby and after delivery. Baby’s blood samples were taken from the umbilical cord vein and artery after delivery. Plasma samples were analyzed by the method of high-performance liquid chromatography (HPLC). The research has shown that drugs administered in premedication of caesarean section went through the transplacental membrane and that none of the tested drugs accumulated in the foetus and had an adverse effect on the newborn. Cefuroxime, ranitidine and metoclopramide were shown to have a low transfer between the mother and her foetus, whereas diazepam showed a high foetal-maternal transfer. Cefuroxime concentrations measured in the pregnant woman’s and foetal plasma at the moment of delivery were ≥8μg/ml and ≥4μg/ml, respectively, that being above the minimum inhibitory concentration (MIC) for most pathogens responsible for the development of infection in obstetrics. Gestational age had no effect on the range of cefuroxime flow through the placenta, which happens mostly by passive diffusion. Pharmacokinetic parameters of cefuroxime differed in the pregnant women having hypertension and diabetes mellitus from the controls; however, these diseases did not significantly reduce the therapeutic efficacy of cefuroxime. Pharmacokinetics of cefuroxime indicated faster elimination of cefuroxime into the maternal blood and greater distribution of the drug into the surrounding tissues in the hypertensive pregnant women. In the group consisting of pregnant women and newborns having diabetes, the cefuroxime concentrations were higher than in other groups, whereas foetal-maternal relation was lower, which suggests the presence of structural and functional change in the placenta in diabetes. Hypertension and diabetes mellitus had no affect either on the flow of ranitidine through the placenta in the pregnant women or on the majority of pharmacokinetic parameters of ranitidine, although a certain reduction in the volume of distribution was recorded in these groups of pregnant women, which could suggest their hemodynamic instability and increased free fractions of ranitidine. The concentration of metocloporamide was higher in the maternal blood than in the foetal blood, and the transport of metocloporamide from the foetus towards the mother was more dominant, particularly in the group of hypertensive and diabetic pregnant women. Metoclopramide tended to retain in the foetuses of mothers having hypertension and diabetes. The concentrations of diazepam in maternal and foetal blood were higher in the controls and hypertensive pregnant women. Hypertension and diabetes in pregnant women increase the transfer of diazepam through the placenta by increasing the concentration of free fatty acids and steroid hormones and by reducing the binding capacity of carrier proteins and the concentration of plasma proteins, thus increasing the potential danger of adverse effects of diazepam and its metabolites on the foetus and the newborn. This doctoral study suggests the necessity for more extensive pharmacokinetic research including both healthy and affected pregnant women that would lead to conclusions based on evidence and help to develop individual therapeutic approach to each pregnant woman.</p>
| Identifer | oai:union.ndltd.org:uns.ac.rs/oai:CRISUNS:(BISIS)87796 |
| Date | 31 October 2014 |
| Creators | Paunković Jovana |
| Contributors | Grujić Zorica, Mikov Momir, Milašinović Ljubomir, Perišić Živko, Tomić Zdenko, Sabo Ana, Vasović Velibor |
| Publisher | Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, University of Novi Sad, Faculty of Medicine at Novi Sad |
| Source Sets | University of Novi Sad |
| Language | Serbian |
| Detected Language | Unknown |
| Type | PhD thesis |
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