Abiainete kasutamine vastsündinutele manustatavates ravimites Euroopas

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Abiained on vajalikud erinevate ravimvormide disainimiseks ja väljatöötamiseks. Neil on ravimites erinevaid funktsioone, mis võimaldavad tehnoloogiliselt ravimvormide valmistamist ja parandavad nii toimeaine (stabiilsus, biosaadavus) kui ka lõpliku ravimvormi omadusi (stabiilsus, maitseomadused jt.). Arvestades ainevahetuse iseärasusi, on teatud abiainete kasutamisega seotud riskid enam väljendunud vastsündinutel. Enam kui tuhandest kasutusel olevast abiainest on kõrvaltoimeid vastsündinutel kirjeldatud vaid üksikutel – parabeenid, polüsorbaat 80, propüleenglükool, etanool, bensoehape, naatriumbensoaat, bensüülalkohol, sorbitool, naatriumsahhariin ja bensalkooniumkloriid. Käesolevas töös keskendusime nende potentsiaalse ohtlikkuse seisukohalt enim huvi pakkuvate abiainete (excipients of interest, EOI) kasutuse uurimisele. Meie töö eesmärkideks oli iseloomustada ravimites olevate EOI kasutamise ulatust Euroopa vastsündinute osakondades, s.h. hinnata uuringumetoodika mõju saadud tulemustele, leida EOI manustamisega seotud riskifaktorid ning hinnata ravimite asendamise võimalusi vältimaks EOI manustamist vastsündinutele. Viisime Euroopa vastsündinute osakondades läbi 3-päevase küsimustik- (service evaluation survey, SES) ja ühepäevase hetklevimusuuringu (point prevalence study, PPS). Kahe uuringu metoodika hea omavaheline korrelatsioon andis võimaluse kasutada kogutud tulemusi teineteist täiendavana. Kokku osales SES ja PPS uuringus vastavalt 20 ja 21 Euroopa riiki 115 ja 89 osakonnaga. SES registreeriti 313 toimeainet, mida manustati 1065 erineva ravimpreparaadina. PPS 726-le vastsündinule registreeriti 2199 ravimikorraldust. Kolmandik ravimitest sisaldasid vähemalt ühte EOI; kaks kolmandikku vastsündinutest said nendest vähemalt ühte. Uuritavate demograafilistele parameetritele ja aktiivainete struktuurile tasakaalustatud regressioonanalüüsis leidsime erinevused Euroopa regioonide vahel. Siit järeldasime, et on võimalik asendada ühes riigis kasutatava EOI sisaldav ravimpreparaat teises riigis kasutusel oleva EOI-vaba analoogiga. Leidsime, et ainuüksi sageli kasutatavate ravimite asendamine vähendaks kõigi EOI saavate vastsündinute arvu peaaegu poole võrra. Euroopa vastsündinutele manustatakse sageli EOI, kusjuures alati pole see tegelikult hädavajalik. Olemasolevate asendamisvõimaluste rakendamine säästaks paljud vastsündinud ebavajalikust ekspositsioonist.Pharmaceutical excipients are essential components of medicines necessary to maintain quality and patient acceptability. Due to organ immaturity there is a higher risk of adverse effects associated with the administration of excipients in neonates compared to adults. While thousands of excipients are in use, only some have been associated with the toxicity in neonates – excipients of interest (EOI). In this work EOI included parabens, polysorbate 80, propylene glycol, ethanol, benzoic acid, sodium benzoate, benzyl alcohol, sorbitol, saccharin sodium and benzalkonium chloride. We aimed to describe the scale of neonatal exposure to EOI in Europe, to identify factors related to EOI administration and explore the opportunity of product substitution to reduce exposure to EOI. We conducted a 3-day questionnaire (service evaluation survey, SES) and a 1-day point prevalence study (PPS). We showed a high correlation in the frequency of medicine use between the two methods. The choice of method in future studies depends on the research question, whether priority is given to a more comprehensive list of products (SES) or individual exposure data (PPS). Altogether 20 and 21 countries with 115 and 89 units participated in the SES and PPS, respectively. In the SES 313 active pharmaceutical ingredients (APIs) representing 1065 products were registered. In the PPS 726 neonates received 2199 prescriptions. One third of products contained EOI and two thirds of the neonates were administered at least one of them. We found regional variations in the administration of some EOI. This indicates possibilities to use EOI-free products available in one but not another country. Substitution of only the most frequently used products would reduce the overall number of exposed neonates almost by a half. In conclusion, EOI are not rare in medicines used in European neonatal intensive care units, whereas EOI-free products available on the European market allow to reduce neonatal exposure to EOI substantially

Krüptorhismi esinemissagedus Eestis

Eesti Arst 2022; 101(8):44

High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement. METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis. RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics – gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin – covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations. CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12887-015-0359-y) contains supplementary material, which is available to authorized users

Posterioorse reversiibelse entsefalopaatia sündroom (PRES): kirjanduse ülevaade ja kahe haigusjuhu kirjeldus

3aastasel ägeda lümfoblastleukeemia ja 5aastasel osteomüeliidi ning septilise šokiga lapsel tekkisid põhihaiguse ravikuuri ajal teadvushäired ja krambid, mille põhjuseks oli posterioorse reversiibelse entsefalopaatia sündroom (PRES). PRES on tänapäeval sagenev tüsistus kriitiliselt haigete, eriti ägeda leukeemiaga laste induktsioonravil. Soodustavaks teguriks neurotoksilise seisundi väljakujunemisel võib olla arteriaalne hüpertensioon või neerupuudulikkus. Nüüdisaegsed neuroradioloogia meetodid võimaldavad kinnitada PRESi diagnoosi, välistada neuroloogilise leiu muid põhjusi, alustada õigeaegset ravi ja vältida pöördumatute ajukahjustuste väljakujunemist. Eesti Arst 2010; 89(3):191−19

Potentially harmful excipients in neonatal medicines: a pan-European observational study

OBJECTIVES We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. METHODS All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. RESULTS Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. CONCLUSIONS European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients