Dušanka Krajnović

From experimental design to quality by design in pharmaceutical legislation

Quality by design (QbD) is a concept first outlined by Juran, who believed that quality could be planned and that most quality crises and problems relate to the way in which quality was planned in the first place. Experimental design is a powerful technique and tool for QbD, used for exploring new processes, gaining increased knowledge of the existing processes and optimizing these processes for achieving internationally competitive performance. It is also used for the investigation of relationship between parameters of ill-defined process. In this paper, the experimental design principles in pharmaceutical development and impact of these principles on pharmaceutical legislation have been reviewed. Also, slow implementation of QbD in pharmaceutical industries has been discussed. Pharmaceutical legislation is necessary for companies to continue benefiting from knowledge gained and to continually improve throughout the process lifecycle by making adaptations to assure that root causes of manufacturing problems are quickly corrected.

Validity of the Food Frequency Questionnaire Assessing the Folate Intake in Women of Reproductive Age Living in a Country without Food Fortification: Application of the Method of Triads

The study aimed to examine the external validity of the Folate Food Frequency Questionnaire (F-FFQ) designed for assessing the folate intake in Serbian women of reproductive age. The F-FFQ was tested against repeated 24 h dietary recalls and correspondent nutritional biomarkers (red blood cells (RBC) and serum folate concentrations) using the method of triads. In a cross sectional study, 503 women aged 18–49 years completed dietary questionnaires and representative validation subsample (n = 50) provided fasting blood samples for biomarker analyses. Correlation coefficients were calculated between each of the dietary methods and three pair-wise correlations were applied for the calculation of validity coefficients. Correlation coefficients observed between F-FFQ and three 24 h recalls were r = 0.56 (p < 0.001) and r = 0.57 (p < 0.001) for total sample and validation group, respectively. Bland–Altman plot and cross-classification analyses indicated good agreement between methods. High validity coefficients were determined between the true intake (I) and dietary assessment methods, F-FFQ (Q) and 24 h dietary recalls (R) (ρQIrbc = 0.871 and ρQIser = 0.814; ρRIrbc = 0.652 and ρRIser = 0.698), and moderate ones for biomarkers (B) (ρBIrbc = 0.428 and ρBIser = 0.421). The F-FFQ is valid instrument for the assessment of dietary folate intake in women living in Serbia, a country without mandatory folic acid food fortification.

Mechanism of Action, Efficacy and Safety of Emergency Hormonal Contraception (levonorgestrel and ulipristal acetate) and Attitudes of Pharmacists

Summary Emergency hormonal contraception is used to prevent unintended pregnancy postcoitally. The mechanism of action of the most frequently used hormonal preparations for emergency contraception, levonorgestrel (LNG) and ulipristal acetate (UPA), is still not fully known, but clinical trials indicate that they act by inhibiting or delaying ovulation. LNG has a long history of use for emergency contraception, proven safety and high efficacy if administered in the preovulation period. The newest emergency contraceptive, UPA, available only with a prescription, is indicated within this period of 120 hours after sexual intercourse and the data indicate that UPA does not lose efficacy within this period. Clinical trials showed its noninferiority versus LNG and its effect on the potentially occurring pregnancy is being additionally monitored. However, many misconceptions and controversial opinions about emergency contraception are still present, even among pharmacists. A search of Medline database identified 20 papers published from January 1993 to December 2012, on pharmacists’ knowledge, attitudes and practices related to emergency contraception. In these papers, the attitudes of pharmacists pertaining to the dispensing regime of emergency contraception were different. Research in Australia has shown that personal attitudes and religious convictions influence the practice of dispensing emergency contraception. In the research conducted in New Mexico, 30% of pharmacists were against prescribing emergency contraception for religious or moral reasons. There were no published data in regards to pharmacists’ knowledge, attitudes and dispensing practice in Serbia and such research is highly recommended. Sažetak Hitna hormonska kontracepcija se koristi za sprečavanje neželjene trudnoće postkoitalno. Mehanizam dejstva najčešće korišćenih preparata hitne kontracepcije, levonorgestrela (LNG) i ulipristal-acetata (UPA) još uvek nije u potpnosti poznat, ali klinička ispitivanja ukazuju da je u pitanju inhibicija ili odlaganje ovulacije. Za hitnu kontracepciju dugo se koristi LNG, jer ima dokazanu bezbednost i visoku efikasnost, ukoliko se primeni u periodu pre ovulacije. Najnoviji preparat iz ove grupe, UPA, koji se izdaje samo na recept, može se primeniti u periodu od 120 sati nakon seksualnog odnosa. U kliničkim ispitivanjima se nije pokazao lošijim u odnosu na LNG, a njegov uticaj na eventualno nastalu trudnoću se dodatno prati. Podaci ukazuju na činjenicu da UPA ne gubi na efikasnosti u periodu od 120 sati. Međutim, prisutne su mnoge zablude i kontroverzna mišljenja o hitnoj kontracepciji, čak i među farmaceutima. Pretraživanjem Medline baze podataka nađeno je 20 radova objavljenih u periodu od januara 1993. do decembra 2012. godine koji razmatraju znanje, stavove i praksu farmaceuta u vezi sa hitnom kontracepcijom. U ovim radovima se stavovi farmaceuta razlikuju po pitanju režima izdavanja hitne kontracepcije. Istraživanje u Australiji pokazalo je da lični stavovi i religijska uverenja utiču na način izdavanja hitne kontracepcije. U istraživanju u Novom Meksiku 30% farmaceuta je bilo protiv propisivanja hitne kontracepcije iz religioznih ili moralnih razloga. Među pronađenim radovima nije bilo podataka o istraživanjima iz Srbije. Preporuka je da se sprovedu istraživanja o znanju, stavovima i praksi farmaceuta u vezi sa hitnom hormonskom kontracepcijom u Srbiji.

Pharmacy network and access to medicines in selected eastern European countries: comparative analysis.

Aim To analyze the pharmacy network (structure and resources) in Bulgaria, Croatia, Serbia, and Slovenia and its relation to public expenditures for medicines. Methods We performed a cross-sectional study using the officially published data for the period 2003-2008 in four selected countries. Data sources were relevant national institutions. Results In 2008, Serbia had 27.5, Bulgaria 66.8, Croatia 59.5, and Slovenia 71.2 pharmacists per 100 000 inhabitants. There was a significant difference in the number of pharmacists per 100 000 inhabitants between all countries except between Bulgaria and Slovenia. The number of inhabitants per one pharmacy was significantly different between all observed countries. The expenditures for medicines per capita in 2008 were between €30.34 in Bulgaria to €137.03 in Slovenia, with a significant difference between all countries except between Bulgaria and Serbia. The number of pharmacists per 100 000 inhabitants and expenditures for medicines per capita were positively correlated in all observed countries, except in Bulgaria. Conclusion There were significant difference in the structure and availability of the pharmacy service in all selected countries. Expenditures for medicines were positively correlated with the number of pharmacists in all countries, except in Bulgaria. Our findings could be valuable to national regulatory bodies for the creation of national drug policies.

Serbian gynecologists’ and pharmacists’ beliefs about emergency contraception

ABSTRACT Emergency contraception (EC) in Serbia is available in two products: Levonorgestel, which has nonprescription status, and Ulipristal acetate, which is a prescription-only medicine. Considering their dispensing statuses, gynecologists and pharmacists are health care professionals (HCPs) with the widest impact on EC use. Yet little is known about their beliefs and practices regarding these medicines. We surveyed 166 gynecologists (during October 2012—October 2013) and 452 community pharmacists (during January–April 2014). Results showed significant differences between these two groups, suggesting that provision of EC to users may be inconsistent. Gynecologists were more convinced than pharmacists that EC would reduce the abortion rate (86% versus 53%, p < .001). However, they were more concerned than pharmacists that easy access to EC would cause less regular contraceptive use (66% versus 29%, p < .001) and risky sexual behaviors, including initiating sexual activity at a younger age (37% versus 19%, p < .001) and having more sexual partners (33% versus 12%, p < .001). Additionally, more pharmacists than gynecologists (12% versus 2%, p < .001) said they would not provide EC to anyone under any circumstance, even to victims of sexual assault. These results indicated a need for reevaluating and establishing official guidelines for dispensing practices.

Serbian gynaecologists ' views on contraception and abortion

Abstract Objectives To examine Serbian gynaecologists’ attitudes and practices related to contraception and abortion, as the principal alternative to contraception. Methods A self-reported questionnaire was administered to a convenience sample of gynaecologists attending educational meetings of a medical society from October 2012 to October 2013. The data gathered were assessed by means of univariate and multivariate analyses. Results Almost half of the respondents had ethical objections and would refuse to provide certain contraceptives to patients. Two thirds of the gynaecologists (63%) considered fertility awareness methods to be a poor option for most women. Twenty-three percent objected to abortion. Those who objected to contraceptives were less likely to object to abortions (OR: 0.422). This attitude was more prevalent in Southern and Eastern Serbia, where gynaecologists were more likely to object (OR: 4.892) and to refuse to prescribe contraceptives (OR: 4.161), but less likely to object to abortion (OR: 0.278) than in other regions. Conclusions A large proportion of Serbian gynaecologists objected to some contraceptive methods and were more in favour of abortions, especially in the least developed regions. Chinese Abstract 摘要 目的：调查塞尔维亚妇产科医生对避孕以及避孕的主要替代方式-流产的态度和行为。 方法：一项自我报告的调查问卷发放给参加2012年10月到2013年10月医学会教育会议的妇产科医生。收集的数据采用单因素及多因素分析。 结果：几乎一半的受访者有伦理上的异议，并拒绝提供某些避孕药给患者。三分之二的妇产科医生（63%）认为生育意识的方法对大多数妇女来说为低劣的选择。20%的妇产科医生反对流产。那些反对避孕药的妇产科医生往往不反对流产（OR：0.422）。这种态度在塞尔维亚南部和东部更为普遍，相比其他地区，这些区域的妇产科医生更可能反对（OR：4.892）和拒绝（OR：4.161）开具避孕药的处方，但不太可能反对流产（OR：0.278）。 结论：很大比例的塞尔维亚妇产科医生反对某些避孕方法，而更喜欢流产，尤其是在最不发达的地区。

Undiagnosed Hyperglycaemia and Hypertension as Indicators of the Various Risk Factors of Future Cardiovascular Disease Among Population of Serbian Students

Summary A number of risk behaviours, such as smoking, overweight, excessive alcohol intake, insufficient physical activity, excessive and frequent intake of salt, reduced fruit and vegetable intake, increased fat intake, which constitute living habits of an individual can influence the occurrence of hypertension and hyperglycaemia. The changing of these lifestyles can reduce the risk of developing prehypertension and prediabetes. The survey was conducted at student’s campuses. The respondents were subjected to the height, weight, blood glucose and blood pressure. Respondents filled in previously created questionnaire that was approved by the Ethics Committee for Biomedical Research Faculty of Pharmacy, University of Belgrade. The percentage of respondents with a glucose value above the reference value was 14.6% (n=19), 2.4% (n=3) had values greater than 7 mmol/L without being diagnosed with diabetes, and accordingly, 2.4% (n=3) had elevated HbA1c values (above 42 mmol/mol or 6.0%). The percentage of respondents with elevated systolic and diastolic blood pressure was 14.9% and 7.4% respectively. Regarding calculated risk scores, they showed parallel increase with increas-ing of BMI (HPS), systolic and diastolic pressure (OHS), and glucose concentration (OPS). When analysing all the factors that could cause the later development of diabetes, which is associated with hypertension as well, it is observed that the student population is very much exposed to those factors. The results of this study cannot be representative for the general population of students, but they can provide recommendations for further research.

Understanding of Information about Medicines Use among Parents of Pre-School Children in Serbia: Parental Pharmacotherapy Literacy Questionnaire (PTHL-SR)

Parental health literacy plays an important role in children’s health. Experiences from pharmacy practice show that is necessary to check if parents understand instructions about use of medicines for children. This study aimed to assess pharmacotherapy literacy of parents of pre-school children and to examine association of parental pharmacotherapy literacy level with parent’s socio-demographic characteristics. The study was cross-sectional, conducted among parents of pre-school children (1–7 years of age), in kindergartens in several municipalities of Belgrade, Serbia, during regular parents meetings, from May to October 2016. Functional health literacy was measured by the Serbian version of the Short Test of Functional Health Literacy in Adults (S-TOFHLA). Parental pharmacotherapy literacy was assessed with newly constructed PTHL-SR questionnaire with good psychometric characteristics (Parental pharmacotherapy literacy questionnaire—Serbian). Overall, 813 parents participated in the study, mostly females (81.30%), between 30 to 40 years of age (70.85%) with two children (56.70%). Almost all of our study participants (99%) had adequate health literacy as assessed by S-TOFHLA. Mean score on PTHL-SR was 72.83% (standard deviation was 13.37), with better results among females than males (72% of women were in the group of highest PTHL-SR results). Our study showed that many parents (76.5%) knew the appropriate usage of non-prescription medicine for children, 57.2% parents were able to correctly calculate the dose of oral syrup for a child, and only 43.3% were able to interpret non-prescription dosage information written on the package. The majority of parents (61.3%) would make a dosage to child based on age and not on their weight. Every fifth parent with adequate functional health literacy measured by S-TOFHLA test, achieved the lowest results measured by PTHL-SR. Higher performance of the PTHL-SR was significantly correlated with education (p < 0.001), female sex (p < 0.001), married parents and those living in common-law (p < 0.001), older parents (p < 0.05) and parents who have more children (p < 0.05), and are non-smokers (p < 0.05). These results provide evidence that limitations in understanding common information about use of medicines are widespread among parents of pre-school children and encourage efforts for further investigation. PTHL-SR questionnaire may be a useful tool for identification of parents who need more instructions and assistance from healthcare providers, above all in providing better communication, written or spoken at community pharmacy settings.

Ethical Considerations in Research Involving Dermal and Transdermal Drug Delivery

Addressing ethical questions related to research studies involving dermal and transdermal drug delivery is very important and can be extensive and related to the vulnerable subjects as participants, research protocols in poor-resources countries, cultural difficulties toward skin and animal testing, bioengineered skin surrogates or difficulties to obtain human skin samples.

Seventy Years of Biochemical Subjects’ Development in Pharmacy Curricula: Experience from Serbia/ Sedamdeset godina razvoja biohemijskih predmeta u kurikulumu farmacije: iskustvo iz srbije

Summary Introduction: The pharmacists played an important role in the development of biochemistry as applied chemistry in Serbia. What is more, the first seven state chemists in Ser bia were pharmacists. State chemists performed the chemicaltoxicological analysis as well as some medical and biochemical ones. When it comes to the education of medical biochemists as health workers, the period after the beginning of the second half of the twentieth century should be taken into account because that is when the training of pharmaceutical staff of the Faculty of Pharmacy, University of Belgrade, begins on the territory of Serbia. This paper presents the development of medical biochemistry through the development of curriculum, personnel and literature since the foundation of the Faculty of Pharmacy in Serbia until today. Objective: The aim of this paper is to present the historical development of biochemistry at the Faculty of Pharmacy, University of Belgrade, through analysis of three indicators: undergraduate and postgraduate education of medical biochemists, teaching literature and professional associations and trade associations. Method: The method of direct data was applied in this paper. Also, desktop analysis was used for analyzing of secondary data, regulations, curricula, documents and bibliographic material. Desktop research was conducted and based on the following sources: Archives of the University of Belgrade- Faculty of Pharmacy, Museum of the History of Pharmacy at the University of Belgrade-Faculty of Pharmacy, the Society of Medical Biochemists of Serbia and the Serbian Chamber of Biochemists. Results and conclusion: The curricula, the Bologna process of improving education, the expansion of the range of subjects, the number of students, professional literature for teaching biochemistry, as well as professional associations and trade associations are presented through the results. Krotak sadržaj Uvod: Značajnu ulogu u razvoju biohemije kao primenjene hemije dali su farmaceuti, pa su čak prvih sedam državnih hemičara u Srbiji bili apotekari. Državni hemičar obavljao je hemijsko-toksikološke analize kao i neke medicinsko-bio- hemijske analize. O školovanju medicinskih biohemičara kao zdravstvenih radnika može se govoriti od druge polovine XX veka, kada na teritoriji Srbije počinje školovanje farmaceutskog kadra na Farmaceutskom fakultetu u Beogradu. U radu je prikazan razvoj medicinske biohemije kroz razvoj nastavnih planova i programa, stručnog kadra i literature na Farmaceutskom fakultetu u Beogradu od njegovog osnivanja do danas. Cilj: Cilj rada je da se prikaže istorijski razvoj biohemije na Farmaceutskom fakultetu Univerziteta u Beogradu analizom tri indikatora: dodiplomskog i poslediplomskog obrazovanja medicinskih biohemičara; nastavne literature i stručnih udruženja i strukovnih asocijacija. Metode: U radu je primenjena metoda direktnih podataka i, gde je bilo potrebno, korišćena je desktop analiza pomoću koje su analizirani sekundarni podaci, uredbe, nastavni planovi i programi, dokumenta i bibliografska grada. Desktop istraživanje je realizovano na osnovu slededh izvora: Arhive Univerziteta u Beogradu - Farmaceutskog fakulteta, Muzeja za istoriju farmacije Univerziteta u Beogradu - Farmaceutskog fakulteta, Društva medicinskih biohemičara Srbije i Komore biohemičara Srbije. Rezultati i zaključak: Kroz rezultate prikazani su nastavni planovi i programi, Bolonjski proces unapređenja nastave, širenje opsega predmeta, broj studenata, stručna literatura za nastavu iz biohemije i stručna udruženja i strukovne asocijacije.