Collaborative study on drug use in pregnancy: the results of the follow-up 10 years after (Novi Sad Centre).

An international multicenter study entitled Collaborative Study on Drug Use in Pregnancy (DUP) was initiated in 1987 by the Mario Negri Institute (Milano) and co-sponsored by the WHO Regional Office for Europe (Copenhagen). The study covered the use of medicines during pregnancy, labour and postpartum period. The Novi Sad centre contributed with 296 questionnaires. The aim of the study was to evaluate the pharmacotherapy by means of comparison, to identify problems in a particular settings and to plan actions toward improvement. The prescribing of some medicines in the Novi Sad center was found to be at the extreme, being among the lowest in the use of iron preparations during pregnancy and among the highest in the use of ergot alkaloids in the postpartum period. Educational efforts have been made to change this practice after the conclusion of the study in 1989. Ten years later, in 1999, the same questionnaire was applied to 100 women in the postpartum period in the same nursery, the Department of Obstetrics and Gynecology in Novi Sad. The results have shown a distinct improvement with the increase of iron prescribing during pregnancy and almost complete abandonment of postpartum use of ergot alkaloids. In the second study period some other inconsistencies with accepted therapeutical principles were identified. For example, although the use of analgesics fell from 22.3 to 8%, the selection changed towards the high use of metamizole (noraminophenazone) and no use of paracetamol (acetaminophen). It was concluded that international pharmacoepidemiological studies such as DUP, could substantially contribute to the improvement of pharmacotherapy if followed by appropriate actions in changing the prescribing behaviour of the physicians and information directed to the target population.

[Drug use during pregnancy, labor and the puerperium and after the Drug Use in Pregnancy Study]. / Upotreba lekova u trudnoci, porodaju i puerperijumu tokom i posle DUP ispitivanja.

INTRODUCTION: An international study on drug use in pregnancy (DUP) started in 1987. There were 22 countries involved, among which two centers from Yugoslavia: Novi Sad and Zagreb. The investigation in Novi Sad comprised 296 parturients. On the basis of obtained results, education of physicians-gynecologists has been organized. 10 years later, a check-up study of 100 parturients was introduced in order to find out possible changes in the applied pharmacotherapy. MATERIAL AND METHODS: An investigation on drug use in pregnancy, delivery and puerperium has been performed at the Department of Obstetrics and Gynecology in Novi Sad. It included 296 parturients in 1989 (1st investigated period) and 100 parturients in 1999 (2nd investigated period). Results obtained in 1999 were compared with the results from 1989. RESULTS AND DISCUSSION: Chronic use of drugs was found similar for both investigated periods (2.38% in 1989 vs 5% in 1999). In this group there were no drugs which could endanger the fetus. In 1989, there were 12.6% of pregnant women using preparations such as iron supply, versus 54% in 1999, so that trends in prevention of pharmacotherapy of anemia approached those in developed countries. In the second investigated period there was a significant decrease in progresterone therapy and two times increased use of beta-adrenergic agonists, which is in accordance with new trends in pharmacology. Use of paracetamol decreased, whereas use of metamizole, known by serious side-effects, increased. Drug administration during delivery decreased in 1999 (77%) in relation to 1989 (94.93%) mostly comprising drugs for autonomous nervous system, analgesics and analgoantipyretics. Administration of ergot-alkaloids decreased: from 65.8% in 1989 to 22% in 1999. Use of drugs after delivery can endanger both the parturient and lactation, i.e. nutrition of the newborn infant and consequently the newborn itself. During 1989 practically every parturient (95.27%) was administered drugs, out of which about 97% belonged to the group of ergot-alkaloids which were routinly administered for acceleration of uterine involution. In 1999 ergot-alkaloids were administered only in 9% of delivered women. Use of oxytocins was also reduced because they were administered not routinely but only on purpose. CONCLUSIONS: The following conclusions were made on the basis of obtained data: 1. During the first period there was a difference in drug use when compared to the countries with developed pharmacotherapeutic practice. 2. Use of progesterones was remarkably decreased in 1999 versus two times increased use of beta-adrenergic agonists administered in prevention of spontaneous abortions. 3. Use of opiate analgesics during delivery was significantly reduced from 43% to 11% in 1999. 4. In the second investigated period use of iron preparations was significantly increased versus decreased use of ergot-alkaloids. 5. Use of paracetamol decreased, whereas use of metamizole (known by serious side-effects) increased.

[Professional and social responsibilities of clinical pharmacology]. / Profesionalna i drustvena odgovornost klinicke farmakologije.

According to the decision of the Scientific and educational board of the Medical Faculty in Novi Sad the Institute for pharmacology toxicology and clinical pharmacology introduced the clinical pharmacology in 1975. Postgraduate studies were organized for those wishing to specialize, i.e. to get their M.Sc. degree in clinical pharmacology. Besides the youngest members of the Institute (now they are all associate professors) these studies were successfully completed by many doctors from other clinics or those employed in pharmaceutical industry. The publications which the Institute published from the field of pediatric clinical pharmacology were the very first ones not only in our country but also in world proportions. International methods for the evaluation (DDD, ATC code) of the scope and structure of drugs usage were introduced and modified according to our conditions and requirements. The studies on the usage of drugs were among the first pharmacoepidemiological studies in country and abroad. On the basis of these activities the Institute was two times the organizer of the scientific meeting sponsored by WHO. As a response to a sudden increase of the need for information on drugs due to disturbed supply and distribution of drugs from abroad (through humanitarian aid) a telephone and modem information service has been organized within the Institute. The printing of the book titled Drugs in Use was initiated (five editions since 1992) together with the issues on computer discs. The publishing of the journal Pharmaca Iugoslavica was also started under the auspices of the Association of Health Care Organizations. The service for adverse events registration was also organized. Through its activities in planning and organization of pharmacokinetic and clinical investigations, development of new analytic methods and performance of pharmacokinetic studies the Institute contributed to the development of new drugs and gave new theoretical solutions in pharmacokinetics. The Institute also initiated the establishment of the Committee for drugs of the Medical Faculty. Its professors are members of the Commission for Social Insurance, Federal Commission for Drugs and Federal Commission for Poisons. Through all mentioned activities the Institute has greatly influenced not only our but also general medical community.

[Therapeutics and clinical pharmacology of pediatric age]. / Pedijatrijska farmakoterapija i klinicka farmakologija.

Therapeutics and clinical pharmacology of pediatric age had a turbulent development ever since H. Shirkey spelled out his dramatic warning in 1968. that children are "therapeutic orphans". This warning was a message that in children drugs are used which are not scientifically studied in this population. With a few years of latency in which the ethical issues have been solved. Food and Drug Administration and other leading drug regulatory authorities requested that in the drug labeling a warning sentence should be included stating that since the drug was not studied in children, its use is not recommended. Thus, the children became therapeutic orphans for the second time. Today, the attitude is prevailing that is based on pharmacokinetic and safety data so that even before the formal studies have been completed for each age group, use of drugs in children should be allowed.

[Medicines and lactation]. / Lekovi i dojenje.

The factors that determine the transfer of medicine from mothernal blood to breast milk are the relative molecular mass of the substance, liposolubility, plasma half-life, binding to plasma proteins, pKa, the rate of metabolism and the dose taken by the breast feeding mother. The transfer of large number of medicines is small, so that the amount reaching the infant is negligible. But, certain drugs pass the milk into quantities sufficient to cause adrverse effects and these drugs should be avoided during breast-feeding. Having these facts in mind, the physician is in most cases in the position to select an appropriate medicine compatibile with breast-feeding.

Red blood cell deformability in diabetes mellitus: effect of phytomenadione.

Decreased deformability of red blood cells (RBC) in diabetes mellitus (DM) is considered to be linked to microcirculatory complications in this condition. As we found that phytomenadione increased RBC deformability in experimental animals, the question was raised, whether phytomenadione had the same effect on the RBC of diabetic patients. The study was performed in 10 patients with insulin-dependent diabetes mellitus, where the erythrocyte deformability was impaired. Patients received 10 mg/day phytomenadione i.m. for five days. Deformability was measured with policarbonate membranes (Nucleopore) with pore diameter 5 microns, under gravity. The results were expressed as the ratio (r) between the flow of 1.5 ml (r1) and 2 ml (r2) of RBC suspension and 1.5 ml of buffer. Phytomenadione increased the erythrocyte deformability in patients with diabetes mellitus, lowering the value r1 from 3.54 +/- 0.84 to 2.32 +/- 0.61 (p 0.02) and r2 from 7.80 +/- 2.41 to 4.65 +/- 1.07 (p 0.01). The values after treatment reached the range of healthy controls (r1 3.11 +/- 0.98, r2 6.52 +/- 3.04). The whole blood viscosity was significantly lowered after phytomenadione (5.28 +/- 0.58 mPas before, 4.64 +/- 0.74 mPas after, p < 0.02) with unchanged plasma viscosity, but significantly lowered internal viscosity of erythrocytes.

Phytomenadione improves red cell deformability in laboratory animals.

The deformability of red blood cells (RBC) is one of the factors that determine whole blood rheology. Derivatives of vitamin K (phytomenadione, menadione, menadione bisulfite) are electron-transporting substances. The aim of this study was to investigate the possible influence of derivatives of vitamin K on erythrocyte deformability in studies in vivo--on rats and rabbits. The influence of vitamin K antagonist on erythrocyte deformability (ethylbiscumacetate) was also determined. Pentoxifylline known to affect RBC deformability was also included in the study as the control treatment. The study was performed on white laboratory rats and domestic rabbits. The blood was obtained from animals after single and multiple dosing of drugs. Blood sample was prepared and RBC filterability was assayed with a gravity driven filtration technique. Pentoxyfylline did not change erythrocyte deformability after single dose, but significantly improved erythrocyte deformability of laboratory animals after multiple application. Filterability values of the RBCs of the rats and rabbits increased significantly after single and multiple treatment with phytomenadione, while the two other derivatives, menadione and menadione bisulfite, did not change RBC deformability. Ethylbiscumacetate did not change erythrocyte deformability in rats after single dose.

[Clinical pharmacology and the selection of drugs]. / Klinicka farmakologija i izbor lekova.

Yugoslavia has a modern drug legislature and a selective drug market. With about 910 substances and 1250 brand names the number of drugs is among the lowest among the European countries. Most products on the market satisfy high criteria of safety to efficacy ratio. Still, the regional health insurance authorities of the Federal republics of Serbia and of Croatia limited the number of drugs to be reimbursed by the insurance scheme. The reason for this move and its justification is given by--the inertia of the complicated procedure of withdrawal from the market of a drug which is obsolete or considered today not possess the ascribed efficacy, existence of unjustly high expectations regarding the efficacy of certain drugs by both the medical profession and the layman and which lead to overprescribing (i.e. vitamin combinations, laxatives and drugs, cerebrovascular insufficiency), and--the responsibility of the public health administration for setting priorities in spending of the available funds. The allocation of funds available for medicinal drugs have been without any kind of regulation and control until now. The introduction of limitations in the reimbursement of price for certain drugs is the first measure initiated to stimulate the optimal use of drugs. As the optimal drug use is considered the therapy with the most favorable safety/efficacy and cost/efficiency ratios. The other measures available and which ought to be initiated are those based on the drug utilization studies. The prescriptions are already computerized im most settings, so the feedback of information ot the prescribing physicians could be possible after adequate analysis of the data. The team of clinical pharmacologist already active in drug utilization studies is available and ready to meet the challenge of improving therapeutic practices.

[Epidemiologic study of anemia in school children with special emphasis on hemoglobinopathies]. / Epidemioloska istrazivanja anemije u skolske dece s posebnim osvrtom na hemoglobinopatije.

A total of 746 schoolchildren of both sex (aged 7-15) were investigated in the community of Backa Palanka and Bac with the view to establishing reference hematologic values of the red lineage: Hemoglobin (Hgb) 135.3 +/- 20.4 g/l, erythrocytes (Er) 4.42 +/- 0.60 x 10(12)/L, hematocrit (HTC) 0.41 +/- 0.06, MCH: 30.5 +/- 2.7 pg, MCHC: 32.8 +/- 3.2 g/l, MCV: 93.2 +/- 5.4 fl. In only 7.3% of children hemoglobin values were below 114.8 g/l (1.5 SD) so that anemia did not represent a socio-medical problem in children aged 7-15 in the area investigated. With regard to the investigation of inherited abnormalities in the synthesis and structure of hemoglobin five children showed a persisting synthesis of fetal hemoglobin with the mildly augmented HbF values: 2.7%, 3.8%, 3.9%, 4.2% and 4.8% while the increase in HbA2 with the values for heterozygotic forms of thalassemia was found in four children thus accounting for 3.3%, 3.5%, 3.5% and 4.3%. It was concluded that although genetically induced anemias were rare they were nevertheless present in this region. They necessitated further epidemiologic studies which had been performed in the greater part of Yugoslavia but not in SAP of Vojvodina nor in the new location of SAP of Vojvodina.

Are we treating enough patients for hypertension?

International comparisons indicate a two- to three-fold overall difference in the therapeutic intensity with antihypertensive drugs. In the District of Novi Sad in Yugoslavia, the use of antihypertensive drugs is among the lowest. The differences cannot be explained from the prevalence of hypertension. The evaluation of the existing practice in the treatment of hypertension was studied in a community of 6017 inhabitants with 756 hypertensive patients within the District of Novi Sad. The intensity of antihypertensive medication expressed in defined daily doses per 1000 inhabitants per day was compared with the number of hypertensive patients requiring drug therapy. Patients requiring therapy were classified into two groups: those having blood pressure above the age adjusted border levels and those who received at least the minimum daily therapeutic dose of antihypertensive medication. It is concluded that the volume of prescribed antihypertensive drugs, although lower compared to Nordic countries, might still be almost sufficient to meet the needs of patients who need drug therapy according to the criteria defined (if borderline hypertension is not treated).

Epidemiological evaluation of anti-infective drug prescribing for children in outpatient practice.

In comparison with other regions in Yugoslavia, in the District of Novi Sad a high prescribing rate for antimicrobial drug were previously found. The aim of this study was to determine whether this high rate applies also to pediatric patients up to the age of 7 years, to define the prescribing pattern of physicians, and ultimately, to direct educational and other measures toward improving the therapeutic practices. The sample consisted of all prescriptions for 1 month for 26,652 children, comprising 8.9% of the total population. The method was based on a drug dose statistics concept, where the most frequently prescribed amount of the active substance, determined by convention as the defined daily dose (DDD), was used as a unit of measurement. The number of such statistical or average doses were expressed per 1,000 children per day. It was found that the prescribing rate in the District exceeds all other regions for which comparable data exist. In the prescribing pattern, the high usage of tetracyclines contributed to final removal of tetracyclines in syrup formulation from the market in Yugoslavia.

Regional and international comparison in utilization of antidiabetic drugs.

Data are expressed in the comparable manner through the method of defined daily doses (DDD), which has been adopted for drugs in our country according to the internationally agreed method of drug utilization [Stanulovic et al. 1981]. Together with Iceland, Novi Sad had the lowest insulin utilization in 1976, the rate being 1.7 DDD/1000 inhabitants per day. Insulin was used 7.2 times less than in Sweden. However, the utilization of biguanide of 6 DDD/1000 inhabitants per day was 10 times greater than in other European countries. Prescribing rate of preparations of sulfonylurea in Novi Sad was high (8.2 DDD/1000 inhabitants per day); only Sweden came closer to these values. Causes contributing to these differences could be found in the relation between juvenile diabetes and adult onset diabetes as well as in physicians' attitudes towards therapy, in nutritional status and degree of obesity in the population, age structure of population, number of dietitians in the diabetological service, etc. Diabetologists and clinical pharmacologists should explain causes leading to these differences and determine side effects of available antidiabetic drugs, either positive or negative, in order to enable their optimum utilization.

Extremes in drug utilization patterns. Low prescribing of antihypertensives in the District of Novi Sad, Yugoslavia.

According to data expressed in defined daily doses (DDD), the utilization of antihypertensives is lower in the district of Novi Sad (Yugoslavia) than in other settings studied so far. The number of actually treated persons is even lower than that indicated by the DDD value, which in 1981 was 23.4 DDD/1 000 inhabitants/day. Currently, the participating members in the WHO coordinated MONICA-project are considering the possibility to incorporate the defined daily dose approach to evaluate drug usage in relation to morbidity data. This offers a realistic prospect for identifying the medical consequences of the regional differences in prescribing patterns.

Drug utilization in paediatrics: non-medical factors affecting decision making by prescribers.

The study was done to show that in certain areas of paediatric pharmacotherapy unexpected discrepancies may arise between accepted therapeutic principles and the actual behaviour of a prescribing doctor. The first example was of a great reduction in penicillin use in a university teaching hospital after certain therapeutic accidents: in one year, there were 2 fatal cases of rhabdomyolysis due to use of procaine benzyl-penicillin. Other antimicrobial drugs inferior to penicillin, such as lincomycin and sulphonamides, replaced penicillins. The second example showed the inverse relationship between the use of antitussives and other drugs in symptomatic treatment of respiratory diseases in outpatients and inpatients; the pressure of unduly optimistic expectations of therapy imposes a high prescribing rate of these drugs in the outpatient population, in contrast to hospitalized patients, whose doctors, being spared such pressure, prescribe antitussives far less often. The third example demonstrates the possibility of inadequate education in the use of antimicrobial drugs. Although doctors from regional hospitals receive their training at an university hospital, they tend to prescribe chloramphenicol ten times more per bed-day than their colleagues in an university hospital. In terms of the cost/effectiveness ratio, a high prescribing rate of cephalosporins is not economically favourable in a university teaching hospital. It is also shown that studies of drug utilization in children are feasible if age--appropriate adaptation of the statistical value expressed as the defined daily dose is performed. The adaptation was evaluated by comparing pharmacy-based drug consumption data expressed in "paediatric defined daily doses", with actual days of treatment with particular drugs, i.e. data from patient records for 244 beds in the University Teaching Hospital.