Pharmacokinetic changes in patients with oedema.

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Adverse drug reactions resulting in hospital admission.

A 14-month (1992/3) prospective study was performed in two departments of the University Hospital Centre (UHC) in Zagreb. The aim of the study was to assess the rate of drug-related hospitalizations, drugs that caused adverse drug reactions (ADRs), and all factors which could have been of importance for their appearance. One hundred and thirty (2.5%) of 5,227 patients were admitted to hospital because of ADRs. The most frequently ADR-related drugs were nonsteroidal anti-inflammatory drugs and analgesics (64.6%). They were followed by cardiovascular agents (20.8%) and antimicrobials (3.8%). Acetylsalicylic acid (aspirin) caused 38.5% of hospital admissions, other nonsteroidal anti-inflammatory drugs (NSAIDs) 23.1% and medigoxin 15.4% of hospitalizations. The most frequent ADRs were upper gastro-intestinal tract bleeding (64.6%), cardiac rhythm disturbances (13.9%), blood cell disorders (4.6%) and hypoglycemia (2.3%). Regarding the patients' age, 52.3% of patients was younger and 47.7% older than 65. Sixty-one point five percent of patients was taking more than one drug, older patients (48 patients--77.4%) have been taking a significantly higher number of drugs than the younger (32 patients--47.1%) (p < 0.0001) ones. Drug interactions caused 23.8% of ADRs. Only 11 (8.5%) of patients suspected themselves that the drug might have caused the ADR. Improvement was observed in the majority of patients (65.4%), 25.4% recovered completely, 4 (3.0%) died in the hospital because of ADRs. 3.0% of patients as well died of their underlying diseases, 2.3% were transferred to other departments for their underlying diseases, and one patient left the hospital on his free will.

Controlled trial of the prophylactic administration of antibiotics in sclerotherapy of esophageal varices.

The aim of this controlled trial was to determine the usefulness of chemoprophylaxis in sclerotherapy of ruptured esophageal varices. Sixty patients bleeding from esophageal varices, without signs of infection at admission, were included in a randomized open trial of one-year duration. Thirty patients received, along with the usual standard therapy (infusions, transfusions) 4x1 g ampicillin intravenously over 3 days, and 30 patients received the standard therapy only. Bleeding varices of the esophagus were sclerosed transendoscopically intravenously using 1% polidocanol solution. Body temperature, general condition, white blood count, differential blood count and sedimentation rate were followed-up over three days. There were no statistically significant differences between the groups in the mean values of the mentioned parameters. There was no correlation between the dose of sclerosant used and body temperature or leukocyte count. Chemoprophylaxis proved to have no effect in this indication.

Determination of bioequivalence of two furosemide preparations; the effect of high doses of furosemide on some pharmacokinetic parameters.

The bioequivalence of two oral preparations of the diuretic furosemide, namely (i) a Croatian pharmaceutical product (test preparation A) and (ii) a reference preparation B, both in a dose of 500 mg was assessed in an open, cross-over, randomized trial in 15 healthy male volunteers, in whom the HPLC method with a fluorescent detector was used to determine its concentrations. The test preparation (A) was found to achieve a considerably higher concentration (17.2 +/- 9.304 mg/l) than the reference preparation (11.1 +/- 6.484 mg/l); the time to peak concentrations was statistically significantly shorter for the test preparation (1.033 +/- 0.743 h) than for the reference preparation (1.656 +/- 0.586), and the areas under the concentration curves were statistically significantly greater for the examined preparation (65.9 mg.h/l) than for the reference preparation (46.845 mg.h/l). The relative bioavailability of the test preparation was 129%, i.e. it was not bioequivalent with the reference preparation. This finding was consistent with the previously performed laboratory quality testing in vitro, where the release of the reference preparation was found to be considerably slower and weaker than that of the test preparation. High doses of furosemide exemplified by 500 mg were found to affect only some of the pharmacokinetic parameters, i.e. they induce an accelerated absorption, an increase in serum concentration, and a prolongation of its half-life.

The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine.

The effect of food and metoclopramide on the pharmacokinetics of bromocriptine was investigated in 7 healthy subjects. Plasma concentrations of bromocriptine were measured by radioimmunoassay after a single oral dose of 7.5 mg bromocriptine. Maximal plasma concentrations of bromocriptine were slightly lower when the drug was given after breakfast. Bioavailability of the drug was not significantly reduced by food nor by metoclopramide pre-treatment. Side effects of bromocriptine were considerably reduced by metoclopramide pre-treatment (0.5 mg/kg); the decrease was about 83% as estimated from Table II.

How safe are bioequivalence studies in healthy volunteers?

Between 1981 and 1994, 58 bioequivalence studies (b.s.) were performed in 885 healthy volunteers. 93.1 per cent were single-dose, mainly of two way cross-over design. According to ATC groups, 13 were of cardiovascular drugs(C), 11 musculoskeletal (M), nine alimentary (A), seven urogenital (G), seven antimicrobial (J), six haematological (B), three nervous (N) and two respiratory (R). 97.2 per cent of volunteers finished the studies. Out of 25 withdrawals, 14 did it by their own will, seven were excluded because of lack of compliance with the protocol, one because of an adverse drug reaction (ADR) (preputial oedema), one because of intercurrent illness, and two for other objective reasons. In 35 studies the probants have been males, in 23 both sexes. Subjects were between 18 and 40 years. 209 adverse events were reported in 18 studies (31 per cent). From 885 volunteers that came to first session at the time, 115 (13 per cent) had ADRs. The association of the drug and ADRs was defined as probable in 91 ADRs (45.9 per cent), definite in 66 (33.4 per cent) and possible in 41 (20.7 per cent). 73 (63.5 per cent) volunteers had one ADR, 22 (19.1 per cent) had two and 20 (17.4 per cent) more than two ADRs. The majority -117 (56 per cent)-of ADRs were mild, 78 (37.3 per cent) moderate and 14 (6.7 per cent) severe. The most frequent ADR was headache (22.9 per cent), followed by nasal congestion (12.9 per cent), sweating (12.4 per cent), nausea (6.7 per cent), restlessness (6.7 per cent), deafness and tinnitus (6.2 per cent), change of biochemical or haematological parameters (5.3 per cent) and other. An unusual and rare ADR was impotence and preputial oedema (two volunteers on frusemide). All studies of G group (7-100 per cent) had ADRs, followed by C group (5-38 per cent) and A (3-33 per cent). Glipizide (5 mg) had highest number of ADRs (64-30.6 per cent), bromocriptine (10 mg) had 31 (14.8 per cent) and frusemide (500 mg) 22 (10.6 per cent). The largest number of subjects with ADRs were on frusemide (13-72 per cent), glipizide (17-68 per cent) and bromocriptine (15-52 per cent). At a time when generic drugs are of increasing importance, the safety of b.s. is of considerable interest. Our data confirm their safety and indicate that the majority of ADRs are mild.

Variations in the risk of gastrointestinal hemorrhage with non-steroidal anti-inflammatory drugs and localization of lesions.

The aim of this prospective study was to determine the effect of ulcerogenic drugs in patients with bleeding peptic ulcers and erosions with respect to their age and sex, ulcer history and additional risk factors such as family medical history, alcohol use, smoking, coffee consumption and stress. Of 367 patients with bleeding gastroduodenal lesions admitted during a period of 15 months, 88 (24%) had previously received ulcerogenic drugs. The most frequently taken drugs were aspirin (44.3%), piroxicam (12.3%) and ibuprofen (7.4%). Bleeding lesions were 1.4 times more frequently found in male users than in female users, and 2.1 times more often in male unusers. Males were more commonly receiving drugs than females (59.8%:40.2%), particularly those aged 34 to 54 years. Forty (45.5%) users had previously suffered from ulcer disease, 48 (54.5%) had negative history. There was no additional risk factor in 48%, whereas 58% of the users had one or more risk factors. It may be concluded with great certainty that NSAIDs caused hemorrhage in 13% of all admissions. Among users, a total of 119 different gastric and duodenal lesions were found. Gastric lesions were more common (54%) than duodenal lesions (46%) in males, while in females an inverse ratio was observed (41% of gastric and 59% of duodenal lesions). Among nonusers, gastric lesions were more frequent in females (M:F, 42%:48%), and duodenal lesions in males (M:F, 58%:52%). The number of lesions increased with age in both users and nonusers. Forty-three percent of all drug users had ulcers in the prepyloric region, 23% on the lesser curvature, and 14% at the posterior wall of the gastric corpus. Gastroduodenal erosions were seen in 11% of the males and 1% of the females. In nonusers, ulcers were found on the posterior wall of the corpus (27%), on the lesser curvature (25%) and in the prepyloric region (24%). Bleeding gastroduodenal erosions were found in 4% of the patients. Distribution of bleeding duodenal ulcers was similar in drug users and in nonusers, i.e. anterior wall (45%:44%), posterior wall (28%:27%), lower wall (16%:16%) and upper wall (3%:4%) of the duodenum. NSAIDs had no influence on the localization of duodenal ulcers. In this study, there was no death from ulcer disease with NSAID use. It may be concluded that NSAIDs are a common cause of damage to gastroduodenal mucosa. The risk of drug therapy should be balanced against the risk of the disease.

[A critical review of the drug field in Yugoslavia 1985-1988]. / Kriticki prikaz podrucja lijekova u nasoj zemlji u razdoblju 1985-1988.

Developments in the drug field are presented under the following headings: 1. Drug approval. About 220 new drugs have been discussed (including new formulations and dosages). The number of drugs belonging to the group A (important) and those which should not, according to the author's opinion, have been approved (group D) is similar 6.3/9.1%. About 64% are clinical or generic repetitions (i.e. "me too" drugs). Considerable difficulties with pricing, which is haphazard, and performed in an unsatisfactory way, is the reason why the industry tries to introduce "new drugs" which are often not new and do not present an advance to pharmacotherapy. 2. Drug regulation got (up till now with modest success) an important impetus through Conclusions of the Federal Council of the Parliament of Yugoslavia asking the Federal Committee for Health to elaborate the Yugoslav Essential Drugs List and revise the list of drugs approved in the country--the Federal Institute for Health Protection to prepare diagnostic and therapeutic standards. 3. Drug legislation was "enriched" by the Regulation of Adverse Drug Reaction Reporting (which dos not exist in other countries) and controversial Regulation on Auxiliary Therapeutic Substances, the latter being greatly insufficient. Finally, the List of Essential (unavoidable) Drugs comprising 1/3 (= 336) of drugs approved in Yugoslavia has been accepted. It is hoped that this will improve the availability of drugs, which availability is essential. The greatest problem in the Yugoslav drug field remains irrational prescribing, inadequate pricing (linear increases without observing the grade of necessity of various agents) and consecutive repetitive deficit even of most needed therapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

[Critical analysis of drugs in 1989]. / Kriticki prikaz podrucja lijekova u 1989. godini.

Changes and trends in the drug field in the world and in Yugoslavia in 1989 are presented and discussed. 1. World. There appeared only a few new drugs all over the world, and new chemical entities (NCE) rather rarely represent a significant contribution to materia medica. Japan is the first in producing NCE (12) followed by United Kingdom and the USA (4 NCE each). 2. Yugoslavia. In Yugoslavia were 125 drugs discussed approval, new dose, new formulation or generic parallel. More than 84% of these have been related to generic or clinical ("me too") parallels; less than 9% of drugs had a certain contribution to materia medica, while, according to the authors, the number of drugs that contributed significantly to the materia medica and of those which should not have been approved was equal (3.2%). Octreotide, erythropoietin, almitrine and flumazenil were placed in category A. Insulin appeared in the largest number of parallels (as many as 19) succeeded by cardiovascular, antimicrobial and gastrointestinal drugs. 3. Drug formularies exist in all the developed countries and represent a way of limiting prescribing. Yugoslav list of drugs expenses of which will be covered by the Health Insurance will be prepared. 4. The Federal Institute for Health Protection through its special committee for diagnostics, pharmacotherapy and side effects represents a useful activity in rationalizing drug use. 5. Yugoslav publication of defined daily doses (DDD) is being prepared. 6. A review of causes of deficient or inadequate drug supply in Yugoslavia, which still represents a major problem in this country, has been given at the end.

[A critical report on drugs in 1991]. / Kriticki prikaz lijekova u 1991. godini.

Principal changes in the drug field in this country in 1991 were caused by the armed aggression committed against Croatia and the succession of disturbances that this aggression induced. Abroad as many as 13.6% of drugs could be ranked as category A. Here dominate some drugs for AIDS, which is a significant problem in medicine, but also some drugs for rare diseases ("orphan drugs"), like Gaucher's disease, precocious puberty etc. In this country (until the sovereignty was reached on October 8, 1991) 13.8% of drugs belonging to category B were approved. In category C ranked were 83.0% of drugs, abroad 75%. Two in this country (rutoside and creatinephosphate), one abroad (ditiocarb) were classed in category D. At preparing new Drug Law of independent Croatia, caution is necessary over numerous details which will enable us to become, in this field too, as soon as possible a part of the developed Europe. The latest List of Drugs that is paid by the Croatian Health Insurance is discussed. It comprises up to 230 generic names, excluding those that are--unjustifiably--most prescribed. The List's aim is to rationalize drug therapy, allowing other modes of prescribing improvement. To a large degree drug prescribing is not rational. The latest data (1990) have shown that only 4 out of 10 most prescribed drugs in Zagreb are undoubtedly efficacious, 9 out of 10 in Ljubljana, 5 out of 10 (1989/90) in former Yugoslavia, and abroad ("in the world") all 10. The characteristics of drug filed in war are reviewed as well as problems connected with drug donations. The importance of concern that "aimed" donations replace those that are not optimally used is stressed. The article ends with the question of the importance of objective information sources in drug field.

[Critical review of drugs in 1990]. / Kriticki prikaz podrucja lijekova u 1990. godini.

New chemical entities approved abroad (43) and in Yugoslavia (37) were presented. Discussions on several "old" drugs (41) open at the Yugoslav Federal Drug Committee for any reason (new formulation, new dose, new packaging, dosage regimen or indication) and renewal of registration (114) were also included. Special attention was given to the drugs which had been refused the renewal of registration (8). Critical drug re-evaluation as an important element of the improvement of pharmacotherapy was emphasized. A total of 78 drugs was discussed or registered in 1990-1.28% of drugs from the group A (vancomycin), 10.2% from the group B (aclarubicin, dexfenfluramine, warfarin, alprazolam, colestipol, lovastatin, combination: cetrimonium + lidocain and estradiol vag.), 87.1% (the greatest number so far!) from the group C and 1.28% from the group D. Surveys of the most prescribed drugs in Zagreb, in Yugoslavia and in the world were also given having proved largely non-rational drug prescribing in this country. Further development of drug formulary concept was discussed, primarily for the drugs paid by the Health Insurance, as well as the unsatisfactory ADR reporting in Yugoslavia. Presented were also the activities of the Committee for Diagnosis, Pharmacotherapy and ADR of the Yugoslav Federal Institute for Health Protection. Publishing of Yugoslav daily defined doses is, according to the authors essential for further systematic monitoring of drug consumption on different levels in this country. It would be impossible to rationalize pharmacotherapy without these data.

Access to information on drug regulation in the countries of Central and Eastern Europe.

Awareness of the importance of transparency and accountability in drug legislation is not universal and is of relatively recent origin. It is not surprising that data on the accessibility of information in the drug regulatory systems of the "Central and Eastern European countries" (CEEC) are virtually non-existent. Where drugs are concerned, these countries tend to have a number of characteristics in common, namely 1) the lack of a national drug policy, i.e., a policy which as one of its elements should set out basic principles for the registration of new drugs and the re-assessment of those approved during the earlier period; 2) a serious lack of competent persons in this field, not only in the registration offices but also within the medical and pharmaceutical profession, i.e., experts who might be called upon by the registration office to provide technical advice on decision making; 3) lack of funds, since fees collected from manufacturers in connection with regulatory activities are regarded as taxes and do not accrue to the regulatory body or the Ministry of Health; and 4) non-availability of objective drug information.For such reasons, decisions based upon the systematic and expert assessment of evidence tend to be lacking, and the transparency of the drug regulatory process leaves much to be desired.No short term solution to this situation exists; long term solutions may be found with the assistance of the World Health Organization and various Non-Governmental Organisations; these could in particular improve the level of competence of governmental staff working with drugs, for example through providing seminars, working groups, educational grants and objective information. In such developments the International Society of Drug Bulletins should play an active role.