How long can an escalation of dose override tolerance to the hypotensive efficacy of nitroglycerin infusion in coronary care patients.

Tolerance to nitroglycerin infusion (NG) can be overridden by dose escalation. The aim of this study was to define for how long it can be done for hypotensive efficacy of NG, in a coronary care setting. A prospective trial with an intra-individual therapeutic comparison was performed in 60 patients with acute myocardial infarction or unstable angina. Initial efficacy of NG was confirmed by a 10% blood pressure decrease (measured by cuff). Seventy-two-hour NG infusion was interrupted, for 30 minutes, every 12 hours. If blood pressure increased by 10% after infusion interruption, the infusion was continued at the previous rate. If blood pressure did not increase (detected tolerance--weakened efficacy of NG), the dose was increased until pressure decreased by 10% and the infusion was continued at the new dose. Failure to achieve hypotensive response, despite a 5-fold dose increase, indicated onset of resistance--completely lost hypotensive efficacy of NG. The majority of patients (49 out of 55) who developed tolerance, developed it during the first 36 hours, while the majority of those who developed resistance (33 out of 40), developed it within 60 hours of the infusion. Tolerance was overridden by dose escalation in 41 out of 55 patients, which was repeated in 31 patients. Complete restoration of NG action was possible over 24 hours in half the patients, and over 48 hours in one third of the patients. Three out of 34 patients who developed tolerance before the 13th hour did not develop resistance during the following 60 hours of dose up-titration. The conclusion is that tolerance to NG can be overridden by dose escalation in the majority of patients for a significant period of time, which is useful in clinical practice.

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.

Problems with drugs in Croatia.

Croatia has 4.8 million inhabitants, 11,800 physicians, 2000 pharmacists, two now shareholding, pharmaceutical companies (about 6500 employees, total sales of about 350 million US dollars). There are a number of problems due to the war (GNP fell from 3800 to about 1500 US dollars), occupation of 25% of its territory, 0.5 million refugees and lack of resources (139 US dollars/capita for health, about 40 US dollars i.e. 30%!! for drugs)--about three times less than before the aggression. The drug situation is controlled with the help of: (1) donations (approximate value of 600 million US dollars since 1991 from Europe and US), (2) (essential) drug formularies--250 for outpatients, and 580 generic names for various levels of hospital use, (3) special efforts to purchase drugs of good quality at a reasonable price (a kind of tender), (4) control of prescribing (prescriptions, specialists referral) especially by GPs. A new Medicines Act is in preparation and about 1000 generic names are on the market. DRUG EDUCATION: Pharmaca: the Croatian journal of pharmacotherapy has been published since 1962, there are several Drug bulletins (one published since 1975); special chapters on clinical pharmacology in textbooks, translation of three editions of Laurence's textbook with special commentary and adaptation to local needs; ADR spontaneous and intensive monitoring (WHO programme) with a personal feedback to the reporters and regular articles on drug use in a number of periodicals. Data on drug consumption indicates that there is room for improvement of prescribing. There is an enthusiasm for 'vasoactive drugs'--after dipirydamole came oxpentifylline and antimicrobials are always overprescribed. All these problems will hopefully decrease when the war finally stops and when industry (especially tourism) starts being fruitful again. In any case the importance of teaching of pharmacotherapy at the under- and postgraduate level should be recognized.

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.

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.

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.

Bioequivalence of two oral cyclosporine preparations.

A comparison of bioequivalence of two cyclosporine (CAS 59865-13-3) preparations was performed. Ten cyclosporine treated patients with transplanted kidneys were included. Criteria were successful transplantation and minimum period from transplantation of at least 6 months. Two months before the experiment, cyclosporine concentrations had to be in therapeutic range without significant oscillation, and kidney function stabile. There had to be no signs of cyclosporine nephrotoxicity. During the objective biochemical analysis it was not allowed to find malfunction in any of the patient's organ important for cyclosporine pharmacokinetics. Cyclosporine concentrations in whole blood were measured with a specific fluoroimmunoassay. Cyclosporine and metabolites concentrations were measured with radioimmunoassay with non-specific antibody. Mean value and standard deviations and shape of distribution were calculated for all numeric data of patients, measured biochemical and other laboratory parameters. Variance analysis for all measured cyclosporine concentrations according to sampling times (C0 to C12, maximal concentrations C(M), time to maximal concentrations t(M), times of absorption delaying t(Lag) and area under the measured concentration curves (AUC) were statistically checked. According to these data it is concluded that the preparations are bioequivalent; a time to reach maximum concentration was slightly shorter for test preparation (2.5 and 3.2 h, respectively), but not statistically significant. There are no significant differences between the areas under the concentration curves (1667 and 1665 ng.h/ml, respectively). After the calculation of pharmacokinetic parameters of concentration data measured by a non-specific method a significant difference for areas under concentration curves was seen (3709 and 4600 ng.h/ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Qualitative analysis of drug prescription in a geriatric population sample.

The rationality of specialist drug prescription in 154 patients older than 64 in 3 Zagreb homes for the aged was analyzed over an 11-month period. Categories analyzed were: number of prescribed drugs, justification of prescription, adequacy of the dose, route, form and therapy duration of the prescribed drugs, adequacy of the type of the prescribed drugs in the advanced age and the presence of contraindications of drugs used. The criterion of the rational drug use was the WHO's modified definition of rational drug therapy: "Application of an appropriate drug by a correct route in an adequate dose over a sufficiently long period of time". This basic criterion was further elaborated in relation to the analyzed categories. There were 2.66 (+/- 1.65) prescribed drugs per visit in which drugs were prescribed. In all analyzed categories, distinctive aberrations from the principles of rational drug prescription were found. One hundred and sixty-four (41.4%) of all drugs were unjustifiably prescribed and 103 (26.4%) were not dosed correctly. The duration of the therapy was inadequate for 60 (15.4%), route for 41 (10.5%), form for 32 (8.2%) of drugs prescribed. Seventy-five (19.3%) were not adequate because of patients' age and 15 (3.9%) were prescribed in spite of existing contraindications.

Clinical pharmacology in Eastern European countries.

The current status of clinical pharmacology (CP) in the countries of the former Eastern block is presented. The difficulties in obtaining an accurate comparative view are pointed out. CP is unevenly developed in Eastern European countries and the number of hours devoted to basic/clinical pharmacology differs considerably 100/nil to 240/50. The same is true for the orientation of clinical pharmacology, where present. It is mainly basic in only a few countries (Rumania, Turkey, some parts of the former Yugoslavia) and mainly clinical in Czecho-Slovakia, Croatia, Hungary, Poland, Greece. The number of CP units and CP specialists varies greatly as well (from none to more than 10 per country). The awareness that CP, in many countries is still young and the branch of (clinical) medicine is of great importance, not only for rational pharmacotherapy but also for other services as well, education and research is growing. In spite of the fact that the present status of CP in Eastern European countries is generally unsatisfactory, there are realistic chances that in the (near?) future, CP will develop to match the activities now present in the more developed countries.

A dynamical model for the separation of secondary resistance from tolerance to nitroglycerin infusion.

A dynamic model for the estimation of a residual hypotensive efficacy of nitroglycerin (NG) infusion was constructed to distinguish secondary resistance from tolerance to NG, as lost vs weakened efficiency. The model was tested by individual comparison in 82 of 92 patients with acute myocardial infarction or unstable angina. Ten patients were excluded from the study protocol due to complications that required therapy modification. NG infusion (20 micrograms/ml) efficiency was initially confirmed by a 10% decrease in the mean brachial artery (cuff) blood pressure. The infusion (63 hours mean duration) was discontinued every 12 hours for 30 minutes and pressure changes were analyzed. If NG hypotensive efficacy was maintained (as proved by at least 10% pressure increase), infusion was carried on using the initial dose. Lack of 10% pressure increase after 30-minute infusion discontinuity (tolerance) indicated the need for an increase in the NG dose until 10% pressure decrease (not below 105/60) was obtained. Lack of 10% pressure decrease, with a 5-fold increase in NG dose (up to 320 micrograms/ml), was considered to be a sign of secondary resistance. There were no proceeding complications and tolerance was found in 72 patients. Beside tolerance, secondary resistance was simultaneously present in 16 patients, while the NG efficacy was restored by dose increase in the remaining 78% of tolerant patients. "Paradoxical" pressure decrease was noted in 12 tolerant patients after the infusion interruption, while "paradoxical" pressure increase was observed in 3 resistant patients during the infusion acceleration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and interactions of digoxin, theophylline and furosemide in diseases with edema.

In diseases with generalized edema caused by decompensated heart and liver diseases or kidney failure digitalis preparations, diuretics and theophylline -- if lung disease accompanies one of the above states -- are often used. Literature dealing with theophylline, digoxin and furosemide pharmacokinetics in edematous diseases was analyzed as well as theophylline or digoxin interactions with furosemide. The results obtained in these investigations are very dissimilar, even contradictory. In all the drugs investigated, it was found that serum drug concentration was reduced, that there were no changes in comparison with non-edematous diseases and that drug concentrations were elevated in edematous diseases. Many problems in this field remain unsolved requiring further investigations of digoxin, theophylline and furosemide pharmacokinetics in liver, heart and kidney diseases accompanied by edema. As these drugs are often administered in these states, and having in mind their narrow therapeutic range (digoxin, theophylline), intoxication or a drug concentration decrease below the possibility of inducing any therapeutic effect are possible.

[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.

Prophylactic administration of ranitidine after sclerotherapy of esophageal varices.

The present trial was carried out to determine the usefulness of H2-receptor antagonist drug therapy for the prevention of esophageal bleeding and esophageal varices in patients who underwent sclerotherapy. According to randomization, out of the 58 patients, 28 received, along with the usual standard therapy, ranitidine and 30 received placebo. Ranitidine, 50 mg, was administered intravenously over a period of 3 days every 8 hours, and then 150 mg of ranitidine was given per os in the evening for one month. For improvement of hemostasis and during the elective sclerotherapies, 1% polidocanol was used as the sclerosant. During each puncture, 2 ml was injected. Injections were paravasal and intravasal. After sclerotherapy, endoscopic examinations were carried out on the third day and one month later. Necrosis was noted in 42% of the patients and esophageal mucosal inflammation in 26%. Esophageal ulcers did not occur. There was no statistically significant difference between the two groups in terms of age, sex ratio, cause of liver cirrhosis, and the Child's classification. The size of the esophageal varices had no effect on the development of esophageal mucosal changes in correlation with the quantity of sclerosant. The comparison of the two groups of patients, sclerosed for hemorrhage and sclerosed electively, showed no statistically significant difference regarding esophageal mucosal changes. No differences between the ranitidine and placebo groups of patients were observed in this indication. It can be concluded that esophageal mucosal changes probably arise as a consequence of the sclerosant, its concentration, quantity and mode of application.(ABSTRACT TRUNCATED AT 250 WORDS)

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.