Relation between urinary cytology abnormalities and cyclosporine A therapy in bone marrow transplant recipients.

The aim of the study was to determine the relationship, if any, between abnormalities in urinary cytology and the administration of cyclosporine A in bone marrow transplant recipients. Specific attention was given to the presence of tubular cells with round inclusions (TCRI). Two bone marrow transplant recipient groups were studied: one with allogeneic bone marrow transplantation (BMT) (20 patients) who were treated with cyclosporine A, and the other with autologous BMT (12 patients) who did not receive cyclosporine A. Urinary cytology showed TCRI in 41.66% of the patients after autologous BMT and in 80% of the patients after allogeneic BMT. In the group of patients treated with allogeneic BMT, the occurrence of TCRI was associated with a high incidence of glycosuria and was followed by an increase in the blood level of cyclosporine A, an increase in the serum creatinine concentration and a decrease in the creatinine clearance. These results demonstrated that TCRI, although related to, were not found to be exclusively specific to the administration of cyclosporine A.

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.

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)

[Paracetamol poisoning--case report]. / Otrovanje paracetamolom--prikaz slucaja.

A case of paracetamol poisoning in 17-month-old girl is presented. Clinical features and therapeutic procedures are described. Differences in paracetamol metabolism between children and adults are compared. Differences in the incidence of paracetamol poisoning between Croatia and USA are surveyed. The role of a physician in the education of parents and medical stuff on paracetamol toxicity is emphasized.

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.

[Changes in plasma proteins and drug distribution in kidney and liver diseases]. / Promjene plazmatskih proteina u bolestima bubrega i jetre i distribucija lijekova.

Kidney and liver diseases induce alterations in drug binding to plasma proteins. These alterations are caused by qualitative and quantitative changes of plasma proteins and the presence of endogenous substances which act as competitive inhibitors of drug binding to plasma proteins. These changes are the most prominent in nephrotic syndrome and uremia among kidney diseases and in cirrhosis among liver diseases. The more important drugs in which the free fraction is changed in these entities are listed in the tables. The changes in drug distribution caused by plasma protein alterations may induce significant changes in entire drug pharmacokinetics. Discussed are theoretically expected and experimentally proven changes in plasma proteins in kidney and liver diseases and their influence to drug action and dosing regimen.

[Analysis of the use of digitalis in a sample of the geriatric population]. / Analiza primjene digitalisa u uzorku gerijatrijske populacije.

Rationality of digitalis use in 20 elderly patients in long term-care institution was analysed using the method of correlation of the past medical history, clinical examination and basic laboratory findings. After consultation of clinical pharmacologist, general practitioner and medical biochemist it was possible to stop the digoxin therapy in 6 (30%) of the patients. Four (20%) patients were hypersaturated with digoxin. Lack of indication was the reason for stopping the digitalis in one of them. Therapy was modified in 3 patients. Use of digitalis was rational in 10 (50%) of the patients. The results suggest that digitalis was prescribed too often in this sample of the elderly patients.

[Blue color vision as a sign of digitalis poisoning]. / Cijanopsija kao znak intoksikacije digitalisom.

The paper deals with the course of the illness in a 66 years old male, who had taken an amount of 0.2 mg of medigoxin for an unknown period of time, because of chronic heart failure due to atherosclerotic heart disease and chronic atrial fibrillation. He have had a cholelithiasis also and reduced renal reserve. He was admitted by an emergency admittance because of nausea, vomiting, color vision disturbances: blue colored vision, and with other signs of digitalis toxicity: diffuse abdominal pain, an absolute arrhythmia with a slow ventricular rate, and with a short corrected Q-T interval in an electrocardiogram of 0.315 seconds and with high serum digoxin level reacted 3.8 nmol/L. After stopping of a digitalis treatment, in a period of time of four days, all signs of digitalis toxicity including blue color vision disturbances disappeared. In the paper that rare sign of digitalis toxicity is discussed.

[The chemical war in Croatia]. / Kemijski rat protiv Hrvatske.

During the present war against the Republic of Croatia, chemical weapons have been used by the Yugoslav Federal Army (YFA) against both civilians and Croatian Army soldiers. The use of irritants was suspected (Vukovar, Bogdanovci and Vinkovci, October-November, 1991; Solin in the Split area, September, 1991) and proved (Velika Gorica in the Zagreb area, September, 1991; Cakovec, November, 1991) in many cases. The use of psychochemical incapacitating agents (Bilje near Osijek, July, 1991), as well as of psychostimulants in YFA own soldiers (Zadar, August, 1991) has been suspected on clinical findings or laboratory tests. The use of acetylcholnesterase inhibitors was proved in one aggressor's diversion (Zadar, Krusevo, July, 1991). Phosphorus from projectiles and fuming boxes caused poisoning and skin burns due to incineration (Vukovar, November, 1991). YFA used the civilian's fear of chemical and biological weapons, throwing untoxic substances all over the Croatian territory. Great ecocide problems have occurred with massive industry devastation (Sisak, Osijek, October, 1991-January, 1992), with enumerous amounts of toxic substances released into the soil and river aquatoria.

[Acute psychoses caused by digitalis poisoning]. / Akutna psihoza kao posljedica intoksikacije digitalisom.

The course of illness in a 76-year-old woman with a history of dyspnea being treated with medigoxin, 0.1 mg daily, is presented. Five days before the symptoms of acute psychosis developed she had used medigoxin, 0.2 mg per day. On the fifth day of that therapy, the patient developed acute psychosis and was admitted to the Department of Psychiatry. An electrocardiogram recorded monomorphous ventricular premature beats at a frequency of 50%, the S-T segment depression of the anterolateral location with the diphasic T-wave and the corrected Q-T interval of 0.377 to 0.355 seconds. Five days after the discontinuation of medigoxin therapy, serum digoxin concentration was 2.2 nmol/L, out of which follows that two days after digitalis was stopped it was 4.0 nmol/L and that concentration was probably higher at the moment when acute psychosis developed. The patient was free of symptoms of acute psychosis after a single promazine dose and discontinuation of medigoxin.

Pharmacokinetics of azithromycin after single oral dosing of experimental animals.

Azithromycin, a macrolide antibiotic with an enhanced antimicrobial spectrum, was found to have a longer half-life than erythromycin, with marked tissue penetration. The pharmacokinetics of azithromycin after oral administration were compared with those of erythromycin in rats (200 mg kg-1) and rabbits (80 mg kg-1). Concentrations of azithromycin in liver, lung, kidney, ileum, and brain were higher than serum concentrations. The slow decline in tissue concentrations was evident from the biphasic elimination profile. Thus, advantageous pharmacokinetic properties and the broader antimicrobial spectrum of azithromycin relative to erythromycin appear to further support its therapeutic potential.

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.

[An increase in plasma digoxin levels after discontinuation of therapy]. / Porast koncentracije digoksina u plazmi nakon prekida terapije.

In this paper, a course of the disease of a 68-year-old patient treated with medigoxin for congestive heart failure is presented. After being withdrawn from his treatment at the hospital, the patient was administered spironolactone and furosemide. The plasma digoxin level at entry was 1.1 nmol/L, after five days it reached 3.2 nmol/L, and after ten days it was 2.3 nmol/L. The patient had a normal renal function. The interference of spironolactone and its metabolites with the digoxin radioimmunoassay was discussed as a possible explanation for this phenomenon.

Combination of cyclosporin and methotrexate for prophylaxis of acute graft-versus-host disease after allogeneic bone marrow transplantation for leukemia.

From May 1985 to July 1989, 76 patients with leukemia (30 acute myelogenous leukemia, 24 acute lymphoblastic leukemia and 22 chronic myeloid leukemia) were randomized to receive either cyclosporin (CSP) alone (n = 39) or CSP combined with methotrexate (CSP + MTX, n = 37) for graft-versus-host disease (GVHD) prophylaxis. Patients were conditioned with total body radiation and cyclophosphamide followed by bone marrow infusion from an HLA-identical sibling. Engraftment of the transplanted bone marrow was similar in both groups. The incidence of moderate to severe acute GVHD was significantly higher in the CSP group compared with the CSP + MTX group (20 (51%) versus 9 (25%), chi 2 = 4.76, p less than 0.02). There was no significant difference in the incidence of chronic GVHD. Survival was significantly better for the CSP + MTX group (63 +/- 16%) compared to CSP alone (42 +/- 18%). Leukemia-free survival tended to be better for the CSP + MTX group (55 +/- 17% versus 32 +/- 16%).

[Is there a correlation between changes in the electrocardiogram and high serum digoxin levels in the aged?]. / Postoji li povezanost promjena u elektrokardiogramu i visoke koncentracije digoksina u serumu u starijih osoba?

In a group of 84 patients aged 65 to 89 years with the high serum digoxin levels, electrocardiograms, as well as serum creatinine and serum potassium levels were analysed. In an electrocardiogram, a rhythm and conduction disturbances, PR interval, PTQ index, corrected QT interval, both a corrected QT interval I using the second root from a heart frequency and a corrected QT interval II using the third root from a heart frequency were studied. A rhythm disturbances were seen in 37% and a conduction disturbances in 39% of the patients, but no changes were observed in 24% of the patients. There was no correlation between serum digoxin levels and the PR interval. There was a slight correlation between serum digoxin levels and the PTQ index, and no correlation could be demonstrated between serum digoxin levels and a corrected QT interval I as well as a corrected QT interval II. Also, no correlation was evident between serum digoxin levels and serum creatinine levels, although many of those patients suffered from chronic renal failure. In an analysis of the influence of digoxin on the heart, electrocardiographic changes together with serum digoxin levels and serum potassium levels have to be followed. Only one of these parameters is not enough for the analysis of the effect of digoxin on the heart. It is concluded that clinical examination is most important in the analysis of digoxin action.

[Ethylene glycol poisoning treated with hemodialysis]. / Otrovanje etilen glikolom lijeceno hemodijalizom.

The paper deals with the course of illness in a patient aged 56 years who had ingested accidentally an unknown amount of alcoholic drink followed by 150 ml of 95 percent solution of ethylene glycol. The patient was admitted to the intensive care unit 28 hours after the accident. The serum ethylene glycol concentration reached 14 mg/100 ml. The slow elimination of ethylene glycol during 28 hours before haemodialysis could be explained by the protective effect of ethanol which the patient had consumed before ethylene glycol. The method of extracorporeal haemodialysis was applied for four hours; the membrane surface was 1.3 m2 and blood velocity 200 ml/min. The rate of clearance of ethylene glycol and its metabolites was 110-150 ml/min. The total amount of ethylene glycol eliminated during four hours of haemodialysis came to about 5 g. Four hours from the beginning of the treatment the serum ethylene glycol concentration was not measurable. As the patient developed signs of acute renal failure the haemodialysis method was applied two more times. The patient was dismissed from hospital in good clinical condition, with normal diuresis and repaired renal function on the 13th day from admission.

Determination of serum diltiazem concentrations in a pharmacokinetic study using gas chromatography with electron capture detection.

An open cross-over randomized clinical trial was performed in nine healthy humans to determine steady-state pharmacokinetics and bioavailability of three oral diltiazem preparations, tablets containing 60 and 90 mg of diltiazem hydrochloride, administered in total daily doses of 180 mg. Serum drug levels were determined by gas chromatography with electron capture detection following a simple extraction procedure. Blood samples were collected before and at several post-dosing intervals after administration of the last dose in steady state, and pharmacokinetic parameters were calculated. The steady-state diltiazem concentrations in sera were determined 48 h after the first dose, and were (mean +/- SD): 46.4 +/- 28.1, 60.8 +/- 36.3 and 36.8 +/- 22.6 micrograms l-1 for Pliva 60, Pliva 90, and Aldizem 90 diltiazem preparations, respectively. The corresponding elimination half-lives were 5.6 +/- 2.0, 5.2 +/- 1.8 and 6.9 +/- 3.2 h; peak concentrations were 88.4 +/- 29.5, 153.5 +/- 86.5 and 139.2 +/- 72.5 micrograms l-1, and areas under the concentration curves (AUC 12 h) were 477.4 +/- 172.5, 989.2 +/- 536.3 and 817.9 +/- 494.5 micrograms h-1, respectively.

Determination of serum atenolol using HPLC with fluorescence detection following isolation with activated charcoal.

In order to determine the bio-availability and pharmacokinetics of two oral 100 mg atenolol preparations, a simple analytical method was developed. Atenolol was determined in serum submitted to an extraction procedure consisting of: (a) adsorption of atenolol to activated charcoal at pH 11, (b) washing the charcoal with water to remove co-extracts and (c) elution of atenolol from the charcoal with organic solvent. The extracts were then analysed by high-performance liquid chromatography (HPLC) with fluorescence detection. The pharmacokinetic parameters obtained from eight healthy humans involved in a clinical bioavailability trial are also presented.