Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab.

OBJECTIVE: This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage METHODS: NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. RESULTS: The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. CONCLUSION: The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.

Effect of cytostatics administration in rats on leukocyte cytochemical markers.

The influence of cytostatic drugs (busulphan, chlorambucil, prednisone, 6-mercaptopurine, L-asparaginase) on the activity of alkaline and acid phosphatase, alpha-naphtolacetate esterase and the content of glycogen and lipids in leukocytes of peripheral blood in healthy rats was investigated. No analogy was reported between the changes of cytochemical reactions in healthy population of leukocytes in rats as compared with the changes (observed in preceding papers) of cytochemical reactions in leukocytes of patients with leukemia under the influence of the same cytostatic drugs.

Influence of chemotherapy on some cytochemical reactions in patients with acute leukemia.

The influence of cytostatic drugs (L-asparaginase, vincristine, 6-mercaptopurine, amethopterine, prednisone) on the activity of alkaline and acid phosphatase, alpha-naphtol-acetate esterase, the content of glycogen and lipids in leukocytes of peripheral blood in patients with acute leukemia was investigated. Under the influence of anti-leukemic drugs some cytochemical reactions typically changed in different forms of acute leukemia showed tendency to normalization being sometimes more distinctive than leukocytosis or even than white blood picture. In patients who did not show any improvement during the treatment the disturbances of cytochemical reactions intensified or, sometimes, remaining unchanged. The repetition of examination of cytochemical reactions changing distinctively in the chemotherapy may simplify the treatment control by better estimation of its efficiency and give some prognostic hints.

Central action of 2-amino- and 2-amino-5-aryltetrahydropyrimidinediones-4,6.

The influence on the central nervous system of five 2-amino- and 2 amino-5-aryltetrahydropyrimidinedione-4,6 derivatives was studied. The most favorable action was exerted by benzylamine-tetrahydropyrimidinedione, which inhibited spontaneous and amphetamine-induced motility most strongly, acted synergistically with hexobarbital, was the only one of the studied group of compound which delayed convulsions induced with pentamethylenetetrazole and amphetamine, and potentiated most strongly the central action of DOPA in mice with inhibited MAO activity. The weakest effects were produced by methylpiperazinephenyl-tetrahydropyrimidinedione.

Effect of chronic exposure to carbon disulfide on biotransformation of phenazone in rabbits.

A significant but reversible inhibition of phenazone elimination was observed in rabbits chronically exposed to CS2. Lack of significant difference of phenazone pharmacokinetics in exposed rabbits 24 h after the last exposure compared with the control group, indicates that alteration of phenazone elimination after chronic exposure to CS2 is reversible. The results obtained with phenazone as a model substance suggest that, during chronic exposure to CS2, elimination of other drugs metabolized by the pathway similar to phenazone may also be altered. This should be taken into account in selecting their dosage.

Monitoring methotrexate therapy in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this work was to study methotrexate (MTX) kinetics and their relation to the effectiveness of the therapy in patients with rheumatoid arthritis (RA). Other aims were to analyze the influence of MTX on liver, kidney, hematopoietic function and to determine the possibility of using early drug concentrations to predict the subsequent value of the treatment. MATERIAL AND METHODS: The observations were carried out in 49 patients with RA after the first dose of MTX and after 7 months of treatment. Methotrexate concentrations in blood serum and urine were determined using fluorescence polarization immunoassay applying a TDx Abbott analyzer. RESULTS: No correlation between concentrations, pharmacokinetic parameters and the duration of the disease, its activity, clinical symptoms, observations pertaining to the disease made by physician and patients and morning stiffness of joints was seen. Of those tests for the evaluation of liver, kidney and hematopoietic function, only the mean activity of N-acetyl-beta-D-glucosaminidase (NAG) in urine was significantly elevated both before and after treatment with MTX when compared to corresponding values in the control group of healthy subjects. We have formulated equations allowing for the early recognition of patients with a risk of adverse effects due to impaired elimination of MTX from the body. CONCLUSION: Our results show that monitoring MTX therapy using concentrations in patients with RA does not significantly improve the effectiveness of the treatment, but it can play an important role in increasing the safety of this drug.

Phenazone as a marker of liver-metabolic function in patients with acute leukemia.

OBJECTIVE: The aim of this work was to study the influence of neoplastic disease, especially acute myeloblastic leukemia (AML), and its chemotherapy on the activity of hepatic microsomal enzymes by using phenazone, as a marker of oxidative drug metabolizing activity. METHODS: The observations were carried out in 21 patients with AML and in 53 healthy volunteers. The influence of disease on phenazone kinetics was studied before chemotherapy and the effect of anticancer drugs administration after the first cycle of chemotherapy. RESULTS: The mean phenazone half-life time was significantly shorter in patients with AML (8.79 (3.01) h) than in control group (11.08 (3.61) h) (p < 0.012). Treatment with anticancer drugs, especially with epirubicine, inhibited phenazone elimination. The mean phenazone half-life time was significantly longer (18.08 (8.80) h) and the mean metabolic clearance rate was significantly smaller (33.92 (15.40) ml/min) after chemotherapy in comparison with the initial value, before treatment (10.22 (2.90) h), (p < 0.01) (50.33 (20.29) ml/min) (p < 0.008). CONCLUSION: Our results lead to the conclusion that phenazone is an important index of hepatic metabolic capacity in patients with acute myeloblastic leukemia. The evaluation of its kinetics allowed to early recognition of the presence and the degree of drug oxidizing modification. Acceleration of phenazone elimination before treatment and its inhibition after chemotherapy, particulary epirubicine, may suggest that in patients with AML elimination of the other drugs metabolized by the pathway similar to phenazone also may be changed. It should be considered in individualization of their dosage regimen.

The influence of locally implanted high doses of gentamicin on hearing and renal function of newborns treated for acute hematogenous osteomyelitis.

BACKGROUND: [corrected] Osteomyelitis and arthritis still present a serious diagnostic and therapeutic problem. Difficulties arise in particular in the treatment of acute hematogenic osteomyelitis (AHO) in newborns where mega-doses of gentamicin are administered locally for about 3 weeks. Gentamicin possesses strong oto- and nephrotoxicity and the occurrence of these adverse effects depends on the duration of treatment and the serum drug concentration. OBJECTIVE: Aim of the study was to evaluate the influence of local gentamicin application on auditory and kidney functions. MATERIAL AND METHODS: Twenty newborns (14 boys and 6 girls) with AHO were treated at the Department of Pediatric Surgery, Marciniak Hospital, Wroclaw, Poland, by local implantation of miniseptopal or gentamicin sponge. Serum urea, creatinine, antibiotic concentrations and NAG activity/g creatinine ratio in urine were estimated before and 1, 4, 8, 16 days after the operation and compared to values in the control group. Brainstem-evoked auditory potentials (BAEP) were examined before, during the first 3 weeks, and 6-11 months after gentamicin implantation. RESULTS: Mean gentamicin serum concentrations were: 0.67 +/- 0.98 mg/l on the 1st day, 0.16 +/- 0.37 mg/l on the 4th day, 0.03 +/- 0.09 mg/l on the 8th day, 0.01 +/- 0.03 mg/l on the 16th day after operation and did not exceed the upper limit of the therapeutic range. N-acetyl-beta-D-glucosaminidase (NAG)/g creatinine in urine ratios were satisfactory: 77.91 +/- 36.22 UI/g before the operation, 146.51 +/- 82.27 UI/g on the 4th, 162 +/- 111 UI/g on the 8th, 168 +/- 59.83 UI/g on the 16th day after operation and were statistically significantly (p < 0.05) higher than values in the control group. Serum urea and creatinine levels were in the normal range in all groups. Initial BAEP were well in the normal range in 15 of 16 children before treatment and in 14 of 16 children after treatment. CONCLUSIONS: Locally applied gentamicin as miniseptopal or sponge in newborns produces gentamicin concentrations close to the minimal therapeutic serum concentration which are present over a prolonged period. The raised NAG values in urine and normal serum urea and creatinine levels during treatment with gentamicin without concomitant clinical symptoms of renal failure suggest subclinical destruction of the renal tubules. Lack of change in BAEPs shows that there is no impairment of auditory function.

Metabolic functions of the liver during chemotherapy in children with acute lymphoblastic leukemia.

OBJECTIVE: The purpose of the present work was estimation of liver function using the phenazone test and commonly used biochemical tests in children with acute lymphoblastic leukemia (ALL) during anticancer treatment. METHODS: Observations were carried out in the same 21 patients with ALL before the beginning of chemotherapy, after Protocol I and after Protocol M of the antileukemic treatment carried out according to the program BFM 86. RESULTS: The applied chemotherapy inhibited phenazone elimination. Both phenazone half-life and metabolic clearance rate were significantly different in patients after treatment with anticancer drugs, especially with high-dose of methotrexate (MTX), from those in patients before the beginning of chemotherapy (p < 0.001). Moreover, after MTX administration transaminases activity and serum bilirubin concentration were significantly higher than before treatment (p < 0.05). CONCLUSION: Our results showed that in children with acute lymphoblastic leukemia, anticancer chemotherapy decreased liver metabolic capacity. Particularly, high-dose methotrexate treatment altered the elimination of phenazone by inhibiting the activity of hepatic mixed function oxidase system. This change may lead to an increase in toxicity of active drugs which are metabolized by this enzyme system. In addition, altered activity of liver metabolic function can impair transformation of prodrugs to active forms. It should be considered in selection of individual drug dosages. The objective estimation of the type and degree of liver dysfunction can only be achieved by the combination of a quantitative phenazone dynamic test and static biochemical tests.

The influence of CYP2D6 polymorphism on the antiarrhythmic efficacy of propafenone in patients with paroxysmal atrial fibrillation during 3 months propafenone prophylactic treatment.

OBJECTIVE: Propafenone (PPF) is an antiarrhythmic, Class Ic agent. Its metabolism is genetically controlled by a cytochrome P450 isoenzyme named CYP2D6, which shows polymorphism in human population. The aim of this paper was to determine the correlation between the antiarrhythmic efficacy of PPF and the oxidation phenotype. SUBJECTS AND MATERIAL: The study group consisted of 42 patients, aged 36 to 75 years, suffering from paroxysmal atrial fibrillation (AF). The oxidation phenotype was described by the metabolic ratio (MR) of sparteine. The MR value separated the group of poor metabolizers (MR > 20) from the group of extensive metabolizers (MR < 20) with the subgroup of very extensive metabolizers (MR < 1). METHOD: The study was conducted during a 3-month PPF therapy for the prophylaxis of paroxysmal atrial fibrillation. PPF was given orally, 300-450 mg/day. The oxidation phenotype was checked prior to the administration of PPF. Serum concentration of PPF at 7, 11 days and the end of PPF therapy were determined. Statistical analysis of data was performed with the chi2 test and the Pearson's correlation methods. RESULTS: In the group of 42 patients, PPF therapy was 100% effective in poor metabolizers (PM). In extensive metabolizers (EM), 61% efficacy was observed with efficacy 0% in very extensive metabolizers (VEM). The correlation between oxidation phenotype and the ability to maintain sinus rhythm (SR) was statistically significant (r = 0.414, p < 0.05). CONCLUSIONS: The antiarrhythmic efficacy of propafenone depends on the oxidation phenotype; 100% efficacy occurred in the group of poor metabolizers whereas PPF, at the dose tested, was ineffective in very extensive metabolizers.

[Clinical significance of the pharmacogenetics in psychiatric and neurological syndromes]. / Kliniczne znaczenie farmakogenetyki w zespolach psychiatrycznych i neurologicznych.

The aim of the paper was the presentation of the newest results of studies in pharmacogenetics of psychiatric and neurological syndromes. It was especially emphasized an important role of pharmacogenetics in safe pharmacotherapy of psychiatric and neurological syndromes.

[Occurrence of the fast acetylation phenotype in persons with the radicular syndrome. Preliminary report]. / Wystepowanie fenotypu szybkiej acetylacji u osób z zespolem korzeniowym. Doniesienie wstepne.

The polymorphism of drug acetylation is an important factor determining the therapeutic effectiveness and toxicity of the drugs metabolized through acetylation. The purpose of the study was determination of the acetylation phenotype in patients with radicular pain syndromes by means of a test with sulphadimidine acetylation. The test was done in 23 cases of radicular pain syndromes and in 45 healthy volunteers serving as controls. In the control group the fast acetylation phenotype was found in 23 cases (51%) while 22 controls (49%) were slow acetylators. In 23 patients with radicular syndromes 15 (65%) were fast acetylators and 8 (35%) were slow acetylators. The percent of fast and slow acetylators was statistically significantly different between the group of patients and the control group. Mathematical analysis of the results by means of the chi 2 test showed significance of the difference at p less than 0.05. These results may show a predisposition of subjects with fast acetylation phenotype for development of radicular syndromes.

[Clinical significance of oxidation and acetylation genetic polymorphism in patients with Parkinson's disease]. / Kliniczne znaczenie polimorfizmu oksydacji sparteiny i acetylacji sulfadimidyny u chorych na chorobe Parkinsona.

The relationship between genetically determined polymorphic oxidation and acetylation and susceptibility to some disease has aroused much interest. The aim of our study was to evaluate whether patients with Parkinson's disease differ from healthy persons in their ability to oxidize sparteine and acetylate sulfadimidine as model drugs. Oxidation and acetylation phenotypes were estimated in 50 patients with Parkinson's disease. The control group consisted of 160 healthy volunteers for comparison of oxidation phenotype and 60 healthy volunteers for comparison of acetylation phenotype. The phenotyping of oxidation revealed two distinct populations among 50 patients with Parkinson's disease: 47 persons (94%) were extensive metabolizers of sparteine and 3 persons (6%) were poor metabolizers. In 160 healthy persons, 146 persons (91.2%) were extensive metabolizers of sparteine and 14 persons (8.8%) were poor metabolizers. The difference between frequency distribution of PMs and EMs in healthy persons and in patients with Parkinson's disease was not statistically significant. The phenotyping of acetylation showed among 50 patients with Parkinson's disease 38 persons (76%) slow acetylators and 12 persons (24%) rapid acetylators. In 60 healthy volunteers the phenotype of slow acetylation was observed in 29 persons (48.3%) and rapid acetylation in 31 persons (51.7%). The prevalence of slow acetylators among patients with Parkinson's disease in comparison to healthy volunteers was statistically significant (chi 2 = 8.7677/p < 0.003). The results of our study may suggest that the slow acetylation phenotype is associated with increased risk of the development of Parkinson's disease.

[Clinical significance of the determination of oxidation and acetylation phenotype in patients with multiple sclerosis]. / Kliniczne znaczenie badania fenotypu oksydacji i acetylacji u chorych na stwardnienie rozsiane.

Genetically determined individual differences in the ability of oxidation and acetylation of certain drugs have raised in recent years a considerable interest in view of their clinical importance. The purpose of the study was finding out of a possible difference in the ability to oxidized sparteine and to acetylate sulfamidine as model drugs between patients with multiple sclerosis and healthy control volunteers. The study was carried out in 23 patients with MS. The control group comprised 160 healthy subjects for comparison of oxidation phenotype. The results of determination of acetylation phenotype were obtained in 45 healthy controls. The study showed that in 160 controls 146 were extensive (rapid) metabolizers (91.3%) and 14 were weak (slow) metabolizers of sparteine (8.7%). In the group of MS patients 21 were extensive metabolizers (91.3%) and 2 were weak metabolizers (8.7%). The determination of acetylation phenotype in 45 controls showed 51% of rapid acetylation (23 subjects) and 49% of slow acetylation (22.

[Effect of contamination of drinking water with sodium fluoride on the alkaline phosphatase activity of peripheral granulocytes in the rat]. / Wplyw zanieczyszczenia wody pitnej fluorkiem sodu na aktywnosc fosfatazy zasadowej w granulocytach krwi obwodowej u szczurów.

During a 4-week administration of water contaminated with sodium fluoride in doses of 20 mg/kg of body weight and above, decreased activity of granulocytes alkaline phosphatase and increased count of leucocytes in peripheral blood were found. This may be indicative of a toxic effect of high doses of sodium fluoride on the leucocytic system. Thus, observation of those parameters in people and animals from the area surrounding the factories, contaminated by fluorine compounds, seems advisable.

[Drug interactions]. / Interakcje leków.

Adverse drug interaction it is therapeutically unwanted effect, which may appear during simultaneous treatment with two or more drugs and as a consequence may reduce or increase their pharmacologic action; may lead to the toxic effects and even to the appearance of qualitatively different from the expected one pharmacologic action. In this article are presented criteria determining the clinical significance, risk factors, kinds and consequences of adverse drug interactions. The drugs which can be the most dangerous in the context of adverse interactions, when are used simultaneously with other medications are: anaesthetics, anticoagulants, antidiabetics, nonsteroidal antiinflammatory drugs, drugs used in cardiac and circulatory system diseases, hypolipaemic drugs, theophylline, antibiotics, psychotropics, antiepileptics, antineoplastics, cyclosporine, tacrolimus.

[Adverse reactions of coumarin derivative interactions]. / Niepozadane nastepstwa interakcji pochodnych kumaryny.

Many drugs interact with warfarin and other oral anticoagulants. Some of them reduce the activity of the anticoagulants and intensify of thrombosis symptoms. Others increase the activity and can cause bleeding if the dosage of the anticoagulant is not reduced appropriately. Both situations are clinically serious and may be fatal. Details of these interactions are given in this article.

[Interactions of nonsteroidal anti-inflammatory drugs]. / Interakcje niesteroidowych leków przeciwzapalnych.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and very commonly prescribed, especially in the elderly population. Many of NSAIDs are over-the-counter (OTC) drugs, which increase risk of interactions with other drugs. Types of interactions, their clinical relevance, groups of patients with increased risk of interactions and prevention methods are shortly described.

[Unwanted drug interaction between anti-arrhythmic drugs and drugs used for heart failure]. / Niepozadane nastepstwa interakcji leków stosowanych w zaburzeniach rytmu serca i w niewydolnosci krazenia.

The appearance of adverse drug reactions may depend on the category of used drugs as well as on the coexistence of a pathological stage. Clinically important are: interactions of digitalis glycoside drugs leading to the occurrence or intensification of toxic symptoms characteristic for those drugs; interactions of antiarrhythmic drugs which may cause proarrhythmic effects and hypotension, and also interactions of nitrates resulting in lowering of the blood pressure. Quinidine, verapamil, nitrendipine, amiodaron, propafenone, captopril, spironolactone decrease renal clearance of digoxin, and amilorid/triamteren lower the extrarenal clearance of this drug. Thus the outcome of those concommitant therapies is the increase of digoxin serum concentration and appearance of toxic symptoms. Clinically dangerous, in the course of the antiarrhythmic therapy, is the increased risk of the arrhythmia appearance when two or more antiarrhythmic drugs are applied concomitantly. Antiarrhythmic drugs class IA (quinidine, disopyramide), class III (sotalol, amiodarone), class IV (calcium channel blockers) used at the same time with potassium depleters diuretics or beta-blocking agents result in the inhibition of repolarization and the increased duration of activation potential with the risk of developing arrhythmia of the torsade de pointes types. Nitrates interactions are mainly of the pharmacodynamic character. Most common adverse drug reaction, observed during the concomitant nitrates and another circulatory drug therapy, is excessive lowering of the blood pressure. These may lead to the decrease in the therapeutic efficacy of these combinations. Interactions of circulatory drugs are numerous, sometimes difficult to predict and they may lead to the intensification of the adverse drug reaction and lowering of their therapeutic efficacy.

[Interactions between drugs and results of laboratory tests]. / Interakcje miedzy lekami a wynikami badan laboratoryjnych.

The aim of the paper was the presentation of the newest results of studies on the effects of drugs on clinical laboratory tests. It was especially emphasized an important and clinical significance of these effects of drugs on laboratory tests.