Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: Position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

Impact of kidney transplantation on restless legs syndrome.

AIM: Our study was to assess the impact of kidney transplantation on restless legs syndrome (RLS) in end stage renal disease (ESRD) patients. METHODS: A total of 75 patients after a successful kidney transplantation (39 males, 36 females) were assessed consecutively. All patients completed the self reported questionnaire focused on RLS 6 months after kidney transplantation with investigation of selected laboratory parameters. The questionnaire met the International Restless Legs Syndrome Study Group criteria for RLS diagnosis. RESULTS: 30 (40.54%) out of 75 patients met the RLS diagnostic criteria. From this RLS positive group, 8 (26.7%) of them reported a complete regression of symptoms, 13 (43.3%) reported symptoms relief, 6 (20.0%) were without any change and 3 (10.0%) reported worsening of symptoms after kidney transplantation. In the RLS positive group, the majority of patients (26-86.7%) reported the occurrence of the symptoms in the evening and 21 (70.0%) of RLS positive patients reported the onset of symptoms after the onset of renal disease. CONCLUSION: Although the secondary RLS in EDRS patients is very common, it is often unrecognized or misdiagnosed. We concluded that kidney transplantation, except the primary benefit to kidney replacement and to its function, has a secondary impact on other conditions such as RLS (Tab. 5, Fig. 4, Ref. 17).

[Personalised antibiotic therapy in a surgical intensive care unit overview of current knowledge and the results of an observational kinetic study]. / Personalizovaná antibiotická terapie na chirurgické jednotce intenzivní péce prehled soucasných znalostí a výsledky observacní kinetické studie.

INTRODUCTION: The current efforts of intensivists focused on individual antibiotic treatment in patients suffering from sepsis has inspired us to conduct an open prospective clinical study to assess the relationship between body fluid retention (>10 L/24 hours) and the efficiency of hydrophilic time-dependent antibiotics used in critically ill patients. Polytrauma and abdominal catastrophes are the most frequent causes of systemic inflammatory response syndrome (SIRS). Consequent body liquid retention is taken for a pathophysiological covariate modifying the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrophilic time-dependent antibiotics (betalactams and carbapenems). Not only body fluid retention but also changes in renal clearance are thought to be responsible for failure in PK/PD target attainment necessary for effective antimicrobial activity. To describe the importance of the pathophysiological covariates for the individual kinetic variables of a representative antibiotic (piperacillin) is the primary goal of this kinetic observational study. MATERIAL AND METHODS: Three patients with polytrauma and SIRS admitted at the ICU of the Surgical Department, Teaching Hospital Hradec Králové, whose condition was characterized by cumulative body fluid retention (>10 L), were eligible for enrolment. As per standard hospital protocol, the patients were administered with 4 g of piperacillin in combination with tazobactam 0.5 g intravenously by 1-hour (h) infusion every 8 h. A series of blood samples were taken 1, 2.5, and 5 h after the termination of the infusion. Urine was collected over each dosing interval and for 24 h. Piperacillin was detected using a previously validated HPLC method. Individual pharmacokinetic variables were estimated using non-compartmental pharmacokinetic analysis. Cumulative body fluid retention was calculated as the difference between fluid intake and output. Creatinine clearance (Cl) was used for renal function evaluation. PK/PD target attainment was analysed according to Carlier (2013). RESULTS: In three patients with polytrauma and SIRS, great interindividual and intraindividual differences in extravascular volume expansion, i.e. cumulative body fluid retention 2030 L and changes in renal function, were recorded. In 2/3 patients these pathophysiological changes as well as the clinical interventions administered resulted in augmented piperacillin clearance and an increase in distribution volume (Vd) (>20 L) with a maximum at Day 28 after initiation of therapy. In such patients treated with a standard dose of piperacillin, only minimum PK/PD target attainment (50% Ft >MIC) was obtained. In contrast, a patient suffering from renal dysfunction attained both minimum (50% ft >MIC) and maximum PK/PD target (100% ft >MIC). CONCLUSIONS: In three critically ill patients with polytrauma and SIRS, pathophysiological changes (covariates) had a profound effect on the key determinants of the pharmacokinetics (Cl and Vd), resulting in significant intraindividual variability in pharmacodynamic /pharmacokinetic target attainment necessary for therapeutic time-dependent antibacterial activity of piperacillin. Consequently, patients with augmented clearance of piperacillin may be at risk for treatment failure, and/or bacterial resistance without dose up-titration. A subsequent clinical study will be conducted to describe personalised kinetically guided antibiotic therapy.

Comparative root anatomy and root bud development after injury in two perennial herbs.

A bud bank is a pool of dormant meristems that enable plants to resprout after injury. While the bud bank on stem organs is established prior to injury as the stem grows, the bud bank on roots is considered at least partly formed as a response to disturbance events. To date, only woody species have been examined, and the establishment of reparative buds after injury without connection to the root vascular system has been confirmed; for herbs, no data are available. We tested whether root buds are formed spontaneously or induced after plant damage by studying root anatomy following plant injury in two congeneric perennial herbs. In a pot experiment with young plants of Inula britannica (root sprouter) and I. salicina (non-root sprouter), whole aboveground biomass was removed. Roots were sampled five times at 1-week intervals after disturbance events to evaluate bud occurrence and size, root and vessel diameters, sclerenchyma areas and carbohydrate storage. Compared to non-root-sprouting I. salicina, root-sprouting I. britannica presented more secondary thickening that was connected to adventitious bud formation and improved the root storage and transport capacity necessary for resprouting. Plant injury, in contrast to expectations, did not cause increased bud formation in I. britannica, and all buds were connected to the root vascular system. No root buds were observed in I. salicina. Our study implies that plants using bud banks on roots might depend on preformed buds. Comparative studies examining more species are needed to assess the generality of our findings.

Idiopathic intracranial hypertension: a retrospective clinical study.

BACKGROUND: Idiopathic intracranial hypertension is a disorder characterized by an increased intracranial pressure, without deformity and obstruction of the ventricular system. There is a predilection of occurrence in obese women of childbearing age. The pathogenesis of idiopathic intracranial hypertension is likely related to abnormalities in the balance between production and drainage of cerebrospinal fluid. Diagnosis is made by excluding the known causes of elevated intracranial pressure. OBJECTIVE: To evaluate the features, possible causes, treatment, and incidence of idiopathic intracranial hypertension as seen in patients attending our Department of Neurology. METHODS: We retrospectively analysed a group of patients diagnosed with idiopathic intracranial hypertension in our Department of Neurology during a twenty-year period (1989 to 2008). RESULTS: In six patients we confirmed the diagnosis of idiopathic intracranial hypertension during this period. Five of them were females and one was male, the average age of the patients was 32.30 years (22 to 52). The calculated incidence of idiopathic intracranial hypertension in our group was 0.15 per 100,000 persons. Out of these six persons there were four cases diagnosed in the last five years, changing the calculated incidence to 0.4 per 100,000 persons in this period. The average body mass index in our patients was 26.33 kg/m2 (20.1 to 31.38). CONCLUSION: We suppose that the increased incidence of idiopathic intracranial hypertension in our patients in the last five years has been associated with an advance in diagnostics. With literary data, half of our patients were obese or overweighted, but all of them underwent also hormonal treatment, some had iron deficiency and one of them was pregnant (Tab. 3, Fig. 1, Ref. 17). Full Text in free PDF www.bmj.sk.

A pilot study of pharmacokinetically guided dosing of oral methotrexate in the initial phase of psoriasis treatment.

BACKGROUND: Clinical studies of low-dose oral methotrexate (MTX) in the treatment of psoriasis and rheumatoid arthritis document a large interpatient variability in the pharmacokinetics of MTX, including its polyglutamates (MTXPGs) in erythrocytes (RBC). This can be a factor contributing to the variability of therapeutic and toxic effects. AIM: This pilot trial aimed to investigate the MTXPG concentrations in RBC as well as their relation to therapeutic and adverse effects during the initial 4 months of pharmacokinetically guided therapy with a divided-dose schedule (three doses of MTX separated by 12-h intervals once a week). SUBJECTS AND METHODS: Sixteen psoriatic patients (4 men and 12 women; mean age, 53 years; range, 28-69 years) with moderate-to-severe chronic plaque psoriasis [mean Psoriasis Area and Severity Index (PASI) = 24; range, 9-42] were enrolled in the study. Concentrations of plasma MTX and that of MTXPGs in RBC were assayed using liquid chromatography methods. The area under the concentration-time curve of plasma MTX in the interval 0-8 h post-dose (AUC(0-8 h)) was measured after a test bolus dose of 10 mg, and the starting weekly dose was individualized in order to achieve the target AUC(0-8 h) of 1800 nmol.h/L. The PASI, biochemistry, and haematology tests and MTXPGs levels in RBC were evaluated at baseline and at 4-week intervals. RESULTS: The AUC(0-8 h )achieved 1360 +/- 425 nmol.h/L (mean +/- SD: range, 778-2400 nmol.h/L). The mean (range) of individualized doses was 14.5 mg/week (7.5-22.5 mg). The mean (SD) steady-state concentration of total MTXPGs observed between days 85 to 110 reached 113 (34.6) nmol/L (range, 66.1-174 nmol/L). The PASI decreased from 24.0 +/- 8.0 (mean +/- SD) at baseline to 8.0 +/- 6.1 at day 110 (P < 0.001). Thirteen patients (87%) achieved a greater than 50% improvement in baseline PASI, and seven (47%) experienced a greater than 75% improvement. There was no relationship between the percent improvement from baseline PASI and the steady-state concentration of MTXPGs in RBC. All patients tolerated MTX well. Throughout the study period, there was a continuous increasing trend in the geometric mean values of the mean corpuscular volume from 92.6 to 96.4 fL (P < 0.001) and of plasma homocysteine from 9.5 to 12.3 micromol/L (P < 0.005). The geometric mean serum alanine aminotransferase (ALT) activity slightly increased from 0.49 to 0.80 microkat/L (P < 0.05). However, only two patients had the ALT activity transiently elevated above twice the upper limit of normal. CONCLUSION: Results of this pilot trial show that the steady-state levels of MTXPGs in RBC vary less than threefold between patients and did not correlate with the change in PASI observed after 4 months of therapy with an individualised weekly dose of MTX. Whether pharmacokinetically guided dosing can improve the results of psoriasis therapy with MTX should be prospectively tested in large controlled studies.

Diurnal variation of 6beta-hydroxycortisol in cardiac patients.

The 24-hour urinary excretion of 6-beta-hydroxycortisol (6beta-OHC) and the urinary ratio of 6beta- hydroxycortisol/cortisol (6beta-OHC/UFC) have been proposed as noninvasive probes for human cytochrome P450 3A4 isoform (CYP3A4). In this study, we evaluated within- and between-day variability of 6beta-OHC excretion and 6beta-OHC/UFC ratio in nine Caucasian men with cardiac disease. Each study participant was asked to collect 24-hour urine specimens during four consecutive days in five standardized time intervals. Concentrations of UFC and 6beta-OHC were determined by immunoassay and the high-performance liquid chromatographic (HPLC) method, respectively. The HPLC method was accurate and precise, as indicated by the recovery rate of 96.5-103.3 % and less than 5.2 % and 6.3 % of the coefficient of variation for within-run and between-run assay, respectively. In patients, diurnal variations in UFC and 6beta-OHC excretion were parallel. Consequently, 6beta-OHC/UFC ratio remained stable during the day. Both, 6beta-OHC excretion and 6beta-OHC/UFC ratio showed significant relationship between 24-hour value and values measured in corresponding collection periods with best correlations obtained from night interval (22.00-06.00, r = 0.86-0.91). These results indicated that urinary 6beta-OHC excretion and 6beta-OHC/UFC ratio measured in overnight/morning urine could precisely reflect 24-hour values even in severely ill patients. In addition, a simple and sensitive HPLC method was described for determination of 6beta-OHC in urine.

Plasma filtration for the controlled removal of liposomal therapeutics - From the apheretic site of view.

INTRODUCTION: Nanoparticle-based drug delivery systems can overcome the dose-limited toxicity of cytostatics. Pegylated doxorubicin-containing liposomes (PLD) are able to reduce cardiotoxicity. PLD quickly (in 2 days) attains therapeutic concentration in tumorous tissue (kinetic targeting), while its distribution in normal tissue, which is a cause of mucocutaneous toxicity (MCT), is delayed. We examined PLD extracorporeal removal effectivity, using plasma filtration (PF) to determine whether the drug could be withheld prior to its organ distribution responsible for MCT toxicity. METHODS: Nine patients suffering from platinum-resistant ovarian cancer were treated with a infusion of 50 mg/m2 of PLD/cycle - for four cycles q4w. Over 44 (46)-47 (49) hours postinfusion, the patients (14 cycles in total) underwent PF using the cascade method. Doxorubicin blood concentration was monitored by the HPLC method during 116 h. Individual pharmacokinetic parameters of doxorubicin were estimated. RESULTS: Over 44 (46)-47 (49) hours postinfusion, a single one-volume plasma filtration removed 35 (22-45) % of the remaining doxorubicin amount in the body. Symptoms of MCT - PPE-like syndrome (grade 3) appeared in one patient. Only one adverse reaction (1/14-7%) - short-term malaise and nausea - was reported as being related to PF. CONCLUSION: PF does remove a clinically important amount of doxorubicin in a kinetic targeting approach, which can be a useful tool for the increased efficacy and tolerability of therapy with PLD. There were no serious signs of drug toxicity and/or PF-related adverse events.

Expression of MRP2 and MDR1 transporters and other hepatic markers in rat and human liver and in WRL 68 cell line.

Here we describe a comparative study of phenotypic properties of hepatic cells in situ and in vitro. We analyzed the expression levels and distribution patterns of ABC transporters MRP2 and MDR1, pan-cytokeratin, cytokeratin 18, albumin, alpha-fetoprotein and the specific hepatocyte marker OCH1E5 in the fetal and adult rat as well as human liver tissue and in human fetal hepatocytes of WRL 68 cell line using peroxidase immunohistochemistry or immunofluorescence. Transporters MRP2 and MDR1 were expressed in all examined liver tissues, except rat ED13 embryo. The immunopositivity of these proteins was localized to the canalicular membrane of differentiating and mature hepatocytes but in the later developmental stages and in the adult liver tissues it was also found in the apical membrane of cholangiocytes. In WRL 68 cells, MRP2 and MDR1 immunoreactivity appeared after 5-6 days of cultivation and both transporters were fully expressed in the plasmalemma and in the cytoplasm 9 days after the passage. In conclusion, we observed only moderate variances reflecting diverse ontogenetic phases between the fetal and adult liver tissue. To study functions of hepatocytes in vitro, WRL 68 cells have to differentiate prior to the examination. Our findings indicate that WRL 68 cells can undergo differentiation in vitro and their antigenic profile closely resembles hepatocytes in the human liver.

Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects.

The aim of the study was to evaluate intra-individual variability in metabolic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to compare the MRs in urine collected 0-4, 0-8 and 0-24 h post-dose. Urinary molar ratios of DM to dextrorphan (MR1) and of DM to methoxymorphinan (MR2) were obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healthy male and four female Caucasians (ten extensive metabolizers (EM) and four poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A, respectively. Seven EM and one PM received DM on three additional occasions within 2 months. For the seven EM, the intra-individual variability (CVw) in the MRs obtained in the three urine collections ranged from 11 to 93% (MR1) and from 8 to 77% (MR2). The mean CVw estimated separately for the 4, 8 and 24 h urines by two-way analysis of variance reached 58, 57 and 44% for the MR1 and 50, 42 and 31% for the MR2, respectively. For all 14 subjects, the log-transformed ratios (MR1) obtained in the 24 h urines were highly correlated with those in either the 8 h (rs = 0.967, P < 0.0001) or 4 h urines (rs = 0.946, P < 0.0001). Correlation between the log-transformed MR2s were weaker (24 h vs. 8 h: rs = 0.829, P < 0.0001, 24 h vs. 4 h: rs = 0.831, P < 0.0001). The MR1s in 4 h and 8 h urines were only 2 and 9% less than those in 24 h urines (median differences) and varied from 48 and 47% below to 85 and 55% above (95% -CI for the differences). However, the MR2s in the 4 h and 8 h urines were shifted towards higher values by 49 and 23% and the corresponding 95% -CI limits were: 16-164% (4 h vs. 24 h) and 30-119% (8 h vs. 24 h). In conclusion, MR1 values in the 4 h urine collection agree well with those in longer collections and their use in epidemiological studies can be recommended. The intra-individual variability of approximately 50% in the MR1 has to be taken into account in clinical studies with within-subject design. Accurate determination of the MR2 requires at least a 24 h period of urine collection.

Bioequivalence of two rimantadine tablet formulations in healthy male volunteers after single dose administration.

AIM: The bioequivalence of two rimantadine tablet formulations was determined. METHODS: The study was designed as a randomized, two-period, two-sequence, crossover study. Twenty-four healthy male volunteers received a single 100 mg dose of rimantadine hydrochloride as test (Rimantadin Lachema 100 tbl. obd., produced by Lachema, a.s., Brno, Czech Republic) and reference formulations (Elumadine 100 tbl. obd., produced by Forest Pharmaceuticals, St. Louis, USA). The two administrations were separated by 14 days and were performed in the fasting state. Blood samples were obtained at 15 time points during the interval 0-120 h after administration. Rimantadine plasma concentrations were determined by gas chromatography with electron-capture detection. RESULTS: The geometric mean concentration-time profiles of rimantadine after administration of the two formulations were superimposable. The following pharmacokinetic parameters refer to the geometric mean [exp(mean +/- SD)] values for the test and reference formulations, respectively: Cmax (ng/ml) 70.5 (60.0-82.7) vs. 70.0 (59.9 to 81.7), AUC(0-infinity) (ng x h/ml) 2872 (2224 to 3707) vs. 2849 (2195-3699), AUC(0-120 h) 2744 (2184-3448) vs. 2712 (2138-3441), t(1/2) (h) 25.8 (20.1-33.0) vs. 25.7 (20.6 to 32.1). Median (range) tmax (h) values were 4.5 (2.0-8.0) and 6.0 (2.0-8.0). Parametric 90% confidence intervals for the expected mean percentage ratios (test/reference) of the pharmacokinetic variables were within the range of 97% to 105%. The median (91.1% confidence interval) difference in tmax was -0.3 h (-2.0-0.5). The point and interval estimates were identical when truncated AUCs (0-96 h, 0-72 h, 0-48 h and 0-24 h) were used in calculations. CONCLUSION: The two rimantadine formulations were equivalent in both the rate and extent ofbioavailability and they were also well tolerated. This study confirms the findings of other studies showing that for immediate release formulations of drugs with long half-lives shortening the duration over which blood samples are collected improves the economics, is more ethical and does not impair the quality of data.

Liver damage induced by intrabiliary turpentine in rats.

Inflammation of the rat bile duct induced by administration of turpentine into it has been used to study the influence of the impaired duct on liver function. Turpentine was dissolved in olive oil 1:1000 and 1:500. A 2 h ligation of the bile duct was used to promote a local effect. Contemporary groups of intact, sham-operated, control rats (given 0.9% NaCl by intrabiliary injection) and animals with total chronic obstruction were compared to assess the significance of changes. Serum concentrations of total and conjugated bilirubin, cholesterol and creatinine, activities of S-alanine-aminotransferase, S-aspartate aminotransferase and alkaline phosphatase, mortality of rats, and also total body weight compared with the weight of the liver, were investigated on days 1, 4, 8, 12, 16, 32 and 64 after surgery and turpentine, or following ligation of the bile duct. An increase in bilirubin and cholesterol, an augmentation of enzymatic activity and the histological changes were indicative of hepatotoxicity or cholestasis. The turpentine concentration--effect, manifested in body-weight change, suggests some specificity of the effect. There were no changes in serum creatinine arterial blood pressure, heart rate or portal blood pressure, when turpentine was administered by the intrabiliary route. These results suggest primary liver damage.

An in vitro study on methotrexate hydroxylation in rat and human liver.

Methotrexate (MTX) was investigated for possible effect on the metabolism of ethoxyresorufin, pentoxyresorufin and ethoxycoumarin, the model substrates of cytochrome P450. The investigation was carried out in liver microsomes of rats pretreated with classical inducers of cytochrome P450 as well as in microsomes of two human livers. Furthermore, we measured the conversion of MTX (100microM) to its main metabolite, 7-hydroxymethotrexate (7-OHMTX), in microsomes and cytosolic fractions of rat and human livers. The inhibition of 7-OHMTX formation by menadion (inhibitor of aldehyde oxidase) and allopurinol (inhibitor of xanthine oxidase) was studied in the cytosol of rat and human livers. In both species, MTX in the concentration range 0.5-500 microM exerted no inhibitory effect on enzymatic activities associated with cytochrome P450. Moreover, we did not observe any measurable formation of 7-OHMTX in liver microsomes. MTX was metabolized at a similar rate in the cytosol of rat and human liver. Allopurinol (100 microM) reduced the rate of MTX hydroxylation by 31.5% in the cytosol of human livers but had no effect in the rat. Menadion (100 microM) decreased the rate of 7-OHMTX formation in the cytosol of human and rat liver by 69% and 94%, respectively. Our results confirmed that MTX is oxidized by a soluble enzymatic system in both the rat and human liver. In human tissues, both aldehyde oxidase and xanthine oxidase may play an important role in the metabolism of MTX. Depression of cytochrome P450 and related enzymatic activities observed in vivo cannot be explained by a direct inhibitory action of MTX on cytochrome P450.

Influence of amiodarone on urinary excretion of 6beta-hydroxycortisol in humans.

The present study was undertaken to evaluate the use of cortisol 6beta-hydroxylation in defining the effect of amiodarone on cytochrome CYP3A activity. To accomplish this goal, the in vivo activity of CYP3A was estimated by measuring the 24-hour urinary excretion of 6beta-hydroxycortisol (6beta-OHC) and by calculating 24-hour ratio of 6beta-hydroxycortisol to urinary free cortisol (6beta-OHC/UFC ratio). Nine cardiac patients scheduled for amiodarone treatment were recruited to participate in this study. Urine was collected over a 24-hour period from each subject before the first amiodarone administration and during the third day of oral administration of amiodarone (200 mg four times daily as a loading dose). Three days of amiodarone treatment caused a significant decrease (p<0.05) in both the 6beta-OHC/UFC ratio and the 24-hour urinary excretion of 6beta3-OHC. These results suggest that amiodarone is an inhibitor of CYP3A activity.

A contribution to the model of biliary infection in rats.

The model of biliary tract infection induced in rats given suspension of E. coli into the bile duct is described. To prevent leakage of microorganisms after the administration, a temporary ligation of the bile duct followed. Contemporary groups of sham-operated and control rats (given saline by intrabiliary injection) were compared to assess the significance of the changes. The effect of biliary infection was concentration dependent. If 0.1 ml of the concentration containing 10(2), 10(3) and 10(6) colony-forming units/ml was injected, the mortality of rats reached 8%, 57% and 65%, respectively within 24 h. Blood and bile cultures from all dead animals grew E. coli. To evaluate the effect of chronic biliary infection, the concentration of 10(2) colony-forming units/ml was used. Serum concentrations of total and conjugated bilirubin, cholesterol and creatinine, activities of S-alanine-aminotransferase, S-aspartate-aminotransferase, alkaline phosphatase, the count of leucocytes in blood, total body weight with weight of the liver were investigated on days 1, 4 and 12 after the treatment. The results showed: an increase in leucocytes (21 +/- 4.2 10(9)/l, p less than 0.02 vs control animals) on day 4, an augmentation of serum cholesterol on day 1, (2.1 +/- 0.9 mmol/l, p less than 0.02 vs control animals), the presence of E. coli in blood on day 1 and its persistence in the bile on days 1, 4 and 12. Except the bile, all of the other symptoms were reversible by day 12.

Influence of CYP3A metabolizer status on the pharmacokinetics and pharmacodynamics of amiodarone.

UNLABELLED: The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. METHODS: 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6 beta-hydroxycortisol (6 beta-OHC and the ratio of 6 beta-hydroxycortisol to urinary free cortisol (6 beta-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 +/- 11 days (2nd period) and after 182 +/- 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 +/- 11 days (during the second period). RESULTS: Both the 6 beta-OHC excretion and 6 beta-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6 beta-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6 beta-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. CONCLUSION: This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.

[Pharmacologic effects on portal circulation]. / Farmakologické ovlivnení portálního reciste.

During the last 10 years interest in pharmacological influencing of functions of the portal circulation in particular an increase of vascular resistance expanded greatly. So far no ideal preparation with significant pharmacotherapeutic action and negligible side-effects was found. In a number of substances adequate evidence is lacking on their declared actions. These data can be obtained only by careful clinical investigations in an adequate number of patients. Data in the literature, however, indicate certain advances in the approach to the solution of these questions. A number of methods were elaborated focused on certain aims. The demands were clarified and unified and have to be respected in experimental as well as clinical investigations. Last not least, interest in new drugs from potentially pharmacodynamic groups was stimulated.

[New findings on the effects of furosemide and its mechanisms]. / Z novejsích poznatku o úcincích furosemidu a jejich mechanismech.

The paper is a review of the recent literature concerned with renal and extrarenal action of furosemide and its mechanisms which were investigated above all in healthy subjects. The author draws attention to the variety of effects, on their partial independence and to the participation of modulators, in particular prostaglandins, in their manifestation. The second part of the article is devoted to the action of furosemide under pathological conditions and to neurohumoral mechanisms which modify it.

[Nonlinear theophylline kinetics in a boy on long-term theophylline therapy for bronchial asthma. Case report]. / Prípad nelineární kinetiky teofylinu u chlapce dlouhodobe léceného teofylinem pro astma bronchiale. Kasuistika.

On the case of a 13-year-old boy the authors demonstrate the possible non-linear relationship between long-term administration of theophylline and its serum concentrations which implies the danger of induction of limital to toxic concentrations of the drug in the blood stream when the doses are increased as required.

[Chronopharmacokinetics of digoxin in compensated cardiac patients]. / Príspevek k chronofarmakokinetice digoxinu u kompenzovaných kardiaku.

The authors provided evidence that the pharmacokinetics of digoxin are influenced by daily rhythms. Using doses of 0.125 mg digoxin by the oral route, after 12 hours they found a statistically higher serum digoxin concentration in the minimum before administration of the morning dose and in the maximum concentration after this dose, as compared with the minimal and maximal concentration before and after administration of the same dose in the evening. The other pharmacokinetic parameters--the area beneath the curve of serum concentrations, the time before the maximum concentration was attained and the total plasma clearance of digoxin did not differ. This chrono-pharmacokinetic relationship in compensated cardiac patients was comparable with data in the literature pertaining to healthy volunteers. To conclude it may be said that on administration of major does in the morning there is a greater risk of serum concentrations beyond the therapeutic range than during the administration of the same amount of digoxin in the evening.