In a simple uncontrolled toxicological study 27 workers of an anesthesiology-resuscitation depart... more In a simple uncontrolled toxicological study 27 workers of an anesthesiology-resuscitation department of a hospital type III were examined. Besides detailed clinical examination, determination of basic hematological and biochemical parameters as well as ultrasonography, also selected parameters of proteosynthetic function of the liver, some so-called proteins of the acute phase and the biological half-life of antipyrine were established in the workers under study. The occurrence of pathological findings in the picture of the examinations performed was related to long-term professional exposure to halothane over the period of one year before the examination. With regard to the possibility of chronic hepatotoxic damage, appropriate attention should be paid to workers of anesthesiology-resuscitation departments, concerning particularly entrance medical examinations and regular screening and follow-up of their health condition, including check-ups hepatic parameters. (Tab. 4, Ref. 23.)
Background: Imipenem is a broad-spectrum β-lactam antibiotic frequently used for infectious compl... more Background: Imipenem is a broad-spectrum β-lactam antibiotic frequently used for infectious complications in ICU patients. Dosing optimisation still remains challenging for clinicians since many factors may influence the pharmacokinetics of imipenem. The aim of our study was to compare the population pharmacokinetics and pharmacodynamics of imipenem in critically ill obese and non-obese patients and in those with augmented renal clearance (ARC, defined as creatinine clearance ≥ 130 ml/min/1.73m 2). Methods: Monte Carlo simulation that involved a two-compartment model with sex, age, body weight, height, body surface area, and creatinine clearance as covariates was performed to generate individual imipenem free serum concentration-time profiles. The simulated population consisted of non-obese (BMI < 30) and obese (BMI ≥ 30) subjects and patients with and without ARC. Various dosage regimens (as standard, extended, and continuous infusions) were evaluated against the pharmacodynamic targets of 40% fT > MIC and 100% fT > MIC. Results: Both obesity and ARC led to lower values of probability of target attainment (PTA). For 40% fT > MIC , the difference was most pronounced for MICs of 2 to 8 mg/l (up to-17%). In nonobese patients, the pharmacokinetic breakpoints (highest MIC with PTA ≥ 90%) achieved by standard infusions were twice the values observed in the obese, whilst with extended/continuous infusions the presence of obesity did not shift the breakpoint. Similar patterns were observed between patients with and without ARC. For 100% fT > MIC , ARC led to lower PTA values in the whole range of tested MICs for both standard and extended infusions, whereas the effect of obesity was of lower magnitude but present across the MICs. Conclusions: In critically ill patients, extended and continuous infusions provide better PTA values than standard infusions. In ARC patients, especially obese ones, higher imipenem doses should be considered, especially if pathogens with higher MICs may be expected.
Introduction: Antibiotic prescribing is very complex process influenced by medical and non-medica... more Introduction: Antibiotic prescribing is very complex process influenced by medical and non-medical aspects. Accordingly, our aim was to evaluate the influence of GPs' sociodemographic and professional characteristics on the quality of antibiotic prescribing, in Portugal. Material and Methods: An observational cross-sectional study was conducted (November 2011 to February 2012) in the catchment area covered by Portugal's Centre Regional Health Administration (1094 General Practitioners (GPs) working at 84 primary care facilities). A validated, self-administered questionnaire was used to assess sociodemographic and clinical practice information. To evaluate the quality of physician antibiotic prescribing, we've assessed the twelve quality indicators validated by Coenen, S. et al (2007), per physician per year (2010, 2011 and 2012). Logistic regression using crude and adjusted analysis was performed. Results: The response rate was 46.6%. Older GPs revealed to have better performance of antibiotic prescribing [OR (95% CI) = 2.21; 1.08-4.54; P < 0.05]. About GPs who also work at the emergency department, statistical significant was found on their relation with poor prescribing [OR (95% CI) = 0.29; 0.16-0.54; P < 0.05]. Workload also revealed to influence the quality of antibiotic prescribing: more patients seen per day [OR (95% CI) = 0.97; 0.94-1.00; P < 0.05] and more patients seen per week in the emergency department [OR (95% CI) = 0.98; 0.97-0.99; P < 0.05] were related with lower quality on antibiotic prescribing. Conclusions: These findings revealed that sociodemographic and professional characteristics could influence the quality of antibiotic prescribing, which is a very important step to understand this complex process aiming to tackle a global concern: the misprescription of antibiotics.
Journal of Chromatography B: Biomedical Sciences and Applications, 1993
A method is presented for the isolation, separation and determination of sparteine and its metabo... more A method is presented for the isolation, separation and determination of sparteine and its metabolites in urine. The isolation is based on rapid extraction with dichloromethane and pentane in a glass separator. For the separation and determination, capillary gas chromatography with nitrogen-phosphorus detection was used. The recovery of the method ranged from 81.6% to 94.8%, and the limit of determination varied between 0.2 and 0.5 microgram ml-1. For quantification, 17-ethylsparteine was used as the internal standard.
The aim of this study was to estimate the occurrence of the phenotype of poor metabolizers of spa... more The aim of this study was to estimate the occurrence of the phenotype of poor metabolizers of sparteine (in the frame of sparteine-debrisoquine-dextromethorphane polymorphism) in Slovakia. The authors examined a group of 216 of healthy volunteers (73 women and 143 men, average age of the group 24, 9 +/- 0.4 years), university students coming from various regions of Slovakia. The test substance-sparteine (1 x 100 mg tbl.) was administered perorally to all probands, in the evening after fasting. A 12-hour gathering of urine was subsequently performed. A sample of urine was subdued to examination. Isolation, separation, identification and assessment of the concentration of sparteine and its metabolites (2- and 5-dehydrosparteine) were performed by the method of gas chromatography. The metabolic MR ratio calculated from the ratio of the detected concentrations of sparteine and (2- and 5-dehydrosparteine) served for the assessment of the phenotype of poor (MR > 20), or rapid (MR < ...
Abstract. In this article, the question is discussed if and how Healthcare Ethics Committees (HEC... more Abstract. In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECsÕ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification...
Profound, multilevel reform of the health care system has recently (2016) been launched in Slovak... more Profound, multilevel reform of the health care system has recently (2016) been launched in Slovakia (SR) by the Ministry of Health. Involvement of all decisive stakeholders was secured. The reform is focused at achieving major improvements in health via increased effectiveness and efficiency of health care delivery, making a patient the subject/collaborator within the necessary change. In the development/implementation of the novel state health and medicinal drugs policies, the roles and responsibilities of clinical pharmacology (CP) are deemed paramount. Therefore, an adequate, up-to-date education and training (ET) of new specialists in CP are urgently required. Moreover, elements of CP expertise are posed to be of good use to the relevant stakeholders involved-regulators, pharma/health industry, health managers, clinicians, patients/patients' representatives. Therefore, the need and potential scope of necessary CP ET broaden considerably. Existing system of postgraduate ET in CP in SR seems to be well posed to play an important role in these efforts. The membership of the Slovak representative in the UEMS Section of CP should be helpful in developing or updating existing national ET standards. Coordinating role within the novel developments in CP ET shall be played by the Institute of Pharmacology, Clinical and Experimental Pharmacology at the Slovak Medical University in Bratislava. It has been developed since 1983, as the leading country's CP postgraduate ET centre. It oversees a comprehensive, state recognised (accredited) system of postgraduate ET of physiciansclinical pharmacologists, including conduct of state board specialization and certification exams. Accredited certification programs are also available in CTs GCP methodology and pharmaco-economics. Special courses for patients/patients' representatives are delivered within EUPATI.SK platform. Moreover, there is a strong collaboration with the Slovak Society of CP, responsible for the organization of CP CME/CPD in SR. Thus, both necessary elements of ET in CP are well coordinated.
Background: Chronic hepatitis B (CHB) is a major cause of morbidity and mortality, despite an eff... more Background: Chronic hepatitis B (CHB) is a major cause of morbidity and mortality, despite an effective vaccine and potent antiviral drugs. Approximately 15% to 25% of chronic HBV carriers may die prematurely of either end-stage liver disease or hepatocellular carcinoma. Objective: To assess the virological characteristics of HBsAgpositive patients newly referred to hepatology reference centers in France between January 2008 and January 2010, assess the relationship between HBsAg and HBV DNA levels according to the HBeAg status, and estimate the prevalence of primary resistance to nucleos(t)ide analogues (NA) in this large prospective cohort of patients. Methods: 480 consecutive patients with CHB referred for the first time to a hepatology reference center during the study period were included. Most of them (91.9%) were treatment-naive and 86.0% of them were HBeAg-negative. HBsAg and HBV DNA levels were measured, the HBV genotype was determined, and the sequence of the reverse transcriptase domain of HBV polymerase was determined by means of ultra-deep pyrosequencing, a novel highly sensitive method for the detection of minority viral populations. Results: At baseline, the median HBsAg level was 3.65 Log 10 IU/mL (range: <1-5.38), and the median HBV DNA level was 3.14 Log 10 IU/mL (<1.2-8.5). 61.5% of patients were inactive carriers. The most prevalent genotypes were genotype D (35.5%), genotype E (26.6%) and genotype A (26.0%). HBsAg levels did not vary according to the HBV genotype, but positively correlated with HBV DNA levels (r = 0.37, P < 0.001) and were significantly related to the HBeAg status (r = 0.33, P < 0.001). The correlation between HBsAg and HBV DNA levels was stronger in HBeAg-positive than HBeAg-negative patients. Ultra-deep pyrosequencing data are under analysis and will be presented. Conclusion: In France, most patients newly seen for chronic hepatitis B in tertiary care centers are HBeAg-negative and inactive carriers. HBV genotypes A, E and D are the most prevalent genotypes. Although HBsAg production by infected hepatocytes does not depend solely on HBV replication, serum HBsAg levels are significantly related to HBV DNA levels, especially in HBeAg-positive patients. The prevalence of primary resistance to NAs by ultra-deep pyroquencing will be presented in this large cohort.
Backgound & Aims: Chemotherapy of hepatocellular involvement of the liver, metastases, advanced h... more Backgound & Aims: Chemotherapy of hepatocellular involvement of the liver, metastases, advanced hepatocelcarcinomas is hampered by the insufficient accumulalular disease, or invasion of the hepatic or portal veins. 3,4 tion of cytostatic drugs within the tumor cells. The aim Transcatheter arterial chemoembolization using doxoruof this study was to evaluate the feasibility of therapeubicin and Lipiodol 5 has been reported by some to improve tic strategies using antineoplastic agents coupled to survival rates, 6-8 whereas a recent study comparing Lipiobile acids. Methods: Expression of the Na /-taurochodol chemoembolization with conservative treatment late-cotransporting polypeptide (NTCP) was analyzed showed no improvement of survival. 9 Systemic chemoin six hepatocellular carcinomas and in nonmalignant therapy for HCC has been largely ineffective, with reliver tissue. Uptake of the cytostatic drug [ 3 H]sponse rates of õ20% 10 and mortality rates of up to chlorambucil-taurocholate (S2676) was measured in 25%. 11 Xenopus laevis oocytes injected with total messenger The major problem with both systemic and regional RNA (mRNA) from the carcinomas or peritumor tissue intra-arterial chemotherapy 12 is the insufficient accumuor with complementary RNA encoding the NTCP or the organic anion-transporting polypeptide (OATP) of hulation of the cytostatic drugs within the tumor cells. A man liver. Results: Expression of hepatocellular carcinovel approach toward enhancing the intracellular accunoma mRNA in oocytes resulted in mainly Na /-depenmulation of antineoplastic agents is the covalent coupling dent uptake of chlorambucil-taurocholate. The level of of these agents to bile acid molecules, which are taken NTCP mRNA in carcinomas amounted to 56% { 27% up into the liver by specific transport proteins of the compared with peritumor tissue. Immunofluorescence basolateral hepatocyte membrane. 13-15 When covalently studies confirmed the expression of NTCP on the surlinked to taurocholic acid in the 3-hydroxy position of face of hepatocellular carcinoma cells. OATP expresthe steroid nucleus, the cytostatic agent chlorambucil, sion, determined by immunoblotting, was similar in hewhich is excreted predominantly by the kidney, 16 compatocellular carcinomas and surrounding liver tissue (n petitively inhibited the sodium-dependent uptake of tau-Å 3). NTCP mediated Na /-dependent uptake of chlorrocholate by isolated rat hepatocytes. 13 The main pharambucil-taurocholate (Michaelis constant, 11 mmol/L), macological action of chlorambucil, the covalent whereas OATP mediated Na /-independent uptake. Conclusions: Hepatocellular carcinomas express the Na /alkylation of proteins, was fully retained by the chloramdependent bile acid transporter NTCP. Because NTCP bucil-bile acid conjugate. 13 Concern about the usemediates high-affinity uptake of chlorambucil-taurochofulness of this chemotherapeutic approach was raised as late, targeting of cytostatic bile acids to hepatocellular a result of reports that HCC cells 17 and hepatoma cell carcinomas could become a feasible therapeutic stratlines, 18,19 in contrast to healthy rat hepatocytes, have a egy. near-absent expression of bile acid uptake carriers on their cell surface. This would favor the distribution of drug-bile acid conjugates to healthy rather than malig-H epatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma. 1 With a Abbreviations used in this paper: NTCP, Na /-taurocholate-cotransporting polypeptide; MDR1, P-glycoprotein multidrug resistance median survival of 14 weeks and a 1-year survival rate gene product 1; OATP, organic anion-transporting polypeptide; SDS, of 13%, 2 HCC represents one of the most malignant sodium dodecyl sulfate; SSC, standard saline citrate.
Evolving process of implementation of the EU Clinical Trials Regulation (N. 536/2014) poses numer... more Evolving process of implementation of the EU Clinical Trials Regulation (N. 536/2014) poses numerous challenges for all parties concerned (national regulators, drug agencies/competent authorities, sponsors, contract research organizations, investigators, and ethics committees (ECs)). In Slovakia (SR), Clinical Pharmacology (CP), as a medical discipline integrating the relevant clinical, methodological, ethical and procedural expertise concerning CTs of medicinal products/drugs for human use, seemed to be especially well positioned to provide the necessary expertise, and even coordination of the complex implementation processes. Indeed, the Slovak Society of CP has initiated, together with all relevant stakeholders, several preparatory activities at the pertinent professional, regulatory and education/training levels. It aimed at providing the necessary knowledge to the implementation process parties concerned. This was achieved via national CTs and GCP conferences, national meetings of ECs, and by an active involvement of physicians-clinical pharmacologists in the informal working groups (WGs) that the Society had coinitiated. Building upon these successful initiatives, the official WG, encompassing all mentioned stakeholders, has been established at the Ministry of Health (in 2016). It embarked upon preparations of necessary national medicinal drug/health care legislation amendments. It also established direct working relationships with respective WGs at the EMA, including participation in EU CTs Portal development/ testing. Besides necessary institutional developments at National Competent Authority (NCA)/National Contact Point levels, especially challenging part has been to ensure adequate and timely ethics review of the CTs submitted to NCA, whether SR performing reporting or concerned Member State roles. Collaboration of national CP representatives within EUREC and EFGCP provided for necessary knowhow and procedural enhancements. Active involvement of CP in establishing effective, safe environment for conducting high quality CTs in SR has brought in novel opportunities of growth and acknowledgement. Those are welcome in re-establishing the role of CP within the national clinical research and health care systems.
In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should ... more In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECsÕ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification, steps should be taken to develop consistent policies for both Eastern and Western European countries.
In a simple uncontrolled toxicological study 27 workers of an anesthesiology-resuscitation depart... more In a simple uncontrolled toxicological study 27 workers of an anesthesiology-resuscitation department of a hospital type III were examined. Besides detailed clinical examination, determination of basic hematological and biochemical parameters as well as ultrasonography, also selected parameters of proteosynthetic function of the liver, some so-called proteins of the acute phase and the biological half-life of antipyrine were established in the workers under study. The occurrence of pathological findings in the picture of the examinations performed was related to long-term professional exposure to halothane over the period of one year before the examination. With regard to the possibility of chronic hepatotoxic damage, appropriate attention should be paid to workers of anesthesiology-resuscitation departments, concerning particularly entrance medical examinations and regular screening and follow-up of their health condition, including check-ups hepatic parameters. (Tab. 4, Ref. 23.)
Background: Imipenem is a broad-spectrum β-lactam antibiotic frequently used for infectious compl... more Background: Imipenem is a broad-spectrum β-lactam antibiotic frequently used for infectious complications in ICU patients. Dosing optimisation still remains challenging for clinicians since many factors may influence the pharmacokinetics of imipenem. The aim of our study was to compare the population pharmacokinetics and pharmacodynamics of imipenem in critically ill obese and non-obese patients and in those with augmented renal clearance (ARC, defined as creatinine clearance ≥ 130 ml/min/1.73m 2). Methods: Monte Carlo simulation that involved a two-compartment model with sex, age, body weight, height, body surface area, and creatinine clearance as covariates was performed to generate individual imipenem free serum concentration-time profiles. The simulated population consisted of non-obese (BMI < 30) and obese (BMI ≥ 30) subjects and patients with and without ARC. Various dosage regimens (as standard, extended, and continuous infusions) were evaluated against the pharmacodynamic targets of 40% fT > MIC and 100% fT > MIC. Results: Both obesity and ARC led to lower values of probability of target attainment (PTA). For 40% fT > MIC , the difference was most pronounced for MICs of 2 to 8 mg/l (up to-17%). In nonobese patients, the pharmacokinetic breakpoints (highest MIC with PTA ≥ 90%) achieved by standard infusions were twice the values observed in the obese, whilst with extended/continuous infusions the presence of obesity did not shift the breakpoint. Similar patterns were observed between patients with and without ARC. For 100% fT > MIC , ARC led to lower PTA values in the whole range of tested MICs for both standard and extended infusions, whereas the effect of obesity was of lower magnitude but present across the MICs. Conclusions: In critically ill patients, extended and continuous infusions provide better PTA values than standard infusions. In ARC patients, especially obese ones, higher imipenem doses should be considered, especially if pathogens with higher MICs may be expected.
Introduction: Antibiotic prescribing is very complex process influenced by medical and non-medica... more Introduction: Antibiotic prescribing is very complex process influenced by medical and non-medical aspects. Accordingly, our aim was to evaluate the influence of GPs' sociodemographic and professional characteristics on the quality of antibiotic prescribing, in Portugal. Material and Methods: An observational cross-sectional study was conducted (November 2011 to February 2012) in the catchment area covered by Portugal's Centre Regional Health Administration (1094 General Practitioners (GPs) working at 84 primary care facilities). A validated, self-administered questionnaire was used to assess sociodemographic and clinical practice information. To evaluate the quality of physician antibiotic prescribing, we've assessed the twelve quality indicators validated by Coenen, S. et al (2007), per physician per year (2010, 2011 and 2012). Logistic regression using crude and adjusted analysis was performed. Results: The response rate was 46.6%. Older GPs revealed to have better performance of antibiotic prescribing [OR (95% CI) = 2.21; 1.08-4.54; P < 0.05]. About GPs who also work at the emergency department, statistical significant was found on their relation with poor prescribing [OR (95% CI) = 0.29; 0.16-0.54; P < 0.05]. Workload also revealed to influence the quality of antibiotic prescribing: more patients seen per day [OR (95% CI) = 0.97; 0.94-1.00; P < 0.05] and more patients seen per week in the emergency department [OR (95% CI) = 0.98; 0.97-0.99; P < 0.05] were related with lower quality on antibiotic prescribing. Conclusions: These findings revealed that sociodemographic and professional characteristics could influence the quality of antibiotic prescribing, which is a very important step to understand this complex process aiming to tackle a global concern: the misprescription of antibiotics.
Journal of Chromatography B: Biomedical Sciences and Applications, 1993
A method is presented for the isolation, separation and determination of sparteine and its metabo... more A method is presented for the isolation, separation and determination of sparteine and its metabolites in urine. The isolation is based on rapid extraction with dichloromethane and pentane in a glass separator. For the separation and determination, capillary gas chromatography with nitrogen-phosphorus detection was used. The recovery of the method ranged from 81.6% to 94.8%, and the limit of determination varied between 0.2 and 0.5 microgram ml-1. For quantification, 17-ethylsparteine was used as the internal standard.
The aim of this study was to estimate the occurrence of the phenotype of poor metabolizers of spa... more The aim of this study was to estimate the occurrence of the phenotype of poor metabolizers of sparteine (in the frame of sparteine-debrisoquine-dextromethorphane polymorphism) in Slovakia. The authors examined a group of 216 of healthy volunteers (73 women and 143 men, average age of the group 24, 9 +/- 0.4 years), university students coming from various regions of Slovakia. The test substance-sparteine (1 x 100 mg tbl.) was administered perorally to all probands, in the evening after fasting. A 12-hour gathering of urine was subsequently performed. A sample of urine was subdued to examination. Isolation, separation, identification and assessment of the concentration of sparteine and its metabolites (2- and 5-dehydrosparteine) were performed by the method of gas chromatography. The metabolic MR ratio calculated from the ratio of the detected concentrations of sparteine and (2- and 5-dehydrosparteine) served for the assessment of the phenotype of poor (MR > 20), or rapid (MR < ...
Abstract. In this article, the question is discussed if and how Healthcare Ethics Committees (HEC... more Abstract. In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECsÕ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification...
Profound, multilevel reform of the health care system has recently (2016) been launched in Slovak... more Profound, multilevel reform of the health care system has recently (2016) been launched in Slovakia (SR) by the Ministry of Health. Involvement of all decisive stakeholders was secured. The reform is focused at achieving major improvements in health via increased effectiveness and efficiency of health care delivery, making a patient the subject/collaborator within the necessary change. In the development/implementation of the novel state health and medicinal drugs policies, the roles and responsibilities of clinical pharmacology (CP) are deemed paramount. Therefore, an adequate, up-to-date education and training (ET) of new specialists in CP are urgently required. Moreover, elements of CP expertise are posed to be of good use to the relevant stakeholders involved-regulators, pharma/health industry, health managers, clinicians, patients/patients' representatives. Therefore, the need and potential scope of necessary CP ET broaden considerably. Existing system of postgraduate ET in CP in SR seems to be well posed to play an important role in these efforts. The membership of the Slovak representative in the UEMS Section of CP should be helpful in developing or updating existing national ET standards. Coordinating role within the novel developments in CP ET shall be played by the Institute of Pharmacology, Clinical and Experimental Pharmacology at the Slovak Medical University in Bratislava. It has been developed since 1983, as the leading country's CP postgraduate ET centre. It oversees a comprehensive, state recognised (accredited) system of postgraduate ET of physiciansclinical pharmacologists, including conduct of state board specialization and certification exams. Accredited certification programs are also available in CTs GCP methodology and pharmaco-economics. Special courses for patients/patients' representatives are delivered within EUPATI.SK platform. Moreover, there is a strong collaboration with the Slovak Society of CP, responsible for the organization of CP CME/CPD in SR. Thus, both necessary elements of ET in CP are well coordinated.
Background: Chronic hepatitis B (CHB) is a major cause of morbidity and mortality, despite an eff... more Background: Chronic hepatitis B (CHB) is a major cause of morbidity and mortality, despite an effective vaccine and potent antiviral drugs. Approximately 15% to 25% of chronic HBV carriers may die prematurely of either end-stage liver disease or hepatocellular carcinoma. Objective: To assess the virological characteristics of HBsAgpositive patients newly referred to hepatology reference centers in France between January 2008 and January 2010, assess the relationship between HBsAg and HBV DNA levels according to the HBeAg status, and estimate the prevalence of primary resistance to nucleos(t)ide analogues (NA) in this large prospective cohort of patients. Methods: 480 consecutive patients with CHB referred for the first time to a hepatology reference center during the study period were included. Most of them (91.9%) were treatment-naive and 86.0% of them were HBeAg-negative. HBsAg and HBV DNA levels were measured, the HBV genotype was determined, and the sequence of the reverse transcriptase domain of HBV polymerase was determined by means of ultra-deep pyrosequencing, a novel highly sensitive method for the detection of minority viral populations. Results: At baseline, the median HBsAg level was 3.65 Log 10 IU/mL (range: <1-5.38), and the median HBV DNA level was 3.14 Log 10 IU/mL (<1.2-8.5). 61.5% of patients were inactive carriers. The most prevalent genotypes were genotype D (35.5%), genotype E (26.6%) and genotype A (26.0%). HBsAg levels did not vary according to the HBV genotype, but positively correlated with HBV DNA levels (r = 0.37, P < 0.001) and were significantly related to the HBeAg status (r = 0.33, P < 0.001). The correlation between HBsAg and HBV DNA levels was stronger in HBeAg-positive than HBeAg-negative patients. Ultra-deep pyrosequencing data are under analysis and will be presented. Conclusion: In France, most patients newly seen for chronic hepatitis B in tertiary care centers are HBeAg-negative and inactive carriers. HBV genotypes A, E and D are the most prevalent genotypes. Although HBsAg production by infected hepatocytes does not depend solely on HBV replication, serum HBsAg levels are significantly related to HBV DNA levels, especially in HBeAg-positive patients. The prevalence of primary resistance to NAs by ultra-deep pyroquencing will be presented in this large cohort.
Backgound & Aims: Chemotherapy of hepatocellular involvement of the liver, metastases, advanced h... more Backgound & Aims: Chemotherapy of hepatocellular involvement of the liver, metastases, advanced hepatocelcarcinomas is hampered by the insufficient accumulalular disease, or invasion of the hepatic or portal veins. 3,4 tion of cytostatic drugs within the tumor cells. The aim Transcatheter arterial chemoembolization using doxoruof this study was to evaluate the feasibility of therapeubicin and Lipiodol 5 has been reported by some to improve tic strategies using antineoplastic agents coupled to survival rates, 6-8 whereas a recent study comparing Lipiobile acids. Methods: Expression of the Na /-taurochodol chemoembolization with conservative treatment late-cotransporting polypeptide (NTCP) was analyzed showed no improvement of survival. 9 Systemic chemoin six hepatocellular carcinomas and in nonmalignant therapy for HCC has been largely ineffective, with reliver tissue. Uptake of the cytostatic drug [ 3 H]sponse rates of õ20% 10 and mortality rates of up to chlorambucil-taurocholate (S2676) was measured in 25%. 11 Xenopus laevis oocytes injected with total messenger The major problem with both systemic and regional RNA (mRNA) from the carcinomas or peritumor tissue intra-arterial chemotherapy 12 is the insufficient accumuor with complementary RNA encoding the NTCP or the organic anion-transporting polypeptide (OATP) of hulation of the cytostatic drugs within the tumor cells. A man liver. Results: Expression of hepatocellular carcinovel approach toward enhancing the intracellular accunoma mRNA in oocytes resulted in mainly Na /-depenmulation of antineoplastic agents is the covalent coupling dent uptake of chlorambucil-taurocholate. The level of of these agents to bile acid molecules, which are taken NTCP mRNA in carcinomas amounted to 56% { 27% up into the liver by specific transport proteins of the compared with peritumor tissue. Immunofluorescence basolateral hepatocyte membrane. 13-15 When covalently studies confirmed the expression of NTCP on the surlinked to taurocholic acid in the 3-hydroxy position of face of hepatocellular carcinoma cells. OATP expresthe steroid nucleus, the cytostatic agent chlorambucil, sion, determined by immunoblotting, was similar in hewhich is excreted predominantly by the kidney, 16 compatocellular carcinomas and surrounding liver tissue (n petitively inhibited the sodium-dependent uptake of tau-Å 3). NTCP mediated Na /-dependent uptake of chlorrocholate by isolated rat hepatocytes. 13 The main pharambucil-taurocholate (Michaelis constant, 11 mmol/L), macological action of chlorambucil, the covalent whereas OATP mediated Na /-independent uptake. Conclusions: Hepatocellular carcinomas express the Na /alkylation of proteins, was fully retained by the chloramdependent bile acid transporter NTCP. Because NTCP bucil-bile acid conjugate. 13 Concern about the usemediates high-affinity uptake of chlorambucil-taurochofulness of this chemotherapeutic approach was raised as late, targeting of cytostatic bile acids to hepatocellular a result of reports that HCC cells 17 and hepatoma cell carcinomas could become a feasible therapeutic stratlines, 18,19 in contrast to healthy rat hepatocytes, have a egy. near-absent expression of bile acid uptake carriers on their cell surface. This would favor the distribution of drug-bile acid conjugates to healthy rather than malig-H epatocellular carcinoma (HCC) is the most common form of primary hepatic carcinoma. 1 With a Abbreviations used in this paper: NTCP, Na /-taurocholate-cotransporting polypeptide; MDR1, P-glycoprotein multidrug resistance median survival of 14 weeks and a 1-year survival rate gene product 1; OATP, organic anion-transporting polypeptide; SDS, of 13%, 2 HCC represents one of the most malignant sodium dodecyl sulfate; SSC, standard saline citrate.
Evolving process of implementation of the EU Clinical Trials Regulation (N. 536/2014) poses numer... more Evolving process of implementation of the EU Clinical Trials Regulation (N. 536/2014) poses numerous challenges for all parties concerned (national regulators, drug agencies/competent authorities, sponsors, contract research organizations, investigators, and ethics committees (ECs)). In Slovakia (SR), Clinical Pharmacology (CP), as a medical discipline integrating the relevant clinical, methodological, ethical and procedural expertise concerning CTs of medicinal products/drugs for human use, seemed to be especially well positioned to provide the necessary expertise, and even coordination of the complex implementation processes. Indeed, the Slovak Society of CP has initiated, together with all relevant stakeholders, several preparatory activities at the pertinent professional, regulatory and education/training levels. It aimed at providing the necessary knowledge to the implementation process parties concerned. This was achieved via national CTs and GCP conferences, national meetings of ECs, and by an active involvement of physicians-clinical pharmacologists in the informal working groups (WGs) that the Society had coinitiated. Building upon these successful initiatives, the official WG, encompassing all mentioned stakeholders, has been established at the Ministry of Health (in 2016). It embarked upon preparations of necessary national medicinal drug/health care legislation amendments. It also established direct working relationships with respective WGs at the EMA, including participation in EU CTs Portal development/ testing. Besides necessary institutional developments at National Competent Authority (NCA)/National Contact Point levels, especially challenging part has been to ensure adequate and timely ethics review of the CTs submitted to NCA, whether SR performing reporting or concerned Member State roles. Collaboration of national CP representatives within EUREC and EFGCP provided for necessary knowhow and procedural enhancements. Active involvement of CP in establishing effective, safe environment for conducting high quality CTs in SR has brought in novel opportunities of growth and acknowledgement. Those are welcome in re-establishing the role of CP within the national clinical research and health care systems.
In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should ... more In this article, the question is discussed if and how Healthcare Ethics Committees (HECs) should be regulated. The paper consists of two parts. First, authors from eight EC member countries describe the status quo in their respective countries, and give reasons as to the form of regulation they consider most adequate. In the second part, the country reports are analysed. It is suggested that regulation of HECs should be central and weak. Central regulation is argued to be apt to improve HECsÕ accountability, relevance and comparability. To facilitate biomedical citizenship and ethical reflection, regulation should at the same time be weak rather than strict. Independence of HECs to deliberate about ethical questions, and to give solicited and unsolicited advice, should be supported and only interfered with by way of exception. One exception is when circumstances become temporary adversarial to ethical deliberation in healthcare institutions. In view of European unification, steps should be taken to develop consistent policies for both Eastern and Western European countries.
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Papers by Jozef Glasa