WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.
- Klíčová slova
- dose optimization, everolimus, pharmacokinetics, sirolimus, therapeutic drug monitoring,
- MeSH
- imunosupresiva MeSH
- lidé MeSH
- mTOR inhibitory MeSH
- sirolimus * farmakokinetika terapeutické užití MeSH
- TOR serin-threoninkinasy MeSH
- transplantace orgánů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- imunosupresiva MeSH
- mTOR inhibitory MeSH
- MTOR protein, human MeSH Prohlížeč
- sirolimus * MeSH
- TOR serin-threoninkinasy MeSH
WHAT IS KNOWN AND OBJECTIVE: Fondaparinux exhibits a similar mechanism of action as LMWH. Since both of these drugs bind to antithrombin and increase its affinity to factor Xa, fondaparinux is not expected to be an effective alternative anticoagulant to LMWH in case of LMWH resistance. CASE SUMMARY: We report on a case of effective anticoagulation using fondaparinux following total unresponsiveness to high doses of nadroparin administered twice daily, as confirmed via repeated anti-Xa measurements. The antithrombin levels were within the normal range. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first report of the effective use of fondaparinux in the case of unresponsiveness to LMWH.
- Klíčová slova
- anticoagulation, antithrombin, heparin resistance, low molecular weight heparin, pentasaccharide,
- MeSH
- antikoagulancia aplikace a dávkování farmakologie terapeutické užití MeSH
- fondaparinux aplikace a dávkování farmakologie terapeutické užití MeSH
- hemokoagulace účinky léků MeSH
- heparin nízkomolekulární aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- nadroparin aplikace a dávkování farmakologie terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- antikoagulancia MeSH
- fondaparinux MeSH
- heparin nízkomolekulární MeSH
- nadroparin MeSH
WHAT IS KNOWN AND OBJECTIVE: Phenobarbital is the first-line treatment of seizures in asphyxiated neonates; however, due to the high pharmacokinetic variability in this population, there is no consensus on the optimal dosage regimen. This study was conducted to identify variables that affect phenobarbital fate during routine clinical care and then to evaluate the dosage schedule that could be applied in term asphyxiated neonates with respect to achieving the target therapeutic range. METHODS: Phenobarbital pharmacokinetics was calculated based on serum concentrations measurements using one-compartmental model. Body weight, body surface area, gestational age, creatinine clearance, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, Apgar scores, umbilical cord arterial pH and base excess were explored as covariates in linear regression models. Based on this analysis, phenobarbital loading and maintenance dose regimen were projected. RESULTS AND DISCUSSION: In the whole study population (N = 36), phenobarbital volume of distribution, clearance and half-life median (interquartile range) values were 0.49 (0.38-0.59) L/kg, 0.0045 (0.0034-0.0055) L/h/kg and 75.1 (60.2-103.3) hours, respectively. The drug volume of distribution was associated with body weight, length and body surface area, whereas clearance was not in relationship with any explored features. Weight-normalized loading dose of 15 mg/kg and weight-normalized daily maintenance dose of 3 mg/kg proved to be optimal in our study population to reach phenobarbital therapeutic range. WHAT IS NEW AND CONCLUSIONS: This study presents basis for phenobarbital initial dosing in term asphyxiated neonates during first week of life. Phenobarbital weight-normalized loading dose of 15 mg/kg lead to simulated target peak concentrations in 72% of neonates, weight-normalized maintenance dose of 3 mg/kg lead to steady state within therapeutic window in the same proportion of patients.
- Klíčová slova
- asphyxia, dosing regimen, neonates, pharmacokinetics, phenobarbital,
- MeSH
- asfyxie farmakoterapie metabolismus MeSH
- fenobarbital aplikace a dávkování farmakokinetika MeSH
- gestační stáří MeSH
- lidé MeSH
- mozková hypoxie a ischemie farmakoterapie metabolismus MeSH
- novorozenec MeSH
- poločas MeSH
- retrospektivní studie MeSH
- tkáňová distribuce MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Názvy látek
- fenobarbital MeSH
WHAT IS KNOWN AND OBJECTIVE: Polypharmacy has a significant impact on patients' health with overall expenditure on over-the-counter (OTC) medicines representing a substantial burden in terms of cost of treatment. The aim of this study, which was conducted within the framework of a European Project funded by the European Union under the Seventh Framework Programme and was entitled OTC-SOCIOMED, was to report on possible determinants of patient behaviour regarding the consumption of medicines, and particularly OTCs, in the context of primary care. METHODS: A multicentre, cross-sectional study was designed and implemented in well-defined primary healthcare settings in Cyprus, the Czech Republic, France, Greece, Malta and Turkey. Patients completed a questionnaire constructed on the basis of the theory of planned behaviour (TPB), which was administered via face-to-face interviews. RESULTS AND DISCUSSION: The percentage of patients who had consumed prescribed medicines over a 6-month period was consistently high, ranging from 79% in the Czech Republic and 82% in Turkey to 97% in Malta and 100% in Cyprus. Reported non-prescribed medicine consumption ranged from 33% in Turkey to 92% in the Czech Republic and 97% in Cyprus. TPB behavioural antecedents explained 43% of the variability of patients' intention to consume medicines in Malta and 24% in Greece, but only 3% in Turkey. Subjective norm was a significant predictor of the intention to consume medicines in all three countries (Greece, Malta and Turkey), whereas attitude towards consumption was a significant predictor of the expectation to consume medicines, if needed. WHAT IS NEW AND CONCLUSION: This study shows that parameters such as patients' beliefs and influence from family and friends could be determining factors in explaining the high rates of medicine consumption. Factors that affect patients' behavioural intention towards medicine consumption may assist in the formulation of evidence-based policy proposals and inform initiatives and interventions aimed at increasing the appropriate use of medicines.
- Klíčová slova
- over-the-counter medicines, patients, prescribing, primary health care, theory of planned behaviour,
- MeSH
- dospělí MeSH
- lékařská praxe - způsoby provádění statistika a číselné údaje MeSH
- lékařství statistika a číselné údaje MeSH
- léky bez předpisu terapeutické užití MeSH
- léky na předpis terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- primární zdravotní péče statistika a číselné údaje MeSH
- průřezové studie MeSH
- průzkumy a dotazníky MeSH
- úmysl MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- Geografické názvy
- Evropa MeSH
- Názvy látek
- léky bez předpisu MeSH
- léky na předpis MeSH
WHAT IS KNOWN AND OBJECTIVE: Drug-induced acute pancreatitis comprises only 0.5%-2% of all cases of acute pancreatitis. Propofol is a potentially dangerous drug that can cause acute pancreatitis, but this complication is extremely rare. CASE SUMMARY: A 57-year-old patient developed acute pancreatitis after a planned thyroidectomy. As the common causes of acute pancreatitis were excluded, we believe that the pancreatitis was drug-induced, in this case by a single dose of propofol administered to the patient during the surgery. WHAT IS NEW AND CONCLUSION: We present a rare case of propofol-induced acute necrotising pancreatitis, which is to the best of our knowledge the first fatal case reported in an adult patient.
- Klíčová slova
- adverse drug reaction, drug-induced acute pancreatitis, propofol,
- MeSH
- akutní nekrotizující pankreatitida chemicky indukované MeSH
- anestetika intravenózní aplikace a dávkování škodlivé účinky MeSH
- fatální výsledek MeSH
- lidé středního věku MeSH
- lidé MeSH
- propofol aplikace a dávkování škodlivé účinky MeSH
- tyreoidektomie metody MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Názvy látek
- anestetika intravenózní MeSH
- propofol MeSH
WHAT IS KNOWN AND OBJECTIVE: Drug-induced lupus erythematosus occurs with some drugs and resolves with their withdrawal. Anti-TNF therapies have been found to be associated with a lupus-like syndrome, which is clinically distinct from classical drug-induced as well as idiopathic lupus erythematosus. CASE DESCRIPTION: We describe a case of a patient with severe psoriasis, who developed muscle pain with paraesthesia accompanied by ANA titres elevation with adalimumab treatment. The condition resolved after adalimumab cessation, and the patient was started on ustekinumab with good results. WHAT IS NEW AND CONCLUSION: Ustekinumab might be a useful treatment option for patients with a history of TNF-induced lupus-like syndrome.
- Klíčová slova
- anti-TNF treatment, drug-induced lupus erythematosus, lupus-like syndrome, ustekinumab,
- MeSH
- adalimumab aplikace a dávkování škodlivé účinky MeSH
- antiflogistika aplikace a dávkování škodlivé účinky MeSH
- dospělí MeSH
- lidé MeSH
- psoriáza farmakoterapie patologie MeSH
- stupeň závažnosti nemoci MeSH
- systémový lupus erythematodes chemicky indukované MeSH
- TNF-alfa antagonisté a inhibitory MeSH
- ustekinumab terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
- Názvy látek
- adalimumab MeSH
- antiflogistika MeSH
- TNF-alfa MeSH
- ustekinumab MeSH
WHAT IS KNOWN AND OBJECTIVES: Parabens have been commonly used as preservatives in pharmaceutical and cosmetics industries for almost 50 years. These compounds are thermostable, pH-stable and inexpensive and have a wide antimicrobial effect. The antimicrobial activity of parabens in emulsion system is limited by their poor solubility in water phase, which is increasing with the length of their alkyl chain. The aim of this work was preparation of 1-O-(4-hydroxybenzoyl)-glycerol, more hydrophilic and naturally occurring analogue of parabens, and comparison of its antimicrobial activity with commercially used parabens (4-hydroxybenzoic acid, methylparaben, ethylparaben, propylparaben). METHODS: 1-O-(4-Hydroxybenzoyl)-glycerol was obtained by the transesterification reaction of methyl paraben with glycerol. Purity was confirmed by determination of melting point and by GC/MSD. Antimicrobial activity of 1-O-(4-hydroxybenzoyl)-glycerol and commercially used parabens was determined by spectrophotometrical monitoring of microbial growth in media containing the testing substances, using spectrophotometers PowerWave XS and Cary 50 Conc. RESULTS AND DISCUSSION: 1-O-(4-Hydroxybenzoyl)-glycerol was prepared with purity >99%. This compound showed antimicrobial activity against all tested microorganisms (Staphylococcus aureus, Escherichia coli, Saccharomyces cerevisiae and Fusarium culmorum). In comparison with other tested substances, 1-O-(4-hydroxybenzoyl)-glycerol showed less inhibitory activity at the highest concentration of 20 mmol/L, with the maximum inhibitory activity ca. 70%. On the other hand, antimicrobial activity of 1-O-(4-hydroxybenzoyl)-glycerol at the lower concentrations (2·5 mmol/L, 1·25 mmol/L) was the same or, in some cases, even higher (S. aureus) in comparison with commercially used parabens. WHAT IS NEW AND CONCLUSION: A novel hydrophilic analogue of parabens was synthetized and tested for its antimicrobial activity against selected microorganisms in model system. This study confirms antimicrobial potential of 1-O-(4-hydroxybenzoyl)-glycerol, which is comparable with other commercially used parabens. Unlike commercial parabens, it is possible to expect more significant antimicrobial activity of 1-O-(4-hydroxybenzoyl)-glycerol in real emulsion systems due to the increased solubility of this substance in water phase and also the lower skin irritation.
- Klíčová slova
- 1-O-(4-hydroxybenzoyl)-glycerol, antimicrobial effect, paraben, preservative,
- MeSH
- antiinfekční látky chemie farmakologie MeSH
- chromatografie plynová metody MeSH
- glycerol chemie MeSH
- konzervační prostředky farmaceutické chemie farmakologie MeSH
- parabeny chemie farmakologie MeSH
- rozpustnost MeSH
- spektrofotometrie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- 4-hydroxybenzoic acid MeSH Prohlížeč
- antiinfekční látky MeSH
- glycerol MeSH
- konzervační prostředky farmaceutické MeSH
- parabeny MeSH
WHAT IS KNOWN AND OBJECTIVE: Paroxetine is both a substrate and an inhibitor of CYP2D6. The objective of the presented study was to determine the persistence of CYP2D6 inhibition after short term (6 weeks) and long term (18·7 ± 10·6 weeks) paroxetine treatment. METHODS: Two the studies consisted of 30 depressive/anxiety patients each. In the first study, patients were subdivided into three groups treated with paroxetine (A1), alprazolam (A2) and paroxetine + alprazolam (A3). After 6 weeks, all the patients (A1+A2+A3) were switched to alprazolam treatment; metabolic activity was evaluated at the beginning, after 6 weeks of paroxetine/alprazolam/alprazolam + paroxetine treatment (A1/A2/A3) and 4 weeks after the switch to alprazolam treatment (Week 0, 6, 10). In the second study patients on previous long term paroxetine treatment were subdivided into two groups treated with mirtazapine (B1) or paroxetine (B2); metabolic activity of CYP2D6 was evaluated at the beginning and after 6 weeks of therapy. RESULTS AND DISCUSSION: Metabolic ratio of dextromethorphan to dextrorphan has normalized in all subjects after 4 weeks of paroxetine wash out in the first study. In the second study, 6 weeks after paroxetine discontinuation, restoration of metabolic activity of CYP2D6 was observed in only five of eight originally poor metabolizers. WHAT IS NEW AND CONCLUSION: We conclude that a wash-out period of 4 weeks seems to be sufficient for CYP2D6 disinhibition after short-term paroxetine treatment (6 weeks). On the other hand, treatment with a CYP2D6 substrate less than 6 weeks after long-term paroxetine treatment (18·7 weeks on average) could result in elevated drug plasma levels and occasionally also in drug toxicity.
- Klíčová slova
- CYP2D6, disinhibition, paroxetine,
- MeSH
- alprazolam farmakologie MeSH
- cytochrom P-450 CYP2D6 metabolismus MeSH
- deprese farmakoterapie enzymologie metabolismus MeSH
- dextromethorfan farmakologie MeSH
- dextrorfan farmakologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- inhibitory cytochromu P450 CYP2D6 * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- paroxetin farmakologie MeSH
- senioři MeSH
- úzkost farmakoterapie enzymologie metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- alprazolam MeSH
- cytochrom P-450 CYP2D6 MeSH
- dextromethorfan MeSH
- dextrorfan MeSH
- inhibitory cytochromu P450 CYP2D6 * MeSH
- paroxetin MeSH
WHAT IS KNOWN AND OBJECTIVE: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR(DEM/DOR)) is well established as a marker of CYP2D6 metabolizer status. The relationship between urine and plasma or serum MR(DEM/DOR) is not well established nor is there evidence of antimode for separation of intermediate and especially poor metabolizers (PM) from extensive metabolizers (EM). This study addressed whether CYP2D6 phenotyping using molar metabolic ratio of dextromethorphan to dextrorphan (MR(DEM/DOR)) in serum is usable and reliable in clinical practice as urinary MR(DEM/DOR). METHODS: We measured MR(DEM/DOR) in serum and CYP2D6 genotype in 51 drug-naive patients and 30 volunteers. Receiver-operator characteristic (ROC) analysis was used for the evaluation of optimum cut-off value for discriminating between extensive, intermediate and PM. In addition, we studied the correlation of serum MR(DEM/DOR) with urine MR(DEM/DOR) in the 30 healthy volunteers. RESULTS AND DISCUSSION: A trimodal distribution of log MR(DEM/DOR) in serum was observed, with substantial overlap between extensive and intermediate metabolizer groups. We obtained an acceptable cut-off serum MR(DEM/DOR) value to discriminate between PM and either extensive or extensive + intermediate metabolizers. Using serum MR(DEM/DOR), it seems to be unreliable to discriminate EM from intermediate metabolizers (IM). A strong correlation between serum MR(DEM/DOR) and urine MR(DEM/DOR) was found. WHAT IS NEW AND CONCLUSION: Serum MR(DEM/DOR) (3 h) correlated with MR(DEM/DOR) in urine (0-8 h). Serum MR(DEM/DOR) discriminated between extensive and PM and between extensive + intermediate and PM. Our CYP2D6 phenotyping using serum dextromethorphan/dextrorphan molar ratio appears reliable but requires independent validation.
- MeSH
- cytochrom P-450 CYP2D6 genetika MeSH
- dextromethorfan aplikace a dávkování farmakokinetika MeSH
- dextrorfan farmakokinetika MeSH
- dospělí MeSH
- fenotyp MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- ROC křivka MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytochrom P-450 CYP2D6 MeSH
- dextromethorfan MeSH
- dextrorfan MeSH
WHAT IS KNOWN AND OBJECTIVE: The opioid effect of tramadol, which can be detected by pupillary response, is predominantly mediated by the O-demethylated metabolite, formed via CYP2D6. This study was designed to evaluate the effects of tramadol using different parameters of pupillometry as biomarkers. METHODS: Sixty-nine healthy volunteers received tramadol hydrochloride drops orally at a dose of 0·7 mg/kg. Pre-dose and 2-h post-dose pupillometric measurements were performed. The polymorphism of CYP2D6 was analysed. RESULTS AND DISCUSSION: Large interindividual variability was observed in the tramadol-induced pupillary reaction. Miosis was induced in 69·6% and mydriasis in 30·4% of the subjects. The pupillary response differed in relation to the CYP2D6 genotype. A maximal difference in initial pupil diameter of 0·81 mm was found in extensive metabolizers. There were significant effects observed on the pupillary light reflex parameters with tramadol administration (P < 0·05) except for the reflex amplitude and constriction velocity. WHAT IS NEW AND CONCLUSION: The pharmacodynamic effects of tramadol were easily detected using both static and dynamic pupil parameters. The pharmacodynamic profiles were markedly influenced by the CYP2D6 phenotype.
- MeSH
- aplikace orální MeSH
- biomarkery farmakologické metabolismus MeSH
- cytochrom P-450 CYP2D6 genetika metabolismus MeSH
- dospělí MeSH
- lidé MeSH
- mióza chemicky indukované MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mydriáza chemicky indukované MeSH
- opioidní analgetika aplikace a dávkování farmakokinetika farmakologie MeSH
- polymorfismus genetický MeSH
- pupila účinky léků MeSH
- tramadol aplikace a dávkování farmakokinetika farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky kontrolované MeSH
- práce podpořená grantem MeSH
- Názvy látek
- biomarkery farmakologické MeSH
- cytochrom P-450 CYP2D6 MeSH
- opioidní analgetika MeSH
- tramadol MeSH
