BACKGROUND: A detailed understanding of alterations in olanzapine pharmacokinetics during acute inflammatory states, associated with infections, remains lacking. This study aimed to investigate the impact of endotoxemia on the pharmacokinetics of olanzapine and desmethylolanzapine (DMO) in mice. METHODS: C57BL/6N mice received an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (controls), followed 24 hours later by single oral or intravenous doses of olanzapine or intravenous DMO. Concentrations and unbound fractions of olanzapine and DMO were measured in the plasma and brain homogenates. RESULTS: In LPS-injected mice, the area under the concentration-time curve (AUCs) for olanzapine increased 3.8-fold in the plasma and 5.2-fold in brain homogenates, in consequence of a higher absolute bioavailability of olanzapine (+200%), a lower plasma clearance (-34%), and a higher brain penetration ratio for the unbound drug relative to controls (Kp,uu,brain 6.2 vs. 4.1). LPS attenuated the hepatic mRNA expression of cytochrome P450 1A2 and the metabolism of olanzapine to DMO. However, the AUC of plasma DMO increased by 140% due to a 4.8-fold decrease in the plasma clearance of DMO. The brain penetration of DMO was minimal (Kp,uu,brain ≤ 0.051). The LPS-injected mice exhibited a downregulation of the hepatic and ileal mRNA expression of P-glycoprotein (Abcb1a), whereas the expression of Abcb1a and Abcb1b in the brain was upregulated. CONCLUSIONS: Endotoxemia notably increases olanzapine concentrations in the plasma and brain following oral administration in mice. Further studies should clarify whether altered pharmacokinetics results in adverse effects in acutely infected patients taking oral olanzapine.

• Klíčová slova
• brain penetration, endotoxemia, lipopolysaccharide, olanzapine, pharmacokinetics,
• MeSH
• antipsychotika * farmakokinetika   krev   aplikace a dávkování   MeSH
• aplikace orální MeSH
• benzodiazepiny * farmakokinetika   krev   aplikace a dávkování   MeSH
• endotoxemie * metabolismus   chemicky indukované   MeSH
• lipopolysacharidy MeSH
• mozek * metabolismus   účinky léků   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• olanzapin farmakokinetika   MeSH
• zánět * chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika * MeSH
• benzodiazepiny * MeSH
• lipopolysacharidy MeSH
• olanzapin MeSH

INTRODUCTION: Previous research has raised concerns about high prevalence of drug-related problems, polypharmacy and inappropriate benzodiazepine prescribing in nursing homes (NHs) and confirmed lack of studies from Central and South-Eastern Europe. The aim of our study was to determine the prevalence and characteristics of polypharmacy, hyperpolypharmacy and inappropriate benzodiazepine prescribing in NH residents in Croatia. METHODS: Data from 226 older NH residents from five Croatian NHs were collected using the InterRAI Long-Term Care Facilities assessment form. The prevalence and determinants of polypharmacy/hyperpolypharmacy and patterns of inappropriate benzodiazepine prescribing were documented. RESULTS: The prevalence of polypharmacy (49.6%) and hyperpolypharmacy (25.7%) among NH residents was high. In our study, 72.1% of NH residents were prescribed at least one psychotropic agent, 36.7% used 2-3 psychotropics and 6.6% used 4+ psychotropics. Among benzodiazepine users (55.8%), 28% of residents were prescribed benzodiazepines in higher than recommended geriatric doses, 75% used them for the long term and 48% were prescribed concomitant interacting medications. The odds of being prescribed polypharmacy/hyperpolypharmacy were significantly higher for older patients with polymorbidity (6+ disorders, proportional odds ratio (POR) = 19.8), type II diabetes (POR = 5.2), ischemic heart disease (POR = 4.6), higher frailty (Clinical Frailty Scale (CFS ≥5); POR = 4.3) and gastrointestinal problems (POR = 4.8). CONCLUSIONS: Our research underscores the persistent challenge of inappropriate medication use and drug-related harms among older NH residents, despite existing evidence and professional campaigns. Effective regulatory and policy interventions, including the implementation of geriatrician and clinical pharmacy services, are essential to address this critical issue and ensure optimal medication management for vulnerable NH populations.

• Klíčová slova
• Nursing home residents, geriatric deprescribing, inappropriate benzodiazepine prescribing, polypharmacy/hyperpolypharmacy, psychiatric polypharmacy/hyperpolypharmacy,
• MeSH
• benzodiazepiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• domovy pro seniory statistika a číselné údaje   MeSH
• lékařská praxe - způsoby provádění statistika a číselné údaje   normy   MeSH
• lidé MeSH
• nevhodné předepisování * statistika a číselné údaje   MeSH
• pečovatelské domovy * statistika a číselné údaje   MeSH
• polypharmacy * MeSH
• prevalence MeSH
• psychotropní léky terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Chorvatsko epidemiologie   MeSH
• Názvy látek
• benzodiazepiny * MeSH
• psychotropní léky MeSH

Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patients comfort during this process. Patients are typically afraid of switching to a more suitable long-acting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.

• Klíčová slova
• Z-drugs, addiction, benzodiazepines, detoxification, tapering, withdrawal,
• MeSH
• abstinenční syndrom prevence a kontrola   MeSH
• benzodiazepiny aplikace a dávkování   škodlivé účinky   MeSH
• diazepam terapeutické užití   MeSH
• lidé MeSH
• metabolická inaktivace MeSH
• poruchy spojené s užíváním psychoaktivních látek farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• benzodiazepiny MeSH
• diazepam MeSH

OBJECTIVE: Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations. METHODS: The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57. RESULTS: The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study. CONCLUSION: This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics.

• Klíčová slova
• Adipokine, Adipose tissue, Dyslipidemia, Leptin, Olanzapine, Sprague-Dawley rats,
• MeSH
• antipsychotika aplikace a dávkování   škodlivé účinky   MeSH
• benzodiazepiny aplikace a dávkování   škodlivé účinky   MeSH
• hmotnostní přírůstek * MeSH
• krysa rodu Rattus MeSH
• leptin krev   MeSH
• nežádoucí účinky léčiv krev   metabolismus   MeSH
• olanzapin MeSH
• potkani Sprague-Dawley MeSH
• triglyceridy krev   MeSH
• tuková tkáň účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika MeSH
• benzodiazepiny MeSH
• leptin MeSH
• olanzapin MeSH
• triglyceridy MeSH

OBJECTIVE: Risperidone in antipsychotic doses induces hyperprolactinemia. The aim of this study was to verify whether the same is true for low doses of risperidone (0.5-2 mg per day) added to antidepressants or anxiolytics. METHODS: Prolactin levels were measured in 4 men (mean age 49.5+/-19.1 years) and 8 women (mean age 31.3+/-8.2 years) inpatients with depressive and anxiety disorders who were treated with risperidone (median doses per day 1.25 mg) for median 15.5 days as an augmentation treatment to antidepressants (n=8), anxiolytics (n=6) and mood stabilizers (n=2). RESULTS: 11 of 12 patients had hyperprolactinemia. Median plasma prolactin level was 1598 mIU/ml, 95% CI 1 040-2 661 mIU/ml. Significant correlation between risperidone daily dose and plasma prolactin level (Spearman's R=0.655, p=0.02) was detected. Two women suffered from galactorrhea and one from amenorrhea. CONCLUSIONS: Even low doses of risperidone used as an augmentation to antidepressants or benzodiazepines are associated with hyperprolactinemia and can induce endocrinological side effects. The co-medication of antidepressants and benzodiazepines can potentially increase intensity of prolactinemia.

• MeSH
• antidepresiva aplikace a dávkování   terapeutické užití   MeSH
• antipsychotika aplikace a dávkování   škodlivé účinky   MeSH
• anxiolytika aplikace a dávkování   terapeutické užití   MeSH
• benzodiazepiny aplikace a dávkování   terapeutické užití   MeSH
• depresivní poruchy krev   farmakoterapie   MeSH
• dospělí MeSH
• hyperprolaktinemie chemicky indukované   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• neparametrická statistika MeSH
• prolaktin krev   MeSH
• risperidon aplikace a dávkování   škodlivé účinky   MeSH
• úzkost krev   farmakoterapie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antidepresiva MeSH
• antipsychotika MeSH
• anxiolytika MeSH
• benzodiazepiny MeSH
• prolaktin MeSH
• risperidon MeSH

• MeSH
• arousal účinky léků   fyziologie   MeSH
• azoly aplikace a dávkování   MeSH
• barbituráty aplikace a dávkování   MeSH
• benzodiazepiny aplikace a dávkování   MeSH
• elektroencefalografie MeSH
• isatin aplikace a dávkování   MeSH
• krysa rodu Rattus MeSH
• tubokurarin aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• azoly MeSH
• barbituráty MeSH
• benzodiazepiny MeSH
• isatin MeSH
• tubokurarin MeSH

• MeSH
• benzodiazepiny aplikace a dávkování   MeSH
• celková anestezie MeSH
• diazepam aplikace a dávkování   MeSH
• lidé MeSH
• premedikace anestezie MeSH
• stomatochirurgie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• benzodiazepiny MeSH
• diazepam MeSH