Antipsychotics are used in the treatment of schizophrenia and other psychiatric disorders. Generally, they are divided into typical and atypical ones, according to the fact that atypical antipsychotics induce fewer side effects and are more effective in terms of social and cognitive improvements. Their pharmacological effects are mediated via broad range of receptors that consequently influence different cellular signalling pathways. Antipsychotics produce undesirable side effects that range from relatively minor to life threatening. In vitro and in vivo studies have pointed to neurotoxic effect exerted by some antipsychotics and have shown that apoptosis might play role in some side effects induced by antipsychotics, including tardive dyskinesia, weight gain, agranulocytosis, osteoporosis, myocarditis, etc. Although cumulative data have suggested safety of atypical antipsychotics use during pregnancy, some of them have been shown to induce apoptotic neurodegenerative and structural changes in fetal brains with long-lasting impact on cognitive impairment of offspring. Typical antipsychotics seem to be more cytotoxic than atypical ones. Recently, epidemiological studies have shown lower incidence of cancer in schizophrenic patients that suggest the ability of antipsychotics to suppress risk of cancer development. Some antipsychotics have been reported to inhibit cancer cell proliferation and induce their apoptosis. Therefore, antipsychotics apoptotic effect may be used as a tool in the treatment of some types of cancer, especially in combinatorial therapies. In this mini-review, we focused on pro- and antiapoptotic or 'Dr. Jekyll and Mr. Hyde' effects of antipsychotics, which can be involved in their side effects, as well as their promising therapeutic indications.

• Klíčová slova
• apoptosis, atypical antipsychotics, side effects, therapeutic effects, typical antipsychotics,
• MeSH
• antipsychotika * škodlivé účinky   MeSH
• apoptóza MeSH
• lidé MeSH
• schizofrenie * chemicky indukované   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antipsychotika * MeSH

Cerebral vasospasm (CVS) is a frequent and serious neurosurgical complication, without sufficient therapy. This retrospective study was performed to analyze if nimodipine can improve prognosis and reduce ischaemia secondary to delayed CVS after intracranial tumour surgery. A retrospective review was performed over the years 2011 to 2012 for patients with an anterior cranial fossa tumour and underwent intracranial tumour surgery. The surgical field was soaked with nimodipine solution or normal saline. Transcranial Doppler ultrasonography was used to measure velocity in the middle cerebral artery (MCA) and the distal extracranial internal carotid artery (eICA). Follow-up was performed using the Glasgow Outcome Scale (GOS) after discharge. There were 94 patients that met the inclusion criteria. They included 50 males and 44 females, with a mean age of 49.6 years. In the nimodipine group, CVS occurred in 13 patients; 9 patients had CVS between 4 and 7 days, and 4 had CVS between 8 and 14 days. In the normal saline group, 19 patients had CVS, 3 presented with CVS within 3 days, 11 between 4-7 days and 5 between 8-14 days. A significant difference in the occurrence of CVS was observed between the two groups. Preoperative and postoperative the MCA velocities were compared, revealing a significant change in the normal saline group but not in the nimodipine group. Nimodipine markedly improves prognosis and significantly reduces ischaemia secondary to delayed CVS after intracranial tumour surgery, as well as the risks of mortality and morbidity.

• Klíčová slova
• cerebral vasospasm, intracranial tumour surgery, ischaemia, nimodipine,
• MeSH
• arteria cerebri media diagnostické zobrazování   chirurgie   účinky léků   MeSH
• časové faktory MeSH
• dospělí MeSH
• intrakraniální vazospazmus * etiologie   farmakoterapie   diagnostické zobrazování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory mozku * chirurgie   MeSH
• nimodipin * terapeutické užití   aplikace a dávkování   MeSH
• pooperační komplikace etiologie   prevence a kontrola   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nimodipin * MeSH

Cardiovascular complications are a side effect of cancer therapy, potentially through reduced blood vessel function. ONC201 (TIC10) is currently used in phase 2 clinical trials to treat high-grade gliomas. TIC10 is a phosphatidylinositol 3-kinase (PI3K)/AKT/extracellular signal-regulated kinase (ERK) inhibitor that induces apoptosis via upregulation of TNF-related apoptosis-inducing ligand, which via stimulation of FOXO and death receptor could increase eNOS upregulation. This has the potential to improve vascular function through increased NO bioavailability. Our aim was to investigate the role of TIC10 on vascular function to determine if it would affect the risk of CVD. Excised abdominal aorta from White New Zealand male rabbits were cut into rings. Vessels were incubated with TIC10 and AS1842856 (FOXO1 inhibitor) followed by cumulative doses of acetylcholine (Ach) to assess vessel function. Vessels were then processed for immunohistochemistry. Incubation of blood vessels with TIC10 resulted in enhanced vasodilatory capacity. Combination treatment with the FOXO1 inhibitor and TIC10 resulted in reduced vascular function compared to control. Immunohistochemical analysis indicated a 3-fold increase in death receptor 5 (DR5) expression in the TIC10-treated blood vessels but the addition of the FOXO1 inhibitor downregulated DR5 expression. The expression of DR4 receptor was not significantly increased in the presence of TIC10; however, addition of the FOXO1 inhibitor downregulated expression. TIC10 has the capacity to improve the function of healthy vessels when stimulated with the vasodilator Ach. This highlights its therapeutic potential not only in cancer treatment without cardiovascular side effects, but also as a possible drug to treat established CVD.

• Klíčová slova
• FOXO1 pathway, acetylcholine, cardiovascular diseases, imipridone (TIC10), nitric oxide, vascular relaxation,
• MeSH
• aorta abdominalis účinky léků   metabolismus   MeSH
• chinolony MeSH
• forkhead box protein O1 * metabolismus   MeSH
• imidazoly farmakologie   MeSH
• králíci MeSH
• pyrimidiny farmakologie   MeSH
• signální transdukce * účinky léků   MeSH
• vazodilatace * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid MeSH Prohlížeč
• chinolony MeSH
• forkhead box protein O1 * MeSH
• imidazoly MeSH
• pyrimidiny MeSH

Daridorexant is a dual orexin receptor antagonist in clinical development for the treatment of insomnia. Breast-cancer resistant protein (BCRP) is an efflux pump expressed in intestinal epithelium and hepatocytes, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds. In vitro, daridorexant inhibits BCRP with an IC50 of 3.0 μmol/L. The BCRP substrate rosuvastatin is a cholesterol-lowering drug, recommended for clinical drug-drug interaction (DDI) studies. In order to exclude an inhibitory effect of daridorexant on BCRP, this single-centre, open-label, two-treatment Phase 1 study investigated the effect of daridorexant at steady state on the pharmacokinetics (PK) of single-dose rosuvastatin in 20 healthy male subjects. In addition, safety and tolerability were assessed. A single oral dose of 10 mg rosuvastatin on Day 1 was followed by 96 hours observation. Thereafter, 25 mg daridorexant was administered once daily (o.d.) on Days 5-8 and in combination with 10 mg rosuvastatin on Day 8. On Days 9-12, subjects received 25 mg daridorexant alone. PK sampling was performed up to 120 hours after treatment administration. The results showed that concomitant administration of 25 mg daridorexant o.d. at steady state did not affect the exposure parameters of rosuvastatin in a relevant way, as indicated by the ratios of geometric means (GMRs) ([rosuvastatin + daridorexant]/[rosuvastatin alone]) of 0.93 for both Cmax and AUC0-∞ . Administration of a single dose of 10 mg rosuvastatin, multiple doses of 25 mg daridorexant alone or in combination were well tolerated. Taken together, daridorexant and BCRP substrates can be safely co-administered.

• Klíčová slova
• BCRP, daridorexant, drug-drug interaction, dual orexin receptor antagonist, pharmacokinetics, rosuvastatin,
• MeSH
• ABC transportér z rodiny G, člen 2 * antagonisté a inhibitory   metabolismus   MeSH
• antagonisté orexinového receptoru * farmakokinetika   farmakologie   aplikace a dávkování   MeSH
• dospělí MeSH
• imidazoly MeSH
• lékové interakce * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové proteiny * antagonisté a inhibitory   metabolismus   MeSH
• pyrimidiny farmakokinetika   aplikace a dávkování   farmakologie   MeSH
• pyrrolidiny MeSH
• rosuvastatin kalcium * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 * MeSH
• ABCG2 protein, human MeSH Prohlížeč
• antagonisté orexinového receptoru * MeSH
• daridorexant MeSH Prohlížeč
• imidazoly MeSH
• nádorové proteiny * MeSH
• pyrimidiny MeSH
• pyrrolidiny MeSH
• rosuvastatin kalcium * MeSH

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.

• Klíčová slova
• B-type natriuretic peptide, clinical effectiveness, heart failure, pharmacotherapy,
• MeSH
• akutní nemoc MeSH
• lidé MeSH
• natriuretický peptid typu B * terapeutické užití   krev   MeSH
• srdeční selhání * farmakoterapie   patofyziologie   krev   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• natriuretický peptid typu B * MeSH

The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.

• Klíčová slova
• angiotensin-converting enzyme II, cardiovascular disease, diminazene aceturate, endothelial dysfunction, renin angiotensin system,
• MeSH
• aktivace enzymů MeSH
• aktivátory enzymů škodlivé účinky   terapeutické užití   MeSH
• angiotensin konvertující enzym 2 metabolismus   MeSH
• diminazen škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   enzymologie   patofyziologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   patofyziologie   MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ACE2 protein, human MeSH Prohlížeč
• aktivátory enzymů MeSH
• angiotensin konvertující enzym 2 MeSH
• diminazen MeSH
• diminazene aceturate MeSH Prohlížeč

The view that genes are constrained within somatic cells is challenged by in vitro evidence, and more recently by in vivo studies which demonstrate that mitochondria with their mitochondrial DNA (mtDNA) payload not only can, but do move between cells in tumour models and in mouse models of tissue damage. Using mouse tumour cell models without mtDNA to reflect mtDNA damage, we have shown that these cells grow tumours only after acquiring mtDNA from cells in the local microenvironment resulting in respiration recovery, tumorigenesis and metastasis. Mitochondrial transfer between cells has also been demonstrated following ischaemia-induced injury in the heart and brain and in lung epithelium, and following lung inflammation. In vitro investigations suggest that stem cells may be mitochondrial donors. The ability of mitochondria to move between cells appears to be an evolutionarily-conserved phenomenon, relevant to diseases with compromised mitochondrial function including neurodegenerative, neuromuscular and cardiovascular diseases as well as cancer and ageing.

• Klíčová slova
• bioenergetics, cancer, disease, intercellular mitochondrial trafficking, mitochondria, mitochondrial DNA damage, rho zero cells,
• MeSH
• biogeneze organel MeSH
• lidé MeSH
• mitochondriální DNA genetika   metabolismus   MeSH
• mitochondrie genetika   metabolismus   patologie   MeSH
• nádorové mikroprostředí MeSH
• nádory genetika   metabolismus   patologie   MeSH
• pohyb buněk * MeSH
• poškození DNA MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• mitochondriální DNA MeSH

The role of hypertension and the renin-angiotensin system (RAS) in sex-related differences in the course of chronic kidney disease (CKD) and congestive heart failure (CHF) remain unclear, especially when the two diseases are combined. In male and female Ren-2 transgenic rats (TGR), a model of hypertension with activation of endogenous RAS, CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of an aorto-caval fistula (ACF). The primary aim of the study was to examine long-term CKD- and CHF-related mortality, especially in animals with CKD and CHF combined, with particular interest in the potential sex-related differences. The follow-up period was 23 weeks after the first intervention (5/6 NX). We found, first, that TGR did not exhibit sexual dimorphism in the course of 5/6 NX-induced CKD. Second, in contrast, TGR exhibited important sex-related differences in the course of ACF-induced CHF-related mortality: intact female TGR showed higher survival rate than male TGR. This situation is reversed in the course of combined 5/6 NX-induced CKD and ACF-induced CHF-related mortality: intact female TGR exhibited poorer survival than male TGR. Third, the survival rate in animals with combined 5/6 NX-induced CKD and ACF-induced CHF was significantly worsened as compared with rat groups that were exposed to 'single organ disease'. Collectively, our present results clearly show that CKD aggravates long-term mortality of animals with CHF. In addition, TGR exhibit remarkable sexual dimorphism with respect to CKD- and CHF-related mortality, especially in animals with combined CKD and CHF.

• Klíčová slova
• 5/6 nephrectomy, aorto-caval fistula, chronic kidney disease, congestive heart failure, hypertension, renin-angiotensin system, sex differences in rats,
• MeSH
• aorta metabolismus   patofyziologie   MeSH
• hypertenze metabolismus   mortalita   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• míra přežití trendy   MeSH
• nefrektomie škodlivé účinky   MeSH
• píštěle komplikace   metabolismus   patofyziologie   MeSH
• pohlavní dimorfismus * MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• renin * metabolismus   MeSH
• srdeční selhání metabolismus   mortalita   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ren2 protein, rat MeSH Prohlížeč
• renin * MeSH

The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.

• Klíčová slova
• angiotensin 1-7, angiotensin II, angiotensin-converting enzyme type 2, malignant hypertension, renin-angiotensin system,
• MeSH
• aktivátory enzymů farmakologie   MeSH
• albuminurie komplikace   MeSH
• angiotensin I metabolismus   MeSH
• angiotensin konvertující enzym 2 MeSH
• angiotensin konvertující enzym metabolismus   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• diminazen analogy a deriváty   farmakologie   MeSH
• hypertenze maligní komplikace   metabolismus   patofyziologie   moč   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• myši MeSH
• peptidové fragmenty metabolismus   MeSH
• peptidy farmakologie   MeSH
• potkani transgenní MeSH
• regulace genové exprese účinky léků   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• sodík moč   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ace2 protein, mouse MeSH Prohlížeč
• Ace2 protein, rat MeSH Prohlížeč
• aktivátory enzymů MeSH
• angiotensin I (1-7) MeSH Prohlížeč
• angiotensin I MeSH
• angiotensin konvertující enzym 2 MeSH
• angiotensin konvertující enzym MeSH
• cytochrom P-450 CYP1A1 MeSH
• diminazen MeSH
• diminazene aceturate MeSH Prohlížeč
• DX600 peptide MeSH Prohlížeč
• peptidové fragmenty MeSH
• peptidy MeSH
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• sodík MeSH

The B-type natriuretic peptide (BNP) may favour natriuresis and diuresis, making it an ideal drug to aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these has resulted in a better outcome. The current challenge for BNP research in acute HF lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP as well as a better integration of basic and clinical science.

• Klíčová slova
• B-type natriuretic peptide, heart failure,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH