Search Results (25)

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study’s findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease. Full article

Background: Cognitive impairment is a core symptom of schizophrenia and is associated with functional outcomes. Improving cognitive function is an important treatment goal. Studies have reported beneficial cognitive effects of the second-generation antipsychotic (SGA) ziprasidone. Reducing the dose of first-generation antipsychotics (FGA) might also improve cognitive function. This study compared the cognitive effects in long-stay patients who were randomized to groups who underwent FGA dose reduction or switched to ziprasidone. Methods: High-dose FGA was reduced to an equivalent of 5 mg of haloperidol in 10 patients (FGA-DR-condition), and 13 patients switched to ziprasidone 80 mg b.i.d. (ZIPRA condition). Five domains of cognitive function were assessed before dose reduction or switching (T0) and after 1 year (T1). This study was approved by the ethics committee of the Open Ankh (CCMO number 338) and registered at the Netherlands Trial Register (code 5864). Results: Non-significant deterioration was seen in all cognitive domains studied in the FGA-DR condition, whereas there was a non-significant improvement in all cognitive domains in the ZIPRA condition. The most robust difference between conditions, in favor of ziprasidone, was in executive function. Conclusions: In patients with severe chronic schizophrenia, ziprasidone had a non-significant and very modest beneficial effect on cognitive function compared with FGA dose reduction. Larger trials are needed to further investigate this effect. Full article

This systematic review compared the efficacy and tolerance of oral antipsychotics (APDs) used in the treatment of schizophrenia following the PRISMA-P© statement (n = 21). The primary outcomes of interest were clinical response measured with symptoms’ improvement, tolerance to side effects and discontinuation reasons. There was better individual patients’ response to aripiprazole vs. ziprasidone and quetiapine ((CDSS p = 0.04), BPRS p = 0.02, YMRS p = 0.001) and ziprasidone vs. quetiapine (CGI p = 0.02, CDSS p = 0.02). Aripiprazole was more tolerated than risperidone, ziprasidone and quetiapine (p < 0.05). Quetiapine was more tolerated than aripiprazole, ziprasidone and risperidone (p < 0.05). Ziprasidone was more tolerated than quetiapine haloperidol and olanzapine (p < 0.05). Risperidone was more tolerated than olanzapine (p = 0.03) and haloperidol was more tolerated than olanzapine and quetiapine (p < 0.05). Olanzapine caused less discontinuation than quetiapine; quetiapine caused less discontinuation than ziprasidone, aripiprazole and haloperidol; ziprasidone caused less discontinuation than quetiapine, aripiprazole and haloperidol; aripiprazole caused less discontinuation than quetiapine, ziprasidone and olanzapine and olanzapine caused less discontinuation than ziprasidone and haloperidol (p < 0.05). It was concluded that individual patient clinical response, tolerance to side effects and life-threatening side effects remain the most reliable basis for selecting and continuing the use of APD. Full article

In this study, an AQbD-compliant chaotropic chromatography method for ziprasidone and the determination of its five impurities was developed. The influence of critical method parameters (initial and final methanol fraction in the mobile phase, gradient duration) on the set of selected critical method attributes (t_{_imp. V}, t_{_imp. V} − t_{_imp. I}, S and <W_USP>) was studied by Box–Behnken design. The errors resulting from the calculation of the model coefficients were propagated to the selected responses by Monte Carlo simulations, and their predictive distribution was obtained. The design space was computed (π ≥ 80%), and a working point was selected: initial methanol fraction 38.5%, final methanol fraction 77.5%, and gradient duration 16.25 min. Furthermore, the quantitative robustness of the developed method was tested using the Plackett–Burman design. P_{_imp II} and P_{_imp V} were found to be significantly affected, the first by mobile phase flow rate and the second by gradient duration. Finally, the method was validated, and its reliability for routine quality control in capsules was confirmed. Full article

The feasibility of using lipid–polymer hybrid (LPH) nanocarriers as a potential platform for the intranasal delivery of ziprasidone (ZP), a second-generation antipsychotic, was explored. Different ZP-loaded LPH composed of a PLGA core and cholesterol-lecithin lipid coat were prepared using a single step nano-precipitation self-assembly technique. Modulation of polymer, lipid and drug amounts, as well as stirring-speed-optimized LPH with a particle size of 97.56 ± 4.55 nm and a ZP entrapment efficiency (EE%) of 97.98 ± 1.22%. The brain deposition and pharmacokinetics studies proved the efficiency of LPH to traverse the blood–brain barrier (BBB) following intranasal delivery with a 3.9-fold increase in targeting efficiency compared to the intravenous (IV) ZP solution with a direct nose-to-brain transport percentage (DTP) of 74.68%. The ZP-LPH showed enhanced antipsychotic activity in terms of animals’ hypermobility over an IV drug solution in schizophrenic rats. The obtained results showed that the fabricated LPH was able to improve ZP brain uptake and proved its antipsychotic efficiency. Full article

Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van’t Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αβ interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~10⁴ M⁻¹), the highest observed for clozapine (2.2 × 10⁴ M⁻¹ at 25 °C). The clozapine binding showed “friendly” effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible “foe”. Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed. Full article

Nanotechnology is used today in a wide range of industries. Weakly water-soluble medications have better solubility and bioavailability when delivered by nano-specific drug delivery methods, such as nanocrystals. Another name for ziprasidone is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, and it is a brand-new “atypical” or “second-generation” antipsychotic drug. Its multipotent G-protein-coupled (GPCR) receptor binding profile is distinctive. It is used to treat bipolar-disorder-related acute manic or mixed episodes as well as schizophrenia. Schizophrenia is a serious mental condition in which a person can experience reality in a strange or different way. Ziprasidone is a highly lipophilic and unstable drug. Ziprasidone nanoparticles, another incarnation of this drug, are used to treat diseases. When ziprasidone is present in the form of particles with an effective average crystal size of less than or equal to 100 nm, the term “nanoparticle” is frequently used to characterize them. A colloidal submicron dispersion of ziprasidone particles is what ziprasidone nanosuspensions and nanoemulsions are made of. One formulation that makes use of solubilization technology is a nanosuspension of a crystalline ziprasidone free base. In order to get around the drug’s solubility issue and investigate its potential for nose-to-brain delivery, a buffered nanoemulsion of ziprasidone HCl has been created. We discuss numerous ziprasidone nanoformulations used to treat psychotic illnesses in this review. Full article

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories. Full article

(1) Background: To systematically review evidence on the safety and efficacy of psychopharmacological treatments available for psychomotor agitation (PA) in children and adolescents. (2) Methods: Studies assessing the safety and efficacy of psychopharmacological treatments for acute PA in children and adolescents that were published between January 1984 and June 2022 on PubMed were systematically reviewed. We included: (i) papers that presented a combination of the search terms specified in the “Search strategy” sub-paragraph; (ii) manuscripts in English; (iii) original papers; (iv) prospective or retrospective/observational studies and experimental or quasi-experimental reports. The exclusion criteria were: (i) review papers; (ii) non-original studies including editorials and book reviews; (iii) studies not specifically designed and focused on the selected topic. (3) Results: We selected 42 papers: 11 case series (11/42, 26.19%), 8 chart reviews (8/42, 19.05%), 8 case reports (8/42, 19.05%), 6 double-blind placebo-controlled randomized studies (6/42, 14.29%), 4 double-blind controlled randomized studies (4/42, 9.52%), 4 open-label trials (4/42, 9.52%) and 1 case control (1/42, 2.38%). (4) Conclusions: The drugs most frequently used to treat agitation in children and adolescents were ziprasidone, risperidone, aripiprazole, olanzapine and valproic acid. Further studies are needed to evaluate the efficacy/safety ratio, considering the limited number of observations in this field. Full article

Sexual dysfunction, as a noticeable adverse effect of atypical antipsychotic drugs (APDs) for the treatment of schizophrenia, has not been investigated in detail. A study was undertaken to investigate whether 28-day long treatment with clozapine, ziprasidone or sertindole (using a recommended daily dose for atypical antipsychotic therapy), induced histopathological changes both in rat testicles and prostate, changed the activity of the antioxidant defence system and altered blood testosterone and prolactin. Clozapine, ziprasidone and sertindole induced histopathological changes in rat testicular tissue, which could be attributed to a disturbed testicular antioxidant defence system in addition to an altered prolactin to testosterone ratio. None of the APD treatments induced histopathological changes in prostate. Our results demonstrate that APDs have the capacity to change both redox and endocrinological balance. One or both outcomes could underline testicular degeneration and disturbed spermatogenesis. Full article

Background: Atypical antipsychotics increase the risk of atrial arrhythmias and sudden cardiac death. This study investigated whether ziprasidone, a second-generation antipsychotic, affected intracellular Ca²⁺ and Na⁺ regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. Methods: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca²⁺ monitoring using Fluo-3, the patch-clamp method for ionic current recordings, and a fluorescence study for the detection of reactive oxygen species and intracellular Na⁺ levels were conducted in enzymatically dissociated atrial myocytes. Results: Ziprasidone-treated atriums showed sustained triggered activities after rapid pacing, which were inhibited by KN-93 and ranolazine. A reduced peak L-type Ca²⁺ channel current and enhanced late Na⁺ current were observed in ziprasidone-treated atrial myocytes, together with an increased cytosolic Na⁺ level. KN-93 suppressed the enhanced late Na⁺ current in ziprasidone-treated atrial myocytes. Atrial myocytes treated with ziprasidone showed reduced Ca²⁺ transient amplitudes and sarcoplasmic reticulum (SR) Ca²⁺ stores, and increased SR Ca²⁺ leakage. Cytosolic and mitochondrial reactive oxygen species production was increased in atrial myocytes treated with ziprasidone. TNF-α and NLRP3 were upregulated in ziprasidone-treated myocytes, and the level of phosphorylated calcium/calmodulin-dependent protein kinase II protein was increased. Conclusions: Our results suggest that ziprasidone increases the occurrence of atrial triggered activity and causes intracellular Ca²⁺ and Na⁺ dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes. Full article

Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions. Full article

Through the years, the available psychopharmacological treatments have expanded with numerous new drugs. Besides weight gain, gastro-intestinal problems or Parkinson-like symptoms, ocular adverse effects of psychiatric drugs have been reported. These adverse effects are not common, but can be dangerous for the patient. This review summarises the current knowledge on the risk of raised intraocular pressure and glaucoma entailed by psychopharmacological treatment. Also, it provides updated data for clinicians involved in the treatment of patients with glaucoma or glaucoma risk factors. For this purpose, we performed an extensive literature search in the PubMed database using specific terms. Selective serotonin and noradrenaline reuptake inhibitors are the best evidenced as having no association with glaucoma. Antipsychotics, and especially first generation, seem to have no correlation with an increased intraocular pressure and therefore possibly with a risk of glaucoma, although a special attention should be paid when using ziprasidone. Tricyclic antidepressants, benzodiazepines and topiramate should be avoided in patients diagnosed with glaucoma or at risk. Clinicians should be aware of the possible psychotropic drug induced glaucoma and monitor at risk patients closely in order to prevent this condition. Irrespective of the psychopharmacological regimen taken into consideration, the glaucoma patient should be under the strict supervision of the ophthalmologist. Full article

The lack of female participation in antipsychotic trials for schizophrenia poses an important issue regarding its applicability, with direct and real-life repercussions to clinical practice. Here, our aim is to systematically review the sampling sex bias among randomized clinical trials (RCTs) of second-generation antipsychotics—namely risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole—as an update to a previous 2005 review. We searched MEDLINE and the Cochrane database for studies published through 7 September 2020 that assessed adult samples of at least 50 subjects with a diagnosis of schizophrenia, schizophrenia spectrum disorder, or broad psychosis, in order to investigate the percentage of women recruited and associated factors. Our review included 148 RCTs, published from 1993 to 2020, encompassing 43,961 subjects. Overall, the mean proportion of women was 34%, but only 17 trials included 50% or more females. Younger samples, studies conducted in North America, pharmaceutical funding and presence of specific exclusion criteria for women (i.e., pregnancy, breast-feeding or lack of reliable contraceptive) were associated with a lower prevalence of women in the trials. Considering the possible different effects of antipsychotics in both sexes, and our lack of knowledge on the subject due to sampling bias, it is imperative to expand actions aimed at bridging this gap. Full article

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well. Full article