Disparities by Socioeconomic Status and Diagnosis of Dementia in the Prescribing of Antipsychotics in a Real-World Data Population Over 60 Years of Age.

Background: Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia. Objective: To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer's disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex. Methods: A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statisticalanalysis. Results: Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52-1.68), age over 80 years (OR: 1.56; CI: 1.47-1.65), institutionalization (OR: 12.61; CI: 11.64-13.65), diagnosis of dementia (OR: 10.18; CI: 9.55-10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58-4.01) and psychosis (OR: 4.96; CI: 4.64-5.30). Conclusions: The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity.

Design of quetiapine fumarate loaded polyethylene glycol decorated graphene oxide nanosheets: Invitro-exvivo characterization.

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R2: 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF.

Post-marketing surveillance of quetiapine fumarate extended-release tablets in patients with bipolar depression.

AIM: This study aimed to verify the real-world efficacy and safety of quetiapine fumarate extended-release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. METHODS: We performed a post-marketing surveillance with an observation period of 12 weeks. RESULTS: In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and "longer time since the onset of the first episode" (p = 0.011) and "presence of complications" (p < 0.001) were identified as significant risk factors for the occurrence of ADRs. In the efficacy analysis group (n = 265), the average changes from baseline in the total Montgomery-Åsberg Depression Rating Scale (MADRS) score were -7.3 ± 8.8, -12.2 ± 10.7, -16.8 ± 12.7, and -13.2 ± 12.7 points after 4, 8, and 12 weeks, and at the last evaluation, respectively. The mean MADRS total score decrease had no significant association with maximum daily dose, diagnosis, and presence or absence of prior or concomitant treatment for bipolar disorder with mood stabilizers/antipsychotics/antidepressants. CONCLUSION: The efficacy of quetiapine fumarate extended-release tablets was confirmed in clinical practice, and no new safety concerns or risks were identified.

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul® MCM, Gelucire® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes.

Severe irritability in a critically ill preterm infant: a case of delirium at the neonatal intensive care unit.

Delirium is a common disorder in intensive care units, being associated with greater morbidity and mortality. However, in neonatal intensive care units, delirium is rarely diagnosed, due to the low familiarity of the neonatologist with the subject and the difficulties in the applicability of diagnostic questionnaires. This case report aimed to assess the presence of this disorder in this group of patients and identify the difficulties encountered in the diagnosis and treatment. We report the case of a premature newborn with necrotizing enterocolitis during hospitalization and underwent three surgical approaches. The newborn exhibited intense irritability, having received high doses of fentanyl, dexmedetomidine, clonidine, ketamine, phenytoin, and methadone, without the control of the symptoms. A diagnosis of delirium was then made and treatment with quetiapine was started, with a complete reversal of the symptoms. This is the first case reported in Brazil and the first describing the withdrawal of the quetiapine.

Delirium é uma síndrome comum em unidades de terapia intensiva, associando-se a maiores morbidade e mortalidade. No entanto, nas unidades de terapia intensiva neonatal, ele raramente é diagnosticado em razão da baixa familiaridade do neonatologista com a suspeita diagnóstica e das dificuldades na aplicabilidade dos questionários diagnósticos. Este relato de caso tem como objetivos mostrar que delirium está presente nesse grupo de pacientes e apontar as dificuldades encontradas no seu diagnóstico e tratamento. Relatamos o caso de um recém-nascido prematuro com enterocolite necrosante, submetido a três abordagens cirúrgicas. O recém-nascido apresentou intensa irritabilidade, tendo recebido altas doses de fentanil, dexmedetomidina, clonidina, cetamina, fenitoína e metadona, sem controle dos sintomas. Em seguida, foi feita a hipótese diagnóstica de delirium e iniciado tratamento com quetiapina, com reversão completa dos sintomas. Este é o primeiro caso notificado no Brasil e o primeiro que descreve a suspensão da quetiapina.

Trace-level determination of potential genotoxic impurities in quetiapine fumarate using LC-MS.

A novel LC-MS method was developed and validated to determine three potential genotoxic impurities, namely 2-(2-aminophenylthio)benzoic acid hydrochloride, 2-aminothiophenol, and 2-(2-aminophenylthio)benzonitrile, at trace level (~1.6 ppm) in quetiapine fumarate drug substance, an antipsychotic drug. These impurities are potentially genotoxic and therefore should be controlled at or below specific acceptance limits. An InertSustain AQ-C18 column (250 × 4.6 mm, 5 µm) in reversed-phase mode with the column temperature at 45°C was used. The mobile phase was 0.1% trifluoroacetic acid in water and acetonitrile with gradient elution mode, and the run time was 45 min. The flow rate was 0.8 ml/min. A mass spectrometer was used to quantify the amount of impurities using electrospray ionization mode at specific m/z 245.9, 126.0, and 226.9 for 2-(2-aminophenylthio)benzoic acid hydrochloride, 2-aminothiophenol, and 2-(2-aminophenylthio) benzonitrile, respectively. The method was found to be sensitive and possessed excellent linearity in the concentration ranges from the limit of quantification to 150% of the permitted level (0.47-2.36 µg/ml) with correlation coefficients above 0.999. The results showed that the method was specific, precise, linear, and accurate for the estimation of these three impurities in quetiapine fumarate.

Severe irritability in a critically ill preterm infant: a case of delirium at the neonatal intensive care unit / Grave irritabilidade em prematuro criticamente doente: um caso de delirium na unidade de terapia intensiva neonatal

ABSTRACT Delirium is a common disorder in intensive care units, being associated with greater morbidity and mortality. However, in neonatal intensive care units, delirium is rarely diagnosed, due to the low familiarity of the neonatologist with the subject and the difficulties in the applicability of diagnostic questionnaires. This case report aimed to assess the presence of this disorder in this group of patients and identify the difficulties encountered in the diagnosis and treatment. We report the case of a premature newborn with necrotizing enterocolitis during hospitalization and underwent three surgical approaches. The newborn exhibited intense irritability, having received high doses of fentanyl, dexmedetomidine, clonidine, ketamine, phenytoin, and methadone, without the control of the symptoms. A diagnosis of delirium was then made and treatment with quetiapine was started, with a complete reversal of the symptoms. This is the first case reported in Brazil and the first describing the withdrawal of the quetiapine.

RESUMO Delirium é uma síndrome comum em unidades de terapia intensiva, associando-se a maiores morbidade e mortalidade. No entanto, nas unidades de terapia intensiva neonatal, ele raramente é diagnosticado em razão da baixa familiaridade do neonatologista com a suspeita diagnóstica e das dificuldades na aplicabilidade dos questionários diagnósticos. Este relato de caso tem como objetivos mostrar que delirium está presente nesse grupo de pacientes e apontar as dificuldades encontradas no seu diagnóstico e tratamento. Relatamos o caso de um recém-nascido prematuro com enterocolite necrosante, submetido a três abordagens cirúrgicas. O recém-nascido apresentou intensa irritabilidade, tendo recebido altas doses de fentanil, dexmedetomidina, clonidina, cetamina, fenitoína e metadona, sem controle dos sintomas. Em seguida, foi feita a hipótese diagnóstica de delirium e iniciado tratamento com quetiapina, com reversão completa dos sintomas. Este é o primeiro caso notificado no Brasil e o primeiro que descreve a suspensão da quetiapina.

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

Brain Targeting of Quetiapine Fumarate via Intranasal Delivery of Loaded Lipospheres: Fabrication, In-Vitro Evaluation, Optimization, and In-Vivo Assessment.

A liposphere system for intranasal delivery of quetiapine fumarate (QTF) was created to assess the potential for enhanced drug delivery. We investigated the effects of particle size, entrapment effectiveness, poly dispersibility index, and pluronic incorporation percentage on these variables. The optimal formula was examined using a TEM, and investigations into DSC, XRD, and FTIR were made. Optimized liposphere formulation in vitro dissolution investigation with a mean diameter of 294.4 ± 18.2 nm revealed about 80% drug release in 6 h. The intranasal injection of QTF-loaded lipospheres showed a shorter Tmax compared to that of intranasal and oral suspension, per the findings of an in vivo tissue distribution investigation in Wistar mice. Lipospheres were able to achieve higher drug transport efficiency (DTE %) and direct nose-to-brain drug transfer (DTP %). A potentially effective method for delivering QTF to specific brain regions is the liposphere system.

Central Composite Optimization of Glycerosomes for the Enhanced Oral Bioavailability and Brain Delivery of Quetiapine Fumarate.

This study aimed to formulate and statistically optimize glycerosomal formulations of Quetiapine fumarate (QTF) to increase its oral bioavailability and enhance its brain delivery. The study was designed using a Central composite rotatable design using Design-Expert® software. The independent variables in the study were glycerol % w/v and cholesterol % w/v, while the dependent variables were vesicle size (VS), zeta potential (ZP), and entrapment efficiency percent (EE%). The numerical optimization process resulted in an optimum formula composed of 29.645 (w/v%) glycerol, 0.8 (w/v%) cholesterol, and 5 (w/v%) lecithin. It showed a vesicle size of 290.4 nm, zeta potential of -34.58, and entrapment efficiency of 80.85%. The optimum formula was further characterized for DSC, XRD, TEM, in-vitro release, the effect of aging, and pharmacokinetic study. DSC thermogram confirmed the compatibility of the drug with the ingredients. XRD revealed the encapsulation of the drug in the glycerosomal nanovesicles. TEM image revealed spherical vesicles with no aggregates. Additionally, it showed enhanced drug release when compared to a drug suspension and also exhibited good stability for one month. Moreover, it showed higher brain Cmax, AUC0-24, and AUC0-∞ and plasma AUC0-24 and AUC0-∞ in comparison to drug suspension. It showed brain and plasma bioavailability enhancement of 153.15 and 179.85%, respectively, compared to the drug suspension. So, the optimum glycerosomal formula may be regarded as a promising carrier to enhance the oral bioavailability and brain delivery of Quetiapine fumarate.

Quantification of quetiapine fumarate based on electrochemical analysis by reduced graphene oxide modified nano-silica functionalized with polydopamine and gold nanostars: A novel pharmaceutical analysis strategy.

Quetiapine fumarate (QF) is an antipsychotic drug that has been most widely prescribed as an antipsychotic. In this regard, sensitive recognition of QF in bodily fluids must be done accurately. In this work, an electrochemical sensor for QF detection was fabricated, using GNSs-PDA@SiO2 modified rGO stabilized on glassy carbon electrode. According to the electrical nature of gold nanoparticles (GNPs), polydopamine (PDA), and its composition with nano-silica, the proposed hybrid material is able to enhance the electro-oxidation signals of QF toward its sensitive detection in complex biological media. The morphology of synthesized polymeric nanocomposites and various surfaces of electrodes were investigated using Field Emission Scanning Electron Microscopy and Energy-Dispersive X-Ray Spectroscopy methods. Using the square wave voltammetry technique, the fabricated electrochemical sensor could detect QF in the linear range of 500 µM to 3 mM, which low limit of quantification was obtained as 500 µM, indicating the sensor's appropriate sensitivity. For the first time, the application of novel hybrid material (GNSs-PDA@SiO2 ) for pharmaceutical analysis in human plasma was studied using electrochemical sensor technology. Based on the obtained analytical results, engineered nano-surface led to entrapment and oxidation of QF in real samples. So, a novel and efficient method for the analysis of QF was designed and validated, which opens a new horizon for pharmaceutical analysis and therapeutic drug monitoring.

Effect of Polymers and Permeation Enhancers in the Release of Quetiapine Fumarate Transdermal Patch through the Dialysis Membrane.

Quetiapine Fumarate is potent, and the daily therapeutic dose can be delivered easily across the skin with the help of permeation enhancers. Quetiapine Fumarate-loaded transdermal patches were prepared by solvent evaporation technique. Various formulation parameters, excipients, and their combinations were optimized to get thin, translucent, smooth, stable, and high permeable character patches. A total number of 10 formulations were prepared. All formulations were subjected to various physicochemical evaluations. Three different formulations were prepared and F1, F2, and F3. Various physicochemical studies were carried out and found no significant difference between the three batches. The in vitro release study showed 74.29%, 82.73%, and 77.27%, respectively, up to 24 h. From the results, F2 has been selected as an optimized formulation and evaluated for skin irritation test. The results revealed that there is no irritation produced. The stability study results showed that there is no significant change from its initial nature till the period of three months in both temperatures. Quetiapine Fumarate Transdermal Patch F2 has achieved the goal of extended-release, cost-effectiveness, lowering the dose and frequency of drug administration, and thus may improve patient compliance.

Use of chlorprothixene and the risk of diabetes and major adverse cardiovascular events: A nationwide cohort study.

Chlorprothixene is commonly used off-label in low doses for sedative-hypnotic purposes although it might carry a risk of cardiometabolic adverse events due to its pharmacodynamic profile. We investigated the risk of diabetes and major adverse cardiovascular events (MACE) with use of low-dose chlorprothixene, compared with use of low-dose quetiapine in a nationwide cohort study, including all new users of low-dose chlorprothixene (n = 81 328) and low-dose quetiapine (n = 91 163) in Denmark 2000-2017. Main outcomes were diabetes and MACE (myocardial infarction, stroke and death from cardiovascular causes). The association between cumulative dose of chlorprothixene and the outcomes was tested in a case-control analysis. Low-dose chlorprothixene use was associated with increased risk of diabetes (intention-to-treat [ITT]-hazard ratio [HR]: 1.16; 95% CI: 1.08-1.25), compared with low-dose quetiapine use. This association strengthened when follow-up was restricted to time on treatment (as-treated [AT]-HR: 1.34; 95% CI: 1.14-1.56). Low-dose chlorprothixene use was also associated with increased risk of MACE (ITT-HR: 1.12; 95% CI: 1.04-1.21) and stroke (ITT-HR: 1.21; 95% CI: 1.06-1.37) but not with myocardial infarction (ITT-HR: 1.11; 95% CI: 0.95-1.30) nor death from cardiovascular causes (ITT-HR: 1.07; 95% CI: 0.96-1.20). Cumulative dose of chlorprothixene ≥6000 mg was associated with increased risk of diabetes (OR: 1.15-1.63; test for trend: p < 0.001), whereas cumulative dose of chlorprothixene ≥1500 mg was associated with increased risk of MACE (OR: 1.10-1.85; test for trend: p < 0.001). In conclusion, low-dose chlorprothixene use is associated with increased risk of cardiometabolic adverse events compared with low-dose quetiapine use.

Síndrome neuroléptico maligno secundario a quetiapina / Neuroleptic malignant syndrome secondary to quetiapine

Objetivo: Describir un caso clínico de una paciente tratada con quetiapina a alta dosis de larga duración en el que produjo una reacción adversa atípica.Descripción del caso clínico: Mujer de 82 años institucionalizada en una residencia para mayores de edad, acude a urgencias con síntomas de fiebre (39º), espasticidad y cambio de estado mental. Se excluyeron los diagnósticos diferenciales iniciales: accidente cerebrovascular e infección, por lo que con los síntomas presentados se diagnosticó de SNM. En el tratamiento farmacológico en el momento del ingreso destacó un dosis de quetiapina 400mg/24h; confirmado con su centro de residencia debido a las discrepancias con su prescripción electrónica. Según informes médicos, la paciente había recibido este tratamiento durante dos meses previo al ingreso, aunque el SNM es un efecto secundario poco común entre los antipsicóticos posee unas consecuencias fatales. El primer día de hospitalización se suspendió la quetiapina y recibió tratamiento específico contra el SNM, compuesto por dantroleno, fluidoterapia y cuidados de apoyo. El SNM se resolvió a los 3 días.Discusión: A pesar de que los antipsicóticos atípicos (AA) se consideren de mayor seguridad debido a su baja potencia para bloquear los receptores D2, pueden causar SNM incluso cuando se prescriben en monoterapia. Por ello, es fundamental un seguimiento de los tratamientos crónicos especialmente en personas mayores con un deterioro cognitivo de base.Esto enfatiza la importancia de la comunicación médico-farmacéutico para promover la seguridad de pacientes y la importancia de las notificaciones. (AU)

Aim: To describe a clinical case of a patient treated with quetiapine at high dose of long duration in which it produced an atypical adverse reaction.Description of the clinical case: An 82-year-old woman institutionalized in a nursing home for the elderly, went to the emergency room with the next symptoms; fever (39º), spasticity and change in mental state. After excluding other pathologies, she was diagnosed NMS. Pharmacological treatment at the time of admission a dose of quetiapine 400mg/24h attracted attention; which was confirmed with her center of residence due to discrepancies with her electronic prescription. According to medical reports, the patient had received this treatment for two months before admission, although NMS is an uncommon side effect among antipsychotics with fatal consequences. Hospitalization first´s day, quetiapine was discontinued and she received specific treatment for NMS, consisting of dantrolene, fluid therapy and supportive care. The NMS was resolved after 3 days.Discussion: Although atypical antipsychotics (AA) are considered safer because of their low potency in blocking D2 receptors, they can cause NMS even when prescribed in monotherapy. Therefore, a follow-up of chronic treatments is essential, especially in older people with a basic cognitive impairment.This case emphasizes the importance of medical-pharmaceutical communication´s to promote patient safety and the importance of reporting. (AU)

The Use of Quetiapine for the Management of Nausea and Vomiting in Idiopathic Parkinson's Disease.

Nausea and vomiting are common in the palliative demographic and can significantly affect quality of life. Initial management strategies involve tailoring antiemetic selection to the underlying cause. Whilst in refractory cases, management is often switched to a broader spectrum antipsychotic agent (such as levomepromazine or olanzapine). Yet in individuals with idiopathic Parkinson's disease antiemetics which antagonize central dopamine are avoided, as they have the potential to exacerbate motor control or even precipitate Parkinsonism-hyperpyrexia syndrome. Consequently, antiemetic options for patients with idiopathic Parkinson's disease are limited. This is the first report of quetiapine being successfully used for the management of nausea and vomiting in an individual with idiopathic Parkinson's disease.

Efficacy of quetiapine fumarate combined with lithium carbonate in the treatment of bipolar disorder in 30 patients / 中国基层医药

Objective:To investigate the efficacy of quetiapine fumarate combined with lithium carbonate in the treatment of bipolar disorder and its effect on cognitive function.Methods:Sixty patients with bipolar disorder, who received treatment in Zhuji Fifth People's Hospital from January 2017 to December 2019, were included in this study. They were randomly assigned to receive either lithium carbonate (control group, n = 30) or quetiapine fumarate combined with lithium carbonate treatment (combined treatment group, n = 30). All patients received 4 weeks of treatment. Manic and depressive symptoms pre- and post-treatment, clinical efficacy, cognitive function, and adverse reactions were compared between the two groups. Fasting venous blood was taken before and 4 weeks after treatment to measure superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GSH-Px) levels. Results:The scores of the Bech-Rafaelsdn Mania Rating Scale (BRMS) and the Hamilton Rating Scale for Depression (HAMD) in each group were significantly decreased after treatment compared with before treatment ( t = 10.39, 12.47, both P < 0.001). The score of the Mini-Mental State Examination in each group significantly increased after treatment compared with before treatment ( t = 8.36, 14.52, both P < 0.001). The scores of BRMS and HAMD post-treatment were significantly lower in the combined treatment group than in the control group ( t = 5.86, 5.54, both P < 0.001). The score of MMSE post-treatment was significantly higher in the combined treatment group than in the control group ( t = 2.40, P = 0.020). The response rate was significantly higher in the combined treatment group than in the control group ( Z = 2.16, P = 0.030). After treatment, serum MDA level significantly decreased in each group compared with before treatment ( t = 8.72, 15.47, both P < 0.001). After treatment, SOD, CAT and GSH-Px levels were significantly increased in each group compared with before treatment (SOD: tcontrol group = 2.84, P = 0.006, tcombined treatment group = 4.05, P < 0.001; CAT: tcontrol group = 5.20, P < 0.001, tcombined treatment group = 9.86, P < 0.001; GSH-Px: tcontrol group = 2.67, P = 0.010, tcombined treatment group = 3.71, P = 0.001). Serum MDA level post-treatment was significantly lower in the combined treatment group than in the control group ( t = 12.38, P < 0.001). Serum SOD and CAT levels post-treatment were significantly higher in the combined treatment group than in the control group ( tSOD = 2.24, P = 0.029; tCAT = 2.72, P = 0.009). There was no significant difference in the incidence of adverse reactions between the combined treatment and control groups [20.00% (6/30) vs. 16.67% (5/30), χ2 = 1.02, P = 0.907). Conclusion:Quetiapine fumarate combined with lithium carbonate can greatly improve clinical symptoms and cognitive function and reduce the over-activation of oxidative stress in patients with bipolar disorder. The combined therapy is of certain clinical application value.

Self-emulsifying Drug Delivery System for Improved Dissolution and Oral Absorption of Quetiapine Fumarate: Investigation of Drug Release Mechanism and In-vitro Intestinal Permeability.

In this study, we focused on quetiapine fumarate (QTF), a class II BCS drug. QTF is an atypical antipsychotic used in the treatment of schizophrenia and bipolar disorders. Our objective was to develop a new QTF-loaded self-emulsifying drug delivery system (SEDDS) to improve the dissolution and absorption of the drug. An experimental design approach was used to develop and optimize QTF-loaded SEDDS. The optimized formulation was characterized for droplets size, zeta potential, PDI, and stability. It was then evaluated using an in-vitro combined test for dissolution and Everted gut sac technique. Mathematical modeling and Transmission electron microscopy (TEM) were used to elucidate the mechanism of release. The optimal formulation was type IIIB SEDDS, constituted of 9.1% of oleic acid, 51.6% of Tween®20, and 39.3% of Transcutol® P. It showed a droplets size of 144.8 ± 4.9nm with an acceptable PDI and zeta potential. For in-vitro evaluation tests, we noticed an enhancement of the dissolution rate of the optimal QTF-loaded SEDDS compared to the free drug (98.82 ± 1.24% for SEDDS after 30 min compared to 85.65 ± 2.5% for the pure drug). The release of QTF fitted with the Hopfenberg model indicating the drug was released by water diffusion and erosion mechanism. This result was confirmed by TEM images which showed a smaller droplet size after release. We also found an amelioration of the permeability of QTF of 1.69-fold from SEDDS compared to the free drug. Hence, the SEDDS formulation represented a new way to improve the dissolution and absorption of QTF.

Quetiapine Fumarate Loaded Nanostructured Lipid Carrier for Enhancing Oral Bioavailability: Design, Development and Pharmacokinetic Assessment.

AIMS: The study aimed at developing and characterizing Nanostructured Lipid Carriers (NLC) of Quetiapine Fumarate (QF) by Design of Experiment (DoE) for the enhancement of bioavailability. BACKGROUND: QF, an anti-psychotic drug, has an oral bioavailability of 9% due to hepatic first- pass metabolism necessitating the use of high doses. Its side effects are dose -related and enhancement in bioavailability would result in minimization of side effects. OBJECTIVE: The objective of the study was the enhancement of bioavailability of the NLC of QF by preferential lymphatic uptake. METHODS: Hot emulsification-ultrasonication was the method of formulation using PrecirolATO5 and Oleic acid as solid and liquid lipids respectively. Poloxamer188 and Phospholipon90G were used as surfactant and stabilizer respectively. Solid:liquid lipid ratio and Phospholipon90G amount were independent variables and percent Entrapment Efficiency (%EE), Particle Size (PS) dependent variables during optimization by Central Composite Design. RESULTS: The optimized formulation showed a %EE of 77.21%, PS of 140.2 nm and surface charge of - 19.9mV. Higuchi kinetic model was followed during the in-vitro release. TEM revealed spherical, smooth nanoparticles. A pharmacokinetic study in rats showed AUC0-∞ of QF-NLC to be 3.93 times that of QF in suspension, suggesting significant enhancement in bioavailability. An increase in AUC0-∞ in cycloheximide untreated rats' group of QF-NLC by 2.43 times as compared to cycloheximide treated group, confirmed lymphatic absorption of QF- NLC. CONCLUSION: The results validated DoE as an appropriate tool for developing QF loaded NLC and proved NLC to be a promising delivery system for the enhancement of oral bioavailability of QF.

General considerations for bioequivalence studies with pharmacokinetic methods for anti-schizophrenic drugs / 中国临床药理学与治疗学

On account of the characteristics of anti-schizophrenic drugs, combined with the technical guidelines for bioequivalence studies of anti-schizophrenic generic drugs in different regulatory institutions at home and abroad, taking some drugs as examples, this paper discusses the key points to be considered in carrying out bioequivalence studies from the perspective of experimental design, so as to provide certain reference for the research and development and evaluation of related products.