Chronic stress accelerates glioblastoma progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop.

BACKGROUND: After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking. METHODS: Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism. RESULTS: Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3ß activity, leading to ß-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and ß-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth. CONCLUSIONS: Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with ß-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.

A Novel Strategy to Improve Tumor Targeting of Hydrophilic Drugs and Nanoparticles for Imaging Guided Synergetic Therapy.

The fast renal clearance of hydrophilic small molecular anticancer drugs and ultrasmall nanoparticles (NPs) results in the low utilization rate and certain side effects, thus improving the tumor targeting is highly desired but faces great challenges. A novel and general ß-cyclodextrin (CD) aggregation-induced assembly strategy to fabricate doxorubicin (DOX) and CD-coated NPs (such as Au) co-encapsulated pH-responsive nanocomposites (NCs) is proposed. By adding DOX×HCl and reducing pH in a reversed microemulsion system, hydrophilic CD-coated AuNPs rapidly assemble into large NCs. Then in situ polymerization of dopamine and sequentially coordinating with Cu2+ on the surface of NCs provide extra weak acid responsiveness, chemodynamic therapy (CDT), and improved biocompatibility as well as stability. The subsequent tumor microenvironment responsive dissociation notably improves their passive tumor targeting, bioavailability, imaging, and therapeutic capabilities, as well as facilitates their internalization by tumor cells and metabolic clearance, thereby reducing side effects. The combination of polymerized dopamine and assembled AuNPs reinforces photothermal capability, thus further boosting CDT through thermally amplifying Cu-catalyzed Fenton-like reaction. Both in vitro and in vivo studies confirm the desirable outcomes of these NCs as photoacoustic imaging guided trimodal (thermally enhanced CDT, photothermal therapy, and chemotherapy) synergistic tumor treatment agents with minimal systemic toxicity.

Brain tissue iron neurophysiology and its relationship with the cognitive effects of dopaminergic modulation in children with and without ADHD.

Children with attention-deficit/hyperactivity disorder (ADHD) exhibit impairments in response inhibition. These impairments are ameliorated by modulating dopamine (DA) via the administration of rewards or stimulant medication like methylphenidate (MPH). It is currently unclear whether intrinsic DA availability impacts these effects of dopaminergic modulation on response inhibition. Thus, we estimated intrinsic DA availability using magnetic resonance-based assessments of basal ganglia and thalamic tissue iron in 36 medication-naïve children with ADHD and 29 typically developing (TD) children (8-12 y) who underwent fMRI scans and completed standard and rewarded go/no-go tasks. Children with ADHD additionally participated in a double-blind, randomized, placebo-controlled, crossover MPH challenge. Using linear regressions covarying for age and sex, we determined there were no group differences in brain tissue iron. We additionally found that higher putamen tissue iron was associated with worse response inhibition performance in all participants. Crucially, we observed that higher putamen and caudate tissue iron was associated with greater responsivity to MPH, as measured by improved task performance, in participants with ADHD. These results begin to clarify the role of subcortical brain tissue iron, a measure associated with intrinsic DA availability, in the cognitive effects of reward- and MPH-related dopaminergic modulation in children with ADHD and TD children.

Treatment and outcome of hepatorenal syndrome in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease. This study aimed to clarify the status of HRS in Japan by analyzing the Japanese Diagnosis Procedure Combination database. METHODS: Patients hospitalized for cirrhosis and HRS from July 2010 to March 2019 were sampled. They were divided into two groups according to their prognosis upon discharge: the transplant-free survival group and the death or liver transplantation group. The two groups' baseline patient characteristics and treatments were compared. RESULTS: The mean age of the 1,412 participants was 67.3 years (standard deviation: 12.3 years), and 65.4% were male. The Child-Pugh grades was B and C in 18.8% and 81.2%, respectively. Hepatocellular carcinoma was present in 27.1% of the patients, and the proportion of spontaneous bacterial peritonitis was 2.3%. Albumin, noradrenaline, and dopamine were administered to 57.9%, 8.0%, and 14.9% of the patients, respectively; 7.0% of the patients underwent renal replacement therapy; and 5.0% were admitted to the intensive care unit. Intravenous antibiotics were administered to 30.8% of the patients. A total of 925 patients (65.5%) died or underwent liver transplantation. In addition to a higher proportion of patients with poor baseline liver function, the death or liver transplantation group included more males, patients with hepatocellular carcinoma, and those with spontaneous bacterial peritonitis. CONCLUSIONS: HRS in Japan has a high mortality rate. Albumin was administered to over 50% of participants. Although noradrenaline is recommended in Japanese clinical guidelines, dopamine was more frequently used as a vasoconstrictor in clinical practice.

Management and clinical outcomes of cardiogenic shock in King Abdulaziz University Hospital: A retrospective study.

OBJECTIVES: To assess frequencies of various management approaches in cardiogenic shock (CS) and their clinical outcomes. Cardiogenic shock is a state of organ hypoperfusion and hypoxia caused by cardiac failure. METHODS: In this retrospective record review, we assessed the presentations, vital signs, laboratory readings, and treatments for 188 consecutive CS inpatients from 2010-2021. Patients were labeled as "ischemic CS" or "non-ischemic CS" based on the occurrence of myocardial infarction as the precipitating cause, and "post-operative CS" if they had undergone cardiac surgery. In-hospital mortality was the primary endpoint of the study. RESULTS: We identified 118 (62.8%) ischemic, 64 (34%) non-ischemic, and 6 (3.2%) postoperative CS patients. The study population had a high mortality rate (85.1%). Logistic regression analysis revealed that dopamine (p=0.040) and epinephrine (p=0.001) were independent predictors of mortality, while dobutamine (p=0.004) and digoxin (p=0.044) associated with increased survival. No significant association with mortality was found between either PCI or IABP. No significant difference in mortality was observed between CS subgroups. CONCLUSION: Variations in outcomes occurred with different medications. Mortality was higher in patients receiving dopamine or epinephrine and lower in those receiving dobutamine or digoxin. Implementation of clinical trials for investigation of the mortality benefit observed with dobutamine can serve towards formulation of new guidelines for improvement of CS mortality rates.

Structural genomics of the human dopamine receptor system.

The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

Neuroleptic malignant syndrome associated with atypical antipsychotics: A case report.

INTRODUCTION: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01%-3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. CASE REPORT: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisulpride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. DISCUSSION: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocytosis and elevated CPK. Differential diagnoses must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. CONCLUSIONS: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

Patient-, Clinician-, and Institution-level Variation in Inotrope Use for Cardiac Surgery: A Multicenter Observational Analysis.

BACKGROUND: Conflicting evidence exists regarding the risks and benefits of inotropic therapies during cardiac surgery, and the extent of variation in clinical practice remains understudied. Therefore, the authors sought to quantify patient-, anesthesiologist-, and hospital-related contributions to variation in inotrope use. METHODS: In this observational study, nonemergent adult cardiac surgeries using cardiopulmonary bypass were reviewed across a multicenter cohort of academic and community hospitals from 2014 to 2019. Patients who were moribund, receiving mechanical circulatory support, or receiving preoperative or home inotropes were excluded. The primary outcome was an inotrope infusion (epinephrine, dobutamine, milrinone, dopamine) administered for greater than 60 consecutive min intraoperatively or ongoing upon transport from the operating room. Institution-, clinician-, and patient-level variance components were studied. RESULTS: Among 51,085 cases across 611 attending anesthesiologists and 29 hospitals, 27,033 (52.9%) cases received at least one intraoperative inotrope, including 21,796 (42.7%) epinephrine, 6,360 (12.4%) milrinone, 2,000 (3.9%) dobutamine, and 602 (1.2%) dopamine (non-mutually exclusive). Variation in inotrope use was 22.6% attributable to the institution, 6.8% attributable to the primary attending anesthesiologist, and 70.6% attributable to the patient. The adjusted median odds ratio for the same patient receiving inotropes was 1.73 between 2 randomly selected clinicians and 3.55 between 2 randomly selected institutions. Factors most strongly associated with increased likelihood of inotrope use were institutional medical school affiliation (adjusted odds ratio, 6.2; 95% CI, 1.39 to 27.8), heart failure (adjusted odds ratio, 2.60; 95% CI, 2.46 to 2.76), pulmonary circulation disorder (adjusted odds ratio, 1.72; 95% CI, 1.58 to 1.87), loop diuretic home medication (adjusted odds ratio, 1.55; 95% CI, 1.42 to 1.69), Black race (adjusted odds ratio, 1.49; 95% CI, 1.32 to 1.68), and digoxin home medication (adjusted odds ratio, 1.48; 95% CI, 1.18 to 1.86). CONCLUSIONS: Variation in inotrope use during cardiac surgery is attributable to the institution and to the clinician, in addition to the patient. Variation across institutions and clinicians suggests a need for future quantitative and qualitative research to understand variation in inotrope use affecting outcomes and develop evidence-based, patient-centered inotrope therapies.

Combination of furosemide, gold, and dopamine as a potential therapy for breast cancer.

Breast cancer is one of the leading causes of death in women worldwide. Initially, it develops in the epithelium of the ducts or lobules of the breast glandular tissues with limited growth and the potential to metastasize. It is a highly heterogeneous malignancy; however, the common molecular mechanisms could help identify new targeted drugs for treating its subtypes. This study uses computational drug repositioning approaches to explore fresh drug candidates for breast cancer treatment. We also implemented reversal gene expression and gene expression-based signatures to explore novel drug candidates computationally. The drug activity profiles and related gene expression changes were acquired from the DrugBank, PubChem, and LINCS databases, and then in silico drug screening, molecular dynamics (MD) simulation, replica exchange MD simulations, and simulated annealing molecular dynamics (SAMD) simulations were conducted to discover and verify the valid drug candidates. We have found that compounds like furosemide, gold, and dopamine showed significant outcomes. Furthermore, the expression of genes related to breast cancer was observed to be reversed by these shortlisted drugs. Therefore, we postulate that combining furosemide, gold, and dopamine would be a potential combination therapy measurement for breast cancer patients.

The immunomodulatory effects of ethosuximide and sodium butyrate on experimentally induced fibromyalgia: The interaction between IL-4, synaptophysin, and TGF-ß1/NF-κB signaling.

BACKGROUND AND AIMS: Fibromyalgia is a widespread chronic pain syndrome associated with several comorbid conditions that affect the quality of patients' life. Its pathogenesis is complex, and the treatment strategies are limited by partial efficacy and potential adverse effects. So, our aim was to investigate the possible ameliorative effects of ethosuximide and sodium butyrate on fibromyalgia and compare their effects to pregabalin. MATERIALS AND METHODS: In a mouse model of reserpine induced fibromyalgia, the effect of ethosuximide, sodium butyrate, and pregabalin was investigated. Evaluation of mechanical allodynia, cold hypersensitivity, anxiety, cognitive impairment, and depression was performed. Also, the brain and spinal cord tissue serotonin, dopamine and glutamate in addition to the serum levels of interleukin (IL)-4 and transforming growth factor beta 1 (TGF-ß1) were assayed. Moreover, the expression of nuclear factor kappa B (NF-κB) synaptophysin was immunoassayed in the hippocampal tissues. KEY FINDINGS: Ethosuximide and sodium butyrate restored the behavioral tests to the normal values except for the antidepressant effect which was evident only with ethosuximide. Both drugs elevated the levels of the anti-inflammatory cytokines IL-4 and TGF-ß1, reduced the hippocampal NF-κB, and increased synaptophysin expression with superiority of sodium butyrate. Ethosuximide reduced only spinal cord and brain glutamate while improved brain dopamine while sodium butyrate elevated spinal cord dopamine and serotonin with no effect on glutamate. Also, sodium butyrate elevated brain serotonin and reduced glutamate with no effect on brain dopamine. SIGNIFICANCE: Each of sodium butyrate and ethosuximide would serve as a promising therapeutic modality for management of fibromyalgia and its comorbid conditions.

In situ photo-crosslinked adhesive hydrogel loaded with mesenchymal stem cell-derived extracellular vesicles promotes diabetic wound healing.

The delayed healing of diabetic wounds is directly affected by the disturbance of wound microenvironment, resulting from persistent inflammation, insufficient angiogenesis, and impaired cell functions. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) showed considerable therapeutic potential in diabetic wound healing. However, the low retention rate of MSC-EVs at wound sites hampers their efficacy. For skin wounds exposed to the outer environment, using a hydrogel with tissue adhesiveness under a moist wound condition is a promising strategy for wound healing. In this study, we modified methacryloyl-modified gelatin (GelMA) hydrogel with catechol motifs of dopamine to fabricate a GelMA-dopamine hydrogel. EVs isolated from MSCs were applied in the synthesized GelMA-dopamine hydrogel to prepare a GelMA-dopamine-EV hydrogel. The results demonstrated that the newly formed GelMA-dopamine hydrogel possessed improved properties of softness, adhesiveness, and absorptive capacity, as well as high biocompatibility in the working concentration (15% w/v). In addition, MSC-EVs were verified to promote cell migration and angiogenesis in vitro. In the skin wound model of diabetic rats, the GelMA-dopamine-EV hydrogel exerted prominent wound healing efficacy estimated by collagen deposition, skin appendage regeneration, and the expression of IL-6, CD31, and TGF-ß. In conclusion, this combination of MSC-EVs and the modified hydrogel not only accelerates wound closure but also promotes skin structure normalization by rescuing the homeostasis of the healing microenvironment of diabetic wounds, which provides a potential approach for the treatment of diabetic wounds.

Metabolic effects of dopamine-agonists treatment among patients with prolactinomas.

PURPOSE: To evaluate the effect of cabergoline treatment on metabolic parameters including the Triglyceride-glucose (TyG) index in newly diagnosed patients with prolactinoma. METHODS: 71 consecutive nondiabetic patients with prolactinoma were enrolled. Anthropometric and laboratory tests including TyG index were measured at baseline, 3 and 6 months visits. Treatment with cabergoline at the dose of 0.25 mg twice weekly was started and increased according to prolactin levels and continued for 6 months. RESULTS: At the baseline examination, the mean (SD) age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) of patients were 36.2 (10.5) years, 29.2 (5.0) kg/m2, 98.2 (13.7) cm, 115.3 (13.3) mmHg, and 71.4 (8.1) mmHg, respectively. Forty-one (57.7%) of patients were women and 46 (64.8%) had microadenoma. Cabergoline treatment significantly improved anthropometric and metabolic measures including BMI, WC, fasting plasma glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, uric acid (only among women), TyG index, and hypogonadism. Blood pressure (both systolic and diastolic) levels remained steady except for a significant decrease in DBP after 6 months of treatment only among women. A declining trend in MetS prevalence was found from baseline to a 3-month evaluation in both genders which was statistically significant among men. CONCLUSION: Short-term treatment with cabergoline can significantly improve cardiovascular risk factors except for blood pressure. Moreover, the TyG index as a surrogate marker of insulin resistance decreased significantly after the reduction of prolactin by treatment. Generally, results were similar among both genders.

The Regional Cerebral Oxygen Saturation Effect of Inotropes/Vasopressors Administered to Treat Intraoperative Hypotension: A Bayesian Network Meta-analysis.

One of the main concerns of intraoperative hypotension is adequacy of cerebral perfusion, as cerebral blood flow decreases passively when mean arterial pressure falls below the lower limit of cerebral autoregulation. Treatment of intraoperative hypotension includes administration of drugs, such as inotropes and vasopressors, which have different pharmacological effects on cerebral hemodynamics; there is no consensus on the preferred drug to use. We performed a network meta-analysis (NMA) to pool and analyze data comparing the effect on cerebral oxygen saturation (ScO 2 ) measured by cerebral oximetry of various inotropes/vasopressors used to treat intraoperative hypotension. We searched randomized control trials in Embase, Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that enrolled adult patients undergoing surgery under general/spinal anesthesia that compared at least 2 inotropes/vasopressors to treat hypotension. We reviewed 51 full-text manuscripts and included 9 randomized controlled trials in our study. The primary outcome was change in ScO 2 . Our results showed the likelihood that dopamine, ephedrine, and norepinephrine had the lowest probability of decreasing ScO 2 . The suggested rank order to maintain ScO 2 , from higher to lower, was dopamine

Study of the Effects of Nicotine and Caffeine for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is considered to be a highly severe neurological disorder. PD occurs due to a decrease in dopamine production by the degeneration of dopamine-secreting neurons. Genetic mutations, environmental toxins and lifestyle are some of the risk factors of the progressive neurodegenerative disorder PD. Parkin protein, which is encoded by the PARK gene, is one of the important proteins, which is one of the causative agents. The Parkin protein has several mutations which lead to the development of the disease. Apart from PD, the mutations in Parkin also showed to be responsible for the onset of diseases like cancers. It is reported that the E28K mutation in the Ubl domain of parkin is highly deleterious and responsible for the onset of melanoma. This necessitates the development of new therapeutics against PD. Molecules like levodopa, carbidopa, monoamine oxidase type B inhibitors (MBO inhibitors), dopamine agonists, anticholinergics and amantadine are some commonly used drugs used to treat PD. Recently, there have been increasing evidence which shows that cigarette smoking and consumptions of coffee and tea could have important roles in modulating the risk of PD. Therefore, we planned to analyse the molecular mechanism of the binding interactions of nicotine, caffeine and the polyphenol ( -)-epigallocatechin-3-gallate (EGCG) from green tea with Parkin protein to predict their therapeutic potentials in PD targeting the E28K mutation. We focused on E28K mutant of Parkin as this mutant form of parkin has been shown to be the most pathogenic one. We could identify the potential therapeutic aspects of these natural products to prevent the onset of PD. This work may therefore be considered to be the first of its kind which would take into consideration the environmental toxicological approach in designing natural product inhibitors against the onset of PD.

Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

Nicotine Treatment and Parkinson's DiseaseIn this randomized, controlled trial, patients with Parkinson's disease not on dopaminergic therapy were randomly assigned to receive transdermal nicotine or placebo. After 1 year, there was no difference in the change in Total Unified Parkinson's Disease Rating Scale score between groups.

Aptamer-Functionalized Ce4+-Ion-Modified C-Dots: Peroxidase Mimicking Aptananozymes for the Oxidation of Dopamine and Cytotoxic Effects toward Cancer Cells.

Aptamer-functionalized Ce4+-ion-modified C-dots act as catalytic hybrid systems, aptananozymes, catalyzing the H2O2 oxidation of dopamine. A series of aptananozymes functionalized with different configurations of the dopamine binding aptamer, DBA, are introduced. All aptananozymes reveal substantially enhanced catalytic activities as compared to the separated Ce4+-ion-modified C-dots and aptamer constituents, and structure-catalytic functions between the structure and binding modes of the aptamers linked to the C-dots are demonstrated. The enhanced catalytic functions of the aptananozymes are attributed to the aptamer-induced concentration of the reaction substrates in spatial proximity to the Ce4+-ion-modified C-dots catalytic sites. The oxidation processes driven by the Ce4+-ion-modified C-dots involve the formation of reactive oxygen species (•OH radicals). Accordingly, Ce4+-ion-modified C-dots with the AS1411 aptamer or MUC1 aptamer, recognizing specific biomarkers associated with cancer cells, are employed as targeted catalytic agents for chemodynamic treatment of cancer cells. Treatment of MDA-MB-231 breast cancer cells and MCF-10A epithelial breast cells, as control, with the AS1411 aptamer- or MUC1 aptamer-modified Ce4+-ion-modified C-dots reveals selective cytotoxicity toward the cancer cells. In vivo experiments reveal that the aptamer-functionalized nanoparticles inhibit MDA-MB-231 tumor growth.

Hydrogels for brain repair: application to Parkinson's disease.

INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Currently, there are no curative therapies, with only symptomatic treatment available. One of the principal reasons for the lack of treatments is the problem of delivering drugs to the brain, mainly due to the blood-brain barrier. Hydrogels are presented as ideal platforms for delivering treatments to the brain ranging from small molecules to cell replacement therapies. AREAS COVERED: The potential application of hydrogel-based therapies for Parkinson's disease is addressed. The desirable composition and mechanical properties of these therapies for brain application are discussed, alongside the preclinical research available with hydrogels in Parkinson's disease. Lastly, translational and manufacturing challenges are presented. EXPERT OPINION: Parkinson's disease urgently needs novel therapies to delay its progression and for advanced stages, at which conventional therapies fail to control motor symptoms. Neurotrophic factor-loaded hydrogels with stem cells offer one of the most promising therapies. This approach may increase the striatal dopamine content while protecting and promoting the differentiation of stem cells although the generation of synapses between engrafted and host cells remains an issue to overcome. Other challenges to consider are related to the route of administration of hydrogels and their large-scale production, required to accelerate their translation toward the clinic.

Bupropion XL unapproved use in the prisons: Two cases focused on the bupropion pharmacology.

BACKGRUND: Bupropion (BUP) is a norepinephrine-dopamine reuptake inhibitor frequently used in prisons. Although its positive effects on depression treatment are often presented, there are many questions about its approved use in prisons and similar facilities. In this context, this article aims to present two case reports of BUP XL unapproved use and a review of the mechanism of action, formulations, and the clinical profile of BUP. METHODS: Two case reports. The patients' data for the case reports were obtained from their medical records. A PubMed search was conducted using the terms BUP, inmates, and efficacy to identify randomized and non-randomized controlled trials and case reports to evaluate the possible effects of BUP in prison settings. Only approved medications were included. RESULTS: The positive effects of BUP XL on major depressive disorder treatment are well-reported, but few reports are on the pharmacokinetics of BUP XL in prisons. The exact mechanism of its effect on the central nervous system is predominantly connected with its unique pharmacokinetics. CONCLUSIONS: This paper shows that BUP XL will continue to play an essential role in treating a major depressive disorder in adults in prisons and other related disorders, although a different treatment strategy should be preferred in patients with high addictive potential. Because of a similar mechanism of action, the most appropriate alternatives for BUP XL could be mirtazapine, agomelatine, aripiprazole, and quetiapine, although clinical trials are needed to confirm these alternatives.

Treatments of psychiatric disorders, hyperprolactinemia and dopamine agonists.

While the prevalence of hyperprolactinemia under antidepressants is very low, its prevalence under antipsychotics, particularly of the first generation, is high. Antipsychotics act by blocking dopamine activity at the level of the dopamine type 2 receptor (D2R). When prolactin levels exceed 80-100 ng/ml, a pituitary adenoma must be ruled out by MRI. Treatment of hyperprolactinemia is necessary only in cases with clinical symptoms of hypogonadism. Three treatment options are possible: switch to a less hyperprolactinemic antipsychotic, sex steroid supplementation or dopamine agonist (which normalizes prolactin levels in only half of cases). Fortunately, psychotic exacerbation due to the opposing effects of antipsychotics and dopamine agonists on the D2R seems very rare. When a patient presents with a macroprolactinoma, particularly with optic chiasm compression, surgery or dopamine agonists may be proposed. The agonists are effective in reducing tumor mass and improving visual defects in the majority of patients but rarely normalize prolactin levels.