NSF evaluation of gadolinium biodistribution in renally impaired rats: Using novel metabolic Gd2O3 nanoparticles coated with ß-cyclodextrin (Gd2O3@PCD) in MR molecular imaging.

The use of conventional gadolinium(Gd)-based contrast agents in magnetic resonance imaging (MRI) poses a significant risk of Nephrogenic Systemic Fibrosis (NSF) syndrome in patients with impaired renal function (grades 4 and 5). To address this issue, a new study has introduced a novel metabolic Gadolinium oxide nanoparticle (Gd2O3 NPs) coated with ß-cyclodextrin (ßCD). The study aims to investigate NSF syndrome by quantifying tissue Gd deposition biodistribution in renal impairment rats using MR molecular imaging. This is the first study of its kind to use this approach. A group of 20 rats were divided into four groups, each containing five rats that underwent 5/6 nephrectomy. The rats received 12 intravenous injections of a novel homemade synthesized gadolinium oxide polycyclodextrin (Gd2O3@PCD) at a dose of 0.1 mmol/kg, conventional contrast agents (CAs) drugs of Omniscan (Gd-DTPA-BMA) and Dotarem (Gd-DOTA), at a dose of 2.5 mmol/kg, and 250 µl saline for two injections per week during six weeks. T1-weighted MR imaging was performed before the injections and once a week for six weeks to quantify Gd deposition in four different organs (skin, liver, heart, and lung) in rats using inductively coupled plasma mass spectrometry (ICP-MS). The relationship between Signal-to-Noise Ratio (SNR) and biodistribution of Gd deposition due to NSF-induced syndrome was also calculated. The results of the study showed that the Gd concentrations in tissues were significantly higher in the Gd2O3@PCD group compared to the other groups, without any significant histopathological changes (P < 0.05). In the Gd2O3@PCD group, Gd was mainly deposited in the skin, followed by the liver, lung, and heart, without any symptoms of thickening or hardening of the skin. The Gd concentrations in the skin, liver, lung, and heart were significantly lower in the Dotarem group than in the Omniscan group (P < 0.05). In the histopathological examinations, the Omniscan group showed increased cellularity in the dermis. A significant hyperintensity was observed in the Gd2O3@PCD-treated rats compared to the Dotarem and Omniscan groups in the liver, heart, and lung. Compared to conventional Gd-based CAs, the novel metabolically Gd2O3@PCD with increased SNR, biosafety, and a considerably lower probability of developing NSF, has potential applicability for diagnosing patients with renal diseases in clinical MR Molecular Imaging (MRMI).

Implementation of a Hospital-based Brexanolone Program.

Postpartum depression (PPD) is a serious complication of childbearing affecting ∼1 in 7 mothers. Left unrecognized and untreated, it is associated with negative outcomes for mothers and their infants. Building upon research suggesting that, for some women, hormonal fluctuations after childbirth contribute to the onset of depression, clinical trials have found promise in a novel treatment approach, brexanolone infusion. In 2019, the Food and Drug Administration (FDA) approved brexanolone as the first medication with an indication specifically for PPD. Delivering brexanolone treatment to patients in need requires overcoming some logistical and clinical challenges that are unique to this approach. This brief report describes the process by which a university-affiliated obstetric-gynecologic hospital in the northeast United States successfully implemented a program to administer this novel treatment to women with PPD.

Lippia grata essential oil complexed with ß-cyclodextrin ameliorates biochemical and behavioral deficits in an animal model of progressive parkinsonism.

Parkinson's disease (PD) is identified by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), and is correlated to aggregates of proteins such as α-synuclein, Lewy's bodies. Although the PD etiology remains poorly understood, evidence suggests a main role of oxidative stress on this process. Lippia grata Schauer, known as "alecrim-do-mato", "alecrim-de-vaqueiro", "alecrim-da-chapada", is a native bush from tropical areas mainly distributed throughout the Central and South America. This plant species is commonly used in traditional medicine for relief of pain and inflammation conditions, and that has proven antioxidant effects. We evaluated the effects of essential oil of the L. grata after its complexed with ß-cyclodextrin (LIP) on PD animal model induced by reserpine (RES). Behavioral assessments were performed across the treatment. Upon completion the treatment, the animals were euthanized, afterwards their brains were isolated and processed for immunohistochemical and oxidative stress analysis. The LIP treatment delayed the onset of the behavior of catalepsy, decreased the number of oral movements and prevented the memory impairment on the novel object recognition task. In addition, the treatment with LIP protected against dopaminergic depletion in the SNpc and dorsal striatum (STRd), and decreased the α-syn immunoreactivity in the SNpc and hippocampus (HIP). Moreover, there was reduction of the oxidative stability index. These findings demonstrated that the LIP treatment has neuroprotective effect in a progressive parkinsonism model, suggesting that LIP could be an important source for novel treatment approaches in PD.

Brexanolone: A Novel Drug for the Treatment of Postpartum Depression.

OBJECTIVES: To review the pharmacology, efficacy, and safety of Brexanolone and define its role in the treatment of postpartum depression. DATE SOURCES: A MEDLINE/PubMed search was conducted (1980-May 2020) using the following keywords: postpartum depression, antidepressants, pharmacologic therapy, drug therapy, and brexanolone to identify relevant articles. STUDY SELECTION/DATA EXTRACTION: Literature search was limited to human studies published in the English language. Phase I, II, and III studies evaluating the pharmacology, efficacy, safety of brexanolone for postpartum depression were included. Bibliographies of relevant articles evaluating postpartum depression and treatment were reviewed for additional citations and background information. DATA SYNTHESIS: Brexanolone is a soluble, proprietary, injectable formulation of allopregnanolone, a neuroactive steroid that modulates neuronal excitability. Allopregnanolone levels increase during pregnancy and decrease substantially after birth. These fluctuations have profound effects on anxiety and depression. Three clinical trials established the efficacy and safety of brexanolone in the treatment of postpartum depression. In all 3 trials, brexanolone had an acceptable safety profile and was well tolerated. The most common adverse effects were loss of consciousness, sedation, dry mouth, headache, dizziness, and flushing. Due to sudden loss of consciousness and excessive sedation, continuous pulse oximetry is recommended. CONCLUSION: Brexanolone has a novel mechanism of action and appears to be safe and effective for the treatment of moderate to severe postpartum depression. At present, high cost, serious adverse effects, and restricted access may limit its use in clinical practice.

A Brexanolone Treatment Program at an Academic Medical Center: Patient Selection, 90-Day Posttreatment Outcomes, and Lessons Learned.

BACKGROUND: Brexanolone is the first U.S. Food and Drug Administration-approved drug for the treatment of postpartum depression. Brexanolone is a positive allosteric modulator of the GABAA receptor and is given over 60 hours by infusion in a medical setting. This drug has been shown to be effective at significantly reducing Hamilton Rating Scale for Depression scores at 60 hours and 30 days after infusion; however, data beyond 30 days have not yet been available. There have been limited clinical programs able to offer brexanolone owing to the complexity of setting up this treatment in a medical setting. PURPOSE: This study sought to obtain follow-up data from 16 patients who received a brexanolone infusion at UNC Hospitals in Chapel Hill, NC, between October 2019 and December 2020 and were beyond the 30-day postinfusion time point. We describe the methods used to successfully implement this treatment program in an academic medical center and discuss associated challenges and lessons learned with patient selection and process improvements. METHODS: Hamilton Rating Scale for Depression scores were collected before and after infusion from 16 patients who received a brexanolone infusion at UNC. Patients were subsequently contacted for a follow-up interview to obtain Hamilton Rating Scale for Depression scores and complete a semistructured interview at least 30 days past treatment end (between 3 and 16 months after infusion). RESULTS: All 16 patients had a significant reduction in Hamilton Rating Scale for Depression scores at 60 hours, scores dropping on average from 23.9 (standard deviation = 2.6) to 7.6 (standard deviation = 2.9). Eleven of 16 patients consented to provide follow-up data. Follow-up Hamilton Rating Scale for Depression scores remained lower than postinfusion at an average of 6.7 points (standard deviation = 5.1). CONCLUSION: With a strategic cross-disciplinary approach, a Clinical Brexanolone Treatment Program was established at UNC Hospitals in 2019. Sixteen patients have been treated in the program, and 11 participated in a follow-up interview. All 11 patients gave very positive feedback about their treatment. Our program has found brexanolone to be a useful clinical tool in treating women with significant symptoms of postpartum depression.

Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders.

OBJECTIVE: This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy. LITERATURE SEARCH: A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer's website. DATA SYNTHESIS: One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache. PLACE IN THERAPY: Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed. CONCLUSION: Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.

Salivary and Nasal Detection of the SARS-CoV-2 Virus After Antiviral Mouthrinses (BBCovid): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: - To describe the evolution of the SARS-CoV-2 salivary viral load of patients infected with Covid-19, performing 7 days of tri-daily mouthwashes with and without antivirals. - To compare the evolution of the SARS-CoV-2 nasal and salivary viral load according to the presence or absence of antivirals in the mouthwash. TRIAL DESIGN: This is a multi-center, randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: Inclusion criteria - Age: 18-85 years old - Clinical diagnosis of Covid-19 infection - Clinical signs have been present for less than 8 days - Virological confirmation - Understanding and acceptance of the trial - Written agreement to participate in the trial Exclusion criteria - Pregnancy, breastfeeding, inability to comply with protocol, lack of written agreement - Patients using mouthwash on a regular basis (more than once a week) - Patient at risk of infectious endocarditis - Patients unable to answer questions - Uncooperative patient The clinical trial is being conducted with the collaboration of three French hospital centers: Hospital Center Emile Roux (Le Puy en Velay, France), Clinic of the Protestant Infirmary (Lyon, France) and Intercommunal Hospital Center (Mont de Marsan, France). INTERVENTION AND COMPARATOR: Eligible participants will be allocated to one of the two study groups. Intervention group: patients perform a tri-daily mouthwash with mouthwash containing antivirals (ß-cyclodextrin and Citrox®) for a period of 7 days. CONTROL GROUP: patients perform a tri-daily mouthwash with a placebo mouthwash for a period of 7 days. MAIN OUTCOMES: Primary Outcome Measures: Change from Baseline amount of SARS-CoV-2 in salivary samples at 4 and 9 hours, 1, 2, 3, 4, 5 and 6 days. Real-time PCR assays are performed to assess salivary SARS-CoV 2 viral load. SECONDARY OUTCOME MEASURES: Change from Baseline amount of SARS-CoV-2 virus in nasal samples at 6 days. Real-time PCR assays are performed to assess nasal SARS-CoV-2 viral load. RANDOMISATION: Participants meeting all eligibility requirements are allocated to one of the two study arms (mouthwash with ß-cyclodextrin and Citrox® or mouthwash without ß-cyclodextrin and Citrox®) in a 1:1 ratio using simple randomisation with computer generated random numbers. BLINDING (MASKING): Participants, doctors and nurses caring for participants, laboratory technicians and investigators assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Both the intervention and control groups will be composed of 103 participants, so the study will include a total of 206 participants. TRIAL STATUS: The current protocol version is 6, August 4th, 2020. Recruitment began on April 6, 2020 and is anticipated to be complete by April 5, 2021. As of October 2, 2020, forty-two participants have been included. TRIAL REGISTRATION: This trial was registered on 20 April 2020 at www.clinicaltrials.gov with the number NCT04352959 . FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol." The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)."

Removal of Remdesivir's Metabolite GS-441524 by Hemodialysis in a Double Lung Transplant Recipient with COVID-19.

Remdesivir has reported efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo Drug-drug interactions limit therapeutic options in transplant patients. Remdesivir and its metabolite GS-441524 are excreted principally in urine. In intensive care unit (ICU) settings, in which multiple-organ dysfunctions can occur rapidly, hemodialysis may be a viable option for maintaining remdesivir treatment, while improving tolerance, by removing both remdesivir's metabolite (GS-441524) and sulfobutylether ß-cyclodextrin sodium (SEBCD). Additional studies may prove informative, particularly in the evaluations of therapeutic options for coronavirus disease 2019 (COVID-19).

Cyclodextrins: Potential therapeutics against atherosclerosis.

Atherosclerosis is an inflammatory disease resulting from subendothelial accumulation of lipoprotein-derived cholesterol in susceptible arterial segments, ultimately leading to the formation of clinically significant atherosclerotic plaques. Despite significant advances in the treatment of atherosclerosis, atherosclerotic cardiovascular diseases remain the leading cause of death and disabilities worldwide. Accordingly, there is an urgent need for novel therapies. Cyclodextrins are cyclic oligosaccharides produced from many sources of starch by enzymatic degradation. The frequently used cyclodextrins are α-, ß-, and γ-cyclodextrins, which are composed of six, seven, and eight glucose moieties, respectively. Especially ß-cyclodextrin can entrap hydrophobic compounds, such as cholesterol, into its hydrophobic cavity and form stable inclusion complexes with cholesterol. This inherent affinity of cyclodextrins has been exploited to extract excess cholesterol from cultured cells, as well as intra- and extracellular cholesterol stores present in atherosclerotic lesions of experimental animals. Accordingly, cyclodextrins could be considered as potentially effective therapeutic agents for the treatment of atherosclerosis. In this review, we address recent advances and the current status of the development of cyclodextrins and provide an update of the latest in vitro and in vivo experiments that pave the way to clinical studies. The emerging therapeutic opportunities by using cyclodextrins could aid us in our efforts to ultimately eradicate the residual risk after other cholesterol-lowering pharmacotherapies, and also reduce the associated burden of premature deaths due to atherosclerotic cardiovascular diseases.

Advances in treatment for postpartum major depressive disorder.

Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD. Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice. Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.

Treating postpartum depression with brexanolone.

The FDA has approved brexanolone specifically for treatment of adults with postpartum depression (PPD). Administered I.V., it can relieve severe signs and symptoms of PPD within days rather than weeks. This article discusses the benefits and risks of brexanolone as a treatment for PPD, including nursing considerations and patient teaching.

Brexanolone for postpartum depression.

PURPOSE: Postpartum depression (PPD) is defined as a major depressive episode occurring during pregnancy or within 4 weeks of delivery that may have significant consequences for mother and infant. Antidepressants are used to treat PPD, but their effectiveness may be limited by a slow time to peak effect. Brexanolone is Food and Drug Administration-approved for the management of PPD; its use requires patient participation in a risk evaluation and mitigation strategies (REMS) program. This review evaluates the efficacy and safety of brexanolone in PPD. SUMMARY: Four completed studies, 1 quasi-experimental study and 3 randomized controlled trials (RCTs), were reviewed. Females who had moderate or severe PPD during the third trimester or within 4 weeks of delivery and were less than 6 months postpartum at initiation of therapy were included. Improvement in Hamilton Rating Scale for Depression (HAM-D) scores was assessed in addition to safety outcomes and scores on other depression rating scales. All studies demonstrated statistical improvement in HAM-D scores from baseline with brexanolone vs placebo use at the end of infusions (ie, hour 60). Results with regard to sustained HAM-D score improvements were mixed in the RCTs at 30-day follow-up. The most frequent adverse events in brexanolone-treated patients were sedation, dizziness, somnolence, and headache. The severe or serious adverse effect of presyncope, syncope, or loss of consciousness was reported by 4% of participants. CONCLUSION: With a rapid onset of action, brexanolone could be considered advantageous over traditional therapies for PPD in patients for whom a rapid response is required due to severity of disease. Significant concerns remain regarding sustained effect and use in patients outside of the clinical trial setting.

Brexanolone (Zulresso): Finally, an FDA-Approved Treatment for Postpartum Depression.

Objective: To review the safety and efficacy of brexanolone for the treatment of moderate to severe postpartum depression (PPD). Data Sources: A literature search through PubMed was conducted (January 2012 to July 2019) using the keyword brexanolone for clinical trials published in the English language. Study Selection and Data Extraction: Articles were selected if they were related to the Food and Drug Administration (FDA) approval of brexanolone or provided novel clinical information regarding this drug entity. Data Synthesis: The findings of the review show that brexanolone administered via IV infusion is both an effective and a fairly safe option for the treatment of PPD. Relevance to Patient Care and Clinical Practice: There are several antidepressants currently used to treat PPD; however, this is the first with FDA approval for this indication. The rapid onset of action of brexanolone may offer a quicker relief of these symptoms and may possibly lead to improved quality of life for both the mother and the child. Conclusion and Relevance: The recent FDA approval of brexanolone may offer an effective treatment of moderate to severe PPD and has been shown to rapidly decrease depression symptoms.

ß-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect.

Obesity has become a worldwide health crisis and is associated with a plethora of comorbidities. The multi-organ effects of obesity have been linked to ectopic lipid accumulation. Thus, there is an urgent need to tackle the obesity crisis by developing effective lipid-lowering therapies. 2-hydroxypropyl-ß-Cyclodextrin (2HP-ß-CD) has been previously shown to reduce lysosomal cholesterol accumulation in a murine model of Niemann Pick Type C (NPC) disease. Using a murine model of Western diet-induced obesity (DIO), we report the effects of 2HP-ß-CD in counteracting weight gain, expansion of adipose tissue mass and ectopic lipid accumulation. Interestingly, DIO caused intracellular storage of neutral lipids in hepatic tissues and of phospholipids in kidneys, both of which were prevented by 2HP-ß-CD. Importantly, this report brings attention to the nephrotoxic effects of 2HP-ß-CD: renal tubular damage, inflammation and fibrosis. These effects may be overlooked, as they are best appreciated upon assessment of renal histology.

Brexanolone for Postpartum Depression: Clinical Evidence and Practical Considerations.

Our aim was to review the efficacy, safety, and pharmacology of brexanolone (Zulresso), a new antidepressant with a novel mechanism of action, in the treatment of postpartum depression (PPD). Pertinent data and information were obtained via PubMed (1993 to August 2018). Articles published in English that evaluated the safety and efficacy of brexanolone and other off-label PPD treatments were included. Literature regarding epidemiology and pathophysiology of PPD was also selected. Brexanolone, administered as an intravenous infusion over 60 hours, produced a statistically significant and clinically meaningful reduction in Hamilton Depression Rating Scale (HAM-D) scores compared with placebo at both 60 and 90 µg/kg/hour in patients with moderate to severe PPD. Brexanolone groups had higher response and remission rates compared with placebo. Common adverse effects were somnolence, dizziness, and headache. A small percentage (4%) of patients required cessation of therapy due to excessive sedation or loss of consciousness. Although the evidence for brexanolone as a novel treatment for PPD looks promising, a Risk Evaluation and Mitigation Strategies (REMS) program requirement and the logistics of prolonged infusions serve as barriers to treatment. A discussion of these obstacles as well as pharmacokinetics, monitoring, and dosing is provided. Brexanolone is a novel antidepressant indicated for the treatment of PPD. Clinical trials demonstrated that brexanolone significantly reduces depression scores in women with moderate to severe PPD. Due to risk of oversedation and loss of consciousness, a REMS program will be put in place to mitigate the risk of adverse events.