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2021 ◽  
Vol 12 ◽  
Author(s):  
Vipul Vilas Wagh ◽  
Parin Vyas ◽  
Suchita Agrawal ◽  
Tejaswini A. Pachpor ◽  
Vasudeo Paralikar ◽  
...  

Schizophrenia is a disorder that is characterized by delusions, hallucinations, disorganized speech or behavior, and socio-occupational impairment. The duration of observation and variability in symptoms can make the accurate diagnosis difficult. Identification of biomarkers for schizophrenia (SCZ) can help in early diagnosis, ascertaining the diagnosis, and development of effective treatment strategies. Here we review peripheral blood-based gene expression studies for identification of gene expression biomarkers for SCZ. A literature search was carried out in PubMed and Web of Science databases for blood-based gene expression studies in SCZ. A list of differentially expressed genes (DEGs) was compiled and analyzed for overlap with genetic markers, differences based on drug status of the participants, functional enrichment, and for effect of antipsychotics. This literature survey identified 61 gene expression studies. Seventeen out of these studies were based on expression microarrays. A comparative analysis of the DEGs (n = 227) from microarray studies revealed differences between drug-naive and drug-treated SCZ participants. We found that of the 227 DEGs, 11 genes (ACOT7, AGO2, DISC1, LDB1, RUNX3, SIGIRR, SLC18A1, NRG1, CHRNB2, PRKAB2, and ZNF74) also showed genetic and epigenetic changes associated with SCZ. Functional enrichment analysis of the DEGs revealed dysregulation of proline and 4-hydroxyproline metabolism. Also, arginine and proline metabolism was the most functionally enriched pathway for SCZ in our analysis. Follow-up studies identified effect of antipsychotic treatment on peripheral blood gene expression. Of the 27 genes compiled from the follow-up studies AKT1, DISC1, HP, and EIF2D had no effect on their expression status as a result of antipsychotic treatment. Despite the differences in the nature of the study, ethnicity of the population, and the gene expression analysis method used, we identified several coherent observations. An overlap, though limited, of genetic, epigenetic and gene expression changes supports interplay of genetic and environmental factors in SCZ. The studies validate the use of blood as a surrogate tissue for biomarker analysis. We conclude that well-designed cohort studies across diverse populations, use of high-throughput sequencing technology, and use of artificial intelligence (AI) based computational analysis will significantly improve our understanding and diagnostic capabilities for this complex disorder.


2021 ◽  
Vol 3 (2) ◽  
pp. 25-28
Author(s):  
Nahit Ata ◽  
Nur Gözde Kulhan

Objective There is no report that anticoagulant or antiplatelet use may lead to abnormal endometrial sonographic findings. This retrospective study reports our first results associated with endometrial sampling in asymptomatic postmenopausal women using anticoagulants or antiplatelet. Materials methods A total of 268 postmenopausal patients who applied to our gynecology outpatient clinic for any reasons except postmenopausal bleeding were included in the study. Patients were divided into three groups according to using drug status: first healty control group [HCG], second anticoagulants agents group [ACG], and third antiplatelet agents group [APG]. The effects of anticoagulant and antiplatelet agents on endometrial thickness were compared with histopathological findings. Results The mean endometrial thickness was significantly greater in group ACG [5.2 mm] and APG [4.1 m]  than in group HCG [3.3 mm]. No significant differences were found in the mean endometrial thickness between groups HCG and APG. However, it is noteworthy that the average endomeric thickness in the ACG group is more than the other two groups and this is statistically significant [p < 0.05].   Conclusion If the thickness of the endometrium was > 4 mm. endometrial sampling may be recommended in in asymptomatic postmenopausal women using anticoagulants or antiplatelet agents.  


2021 ◽  
Vol 11 ◽  
Author(s):  
Theodore A. Petti ◽  
John Calvin Chatlos

Background: Issues related to the legalization of cannabis have significantly increased over the past 25 years. Federal policy has become minimally more flexible but essentially maintains marijuana’s dangerous drug status. Myriad laws and regulations characterize the legal status of cannabis across the US and internationally. Contradictory laws and regulations across states result from a lack of coherent federal policy, thus leaving states to address public health, cannabis industry and consumer pressures. Research prohibition has made public policy development difficult and informed by inadequately supported, restricted science. Objective: 1: Consider key issues related to cannabis legalization and distinctions between gradients to access for medical purposes, decriminalization or adult recreational use. Objective 2: To consider the status of cannabis legalization on a state and global basis. Methods:: A review of the background to cannabis legalization intends to provide insight into cannabis’ current legal status and options being considered for advocacy and policy development. The three major classifications of legalized marijuana are detailed; cannabidiol or hemp and synthetic cannabinoids are considered separately. Results: The status of cannabis within the US and globally has often been discordant with reality and science, and rigid with pressures to effect change. The diversity of state and international laws is significant, even within the same designation into one of the three major classes or cannabidiol. Conclusion: Science-based standardized federal and state laws and regulations to meet the special needs of adolescents and emerging adults must be pursued.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tai L. S. Pasquini ◽  
Sarah L. Goff ◽  
Jennifer M. Whitehill

Abstract Background Parents of children with rare diseases often face uncertainty about diagnosis, treatment, and costs associated with healthcare for their child. Health insurance status impacts each of these areas, but no U.S. study has explored parents’ perceptions of the health insurance impacts on their child’s care. This study aimed to qualitatively explore how these parents navigate the complex health insurance system for their children and their experiences in doing so. Methods Semi-structured interviews were conducted with parents of children with metachromatic leukodystrophy (MLD) and spinal muscular atrophy (SMA), chosen for specific disease characteristics and orphan drug status. Participants were recruited via e-mail through patient advocacy organizations between September and December 2018. Interviews were conducted via Skype, were recorded, and professionally transcribed. Modified grounded theory was utilized as a methodology to analyze transcripts in an iterative process to determine themes and sub-themes based on participant described experiences. Results Major themes and subthemes that emerged across the 15 interviews included: (1) difficulties obtaining secondary insurance based on state eligibility criteria; (2) difficulty accessing needed healthcare services; and (3) need for repeated interactions with insurance representatives. The absence of clearly documented or widely recognized clinical guidelines exacerbated the difficulty accessing care identified as necessary by their healthcare team, such as therapy and equipment. An explanatory model for parent’s experiences was developed from the themes and subthemes. The model includes the cyclical nature of interacting with insurance for redundant reauthorizations and the outside support and financial assistance that is often necessary to address their child’s healthcare needs. Conclusions With complex health conditions, small setbacks can become costly and disruptive to the health of the child and the life of the family. This study suggests that patients with rare diseases may benefit from time limits for processing coverage decisions, increasing transparency in the claims and preauthorization processes, and more expansive authorizations for on-going needs. Additional studies are needed to understand the full scope of barriers and to inform policies that can facilitate better access for families living with rare diseases.


Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 991
Author(s):  
Diego Caprioglio ◽  
Daiana Mattoteia ◽  
Orazio Taglialatela-Scafati ◽  
Eduardo Muñoz ◽  
Giovanni Appendino

Neutral cannabinoids are oxidatively unstable and are converted into quinone derivatives by atmospheric- and/or chemical oxidative dearomatization. The study of cannabinoquinones has long been plagued by their lability toward additional oxidative degradation, but full substitution of the quinone ring, as well as the introduction of steric hindrance on the alkyl substituent, have provided sufficient stability for a systematic investigation of their bioactivity and for further clinical development. These studies culminated in the discovery of the aminocannabinoquinone VCE-004.8 (5), a compound under phase 2 clinical development with orphan drug status by EMA and FDA for the management of scleroderma. The synthesis and rich chemistry of these compounds will be described, summarizing their biological profile and clinical potential.


Author(s):  
Nahit Ata ◽  
Nur Kulhan

Objective There is no report that anticoagulant or antiplatelet use may lead to abnormal endometrial sonographic findings. This retrospective study reports our first results associated with endometrial sampling in asymptomatic postmenopausal women using anticoagulants or antiplatelet. Materials methods A total of 268 postmenopausal patients who applied to our gynecology outpatient clinic for any reasons except postmenopausal bleeding were included in the study. Patients were divided into three groups according to using drug status: first healty control group (HCG), second anticoagulants agents group (ACG), and third antiplatelet agents group (APG). The effects of anticoagulant and antiplatelet agents on endometrial thickness were compared with histopathological findings. Results The mean endometrial thickness was significantly greater in group ACG (5.2 mm) and APG (4.1 m) than in group HCG (3.3 mm). No significant differences were found in the mean endometrial thickness between groups HCG and APG. However, it is noteworthy that the average endomeric thickness in the ACG group is more than the other two groups and this is statistically significant (p < 0.05). Conclusion If the thickness of the endometrium was > 4 mm. endometrial sampling may be recommended in in asymptomatic postmenopausal women using anticoagulants or antiplatelet agents. Key words: Anticoagulants, antiplatelets, biopsy, endometrial thickness, menopause, ultrasonography


Author(s):  
Ina Liu ◽  
Evan Colmenares ◽  
Casey Tak ◽  
Mary-Haston Vest ◽  
Henry Clark ◽  
...  

Abstract Purpose Pharmacy departments across the country are problem-solving the growing issue of drug shortages. We aim to change the drug shortage management strategy from a reactive process to a more proactive approach using predictive data analytics. By doing so, we can drive our decision-making to more efficiently manage drug shortages. Methods Internal purchasing, formulary, and drug shortage data were reviewed to identify drugs subject to a high shortage risk (“shortage drugs”) or not subject to a high shortage risk (“nonshortage drugs”). Potential candidate predictors of drug shortage risk were collected from previous literature. The dataset was trained and tested using 2 methods, including k-fold cross-validation and a 70/30 partition into a training dataset and a testing dataset, respectively. Results A total of 1,517 shortage and nonshortage drugs were included. The following candidate predictors were used to build the dataset: dosage form, therapeutic class, controlled substance schedule (Schedule II or Schedules III-V), orphan drug status, generic versus branded status, and number of manufacturers. Predictors that positively predicted shortages included classification of drugs as intravenous-only, both oral and intravenous, antimicrobials, analgesics, electrolytes, anesthetics, and cardiovascular agents. Predictors that negatively predicted a shortage included classification as an oral-only agent, branded-only agent, antipsychotic, Schedule II agent, or orphan drug, as well as the total number of manufacturers. The calculated sensitivity was 0.71; the specificity, 0.93; the accuracy, 0.87; and the C statistic, 0.93. Conclusion The study demonstrated the use of predictive analytics to create a drug shortage model using drug characteristics and manufacturing variables.


PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247853
Author(s):  
Rosângela Caetano ◽  
Marilena Cordeiro Dias Villela Correa ◽  
Pedro Villardi ◽  
Paulo Henrique Almeida Rodrigues ◽  
Claudia Garcia Serpa Osorio-de-Castro

Background This study examines the dynamics of the eculizumab patenting, orphan designation, and marketing authorization process in different countries and regulatory systems and analyzes drug revenues since its first marketing authorization. Methods A retrospective case study was conducted. Multiple information sources were used to: determine the status of eculizumab patents; examine the designation of orphan drug status by US, European, Japanese, and Brazilian regulatory authorities to determine registration status and approved clinical indications; estimate the prevalence of associated clinical conditions; investigate the history of the drug manufacturer, Alexion Pharmaceuticals, Inc., and its financialized business model; and examine global eculizumab sales revenues since its first marketing authorization. Results Our search yielded 32 patent families divided into 98 applications. The first patent granted was filed in 1995 by Alexion Pharmaceuticals, Inc. in the US. Eculizumab has always been as an orphan drug, except in the Brazilian regulatory agency. All clinical indications approved thus far refer to rare diseases (e.g., paroxysmal nocturnal hemoglobinuria syndrome, atypical hemolytic-uremic syndrome, refractory and generalized myasthenia gravis, and neuromyelitis optica spectrum disorder). Alexion’s revenues amounted to more than US$25 billion between 2007 and 2019, showing a growing trend. Eculizumab led sales from the beginning, being the only product in the company’s portfolio until 2015. In 2019, the drug accounted for 79.1% of all revenues. Discussion Our findings show that a strategy focused on obtaining orphan drug designation, expanding therapeutic indications and the geographic range of marketing approvals, extending monopoly periods, and prioritizing public procurement niches has enhanced revenues and helped the company achieve leadership in a highly specific and profitable market.


Author(s):  
Stephanie Annett ◽  
Shaun Spence ◽  
Carolina Garciarena ◽  
Ciaran Campbell ◽  
Margaret Dennehy ◽  
...  

AbstractA breakdown in vascular integrity and excessive inflammation are hallmarks of serious pathological conditions including sepsis, acute respiratory distress syndrome (ARDs) and most recently, severe COVID-19. FK506 – binding protein like (FKBPL) is a member of the immunophilin protein superfamily with potent anti-tumor activity through inhibition of angiogenesis and cancer stemness. An FKBPL-based 23mer peptide, ALM201, displayed a good safety and pharmacokinetic profile in a Phase 1a oncology clinical trial and was subsequently designated orphan drug status by the FDA in ovarian cancer. Here we describe a novel role for FKBPL and its peptides in regulating vascular integrity and cytokine production though modulating NF-κB signaling. FKBPL knockdown promoted endothelial cell barrier permeability, which was further exacerbated upon stimulation with lipopolysaccharide (LPS) and accompanied by increased expression of TNF mRNA and phosphorylation of p65(RelA). Whilst treatment with the FKBPL based pre-clinical peptide, AD-01, increased VE-cadherin endothelial tight junctions following LPS stimulation. Bone marrow derived macrophages (BMDM) from FKBPL haploinsufficient mice (Fkbpl+/−) also demonstrated increased phosphorylation of p65(RelA) in response to LPS stimulation compared to wild-type mice. Furthermore, treatment with AD-01 inhibited p65(RelA) phosphorylation following LPS stimulation resulting in reduced NF-κB target gene expression and proinflammatory cytokine production. In an in vivo LPS survival model, Fkbpl+/− mice have reduced survival compared to wild-type mice. Moreover, treatment of wild-type mice with the clinical FKBPL-based peptide, ALM201, following LPS injection resulted in a 100% survival rate in mice at experimental endpoint, as well as an abrogation of production of pro-inflammatory cytokines, TNF and IL-6, in peritoneal lavage washings. Analysis of human genetic biobanks found an association between common genetic variants associated with FKBPL and traits associated with inflammatory disorders such as psoriasis, rheumatoid arthritis and high lymphocyte count. In summary, for the first time, we describe a novel role for FKBPL as a regulator of inflammation and vascular integrity through modulating NF-κB signaling and FKBPL based therapies demonstrate potent anti-inflammatory activity.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Güvenç Koçkaya ◽  
Sibel Atalay ◽  
Gülpembe Oğuzhan ◽  
Mustafa Kurnaz ◽  
Selin Ökçün ◽  
...  

Abstract Background Rare diseases are life-threatening, serious, and chronic conditions that require complex care and have a low prevalence. An estimated one in 15 people worldwide are affected by rare diseases. This study aims to analyze the accessibility, reimbursement status, licensed status, and Anatomical Therapeutic Chemical (ATC) codes of drugs that the European Medicines Agency (EMA) in Turkey considers to be “orphan” pharmaceuticals. Methods The drugs included in this analysis were obtained from the list of orphan drugs published by the EMA. Orphan drugs’ accessibility and licensing status in Turkey were obtained from the Health Implementation Communiqué published by the Social Security Institution (SGK) and the List of Abroad Active Substance and List of Licensed Products published by the Turkey Pharmaceuticals and Medical Devices Agency (TİTCK). Descriptive analysis was applied to determine the accessibility status of orphan drugs identified by the EMA in Turkey. Results Based on the EMA, 105 pharmaceuticals were approved with “orphan drug” status except for drugs that have lost orphan drug status, decommissioned in the European Union and withdrawn from the European Community Register by January 2020. Of the 105 rare drugs on the EMA list, 34 were inaccessible in Turkey. Of the 71 available drugs, 23 (32%) were licensed and 48 (68%) were unlicensed in Turkey. 17 (74%) of licensed products and 17 (35%) of unlicensed products were covered by reimbursement. When orphan drugs’ ATC codes were examined, the most common ATC group was found to be “L—Antineoplastic and Immunomodulatory” agents. Conclusion An orphan drug incentive policy is very important to ensure early access to the drugs used to treat rare diseases. Considering the capacity and prices for orphan drugs in Turkey, it can be said that many patients with rare diseases have difficulty in their treatment. It is obvious that such a policy must prepare for the regulation of orphan drugs in Turkey.


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