Safety vs price in the generic drug market: metformin.

OBJECTIVES: Generic medications represent 90% of prescriptions in the US market and provide a tremendous financial benefit for patients. Recently, multiple generic drugs have been recalled due to the presence of carcinogens, predominantly N-nitrosodimethylamine (NDMA), including an extensive recall of extended-release (ER) metformin products in 2020. STUDY DESIGN: Primary pharmaceutical quality testing and database analysis. METHODS: We tested marketed metformin immediate-release (IR) and ER tablets from a wide sample of generic manufacturers for the presence of carcinogenic impurities NDMA and N,N-dimethylformamide (DMF). We examined the association of level of impurity with drug price and the impact of the 2020 FDA recalls on unit price and prescription fill rate. RESULTS: Postrecall NDMA levels were significantly lower in metformin ER samples (standardized mean difference = -2.0; P = .01); however, we found continued presence of carcinogens above the FDA threshold in 2 of 30 IR samples (6.67%). Overall, the presence of contaminant levels was not significantly associated with price for either IR (NDMA: R2 = 0.142; P = .981; DMF: R2 = 0.382; P = .436) or ER (NDMA: R2 = 0.124; P = .142; DMF: R2 = 0.199; P = .073) samples. Despite recalls, metformin ER prescription fills increased by 8.9% while unit price decreased by 19.61% (P < .05). CONCLUSIONS: Recalls of metformin ER medications were effective in lowering NDMA levels below the FDA threshold; however, some samples of generic metformin still contained carcinogens even after FDA-announced recalls. The absence of any correlation with price indicates that potentially safer products are available on the market for the same price as poorer-quality products.

Branding a Plastic Surgery Group Practice: A Case Study.

BACKGROUND: You only get one opportunity to make a first impression. In today's era, that first impression is frequently a digital one. The authors' old digital brand "face" was stale and not a true representation of how they view themselves as a practice. In an evolving arena of competition and surgical scope, the authors felt compelled to engage in rebranding their practice. METHODS: This article details the steps the authors took to launch a new website, generate collateral branded material, and execute a social media marketing plan. The authors attempt to keep the outline general enough to be applicable to the range of practice types of the Journal 's readership, and present relevant results of the process. RESULTS: Samples of "creative" products are shown. Quantifiable outcomes were direct website traffic (91% increase), website sessions (82% increase), unique users (55% increase), page views (118% increase), and time spent browsing (100% increase). The authors experienced a 21% increase in new patient volume and a similar increase in total cases performed. CONCLUSIONS: This article outlines steps the authors took to rebrand their practice in the face of current challenges in the plastic surgery landscape and how prospective patients seek surgeons. Benchmarking the steps of a successful branding process is crucial and informative to developing and executing a plan. Although there are many potential contributors to the growth of a practice, the impact of our branding appears to be a significant factor.

A data-driven quality-score system for rating drug products and its implications for the health care industry.

The quality of drug products in the United States has been a matter of growing concern. Buyers and payers of pharmaceuticals have limited insight into measures of drug-product quality. Therefore, a quality-score system driven by data collection is proposed to differentiate between the qualities of drug products produced by different manufacturers. The quality scores derived using this proposed system would be based upon public regulatory data and independently-derived chemical data. A workflow for integrating the system into procurement decisions within health care organizations is also suggested. The implementation of such a quality-score system would benefit health care organizations by including the consideration of the quality of products while also considering price as a part of the drug procurement process. Such a system would also benefit the U.S. health care industry by bringing accountability and transparency into the drug supply chain and incentivizing manufacturers to place an increased emphasis on the quality and safety of their drug products.

Presence of unsafe chemical impurities, accelerated evaporation of alcohol, and lack of key labeling requirements are risks and concerns for some alcohol-based hand sanitizers and dispenser practices during the COVID-19 pandemic.

Alcohol-based hand sanitizers (ABHS) have been an important hand hygiene tool during the COVID-19 pandemic. Recently, ABHS from non-traditional drug manufacturers have entered the market, triggered by a lack of ABHS availability. Some of these ABHS contain high levels of chemical impurities that may be harmful with frequent exposure. Additionally, the use of refillable dispensers designed to accept ABHS from bulk containers allows for mixing and evaporation that may compromise ABHS integrity. To understand the risks associated with low quality ABHS and bulk refilling practices, we collected 77 ABHS samples sourced from community settings (restaurants, grocery stores, etc.) and 40 samples from a single school district. All samples were obtained from bulk refillable dispensers that were in use. Samples were analyzed for alcohol content, chemical impurities, aesthetic qualities, and presence of drug labeling information. Additionally, we performed laboratory-based experiments to determine the impact of dispenser design on alcohol evaporation rates. Over 70% of samples for which photos were available showed lack of essential labeling information, including missing "Drug Facts Labels". For ABHS samples acquired from community settings, nearly 14% of samples had visible impurities, and over 30% of samples had concentrations of acetal and acetaldehyde in excess of FDA interim limits. Subpotent ethanol concentrations were observed in 9.09% and 82.05% of samples from community settings and the school district, respectively, with the school district sample results being associated with dispenser misuse. Laboratory-based experiments show dispenser design significantly impacts the rate of ethanol evaporation of ABHS products, especially if stored in open refillable dispensers without an internal reservoir. This study demonstrates risks associated with use of inferior ABHS and bulk refilling practices. Regulatory agencies should issue guidance on best practices in community settings to ensure the integrity of ABHS as an essential public health tool to prevent the spread of COVID-19 and other transmissible diseases.

MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease.

Sickle cell disease (SCD) is associated with hemolysis, vascular inflammation, and organ damage. Affected patients experience chronic painful vaso-occlusive events requiring hospitalization. Hypoxia-induced polymerization of sickle hemoglobin S (HbS) contributes to sickling of red blood cells (RBCs) and disease pathophysiology. Dilution of HbS with nonsickling hemoglobin or hemoglobin with increased oxygen affinity, such as fetal hemoglobin or HbS bound to aromatic aldehydes, is clinically beneficial in decreasing polymerization. We investigated a novel alternate approach to modify HbS and decrease polymerization by inhibiting methionine aminopeptidase 2 (MetAP2), which cleaves the initiator methionine (iMet) from Val1 of α-globin and ßS-globin. Kinetic studies with MetAP2 show that ßS-globin is a fivefold better substrate than α-globin. Knockdown of MetAP2 in human umbilical cord blood-derived erythroid progenitor 2 cells shows more extensive modification of α-globin than ß-globin, consistent with kinetic data. Treatment of human erythroid cells in vitro or Townes SCD mice in vivo with selective MetAP2 inhibitors extensively modifies both globins with N-terminal iMet and acetylated iMet. HbS modification by MetAP2 inhibition increases oxygen affinity, as measured by decreased oxygen tension at which hemoglobin is 50% saturated. Acetyl-iMet modification on ßS-globin delays HbS polymerization under hypoxia. MetAP2 inhibitor-treated Townes mice reach 50% total HbS modification, significantly increasing the affinity of RBCs for oxygen, increasing whole blood single-cell RBC oxygen saturation, and decreasing fractional flow velocity losses in blood rheology under decreased oxygen pressures. Crystal structures of modified HbS variants show stabilization of the nonpolymerizing high O2-affinity R2 state, explaining modified HbS antisickling activity. Further study of MetAP2 inhibition as a potential therapeutic target for SCD is warranted.

Umbilical Ablation During Deep Inferior Epigastric Perforator Flap Harvest Decreases Donor Site Complications.

BACKGROUND: Donor site complications are a significant source of morbidity for patients undergoing abdominal-based free flap breast reconstruction, but there is a paucity of data regarding minimizing these postoperative complications. We hypothesize that selective ablation of the umbilicus at the time of deep inferior epigastric perforator (DIEP) harvest decreases the incidence of umbilical and abdominal wall complications in high-risk patients. METHODS: A retrospective review was performed of all patients (n = 117) who underwent DIEP harvest with concomitant umbilical ablation from 2010 to 2015. This cohort was paired with 117 patients who underwent DIEP harvest without umbilical ablation. Preoperative risk factors, intraoperative factors, and postoperative complications were compared. RESULTS: The umbilical ablation group had significantly higher body mass index (30.9 vs 27.4 kg/m, P < 0.001), presence of umbilical scar (20.9% vs 5.3%, P < 0.001), umbilical hernia (82.9% vs 8.5% P < 0.001), ventral hernia (23.9% vs 1.7%, P < 0.001), and rectus diastasis (10.3% vs 2.6%, P = 0.016). There were no significant differences of smoking, diabetes mellitus, hypertension, prior abdominal surgery, or midline abdominal scar. The umbilical ablation group had a significantly lower rate of postoperative abdominal wound dehiscence and skin loss (11.1% vs 22.2%, P = 0.023) and overall donor site complications (24.8% vs 39.3%, P = 0.017). There was no significant difference in incidence of cellulitis, seroma, or abscess. Mean follow-up time was 1.8 years. CONCLUSIONS: Selective umbilical ablation in high-risk patients at the time of abdominal flap harvest can result in significantly fewer donor site wound complications, even in the setting of increased risk factors for poor wound healing. This is likely due to avoidance of umbilical incisions and decreased upper abdominal skin undermining. We conclude that umbilical ablation is a viable option to minimize donor site complications, especially in high-risk patients.

Real-World Outcomes of Patients with Metastatic Non-Small Cell Lung Cancer Treated with Programmed Cell Death Protein 1 Inhibitors in the Year Following U.S. Regulatory Approval.

BACKGROUND: Evidence from cancer clinical trials has strong internal validity but can be difficult to generalize to real-world patient populations. Here we analyzed real-world outcomes of patients with metastatic non-small cell lung cancer (mNSCLC) treated with programmed cell death protein 1 (PD-1) inhibitors in the first year following U.S. regulatory approval. MATERIALS AND METHODS: This retrospective study leveraged electronic health record (EHR) data collected during routine patient care in community cancer care clinics. The cohort included patients with mNSCLC who had received nivolumab or pembrolizumab for metastatic disease (n = 1,344) with >1 EHR-documented visit from January 1, 2011, to March 31, 2016. Patients with a > 90-day gap between advanced disease diagnosis and first EHR structured data entry were excluded. RESULTS: Estimated median overall survival (OS) was 8.0 months (95% confidence interval 7.4-9.0 months). Estimated median OS was 4.7 months (3.4-6.6) for patients with anaplastic lymphoma kinase rearrangement- and epidermal growth factor receptor mutation-positive tumors, and 8.6 months (7.7-10.6) for patients without such mutations. Age at PD-1 inhibitor initiation or line of therapy did not impact OS. CONCLUSION: This analysis suggests OS in real-world patients may be shorter than in conventional clinical trial patient cohorts, potentially due to narrow trial eligibility criteria. The lack of difference in OS by line of therapy or age at immunotherapy initiation suggests sustained benefit of PD-1 inhibitors in multitreated patients with mNSCLC and that age is not a predictor of outcome. Further studies are underway in patients with comorbidities, organ dysfunction, and multiple prior therapies. IMPLICATIONS FOR PRACTICE: This study evaluated data derived from electronic health records of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 (PD-1) inhibitors in the year following regulatory approval. This real-world cohort had shorter overall survival (OS) indexed to PD-1 inhibitor initiation than reported in clinical trials. Late-line treatment did not influence OS, and patients aged >75 at immunotherapy initiation did not have worse outcomes than younger patients. As new therapies enter clinical practice, real-world data can complement clinical trial evidence providing information on generalizability and helping inform clinical treatment decisions.

Discovery of selective urokinase plasminogen activator (uPA) inhibitors as a potential treatment for multiple sclerosis.

We report here the design and synthesis of a novel series of benzylamines that are potent and selective inhibitors of uPA with promising oral availability in rat. Further evaluation of one representative (ZK824859) of the new structural class showed that this compound lowered clinical scores when dosed in either acute or chronic mouse EAE models, suggesting that uPA inhibitors of this type could be useful for the treatment of multiple sclerosis.

Characteristics of Real-World Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval.

BACKGROUND: Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS: We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS: Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION: During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE: Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease.

Sickle cell disease (SCD) results from a point mutation in the ß-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)-like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell-derived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate γ-globin transcription and enhance HbF in tissue culture and in murine and primate models. DMF recruited Nrf2 to the γ-globin promoters and the locus control region of the ß-globin locus in erythroleukemia cells, elevated HbF in SCD donor-derived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased γ-globin mRNA in BM and HbF protein in rbc. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification.

Total Abdominal Wall Transplantation: An Anatomical Study and Classification System.

BACKGROUND: Candidates for multivisceral transplantation present with complex defects often beyond traditional reconstructive options. In this study, the authors describe a dissection technique for a total abdominal wall vascularized composite flap. In addition, the authors suggest a classification system for complex abdominal wall defects. METHODS: Forty fresh, cadaveric hemiabdomens were dissected, with care taken to preserve the iliofemoral, deep circumflex iliac, superficial circumflex iliac, deep inferior epigastric, and superficial inferior epigastric arteries and corresponding veins. Perfusion patterns of the flaps were then studied using computed tomographic angiography. RESULTS: The deep circumflex iliac, superficial circumflex iliac, deep inferior epigastric, and superficial inferior epigastric arteries were identified along a 5-cm cuff of the iliofemoral artery centered on the inguinal ligament. Perfusion with an intact deep circumflex iliac artery yielded improvement in lateral perfusion based on computed tomographic angiography. CONCLUSIONS: The authors propose an algorithm for abdominal wall reconstruction based on defect size and abdominal wall perfusion, and their technique for harvesting a total vascularized composite abdominal wall flap for allotransplantation. Total abdominal wall transplantation should be considered in the subset of patients already receiving visceral organ transplants who also have concomitant abdominal wall defects.

VLA-4 blockade by natalizumab inhibits sickle reticulocyte and leucocyte adhesion during simulated blood flow.

Very Late Antigen-4 (VLA-4, α4ß1-integrin, ITGA4) orchestrates cell-cell and cell-endothelium adhesion. Given the proposed role of VLA-4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA-4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface VLA-4 on leucocytes and reticulocytes in whole blood from SCD subjects. SCD reticulocytes were positive for VLA-4, while VLA-4 staining of non-SCD reticulocytes was undetectable. Titrations with natalizumab revealed the presence of saturable levels of VLA-4 on both SCD reticulocytes and leucocytes similar to healthy subject leucocytes. Under physiological flow conditions, the adhesion of SCD whole blood cells and isolated SCD leucocytes to immobilized vascular cell adhesion molecule 1 (VCAM-1) was blocked by natalizumab in a dose-dependent manner, which correlated with cell surface receptor binding. Natalizumab also inhibited >50% of whole blood cell binding to TNF-α activated human umbilical vein endothelial cell monolayers under physiological flow at clinically relevant concentrations (10 to 100 µg/ml). This indicates that VLA-4 is the dominant receptor that drives SCD reticulocyte and mononuclear cell adhesion to VCAM-1 and that the VLA-4 adhesion to VCAM-1 is a significant contributor to SCD blood cell adhesion to endothelium. Thus, VLA-4 blockade may be beneficial in sickle cell disease.

Evaluation of the toxicology and pharmacokinetics of recombinant factor VIII Fc fusion protein in animals.

INTRODUCTION: Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a novel recombinant factor VIII with a prolonged half-life, developed for the treatment of hemophilia A. Studies that evaluated the toxicological effects of rFVIIIFc in 2 pharmacologically relevant species, cynomolgus monkeys and Sprague Dawley rats, are reported here. MATERIALS AND METHODS: In repeat-dose toxicology studies, rats and monkeys received 0, 50, 250, or 1000 IU/kg rFVIIIFc every other day for 4 weeks. In a high-dose tolerance study, monkeys received 1 rFVIIIFc dose of 3000, 10,000, or 20,000 IU/kg. Evaluations included in-life observations, laboratory and post-mortem evaluations, pharmacokinetics, and local tolerance. Allometric scaling, using data from 4 animal species and humans, was used to evaluate the relationship between animal and human pharmacokinetics. RESULTS: rFVIIIFc was well tolerated with no adverse toxicological findings directly attributable to rFVIIIFc. As expected, antibodies to this fully human protein developed in rats and monkeys in a time-dependent fashion following repeated dosing, leading to increased clearance in both species. There were no local reactions (infusion site) or evidence of thrombosis at high doses in rats and monkeys. Allometric scaling demonstrated more rapid clearance in small animals compared with humans and a volume of distribution (steady state) proportional to body weight across species, suggesting that animal pharmacokinetics are predictive of human pharmacokinetics. CONCLUSIONS: Repeated doses of rFVIIIFc in 2 relevant animal species and high doses of rFVIIIFc in monkeys were well tolerated. These results supported the clinical safety of rFVIIIFc observed in phase 1/2a and phase 3 clinical trials.

FcRn Rescues Recombinant Factor VIII Fc Fusion Protein from a VWF Independent FVIII Clearance Pathway in Mouse Hepatocytes.

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and into circulation, enabling the elongated half-life of rFVIIIFc.