A case of the effective inhalation of nitric oxide therapy for caused severe pulmonary hypertension with protamine neutralization of systemic heparinization during totally endoscopic minimally invasive cardiac surgery.

Severe pulmonary vasoconstriction induced by protamine is a rare complication. We report a case of a 77-year-old male patient with a history of mitral valve plasty (MVP). He underwent redo MVP via right thoracotomy under the totally endoscopic procedure (MICS redo-MVP). Immediately after weaning cardiopulmonary bypass (CPB), protamine was administrated. 10 min later peak systolic pulmonary arterial pressure (sys PAP) rose to 62 mmHg, and 30 min later to 80 mmHg. Due to the negative impact of protamine administration, nitric oxide inhalation (iNO) therapy was started with a concentration of 20 ppm. 10 min after iNO therapy started, sys PAP decreased to 63 mmHg. After entering the intensive care unit (ICU), sys PAP decreased to 35 mmHg. Here, we present an effective iNO therapy case for pulmonary hypertension due to protamine and the patient had a good postoperative recovery. This study was approved by the Institutional Review Board at Kitaharima Medical Center (IRB-0602) with the waiver of informed consent.

Routine Protamine Administration for Bleeding in Transcatheter Aortic Valve Implantation: The ACE-PROTAVI Randomized Clinical Trial.

Importance: Vascular complications after transfemoral transcatheter aortic valve implantation (TAVI) remain an important cause of procedure-related morbidity. Routine reversal of anticoagulation with protamine at the conclusion of transfemoral TAVI could reduce complications, but data remain scarce. Objective: To evaluate the efficacy and safety of routine protamine administration after transfemoral TAVI. Design, Setting, and Participants: The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals between December 2021 and June 2023 with a 1-year follow-up period. All patients accepted for transfemoral TAVI by a multidisciplinary heart team were eligible for enrollment. Interventions: Eligible patients were randomized 1:1 between routine protamine administration and placebo. Main Outcomes and Measures: The coprimary outcomes were the rate of hemostasis success and time to hemostasis (TTH), presented as categorical variables and compared with a χ2 test or as continuous variables as mean (SD) or median (IQR), depending on distribution. The major secondary outcome was a composite of all-cause death, major and minor bleeding complications, and major and minor vascular complications after 30 days, reported in odds ratios (ORs) with 95% CIs and P values. Results: The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients [97.9%]) than patients in the placebo group (186 of 203 patients [91.6%]; absolute risk difference, 6.3%; 95% CI, 2.0%-10.6%; P = .006); in addition, patients receiving up-front protamine had a shorter median (IQR) TTH (181 [120-420] seconds vs 279 [122-600] seconds; P = .002). Routine protamine administration resulted in a reduced risk of the composite outcome in the protamine group (10 of 192 [5.2%]) vs the placebo group (26 of 203 [12.8%]; OR, 0.37; 95% CI, 0.1-0.8; P = .01). This difference was predominantly driven by the difference in the prevalence of minor vascular complications. There were no adverse events associated with protamine use. Conclusions and Relevance: In the ACE-PROTAVI randomized clinical trial, routine administration of protamine increased the rate of hemostasis success and decreased TTH. The beneficial effect of protamine was reflected in a reduction in minor vascular complications, procedural time, and postprocedural hospital stay duration in patients receiving routine protamine compared with patients receiving placebo. Trial Registration: anzctr.org.au Identifier: ACTRN12621001261808.

Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Protamine dosing and its impact in cardiac surgery transfusion practice-A retrospective bi-institutional analysis.

BACKGROUND: Bleeding after cardiac surgery is common and continues to require 10-20% of the national blood supply. Transfusion of allogeneic blood is associated with increased morbidity and mortality. Excessive protamine in the absence of circulating heparin after weaning off CPB can cause anticoagulation and precipitate bleeding. Hence, adequate dose calculation of protamine is crucial yet under evaluated. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a retrospective bi-institutional analysis of cardiac surgical patients who underwent cardiopulmonary bypass (CPB)-assisted cardiac surgery to assess the impact of protamine dosing in transfusion practice. Total 762 patients were identified from two institutions using electronic medical records and the Society of Thoracic Surgery (STS) database who underwent cardiac surgery using CPB. Patients were similar in demographics and other baseline characteristics. We divided patients into two groups based on mg of protamine administered to neutralize each 100 U of unfractionated heparin (UFH)-low-ratio group (Protamine: UFH ≤ 0.8) and high-ratio group (Protamine: UFH > 0.8). RESULTS: We observed a higher rate of blood transfusion required in high-ratio group (ratio >0.8) compared with low-ratio group (ratio ≤0.8) (p < .001). The increased requirement was consistently demonstrated for intraoperative transfusions of red blood cells, plasma, platelets, and cryoprecipitate. CONCLUSION: High protamine to heparin ratio may cause increased bleeding and transfusion in cardiac surgical patients. Protamine to heparin ratio of 0.8 or lower is sufficient to neutralize circulating heparin after weaning off cardiopulmonary bypass.

Clues of incomplete reversal of heparin in cardiac surgery.

OBJECTIVES: In our center, an unusual rate of patients had abnormalities of hemostasis in immediate postoperative period of cardiac surgery. Our objectives were to identify the cause of these sudden hemostasis abnormalities and to evaluate the performances of point of care coagulation testing. METHODS: In this prospective and descriptive study, we included 33 consecutive patients undergoing elective cardiac surgery for 1 month. Heparin-induced anticoagulation and calculation of the protamine dose were tested by the Hemostasis Management System Plus device (Medtronic, Minneapolis, MN, USA). Fifteen minutes after the end of the protamine infusion, activated clotting time (ACT), activated partial thromboplastin time and anti Xa activity were measured. In case of unusual clinical bleeding, a Quantra analysis (Stago, HemoSonics LLC, Charlottesville, VA) was added. RESULTS: Residual antiXa activity >0.2 IU/mL after neutralization was present in 44% of patients. Our investigation concluded incomplete heparin reversal. There was no association between cellular reinfusate and the presence of heparin. The unusual rate of hemostasis abnormalities was explained by a less efficient protamine reversal of heparin. ACT and Clot Time Ratio (CTR, Quantra system) correlated with AntiXa with Spearman's coefficients of 0.85 (p < .0001) and 0.95 (p = .0012), respectively. About ACT, a threshold of 150 seconds had a sensitivity of 85% [58-97] and a specificity of 85% [58-97%] for detection of AntiXa>0.2. For CTR, a threshold of 1.4 had a sensitivity of 67% [30-94] and a specificity of 100% [18-100]. CONCLUSION: The use of point of care coagulation testing is effective in detecting incomplete reversal of heparin.

Management of an unintentional enoxaparin overdose: A case report and literature review.

PURPOSE: The aim of this article is to describe a case in which protamine was used for a low-molecular-weight heparin (LMWH) overdose and present an up-to-date review of the literature on the management of LMWH overdose in adults. SUMMARY: An unintentional administration of enoxaparin 900 mg occurred in a 73-year-old man with coronavirus disease 2019-related pulmonary embolism. Management of the overdose included a protamine bolus followed by an infusion. Anti-factor Xa levels and activated partial thromboplastin time were monitored. Anti-factor Xa levels declined in a linear fashion irrespective of protamine administration. No bleeding or further thrombotic complications occurred in the patient. A review of the literature revealed that the optimal strategy to treat an LMWH overdose is unknown, with treatment of overdoses ranging from clinical observation to aggressive protamine dosing in reported cases. Although protamine effectively neutralizes unfractionated heparin, it is unable to completely reverse LMWH activity and has variable effects on laboratory measures of LMWH anticoagulant activity. CONCLUSION: The current case report provides additional data to previous literature suggesting that protamine may have a limited effect in decreasing anti-factor Xa levels in LMWH overdose. Continued reporting on the management of LMWH overdoses is warranted to clarify the optimal treatment strategy.

Heparin reversal with protamine sulfate after Percutaneous Hepatic Perfusion (PHP): is less more?

PURPOSE: Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP. MATERIALS AND METHODS: All patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0). RESULTS: Thromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine. CONCLUSION: Our retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Gene network analysis of oxaliplatin-resistant colorectal cancer to target a crucial gene using chitosan/hyaluronic acid/protamine polyplexes containing CRISPR-Cas9.

Colorectal cancer (CRC) treatment is dramatically hampered by resistance to oxaliplatin alone or in the combination of irinotecan or 5-fluorouracil and leucovorin. This study aims to design and assess Chitosan/Hyaluronic Acid/Protamine sulfate (CS/HA/PS) polyplexes loaded with CRISPR plasmid for targeting a key gene in cancer drug resistance. Here, recent findings were considered to validate oxaliplatin-resistant CRC-related genes and systems biology approaches employed to detect the critical gene. The polyplexes were characterized according to particle size, zeta potential, and stability. Moreover, carrier toxicity and transfection efficiency were assessed on oxaliplatin-resistant HT-29 cells. The post-transfection evaluations were performed to confirm gene disruption-mediated CRISPR. Eventually, excision cross complementation group 1(ERCC1), a crucial member of the nucleotide excision repair pathway, was selected to be targeted using CRISPR/Cas9 to reverse oxaliplatin resistance in HT-29 cells. CS/HA/PS polyplexes containing CRISPR/Cas9 plasmid exhibited negligible toxicity and comparable transfection efficiency with Lipofectamine™. Following the efficient gene delivery, sequences in CRISPR/Cas9 target sites were altered, ERCC1 was downregulated, and drug sensitivity was successfully restored in oxaliplatin-resistant cells. Findings indicate that CS/HA/PS/CRISPR polyplexes provide a potential strategy for delivering cargo and targeting oxaliplatin resistance-related gene to manipulate drug resistance as a rising concern in cancer therapeutic approaches.

Complete Heparin Reversal by Protamine during Off-Pump Coronary Artery Bypass Surgery (OPCAB): A Necessity or Myth?

In our country majority of the coronary artery bypass surgery (CABG) are done off-pump and was reported having excellent clinical outcome along with cost efficiency by various investigators. Heparin is commonly used as most effective anticoagulant, and protamine sulfate is now generally used to reverse the anticoagulant action of heparin. While under dosing of protamine may result in incomplete heparin reversal and prolonged anticoagulation, protamine overdosing is associated with impaired clot formation exerted by the intrinsic anti-coagulation properties of protamine itself, moreover protamine administration is associated with mild to severe cardiovascular and pulmonary complications. Apart from traditional full neutralization of heparin now-a-days, half dose protamine was also introduced showing good outcome regarding lower activated clotting time (ACT), overall, less surgical bleeding with less transfusion. This comparative study was designed to detect differences between traditional and decreased protamine dosing in Off-Pump Coronary Artery Bypass (OPCAB) surgery. Four hundred (400) patients who underwent Off-Pump Coronary Artery Bypass Surgery (OPCAB) surgery at our institution over a period of 12 months were analyzed and were divided into two groups. Group A- received 0.5mg of protamine per 100 unit of heparin; Group B-received 1.0mg of protamine per 100 unit of heparin. ACT, blood loss, hemoglobin and platelet count units of blood and blood product transfusion requirements, clinical outcome and hospital stay were assessed in each patient. This study showed that 0.5mg of protamine per 100 unit of heparin was always able to reverse the anticoagulant effect of heparin with no significant difference in hemodynamic parameters, amount of blood loss and requirements of blood transfusion in between the groups. A standard protamine dosing formula (protamine-heparin at ratio of 1:1) adequate for on-pump cardiac surgical procedures significantly overestimates protamine requirements for OPCAB. Patients treated with decreased protamine do not appear to have adverse outcomes in terms of post-operative bleeding.

Hypoglycemic and hypolipidemic effect of pentaamino acid fullerene C60 derivative in rats with metabolic disorder.

Pentaamino acid fullerene C60 derivative is a promising nanomaterial, which exhibited antihyperglycemic activity in high-fat diet and streptozotocin-induced diabetic rats. This study investigates the effect of pentaaminoacid C60 derivative (PFD) in rats with metabolic disorders. Rats were assigned to 3 groups (of 10 rats each) as follows: Group 1 (normal control), group 2 included the protamine-sulfate-treated rats (the untreated group of animals with the model metabolic disorder); group 3 (Protamine sulfate + PFD) included the protamine-sulfate-treated model rats that received an intraperitoneal injection of PFD. Metabolic disorder in rats was initiated by protamine sulfate (PS) administration. The PS + PFD group was injected intraperitoneally with PFD solution (3 mg/kg). Protamine sulfate induces biochemical changes (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) in the blood and morphological lesions in rat liver and pancreas. The potassium salt of fullerenylpenta-N-dihydroxytyrosine in protamine sulfate-induced rats normalized blood glucose level and the serum lipid profile and improved hepatic function markers. Treatment with PFD restored pancreas islets and liver structure of protamine sulfate-induced rats compared to the untreated group. PFD is a promising compound for further study as a drug against metabolic disorders.

The emerging role of adopting protamine for reducing the risk of bleeding complications during the percutaneous coronary intervention: A meta-analysis.

BACKGROUND: The safety and the benefits of reducing the risk of bleeding complications via protamine administration during the percutaneous coronary intervention (PCI) remains unclear. This study aimed to systematically assessed the efficacy and safety of using protamine in PCI. METHOD: Potential academic studies were identified from PubMed, Cochrane Library, EMBASE, and Web of Science. The time range we retrieved from was that from the inception of electronic databases to March 31, 2022. Gray studies were identified from the references of included literature reports. Stata version 12.0 statistical software (StataCorp LP) was used to analyze the pooled data. RESULTS: A total of seven studies were involved in our study. The overall participants of the protamine group were 4983, whereas it was 1953 in the nonprotamine group. This meta-analysis indicated that protamine was preferable for PCI as its lower value of major bleeding (odds ratio [OR] = 0.489, 95% confidence interval [CI]: 0.362-0.661, p < .001) and minor bleeding (OR = 0.281, 95% CI: 0.123-0.643, p = .003). Additionally, the protamine did not tend to be related a higher incidence of mortality (p = .143), myocardial infarction (p = .990), and stent thrombosis (p = .698). CONCLUSIONS: Based on available evidence, use of protamine may reduce the risk of bleeding complications without increasing the risk of mortality, myocardial infarction, and stent thrombosis. Given the relevant possible biases in our study, adequately powered and better-designed studies with long-term follow-up are required to reach a firmer conclusion.

Blood and Blood Product Conservation: Results of Strategies to Improve Clinical Outcomes in Open Heart Surgery Patients at a Tertiary Hospital Are Maintained 4 Years after Initiation.

Blood product usage is an important outcome for patients undergoing cardiac surgery. In 2015, our center made a concerted effort with multiple departments to focus on reducing transfusion rates in surgical patients requiring cardiopulmonary bypass (CPB). Specific changes included an upgrade of the oxygenator in mid-2015 and, in early 2016, implementation of a hemostasis management system (HMS) that used heparin dose-response titration assays for heparin and protamine management. A retrospective chart review demonstrated significant decreases in the quarterly average of patients receiving packed red blood cells (PRBCs) from a baseline of 26.7% to 22.7% following the oxygenator upgrade (p = .021) and from 22.7% to 8.8% following implementation of the HMS (p = .0017). Platelet usage decreased from an average of 50.5% during the baseline and oxygenator upgrade periods to 22.2% following implementation of the HMS (p < .0001). Usage of fresh frozen plasma (FFP) decreased from an average of 28.2% of cases during the baseline and oxygenator upgrade periods to 10.4% during 2016, and cryoprecipitate usage decreased from 38.5% to 15.4%. Heparin usage averaged 56,903 units before implementation of the HMS, decreasing to an average of 43,796 units following HMS implementation (p < .0001). During the same time periods, protamine usage averaged 340.3 mg and 183.2 mg, respectively. Because improvements achieved during quality initiatives may revert back to their pre-intervention state once the assessment period is over, we performed a second retrospective analysis to determine whether the improvements achieved were maintained during the 48 months following the initial study. During 2017-2020, quarterly average usage of blood products was as follows: PRBCs, 11.9%; platelets, 14.7%; FFP, 6.2%; and cryoprecipitate, 11.5%. Quarterly, average use of heparin and protamine were 31,556 ± 2,757 units and 189 ± 113 mg, respectively. These findings indicate that the improvements achieved were not limited to the duration of the initial quality initiative.

Evaluation of the efficacy and safety of chum salmon milt deoxyribonucleic acid for improvement of hepatic functions: a placebo-controlled, randomised, double-blind, and parallel-group, pilot clinical trial.

The increased prevalence of nonalcoholic fatty liver disease (NAFLD) is a critical public health concern. Deoxyribonucleic acid (DNA) from chum salmon (Oncorhynchus keta) milt (salmon milt DNA; SM DNA), a by-product obtained during industrial processing of the pharmaceutical raw material protamine, ameliorates hepatosteatosis in animals. This randomised, double-blind, parallel-group comparative study evaluated the effects of SM DNA on hepatic function in healthy Japanese participants with slightly decreased liver function and high alanine aminotransferase level and body mass index. Fifty participants were included in the study. The participants were divided into the placebo (n = 24) and SM DNA (n = 26) groups and administered equal doses of placebo (dextrin) and SM DNA (530 mg day-1), respectively. No significant alleviating effects of SM DNA were observed on the primary (hepatic functions and liver-to-spleen ratio), and secondary (NAFLD fibrosis score, serum protein levels, blood glucose, blood lipids, inflammatory markers, adipokines, cytokines, fatigue scoring, and skin conditions) endpoints. Subsequently, a sex-based subgroup analysis revealed a significant improvement in the primary and secondary outcomes in males ingesting SM DNA compared with those in males who were administered placebo. However, no such effect was observed in females. Overall, this clinical study demonstrated the anti-obesity potential of SM DNA and suggested that SM DNA can benefit hepatic function in males.

Reversal of life-threatening bleeding with protamine sulfate in a patient with plasma cell leukemia.

Plasma cell disorders, such as multiple myeloma, can cause numerous derangements of hemostasis. In this case report, we present a life-threatening coagulopathy in a patient with progressing multiple myeloma in which the antibody-producing heparin-like activity is a free light chain. The patient's bleeding was successfully treated using protamine sulfate, which then allowed treatment of her plasma cell leukemia. In the literature, other authors have reported similar patients who have responded to protamine sulphate either in vitro or in vivo , providing further evidence for the role of protamine sulfate in the reversal of coagulopathy and resolution of bleeding diathesis. Standard treatments of transfusion with fresh frozen plasma and cryoprecipitate are likely to be ineffective in life-threatening bleeding related to this mechanism (heparin-like effect), and it is essential that treating physicians are aware of this potential mechanism of bleeding in their patients.

PEGylated Protamine Letrozole Nanoparticles: A Promising Strategy to Combat Human Breast Cancer via MCF-7 Cell Lines.

The objective of the study was to develop PEGylated protamine letrozole nanoparticles to combat human breast cancer by modifying the release pattern of letrozole. Breast cancer is amongst the most prevalent diseases in women due to overactivity of human epidermal growth factor receptor 2 (HER2). PEG-protamine letrozole nanoparticle formulation was designed and optimized to alter the release pattern of the drug. The size, morphology, and structure of PEG-protamine letrozole NP were characterized by FTIR, XRD, Zetasizer, and SEM analysis. The result showed the PEG-protamine letrozole nanoparticles were irregular in shape and have size ranging from 258 nm to 388 nm, polydispersity index 0.114 to 0.45, zeta potential of 11.2 mV, and entrapment efficiency 89.93%. XRD studies have confirmed that the crystal structure of letrozole has become amorphous. The drug release study maintained the prolonged release for 72 hours. Moreover, the PEG-protamine letrozole NPs displayed a strong anticancer action compared to MCF-7 cells with an IC50 70 µM for letrozole and 50 µM for PEG-protamine letrozole NPs. Overall, our results indicate that letrozole PEG-protamine NPs alter the release profile of letrozole, which could be an excellent approach for overcoming letrozole resistance in human breast cancer.

The association of long-acting insulin analogue use versus neutral protamine Hagedorn insulin use and the risk of major adverse cardiovascular events among individuals with type 2 diabetes: A population-based cohort study.

AIMS: To compare the risk of cardiovascular outcomes associated with long-acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes. MATERIALS AND METHODS: We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long-acting insulin analogues or NPH insulin, defined using a time-varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long-acting insulin analogues versus NPH insulin, and in secondary analyses, by long-acting insulin molecule. RESULTS: Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow-up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person-years). Long-acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96). CONCLUSIONS: Current use of long-acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline-writing committees for recommendations of insulin treatment for type 2 diabetes.

One hundred years of insulin: Is it time for smart?

Smarter understanding of diabetes pathophysiology and pharmacology of insulin therapy can lead to better clinical outcomes. Rather than looking for an insulin formulation that is considered "best" for a general population, it could be appropriate to seek the "smart" insulin choice, tailored to the specific clinical situation. Different treatment goals should be considered, with pros and cons to each. Ideally, insulin therapy in most diabetic dogs should mimic a "basal-bolus" pattern. The "intermediate"-acting insulin formulations might provide better "bolus" treatment in dogs than the rapid-acting formulations used in people. In patients with some residual beta cell function such as many diabetic cats, administering only a "basal" insulin might lead to complete normalisation of blood glucose concentrations. Insulin suspensions (neutral protamine Hagedorn, neutral protamine Hagedorn/regular mixes, lente and protamine zinc insulin) as well as insulin glargine U100 and detemir are "intermediate"-acting formulations that are administered twice daily. For a formulation to be an effective and safe "basal" insulin, its action should be roughly the same every hour of the day. Currently, only insulin glargine U300 and insulin degludec meet this standard in dogs, whereas in cats, insulin glargine U300 is the closest option.

Anticoagulation and bleeding in the cancer patient.

Cancer patients have an increased risk of bleeding compared to non-cancer patients with anticoagulant therapy. A bleeding risk assessment before initiation of anticoagulation is recommended. Currently low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) are the mainstays of treatment for cancer-associated venous thromboembolism (VTE). Since DOACs are administered orally, they offer some convenience and ease of administration; however, LMWH may be preferred in certain cancers. Given the prevalence of anticoagulant therapies in cancer patients, clinical providers must be able to recognize potentially critical bleeding sites and modalities to reverse major hemorrhage. Reversal agents or antidotes to bleeding may be required when bleeding is persistent or life-threatening. These include vitamin K, fresh frozen plasma (FFP), protamine, prothrombin complex concentrate (PCC) or andexanet alfa, and idarucizumab. Inferior vena cava (IVC) filter insertion can be also considered in those with major bleeding. Evidence for timing and need for re-initiation of anticoagulant therapy after a major bleeding remains sparse, but a multi-disciplinary approach and shared decision-making can be implemented in the interim.