Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis.

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis.

von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.

Graves Disease Following the SARS-CoV-2 Vaccine: Case Series.

Widespread vaccination is a principal strategy to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lessen the global burden of coronavirus disease 2019 (COVID-19). Information is rapidly evolving about the impact of SARS-CoV-2 vaccines on the immune and endocrine systems. This case series heightens clinical awareness of possible thyroid effects and conveys knowledge of what to monitor, which are fundamental components of public health and pharmacovigilance. We present a case series of Graves disease following mRNA SARS-CoV-2 vaccination, with symptoms and altered thyroid function tests developing within 7 days of the first dose in 2 women aged 38 and 63 years, and 28 days after the second dose in a 30-year-old man. New-onset Graves disease occurred following administration of mRNA vaccines against SARS-CoV-2. Based on the timing of signs and symptoms relative to administration of the vaccine and the absence of other probable causes, we consider the vaccine as a potential contributor to the diagnosis. The viral spike protein, delivered indirectly through an encoded mRNA vaccine, may be capable of triggering an inflammatory cascade and immune response triggering thyroid dysfunction.

Bleeding assessment tools in the diagnosis of VWD in adults and children: a systematic review and meta-analysis of test accuracy.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.

Revamping the ever-changing landscape of drug development processes in the midst of COVID-19 pandemic.

Oncology is the frontline of drug development. The current pharmaceutical pipeline is disproportional focused on oncology, where about 1/3 of all phases of development is in this therapeutic area. The emphasis brings about substantial breakthroughs and has made positive impact on the quality of life. However, oncology remains a threat to human existence. To facilitate this process, a comprehensive list of novel/first molecularly targeted oncology drug approvals by the FDA from 2017 to 2020 is assessed. Here, we focus on molecularly targeted oncology drugs and not cytotoxic ones, although the latter remain important. To achieve this purpose, besides their sponsors, years of approval, drug classes, and cancer indications, clinical significance is included. The results show that approved molecularly targeted drugs span across diverse classes, including small molecule receptor inhibitors, and biologics such as monoclonal antibodies, antibody-drug conjugates, check-point inhibitors (i.e., PD1, PDL1, CTLA4) and CAR-T cell therapies. Although complete cure of cancer remains limited, we have made substantial inroads and more is yet to come. Moreover, many of these new knowledge can be extrapolated to other therapeutic areas, especially to those of currently unmet medical needs such as in neurology and other chronic diseases.

ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease.

BACKGROUND: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. METHODS: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment. RESULTS: The panel agreed on 11 recommendations. CONCLUSIONS: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.

Dosing Common Medications in Hospitalized Pediatric Patients with Obesity: A Review.

Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight-based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment.

Pediatric Obesity: Influence on Drug Dosing and Therapeutics.

Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of U.S. children and adolescents. Severe obesity (≥120% of the 95th percentile of body mass index (BMI) for age, or a BMI ≥ 35 kg/m2 ) is the fastest-growing subgroup and now approaches 6% of all U.S. youth. Health consequences (eg, type 2 diabetes, coronary heart disease) are related in a dose-dependent manner to severity of obesity. Because therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition, and exercise achieve limited success. Only one drug, orlistat, is U.S. Food and Drug Administration approved for long-term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as the pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat-storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity.

Improved treatment satisfaction in patients with type 1 diabetes treated with insulin glargine 100U/mL versus neutral protamine Hagedorn insulin: An exploration of key predictors from two randomized controlled trials.

AIM: Investigate contributors to treatment satisfaction in type 1 diabetes (T1D). METHODS: Post-hoc analysis using the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) in 771 T1D patients from two 28-week trials comparing once-daily insulin glargine 100U/mL (Gla-100) with once- or twice-daily NPH neutral protamine Hagedorn (NPH) insulin. RESULTS: Gla-100 was associated with a significant improvement in treatment satisfaction versus NPH (overall population adjusted mean [standard error] DTSQs change from baseline: +1.13 [0.30] versus -0.04 [0.31]; p=0.006). In the overall population, treatment satisfaction improvement with all insulin regimens was related to less frequent severe hypoglycemia (coefficient-0.077; p=0.040) and HbA1c reduction (-0.066; p=0.082). By treatment regimen, relationships between treatment satisfaction and these outcomes approached or attained statistical significance for NPH insulin, but not Gla-100. In the overall population, predictors of treatment satisfaction improvement included: Gla-100 treatment (estimate 1.17, p=0.006), lower baseline DTSQs (-0.57, p<0.001), study (-1.01, p=0.019), lower severe hypoglycemia rate (0.17, p=0.012), and higher baseline HbA1c (0.44, p=0.014). By treatment regimen, these predictors remained significant for NPH insulin. CONCLUSIONS: Gla-100 resulted in a significant improvement in treatment satisfaction versus NPH insulin, independent of baseline disease characteristics and clinical outcomes.

Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents.

This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50 of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.

Patterns of postprandial hyperglycemia after basal insulin therapy: individual and regional differences.

BACKGROUND: Treatment of postprandial hyperglycemia could be needed when basal insulin added to oral therapy does not maintain glycated haemoglobin (HbA1C ) targets in type 2 diabetes mellitus. Knowing individual and regional patterns of postprandial hyperglycemia in this setting might improve therapeutic decisions. METHODS: Patient-level self-monitored blood glucose data were pooled from six studies of insulin glargine for patients with HbA1C ≥ 7.0% after 24 weeks. Percentages of participants with highest daily postprandial blood glucose and greatest postprandial increments after each of the three daily meals were calculated and compared between four geographical regions; USA, Canada, Germany, and other European countries. RESULTS: For 494 participants (mean age 60.1 years, diabetes duration 9.6 years, and BMI 29.8 kg/m(2) ), mean endpoint HbA1C was 7.8%. On insulin glargine treatment, highest postprandial blood glucose most often occurred post-dinner (44% of participants) and greatest postprandial increments post-breakfast (46% of participants) in all regions. Participants with greatest postprandial increments post-breakfast were older and experienced less HbA1C improvement with insulin glargine than those with greatest postprandial increments after other meals. Post-breakfast and post-dinner postprandial blood glucose was higher in the USA and Canada versus Germany, and in the USA versus Other European countries (all p < 0.05). Postprandial increments after dinner were greater in the USA versus all other regions. CONCLUSIONS: Generally, highest postprandial blood glucose follows dinner and greatest postprandial increments follow breakfast. Variations in patient characteristics and eating patterns might underlie differences both within and between regions. Awareness of regional differences and evaluation of an individual's typical eating pattern might facilitate appropriate prandial therapy.

Comparison of three algorithms for initiation and titration of insulin glargine in insulin-naive patients with type 2 diabetes mellitus.

BACKGROUND: Several titration algorithms can be used to adjust insulin dose and attain blood glucose targets. We compared clinical outcomes using three initiation and titration algorithms for insulin glargine in insulin-naive patients with type 2 diabetes mellitus (T2DM); focusing on those receiving both metformin and sulfonylurea (SU) at baseline. METHODS: This was a pooled analysis of patient-level data from prospective, randomized, controlled 24-week trials. Patients received algorithm 1 (1 IU increase once daily, if fasting plasma glucose [FPG] > target), algorithm 2 (2 IU increase every 3 days, if FPG > target), or algorithm 3 (treat-to-target, generally 2-8 IU increase weekly based on 2-day mean FPG levels). Glycemic control, insulin dose, and hypoglycemic events were compared between algorithms. RESULTS: Overall, 1380 patients were included. In patients receiving metformin and SU at baseline, there were no significant differences in glycemic control between algorithms. Weight-adjusted dose was higher for algorithm 2 vs algorithms 1 and 3 (P = 0.0037 and P < 0.0001, respectively), though results were not significantly different when adjusted for reductions in HbA1c (0.36 IU/kg, 0.43 IU/kg, and 0.31 IU/kg for algorithms 1, 2, and 3, respectively). Yearly hypoglycemic event rates (confirmed blood glucose <56 mg/dL) were higher for algorithm 3 than algorithms 1 (P = 0.0003) and 2 (P < 0.0001). CONCLUSIONS: Three algorithms for initiation and titration of insulin glargine in patients with T2DM resulted in similar levels of glycemic control, with lower rates of hypoglycemia for patients treated using simpler algorithms 1 and 2.

Novel trial design: a report from the 19th frontiers symposium of ACCP.

Novel approaches to drug development along with incentives to reward risk undertaken during early drug development have been proposed to improve the medical product development process. The American College of Clinical Pharmacology held its 19th Frontiers Symposium in mid-2007 to provide a forum to share new knowledge about disease progression models and adaptive and other novel trial designs. These topics reflect the changing paradigm of drug development and regulatory innovation as outlined in the Food and Drug Administration's Critical Path Initiative. This meeting report summarizes some of the presentations and panel discussions among academic, industrial, and regulatory participants regarding clinical trial design, including adaptive Bayesian approaches.

Extending worldwide clinical pharmacology education through a pricing approach.

Financial instruments, such as professional membership fees, are part of the science and technology policy toolkit for creating an environment conducive to developing an international health knowledge network. To minimize a hurdle to global knowledge exchange in clinical pharmacology, the American College of Clinical Pharmacology reevaluated fees for its international members. Secondary market research was conducted on salary data available from US-based multinational firms. Salary comparisons for the same position based in the United States and in a developing economy were used to generate an index ratio. Applying this ratio, a tiered-membership fee structure was constructed for the approximately 120 countries where gross national income meets the World Bank classification of "developing economy." The index ratio serves as a paradigm for structuring fees across a variety of programs. With the implementation of an adjusted dues structure, information and networks of colleagues are now more accessible to clinical pharmacologists in developing economies.