Continuous infusion of coagulation factor concentrates during intensive treatment.

In clinical management of bleeds and surgical procedures in patients suffering from bleeding disorders either repetitive bolus injections (BI) or continuous infusion (CI) can be used for coagulation factor replacement. Continuous infusion seems to be an attractive route of administration and may be considered if replacement therapy is required for more than 3 days. The strongest argument favouring continuous infusion is its superiority in providing the patient with a safe and constant level of the deficient coagulation factor by balancing input with clearance. Furthermore, several studies have shown that coagulation factor consumption may be reduced by CI compared to repetitive bolus injections (BI) since unnecessary peaks of factor level are avoided. Concerns have been raised whether continuous infusion of coagulation concentrates is associated with an increased risk of developing inhibitors. However, available data have so far not shown an increased risk for inhibitor development in severe haemophilia patients with more than 50 exposure days of coagulation factor concentrates. Further, previously reported complications when using CI such as phlebitis at the infusion site and pump failure are nowadays very seldom seen when small amounts of heparin are added to the infusion bag, and increased quality of the pumps are available. Over the last decades, numerous reports have confirmed CI to be a safe and effective mode of coagulation factor replacement even in the most challenging surgical procedures, such as total joint arthroplasties.

The association between health utility and joint status among people with severe haemophilia A: findings from the KAPPA register.

INTRODUCTION: People with severe haemophilia A have reportedly impaired health related quality of life (utility) mainly due to recurrent bleeding, arthropathy and treatment burden. AIM: To estimate utilities and evaluate their potential correlates - most importantly the joint status - among people with severe haemophilia A. METHODS: In this cross-sectional study, eligible participants had severe haemophilia A, were aged ≥15, negative for factor VIII inhibitor and included in the KAPPA register of Denmark, Norway and Sweden. Data on demographics, treatment history, haemophilia joint health score, and EQ-5D utility were obtained from the register. We used box plots to present utilities and joint status and ordinary least squares regression to evaluate correlates of utilities. Participants were consecutively enrolled in the KAPPA register between April 2013 and June 2016. RESULTS: Overall, 173 participants with median age of 34 (interquartile range: 25-45) were included. Twelve (6.9%) participants were on episodic treatment while 161 (93.1%) were treated using prophylaxis. Concomitant diseases and positive inhibitor history were reported for 73 (43.2%) and 21 (12.1%) participants, respectively. The highest median utility (1.0) was observed among those aged <29 on prophylaxis and those aged 30-44 who had started prophylaxis by age 3. In the multi-variable regression, joint scores of 16-25 (Coef. -0.18, 95% CI: -0.30, -0.06), 26-35 (Coef. -0.21, 95% CI: -0.36, -0.06) and >35 (Coef. -0.37, 95% CI: -0.52, -0.23) were associated with lower utilities. CONCLUSION: Moderate to severe joint manifestations are associated with reduced utilities among persons with severe haemophilia A.

Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe.

BACKGROUND AND OBJECTIVES: This cross-sectional, epidemiological study sought to assess the prevalence and extent of potential risk factors for hypertension, particularly renal function related to haematuria and their associations in people with haemophilia. METHODOLOGY: Demographic and medical data were collected at a single time-point in patients with haemophilia over 40 years of age from 16 European centres. Associations with diagnosis of hypertension were tested in univariate and multivariate analyses. RESULTS: We enrolled 532 patients (median age 52 years, range 40-98) with haemophilia A (n = 467) or haemophilia B (n = 65). Haemophilia was severe (<0.01 IU mL-1 ) in 313 patients (59%). Hypertension was diagnosed in 239 patients (45%). In multivariate analyses, age and body mass index (BMI) were significantly and independently associated with hypertension (adjusted odds ratio (OR) 18.1, P < 0.001, in elderly patients and OR = 25.1, P < 0.001, in patients with BMI >30 kg m-2 ). Estimated glomerular filtration rate (eGFR) <70 mL min-1 (OR = 2.7, P = 0.047) was significantly associated with hypertension, but mean eGFR was significantly higher for severe than mild haemophilia. Further variables with OR > 2.8 were diabetes (OR = 2.8, P = 0.04), coronary artery disease (OR = 3.3, P = 0.052) and family history of hypertension (OR = 4.4, P < 0.001). Neither severity of haemophilia nor history of haematuria was significantly associated with hypertension in univariate or multivariate analyses. CONCLUSION: As in the general population, age and BMI were major risk factors for hypertension in people with haemophilia. Renal dysfunction was associated with hypertension, but the prevalence of renal dysfunction was not extensive and furthermore not significantly correlated with haematuria. The associations of other variables with hypertension require further studies to confirm causal relationships over time.

How to compare cardiovascular disease and risk factors in elderly patients with haemophilia with the general population.

INTRODUCTION: Studies on the prevalence of cardiovascular disease (CVD) and risk factors in patients with haemophilia (PWH) in comparison to the general population have generated inconsistent results. The ADVANCE Working Group collected data on CV comorbidities in PWH aged ≥40 years (H(3) Study). AIM: Identification of German epidemiological data on CVD for the general population, evaluation for appropriateness, and execution of comparisons with PWH. METHODS: Identification of data sources by structured literature (EMBASE, MEDLINE) searches. INCLUSION CRITERIA: German general population, CVD and risk factors, gender/age stratification, sample size >500 male persons, age groups ≥40 years, current data collection, language English/German. Comparison of data on CVD and risk factors in PWH (H(3)  Study) with published German general population data. RESULTS: Criteria for data source appropriateness were defined. Of five national and three international epidemiological studies, the DEGS1 Study (German Health Interview and Examination Survey for Adults) was identified as the most suitable comparator. Compared with men from DEGS1, hypertension was significantly more prevalent in PWH aged 50-59 years (41.7% [95% CI: 37.3-46.2] vs. 52.0% [95% CI: 43.7-60.1], P = 0.03). Coronary artery/heart disease (CHD) was significantly less prevalent in PWH aged ≥60 years (60-69 years: 19.5% [95% CI: 15.9-23.7] vs. 8.1% [95% CI: 3.3-16.1], P = 0.02; 70-79 years: 30.5% [95% CI: 25.9-35.5] vs. 11.8% [95% CI: 5.2-21.9], P = 0.002). No statistically significant difference for ischaemic cerebrovascular disease/stroke was detected. CONCLUSION: Increased prevalence of hypertension in PWH should trigger regular screening. CHD does occur in PWH aged ≥60 years though apparently with lower prevalence. Given the growing population of elderly PWH, guidelines for prevention and treatment of CVD should be developed.

Evaluation of the utility of the ISTH-BAT in haemophilia carriers: a multinational study.

INTRODUCTION: There has been increasing recognition in recent years that female carriers of haemophilia manifest abnormal bleeding; however, data on the use of bleeding assessment tools in this population are lacking. AIM: Our objective was to validate the ISTH-BAT in haemophilia carriers to describe bleeding symptoms and allow for comparisons with factor levels and other patient groups. METHODS: This was a prospective, observational, cross-sectional study performed by members of Global Emerging HEmostasis Panel (GEHEP). Unselected consecutive haemophilia carriers were recruited and a CRF and the ISTH-BAT were completed by study personnel. RESULTS: A total of 168 haemophilia carriers were enrolled: 155 haemophilia A and 13 haemophilia B. The mean age was 40 years (range: 20-82). Carriers had higher mean bleeding scores (BS) compared with age-matched controls (n = 46; 5.7 vs. 1.43; P < 0.0001) and Type 3 VWD OC (n = 32; 3.0; P = 0.009), but lower BS compared with women with Type 1 VWD (n = 83; 8.7; P < 0.0001). Fifteen carriers reported haemarthrosis, and of those six had normal FVIII/FIX levels. There was a significant but weak negative correlation between BS and factor level (Spearman's r2  = -0.36, P < 0.001). CONCLUSION: Our results show that haemophilia carriers experience abnormal bleeding, including haemarthrosis. Overall, BS in women with Type 1 VWD > haemophilia carriers > Type 3 VWD OC > controls. Understanding the performance of the ISTH-BAT in this population is a critical step in future research aimed at investigating the underlying pathophysiology of abnormal bleeding, with the ultimate goal of optimizing treatment.

Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly?

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings.

Monitoring bypassing agent therapy - a prospective crossover study comparing thromboelastometry and thrombin generation assay.

The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg(-1) activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post-infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 µg kg(-1) and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2-3 folds from baseline 15-30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two-fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive.

Presentation and management of acute coronary syndromes among adult persons with haemophilia: results of an international, retrospective, 10-year survey.

Sparse data are available on presentation and management of acute coronary syndromes (ACS), including unstable angina and non-ST- and ST-elevation myocardial infarction, among persons with haemophilia (PWH). The aim of this study was to determine demographics, bleeding disorder characteristics, cardiovascular risk factors (CRFs), interventions, haemostatic protocol, revascularization outcomes and complications among PWH with ACS. Members of an international consortium comprising >2000 adult PWH retrospectively completed case report forms for episodes of ACS in a >10-year follow-up period (2003-2013). Twenty ACS episodes occurred among 19 patients [rate, 0.8% (95% CI 0.4, 1.2)]. Seven patients (37%) were aged <50 years; 10 (53%) had ≥3 CRFs. In 5/20 episodes (25%), the initial ACS management protocol was altered because of the bleeding disorder. None of the eight patients with severe haemophilia underwent coronary artery bypass grafting (CABG), compared with 54.5% of patients with non-severe disease (P = 0.02). Revascularization with percutaneous coronary intervention (PCI) or CABG was rated successful in 13/13 cases, with no excessive bleeding during initial management. During chronic exposure to antiplatelet agents, secondary haemophilia prophylaxis was more prevalent in patients with severe haemophilia compared with non-severe haemophilia (85.7% vs. 30%, P = 0.05). No ACS-related deaths occurred during initial management, but one patient with severe haemophilia A died of undetermined cause 36 months after the ACS event while on aspirin therapy. ACS occurs even among relatively younger PWH, typically in association with multiple CRFs. Revascularization with PCI/CABG is feasible, and antiplatelet agents plus secondary prophylaxis appears to be well tolerated in selected PWH with ACS.

Use of thromboelastography and thrombin generation assay to predict clinical phenotype in patients with severe FVII deficiency.

Bleeding tendency is weakly correlated with the activity of factor VII (FVII) in the plasma of patients with FVII deficiency. A laboratory method for predicting bleeding risk in patients with this coagulation disorder is lacking. We investigated whether global coagulation assays, specifically thromboelastography (TEG) and thrombin generation assay (TGA), could be used to predict bleeding risk. We also sought to identify factors that may explain the differences in bleeding phenotype observed among individuals with severe FVII deficiency. The study comprised 12 patients with severe FVII deficiency (FVII activity <1%). Eleven patients were homozygous for the Gln100Arg mutation and one patient was compound heterozygous. Clinically, 10 patients had increased haemorrhagic diathesis, whereas two patients were asymptomatic. Blood sampling was performed at baseline for TEG and TGA analyses. The platelet aggregation assay was performed and the plasma level of anticoagulation inhibitors and thrombophilic risk factors assessed. No difference in the TEG and TGA results was observed in all FVII-deficient individuals. The level of free tissue factor pathway inhibitor was within the normal range and similar in symptomatic and asymptomatic subjects. None of the participants had the FV Leiden mutation, prothrombin gene mutation, or abnormal anticoagulant inhibitor levels. Asymptomatic subjects showed normal platelet aggregation. These data suggested that TEG and TGA were not suitable methods for predicting the clinical phenotype in FVII-deficient subjects.

Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors.

Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N = 5) and haemophilia inhibitor patients (N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg(-1) orally (O.R.) Patients were treated with aPCC 75 IU kg(-1) intravenous (I.V.) on day 1 followed by TXA 20 mg kg(-1) O.R. combined with aPCC 75 IU kg(-1) I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90 µg kg(-1) I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.

Combined treatment with APCC (FEIBA®) and tranexamic acid in patients with haemophilia A with inhibitors and in patients with acquired haemophilia A--a two-centre experience.

The management of bleeding in haemophilia patients with inhibitors can be challenging when using monotherapy with either activated prothrombin complex concentrate (APCC) or recombinant activated FVII (rFVIIa) fail. The antifibrinolytic agent tranexamic acid (TXA) increases clot stability and is used concomitantly with coagulation factor replacement to improve haemostasis in haemophilia patients without inhibitors in many countries in Europe. Combined treatment with TXA and rFVIIa is not contraindicated in haemophilia patients with inhibitors. However, the combined approach of TXA and APCC has not been investigated due to safety concerns of increased risk of thrombosis or disseminated intravasal coagulation (DIC). The aim of this study is to report our experience of concomitant use of APCC and TXA in haemophilia A patients with inhibitor and in patients with acquired haemophilia A with respect to safety and efficacy. Seven (n = 6) haemophilia A patients with inhibitors and one (n = 1) with acquired haemophilia A from Oslo (Norway) and Stockholm (Sweden) were included in the study. The APCC was given at doses consistent to the manufacturers' recommendation. TXA was administered concomitantly either 10 mg kg(-1) every 6-8 h intravenously or 20 mg kg(-1) every 6-8 h orally. Haemostatic response was assessed by thromboelastography (TEG) and thrombin generation assay (TGA) in three of the patients. A total number of three bleeding episodes and two minor and six major surgical procedures were performed under the coverage with APCC and TXA. Haemostatic outcome was rated excellent or good in 10 of 11 (91%) treatment episodes. One episode was rated with poor effect. No episodes of arterial, venous thrombosis or DIC occurred during or after the treatment. Data from TEG and TGA analysis showed no signs of hypercoagulability following the combined treatment. This report demonstrates that, in a limited number of patients, combined treatment with APCC and TXA seemed to be safe, tolerated and relatively effective in management of bleeding episodes and in preventing haemorrhage during surgery in haemophilia patients with inhibitors and in a patient with acquired haemophilia A. Further studies should be performed to confirm these data.

Continuous infusion in haemophilia: current practice in Europe.

Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri-operatively or for major bleeds, in 742 patients. Most centres used 'adjusted dose' CI aimed at median target FVIII level of 0.8 IU mL(-1). CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2-11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady-state factor levels during CI, high-risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitors cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded.

rFVIIa administered by continuous infusion during surgery in patients with severe congenital FVII deficiency.

The use of recombinant FVIIa (rFVIIa) to control bleed in individuals with FVII deficiency has been proven to be effective. The main problems associated with its use are that it requires frequent bolus injections to counteract its short half-life and high cost. Our study aimed to evaluate whether any advantage could be gained by providing rFVIIa by continuous infusion during surgery with regard to haemostatic efficacy, safety and cost. The prospective study included 10 patients with severe FVII deficiency, who underwent 25 surgical procedures (13 major and 12 minor procedures) and were treated with rFVIIa administered by continuous infusion. Tranexamic acid was given concomitantly every 8 h. Prothrombin time, FVII:C assay and thrombin generation assay were used to monitor the treatment. The mean total dose given was 10 mg during a major surgery and 4.4 mg during a minor surgery for a mean treatment duration of 7.5 and 4.0 days respectively. This corresponds to a reduction of 70-90% in drug usage and medication cost compared with bolus injections. Except for one major perioperative bleeding, excellent haemostasis was achieved in all procedures. One patient developed a transient inhibitory activity. None of these events affected the postoperative course or prolonged the hospital stay. Our study demonstrated that continuous infusion of rFVIIa during surgery is safe, effective and highly cost effective.

FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations.

In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.

Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report.

SUMMARY: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.

Home treatment with bypassing products in inhibitor patients: a 7.5-year experience.

The advantages of early treatment of bleeds include minimizing the damage caused by the haemorrhage as well as offering increased convenience and time saved for the patient. The objectives of this prospective, single-centre study were to evaluate the efficacy, safety and feasibility of long-term home treatment with bypassing product in inhibitor patients. Since May 2000, 10 haemophilia A patients with high-titre inhibitors have been included in the study. Nine patients were treated with activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing activity, FEIBA; Baxter AG, Vienna, Austria) and one patient with both aPCC and recombinant activated factor VII (rFVIIa; NovoSeven; NovoNordisk A/S, Bagsvaerd, Denmark). A total of 1008 infusions of aPCC and 17 infusions of rFVIIa were given in a home treatment setting. The numbers include 448 infusions of aPCC and 10 infusions of rFVIIa given as prophylactic treatment. During the 7.5 years of follow-up, the patients experienced 431 bleeds. Five hundred and sixty infusions of aPCC and seven infusions of rFVIIa were given to treat these bleeds. Haemostasis was rated as effective in 88% (372/424) and partially effective in 10% (43/424) of the bleeds after a mean number of 1.3 injections. The number of treatments rated as effective was comparable for muscle (90%), joint (85%) and mucocutaneous (86%) bleeds. The safety of the treatment was very good. Only two mild adverse events were reported in total. No thrombotic adverse event has been observed. In conclusion, home treatment with bypassing agents in inhibitor patients is feasible, effective and safe in a long-term perspective.

Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats.

BACKGROUND AND PURPOSE: Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in beta-cells. Here we examine whether the lowering of blood glucose levels in the rat by small molecule glucokinase activators (GKAs) can be predicted from in vitro enzyme potencies and plasma compound exposure. EXPERIMENTAL APPROACH: We developed an insulin resistant and hyperinsulinemic animal model, the high fat fed female Zucker (fa/fa) rat (HFFZ), and measured the acute in vivo glucose-lowering efficacy of a number of GKAs in an oral glucose tolerance test. KEY RESULTS: Four GKAs (at 1 to 30 mg kg(-1)), with different in vitro enzyme potencies, dose-dependently improved oral glucose tolerance in HFFZ rats (10-40% decrease glucose area under the curve (AUC) from vehicle control). The extent of glucose lowering, or the pharmacodynamic (PD) effect, of a GKA was directly related to the total compound concentration in the plasma; the pharmacokinetic (PK) measurement. This PK-PD relationship was extended across a series of GKAs by accounting for differences in protein binding and in the in vitro potency. CONCLUSIONS AND IMPLICATIONS: When the unbound GKA compound level is greater than the in vitro enzyme potency there was significant blood glucose lowering in vivo. This latter relationship was upheld in non-diabetic Wistar rats orally dosed with a GKA. The robust and predictive nature of the PK-PD relationship for GKAs may prove of value in testing these agents in early human clinical studies.

Current view and outcome of ITI therapy - A change over time?

INTRODUCTION: Inhibitor development in people with haemophilia is a serious complication that may require intensive and costly interventions. The goal of inhibitor management should be permanent inhibitor eradication through immune tolerance induction (ITI), but well-designed studies are lacking and the management of patients is therefore defined by the experience and views of the clinician. OBJECTIVES: To explore the current clinical practice and outcome of ITI therapy in Europe and how this may have changed over the last decade, as well as to provide consensus recommendations to guide clinicians in their clinical practice. METHODS: A survey was conducted among 16 European haemophilia comprehensive care centres to evaluate current ITI treatment regimens and success rates in severe and mild/moderate haemophilia A and haemophilia B. In addition, an updated literature review was performed as guidance for providing recommendations. RESULTS: We demonstrated successful inhibitor treatment in 86% of severe haemophilia A patients with low responding (LR) and 59% of patients with high responding (HR) inhibitors. Some new trends in the management of patients with inhibitors were identified, including a tendency to use low-dose regimens (<50IU/kg/d) in both children and adults with HR inhibitors possibly based on similar success rates demonstrated in the I-ITI study compared to a high-dose protocol. Data on ITI therapy in mild and moderate haemophilia as well as haemophilia B were limited. CONCLUSIONS: The outcome of ITI therapy seems to be stable over time, and treatment regimens remain heterogeneous. The use of low dose regimens however is considered more frequently.

Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination.

In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.

Are all aciclovir cream formulations bioequivalent?

Topical aciclovir cream (ACV, Zovirax Cream) containing 40% propylene glycol (PG), the optimum found for skin penetration, is clinically effective in the treatment of recurrent herpes labialis. One hundred and thirty-nine ACV generic creams were analysed and 80% of these contained less than 20% PG. From this, we hypothesised that these generics might be bioinequivalent to the innovator cream. A pilot in vitro skin permeation study compared the innovator cream with two generics containing about 15% PG. Next, 10 generics containing 0-15% PG were tested in an independent laboratory. Finally, a PG dose-ranging study was conducted in Zovirax cream base. In all studies, human skin was used and ACV analysed by LC-MS-MS. In the pilot study, the innovator cream delivered 7.5-fold more ACV than the two generics. Superiority was confirmed in the second study against all 10 ACV generic creams. By grouping the creams according to PG content, a relationship to ACV skin permeation was suggested. The PG dose effect was confirmed in the third study. These studies suggest that not all marketed ACV creams are bioequivalent to the clinically proven innovator. Given the magnitude of the differences seen, there is concern over therapeutic inequivalence of generic ACV creams to the innovator cream.