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  1. Abu Bakar MF, Abdul Karim F, Suleiman M, Isha A, Rahmat A
    PMID: 26640502 DOI: 10.1155/2015/936215
    The study aimed to investigate the phytochemical contents, antioxidant and antiproliferative activity of 80% methanol extract of Lepidozia borneensis. The total phenolic and total flavonoid contents were analysed using Folin-Ciocalteu and aluminium chloride colorimetric methods. Antioxidant properties were evaluated by using FRAP, ABTS, and DPPH assays while the effects of L. borneensis on the proliferation of MCF-7 cell line were evaluated by using MTT assay. The results showed that the total phenolic and flavonoid contents were 12.42 ± 0.47 mg GAE/g and 9.36 ± 1.29 mg CE/g, respectively. The GC-MS analysis revealed the presence of at least 35 compounds. The extract was found to induce cytotoxicity against MCF-7 cell line with IC50 value of 47.33 ± 7.37 µg/mL. Cell cycle analysis showed that the extract induced significant arrest at G0/G1 at 24 hours of treatment. After 72 hours of treatment, the proportion of cells in G0/G1 and G2-M phases had decreased significantly as compared to their control. Apoptosis occurred during the first 24 hours and significantly increased to 30.8% after 72 hours of treatment. No activation of caspase 3 was observed. These findings suggest that L. borneensis extract has the potential as natural antioxidant and anticancer agents.
  2. Kavakli K, Smith L, Kuliczkowski K, Korth-Bradley J, You CW, Fuiman J, et al.
    Haemophilia, 2016 May;22(3):381-8.
    PMID: 26823276 DOI: 10.1111/hae.12878
    Limited data are available on optimal prophylaxis regimens of factor IX (FIX) replacements for patients with haemophilia B.
  3. Negrier C, Young G, Abdul Karim F, Collins PW, Hanabusa H, Colberg T, et al.
    Haemophilia, 2016 Jul;22(4):507-13.
    PMID: 26936227 DOI: 10.1111/hae.12902
    BACKGROUND: The paradigm(™) 2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in previously treated haemophilia B patients.

    AIM: These post hoc analyses investigated the bleeding patterns in target joints.

    METHODS: Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used.

    RESULTS: A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm(™) 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm(™) 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm(™) 2 trial. At the end of the paradigm(™) 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints.

    CONCLUSION: Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients.

  4. Négrier C, Abdul Karim F, Lepatan LM, Lienhart A, López-Fernández MF, Mahlangu J, et al.
    Haemophilia, 2016 Jul;22(4):e259-66.
    PMID: 27333467 DOI: 10.1111/hae.12972
    INTRODUCTION: Recombinant factor IX fusion protein (rIX-FP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment.
    AIM: To determine the efficacy and safety of rIX-FP in the perioperative setting.
    METHODS: Subjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX ≤ 2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required.
    RESULTS: Twenty-one, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6-12) rIX-FP injections during surgery and the 14-day postoperative period. Median rIX-FP consumption for orthopaedic surgeries was 87 IU kg(-1) preoperatively and 375 IU kg(-1) overall. No subject developed inhibitors to FIX or antibodies to rIX-FP.
    CONCLUSION: Recombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant FIX.
    KEYWORDS: albumin fusion proteins; factor IX; haemophilia B; orthopaedic surgery; recombinant fusion proteins
  5. Carcao M, Zak M, Abdul Karim F, Hanabusa H, Kearney S, Lu MY, et al.
    J Thromb Haemost, 2016 Aug;14(8):1521-9.
    PMID: 27174727 DOI: 10.1111/jth.13360
    Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys ≤ 12 years. A 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys ≤ 12 years with hemophilia B.

    SUMMARY: Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm(™) 5, enrolled and treated 25 children (aged ≤ 12 years) with hemophilia B (FIX ≤ 2%). Patients were stratified by age (0-6 years and 7-12 years), and received once-weekly prophylaxis with 40 IU kg(-1) nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated.

  6. Tiede A, Abdul-Karim F, Carcao M, Persson P, Clausen WHO, Kearney S, et al.
    Haemophilia, 2017 Jul;23(4):547-555.
    PMID: 28233381 DOI: 10.1111/hae.13191
    INTRODUCTION: Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (FIX) with an extended half-life developed for routine prophylaxis and the prevention and treatment of bleeding episodes in patients with haemophilia B.

    AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP.

    METHODS: Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL-1) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg-1or 40 IU kg-1in adolescents/adults and 40 IU kg-1in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed.

    RESULTS: Incremental recoveries were 0.02 (IU mL-1)/(IU kg-1) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL-1for adolescents/adults and 0.17 IU mL-1for children at steady-state after weekly dosing at 40 IU kg-1. The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL-1at all times and 6.4 days week-1in children.

    CONCLUSION: N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

  7. Ramli R, Che Man Z, Nordin R, Abdul Karim F, Rashdi MF, Oxley J, et al.
    Traffic Inj Prev, 2016 Sep;17 Suppl 1:79-85.
    PMID: 27586107 DOI: 10.1080/15389588.2016.1203428
    OBJECTIVE: Vietnamese spend hours travelling on the road using their motorcycles. Their helmets are exposed continuously to sunlight and rain. The objectives of this study were to determine the association between the effect of photo-oxidative degradation (POD) of the outer shells and helmet age on helmet damage. The micro-structural change of the outer shell was also investigated.

    METHODS: This was a prospective, cross sectional study recruiting injured motorcyclists from Hanoi, Vietnam hospital. The participants were interviewed by a trained researcher. The participants' helmets were collected post-crash. Initially, the helmets were examined for their type and external characteristics. A 3 cm × 3 cm cut was made on the helmet in the impacted and non-impacted areas (control). These areas were investigated for evidence of POD and presence of micro-cracks and material disintegration. 50 participants were enrolled. Sources of information included questionnaire and laboratory analyses. The helmet factors of interest were age of the helmet, exposure of helmet to sunlight and rain (duration/day) and history of previous impact. Laboratory analyses included Fourier Transform Infra Red (FTIR) for degradation and scanning electron microscopy (SEM) for micro-structural examination.

    RESULTS: Majority of the helmets was the open-face type, 40 (80.0%). 31 (62.0%) helmets aged less than three years (LTY) and 19 (38.0%) were three years old or more (MTY). 19 (61.3%) of the LTY helmets and 12 (63.2%) MTY helmets showed evidence of POD. The duration of helmet exposure to sunlight was between 93 to 6570 hours (mean 2347.74 hours; SD 1733.39). The SEM showed 15 helmets (30%) with micro-fractures, 21 helmets (42.0%) with material disintegration. Prolonged uv exposure to the ABS helmets resulted in changes in the helmet material in the form of material disintegration and microcracks and this association was statistically significant (p = 0.03).

    CONCLUSION: POD occurs due to routine exposure to the ultraviolet light. Prolonged uv exposure affects outer shell surface material integrity.

  8. Stasyshyn O, Djambas Khayat C, Iosava G, Ong J, Abdul Karim F, Fischer K, et al.
    J Thromb Haemost, 2017 04;15(4):636-644.
    PMID: 28166608 DOI: 10.1111/jth.13647
    Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile.

    SUMMARY: Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A.

  9. Tiede A, Abdul Karim F, Jiménez-Yuste V, Klamroth R, Lejniece S, Suzuki T, et al.
    Haematologica, 2020 Apr 23.
    PMID: 32327501 DOI: 10.3324/haematol.2019.241554
    During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. Maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and bleed information from patient diaries. Each patients' time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and bleed number (from patient diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (N=187; 815 patient-years' exposure), factor VIII activity was predicted to reach >1% for 85.64% of the time. Annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase, and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. Target trough and prophylactic regimen should consider patient age, joint disease activity, and other bleeding risk determinants.
  10. Giangrande P, Abdul Karim F, Nemes L, You CW, Landorph A, Geybels MS, et al.
    J Thromb Haemost, 2020 Sep;18 Suppl 1:5-14.
    PMID: 32544297 DOI: 10.1111/jth.14959
    BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated human recombinant factor VIII with a half-life of ~1.6-fold of standard FVIII products. pathfinder2 (NCT01480180) was a multi-national, open-label trial of N8-GP in previously treated adolescent and adult patients with severe hemophilia A.

    OBJECTIVE: We report end-of-trial efficacy and safety of N8-GP from pathfinder2.

    METHODS: pathfinder2 main phase and extension phase part 1 results have been previously reported. During extension phase part 2, patients could switch from N8-GP prophylaxis 50 IU/kg every fourth day (Q4D) or 75 IU/kg once weekly (Q7D), depending on bleeding status. Extension phase part 2 collected long-term safety and efficacy data for all regimens until trial end (first patient in main phase, 30 January 2012; trial end, 10 December 2018).

    RESULTS: Overall, 186 patients were exposed to N8-GP for up to 6.6 years (median 5.4 years). The estimated annualized bleeding rate (ABR) was 2.14 (median 0.84) for the Q4D prophylaxis arm and 1.31 (median 1.67) for the Q7D prophylaxis arm. Nearly 30% of patients experienced zero bleeds throughout the entire duration of the trial, the hemostatic response was 83.2% across all treatment arms, and patient-reported outcomes were maintained or slightly improved. No safety concerns were detected.

    CONCLUSION: Data from the completed pathfinder2 trial, one of the largest and longest-running clinical trials to investigate treatment of severe hemophilia A, demonstrate the efficacy and safety of N8-GP in previously treated adolescent and adult patients.

  11. Periayah MH, Halim AS, Mat Saad AZ, Yaacob NS, Hussein AR, Abdul Karim F, et al.
    Thromb. Res., 2015 Sep;136(3):625-33.
    PMID: 26254703 DOI: 10.1016/j.thromres.2015.07.027
    Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD.
  12. Ramli R, Abdul Rahman R, Abdul Rahman N, Abdul Karim F, Krsna Rajandram R, Mohamad MS, et al.
    J Craniofac Surg, 2008 Mar;19(2):316-21.
    PMID: 18362705 DOI: 10.1097/SCS.0b013e318163f94d
    Motorcycle casualties represent significant number in road traffic accidents in Malaysia, and among all the injuries, facial injuries pose many significant problems physiologically, functionally, and aesthetically. The aim of this study was to analyze the pattern of maxillofacial as well as other injuries in motorcyclists who were seen at Hospital Universiti Kebangsaan Malaysia.Patients' records from January 2004 to December 2005 were reviewed. Data related to demographics, vehicle/object involved in collision, involvement as a rider or pillion, whether a helmet was worn or not, location of injuries on the face/facial bones, and other associated injuries were collected.A total of 113 cases of motorcycle accidents were recorded; 106 males and 7 females were involved. Mean age was 25.8 years. Among all the races, Malay had the highest involvement (72.3%), followed by Chinese (14.3%), Indians (8.9%), and others (5.4%). The types of collision were either a single-vehicle collision (i.e., skidded) or with another vehicle/s or object (e.g., tree, stone, or lamppost). The injuries were mainly seen on the lower face (46.9%) followed by midface (25.7%) and a combination of the midface and lower face (15%) and others (12.4%). The most frequent other associated injuries recorded were orthopedic and head injuries.
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