Efficacy Of Replacement Therapy Research Articles

Impact of Replacement Therapy on Pregnancy Outcomes in Hemophilia Carriers: A Historical Cohort Study in Saudi Arabia.

This retrospective cohort study evaluates the safety and efficacy of replacement therapy with regard to pregnancy outcomes in hemophilia carriers. Hemophilia carriers face elevated bleeding risks during pregnancy, necessitating meticulous management, including replacement therapy with clotting factors. This research examines the records of 64 pregnant hemophilia carriers at King Fahad Medical City, Riyadh, from January 2010 to December 2023, analyzing their demographic details, hemophilia type and severity, replacement therapy specifics, and pregnancy outcomes. The study found that 62.5% of the participants had hemophilia A, with 43.8% categorized as severe. Most subjects (87.5%) received recombinant factor VIII at a median dosage of 30 IU/kg weekly. Adverse pregnancy outcomes included gestational hypertension (15.6%), preterm labor (18.8%), and postpartum hemorrhage (12.5%). The cesarean section rate was 28.1%. Neonatal outcomes were generally favorable, with median birth weights at 3100 g and mean Apgar scores of 8.2 and 9.1 at 1 and 5 min, respectively. Logistic regression analysis revealed no significant association between adverse events and therapy type or dosage, though a trend towards significance was noted with once-weekly administration (p = 0.082). The study concludes that replacement therapy is a viable method for managing hemophilia in pregnant carriers, leading to generally favorable maternal and neonatal outcomes. However, it underscores the importance of individualized treatment plans and close monitoring to effectively manage the risks associated with hemophilia during pregnancy.

The role of two dimensional speckle tracking echocardiography in determining cardiac prognosis and monitoring enzyme replacement therapy efficacy in patients with Anderson-Fabry disease.

The role of two dimensional speckle tracking echocardiography in determining cardiac prognosis and monitoring enzyme replacement therapy efficacy in patients with Anderson-Fabry disease.

The Impact of Thyroid Function on Human Reproduction: A Comprehensive Mini-Review

Thyroid disorders are common endocrine disorders affecting millions of individuals worldwide. The thyroid gland plays a crucial role in regulating various physiological processes, including reproductive health. This scientific article aims to provide a comprehensive review of the current understanding of the impact of thyroid function on human reproduction. We discuss the physiological role of thyroid hormones, the effects of thyroid dysfunction on fertility, pregnancy outcomes, and the management of thyroid disorders in the context of reproductive health. The effect of hypothyroidism on human embryo’s implantation as well as the replacement therapy efficacy in reversal detrimental effects are discussed. Keywords: Thyroid; Thyroid dysfunction; Human reproduction; Fertility; Pregnancy outcomes; Thyroid hormones; Hypothalamic-pituitary-thyroid axis; Reproductive health; Preconception care; Pregnancy management; Embryo’s implantation

Особенности оказания трансфузиологической поддержки пациентам с гипопродукционной тромбоцитопенией в условиях дневного стационара ГБУЗ НСО «Новосибирский клинический центр крови»

Introduction. Hypoproductive thrombocytopenias caused by insufficient platelet formation in the bone marrow are usually a manifestation of the underlying process characterized by inhibition of thrombocytopoiesis. They accompany aplastic anemia, acute leukemia, primary myelofibrosis, myelodysplastic syndrome, may be the result of tumor metastasis to the bone marrow, with the substitution of the megakaryocyte lineage, as well as a complication of radiation therapy and chemotherapy. Aim. To analyze the features of the provision of transfusion support to patients with hypoproductive thrombocytopenia due to oncological or hematological diseases in the day hospital at the Novosibirsk Clinical Blood Center (NCBC). Materials and methods. The study included 222 patients of the NCBC day hospital who underwent replacement therapy with platelet concentrate to correct thrombocytopenia and hemorrhagic syndrome for the period 2017–2022. Results. Correction of thrombocytopenia due to malignant neoplasms (solid tumors) was performed in 69 patients and due to hematological diseases – in 153 patients. The average number of doses of platelet concentrate was 3.7 ± 2.4 for patients with solid tumors; the clinical efficacy of replacement therapy was achieved in this group of patients in all cases. For patients with hematologic-related thrombocytopenia, the average number of doses of platelet concentrate was 3.2 ± 1.3; the clinical efficacy in this group of patients was achieved in 131 cases out of 153. Conclusion. Replacement therapy with blood components in transfusion-dependent and comorbid patients in a day hospital allows in most cases (85.6%) to carry out effective clinical correction of thrombocytopenia and achieve complete reverse of manifestations of hemorrhagic syndrome (100% of cases).

Application Value of a New Lung Ultrasound Scoring Method in Neonatal Respiratory Distress Syndrome Treatment

The study was aimed at exploring the clinical value of a 14-zone lung ultrasound scoring (LUS) method in treating neonatal respiratory distress syndrome (NRDS) with pulmonary surfactant (PS) and determining the timing of mechanical ventilation (MV). In this study, 88 neonates with NRDS who received PS replacement therapy were selected. We applied a new 14-zone LUS method before and 12, 24, 48 and 72 h after PS treatment to explore the clinical value of assessing PS replacement therapy efficacy in NRDS. Additionally, 67 patients with NRDS under MV received LUS during extubation. The receiver operating characteristic curve was used to analyze the diagnostic efficacy of LUS in the timing of extubation. LUS score was inversely associated with PS treatment. At 12 h after PS, only the 14-zone LUS method was significantly different (t=4.08, p < 0.05) as compared with before PS, which was consistent with the change on chest x-ray (CXR); the other LUS methods did not differ (p > 0.05). The 14-zone LUS method exhibited better diagnostic performance for withdrawal time. A score of 41.0 points was used as the diagnostic threshold to predict the risk of withdrawal failure, with an area under the curve of 0.955, sensitivity of 92.4% and specificity of 93.8%. The new 14-zone LUS method improved scoring in the early efficacy of PS and had good diagnostic efficiency for timing the removal of MV in NRDS.

Non-Neuropathic Form of Mucopolysaccharidosis Type II: Clinical Cases

Background. Mucopolysaccharidosis (MPS) type II is an X-linked hereditary disease from the lysosomal storage diseases group. The absence or malfunctioning of the iduronate-2-sulfatase enzyme leads to disruption in glycosaminoglycans (GAG) degradation. The GAG accumulation in lysosomes leads to dysfunction of various tissues and organs. There are neuropathic (severe) and non-neuropathic (relatively mild) forms of the disease. Early diagnostics of non-neuropathic form of MPS II is quite difficult due to slow disease progression and because early symptoms are hard to notice. Clinical Cases Description. This article describes three clinical cases of non-neuropathic form of MPS II. Patients had following symptoms: non-rough facial features changes (gargoylism), hepatomegaly, hernias, recurrent otitis, non-inflammatory joint contractures, and cardiac valves involvement. The children height conformed to the age or was little lower than reference values. The described form of MPS II is characterized with the absence of cognitive impairment. Conclusion. Enzyme replacement therapy efficacy has been shown via disease progression slowing down, significant improvement of clinical symptoms and quality of life.

In silico comparison of pharmacokinetic properties of three extended half-life factor IX concentrates

PurposePharmacokinetic (PK) differences between the extended half-life (EHL) factor IX (FIX) concentrates for hemophilia B exist, which may influence hemostatic efficacy of replacement therapy in patients. Therefore, we aimed to evaluate the PK properties of three EHL-FIX concentrates and compare them to a standard half-life (SHL) recombinant FIX (rFIX) concentrate.MethodsActivity-time profiles of PEGylated FIX (N9-GP), FIX linked with human albumin (rIX-FP), FIX coupled to human IgG1 Fc-domain (rFIXFc), and SHL rFIX were simulated for 10,000 patients during steady-state dosing of 40 IU/kg once weekly (EHL-FIX) and biweekly (rFIX) using published concentrate specific population PK models.ResultsHalf-lives were respectively 80, 104, and 82 h for N9-GP, rIX-FP, and rFIXFc versus 22 h for rFIX. Between the EHL concentrates, exposure was different with area under the curve (AUC) values of 78.5, 49.6, and 12.1 IU/h/mL and time above FIX target values of 0.10 IU/mL of 168, 168, and 36 h for N9-GP, rIX-FP, and rFIXFc, respectively. N9-GP produced the highest median in vivo recovery value (1.70 IU/dL per IU/kg) compared with 1.18, 1.00, and 1.05 IU/dL per IU/kg for rIX-FP, rFIXFc, and rFIX, respectively.ConclusionsWhen comparing EHL products, not only half-life but also exposure must be considered. In addition, variation in extravascular distribution of the FIX concentrates must be taken into account. This study provides insight into the different PK properties of these concentrates and may aid in determination of dosing regimens of EHL-FIX concentrates in real-life.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries. Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 19 March 2020. Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. No randomized controlled trials matching the selection criteria were eligible for inclusion. No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

SUN-LB003 The Steroid Sulfatase Dictates the Hormone Replacement Therapy Efficacy of the Conjugated Equine Estrogen

Conjugated equine estrogen (CEE) is widely used in hormone replacement therapy in postmenopausal women. Extracted from pregnant mare urine, CEE is composed of nearly a dozen estrogens existing in their inactively sulfated forms. The goal of this study is to determine whether the steroid sulfatase (STS), the enzyme responsible for steroid desulfation and re-activation, is the major contributor to the hormone replacement therapy effect of CEE. To study the role of STS in CEE’s effect, we performed estrogen responsive element (ERE) reporter gene assay, real-time PCR and UPLC/MS-MS to measure the STS dependent estrogenic activity of CEE in HepG2 cells and human primary hepatocytes (HPH). The effect of STS on the estrogenic activity of CEE was also valuated in vivo by using the STS transgenic mice. Our results showed that the activity of ERE reporter was induced by CEE in a STS-dependent manner, because the estrogenic activity of CEE was attenuated by genetic or pharmacological inhibition of STS. In HepG2 cells and HPH, the estrogenic activity of CEE was enhanced by inflammation via the induction of endogenous STS gene expression. The inflammatory responsive estrogenic activity of CEE in return can attenuate inflammation due to the anti-inflammatory activity of estrogens. In vivo, STS transgenic mice exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus. In conclusion, our results revealed an essential role of STS in mediating the hormone replacement activity of CEE. Cautions need to apply when CEE is used in patients of chronic inflammatory disease, because these patients may have heightened sensitivity to CEE due to the inflammatory induction of STS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

“Prevalence of Inhibitors in Hemophilia Patients and its Clinical Implications”: A Study of 276 Patients in Western India

Introduction: Hemophilia is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII) in hemophilia A (HA) or factor IX (FIX) in hemophilia B (HB). Accurate diagnosis of hemophilia by factor assay to demonstrate deficiency of FVIII or FIX is essential for appropriate management. Inhibitor development results in partial or complete lack of the efficacy of replacement therapy, and it makes the management of patients more difficult with an increased risk of morbidity, serious bleeding, and disability, resulting in a substantial impact on patient's quality of life and health-care costs, compared to patients without inhibitors. Aims and Objectives: To assess the incidence of inhibitor development in HA and HB patients along with its consequences. Materials and Methods: The present study was carried out at a tertiary care teaching hospital in Western India. A total of 276 patients of hemophilia were included in the study. FVIII, FIX, and inhibitor screening were carried out in all patients sample as routine testing. Patients who were found positive in inhibitor screening were further evaluated for quantitative assay (Bethesda assay). Results: Out of total 276 patients, 243 patients of HA and 33 patients of HB were observed. The incidence of inhibitor development is 20.57% in HA and 6.06% in HB. The maximum number of patients and maximum number of inhibitors was between the age group of 11 and 30 years. There was more number of patients with severe disease as compared to mild and moderate forms. The concentration of inhibitor >5 BU was seen in 76% of HA patients and 100% of HB patients with inhibitor. Sixty-one patients came for follow-up. In three patients, inhibitor disappeared. The incidence of complications was more in patients who had developed inhibitor which increases the cost of treatment and increases the social suffering of the patients. Conclusion: Inhibitor development affect the severity and treatment of the disease significantly and there by increases the suffering and cost to the patient.

Disturbances in melatonin secretion and the efficacy of replacement therapy in sleep disorders

The review presents data on the dependence of endogenous melatonin synthesis on the time of day, age, pineal gland size, lighting conditions, administration of beta-blockers and a number of other medications. The results of studies on parasecretion and efficacy of exogenous melatonin use in sleep-wake cycle disturbances, insomnia, neurodegeneration, diabetes mellitus and oncological diseases are discussed.

Atg5flox-Derived Autophagy-Deficient Model of Pompe Disease: Does It Tell the Whole Story?

Defective autophagy is a prominent feature in Pompe disease, an inherited deficiency of acid alpha-glucosidase. An absence of this enzyme leaves cells unable to digest glycogen in the lysosome. The major tissues affected by glycogen accumulation are cardiac and skeletal muscles. The currently available enzyme replacement therapy (ERT) works well in cardiac, but not in skeletal muscle. The disappointing response to therapy is linked to the presence of large areas of autophagic debris in muscle fibers.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 16 February 2017. Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. No randomized controlled trials matching the selection criteria were eligible for inclusion. No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies.Date of last search: 27 January 2015. Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. No randomized controlled trials matching the selection criteria were eligible for inclusion. No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

Ключове питання замісної терапії акушерських кровотеч — фібриноген

У статті на підставі ретроспективного аналізу історій пологів жінок, які перенесли різні за тяжкістю акушерські кровотечі, вивчається рівень фібриногену у строк пологів, а також на першу добу після кровотечі. З огляду на рівні фібриногену проводиться оцінка ефективності інфузійно-трансфузійної замісної терапії, аналізується частота виникнення показань до призначення препаратів, що містять фібриноген (кріопреципітат, концентрат фібриногену).

Rare Genetic Variants Of The Protein-Coding Area Of The Genome and The Risk Of Inhibitor Development: An Exome-Sequencing Study Of 28 Patients With Severe Hemophilia A

BackgroundThe development of inhibitors directed against coagulation factor VIII (FVIII) is a common and severe complication of hemophilia replacement therapy, occurring in up to one third of patients with severe hemophilia A (HA). Inhibitors impair efficacy of replacement therapy, rendering management of bleeds difficult and prophylaxis unfeasible. There is evidence that various genetic risk factors play an important role in inhibitor development; in particular, F8 mutation type. However, patients sharing the same mutation may have different inhibitor risk suggesting the presence of other genetic risk factors. Because most variants in the genome are rare and since variants within the protein-coding area (i.e. the exome) are expected to have a strong effect on phenotypes, we designed an exome sequencing study with the goal of assessing the role of rare, functional variants of the exome in inhibitor development. MethodsA total of 28 HA patients (8 pairs of related individuals and 12 unrelated subjects) underwent sequencing of the exome on Illumina HiSeq 2000 platforms following capture by hybridization on VCRome V2.1 liquid probes. Patients were selected among those followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center (Milan, Italy). Inclusion criteria were (a) diagnosis of severe HA, with plasmatic FVIII activity below 1%, and the presence of intron 22 or intron 1 inversion of F8. Mapping of reads onto the human reference genome (hg19/NCBI build 37.1) was performed by BWA and variant calling by GATK. We restricted our analysis to functional variants (i.e. missense, nonsense, splice-site variants and coding indels) that are rare in Caucasian populations (i.e. with a minor allele frequency below 0.5% in the European Americans of the exome variant server). For association analysis, we carried out burden-testing association using (a) SKAT-O test, as well as gene-based association by (b) Fisher's exact testing and (c) mixed-effects logistic regression analysis adjusted for familial clustering. The lists of top 100-genes and genes with p<0.05 identified with each approach were studied for their overlapping and enrichment for immunity genes (immunome knowledge base). ResultsA total of 1.9 billion reads were generated to sequence the exome of 28 HA patients at an average coverage of 77X (range: 49-96X). Coverage was homogeneous, with an average of 95% (range: 93-96%) of the 43 Mb of target being covered by at least 10 high-quality reads. On average, patients had 695 (range: 569-838) rare, functional variants in their exome, with a total of 6654 genes having at least one variant of that type in at least one individual. Association analysis revealed a total of 252 genes associated with inhibitor development at p<0.05 with SKAT-O test, 45 with Fisher's exact test and 19 with mixed-effects logistic regression. Genes associated with inhibitor development using different tests showed good overlapping, especially Fisher's exact test and mixed-effects logistic regression (Figure). A total of 8 genes were associated with inhibitors using all three techniques (i.e. RHBG, CEACAM7, CTAGE6P, SEC22B, C5orf49, DAB1, SORL1, PKD1L1). These encode proteins involved in cell-adhesion, ammonium transportation, vesicle trafficking and endocytosis. The lists of associated genes showed slight (if any) enrichment for genes of the immune system using SKAT-O (odds ratio [OR]: 1.3; 95% confidence interval [CI]: 0.7-2.3) and mixed-effect logistic regression (OR: 2.6; 95% CI: 0.3-11.0), and no enrichment at Fisher's exact test (OR: 1.0; 95% CI: 0.1-4.0). [Display omitted] Summary/ConclusionsOur exome-sequencing analysis highlights genes at which rare, functional variants may be associated with the development of inhibitors in patients with HA. Disclosures:Lotta:Bayer Health Care: Bayer Hemophilia Award 2012 - research funding Other. Peyvandi:Bayer Health Care: Bayer Hemophilia Award 2011 - research funding Other.

Morphological and functional alterations of small intestine in chronic pancreatitis.

The small intestine in chronic pancreatitis has not been investigated yet thoroughly. It would be important to understand fat metabolism in the course of this disease and could be explained if the small intestine has some pathological conditions and, due to this reason, pancreatic enzyme substitution does not work in all patients.To investigate the pathophysiology of small intestine in chronic pancreatitis and to show the reason why in some cases pancreatic enzyme substitution does not work properly.In the process of the study 33 chronic pancreatitis patients have been examined.The control group includes 30 subjects without chronic pancreatitis similar for age, sex and alcohol consumption to the patients with chronic pancreatitis patients.Aspiration biopsy of jejunum mucosa followed by histological examination and investigation of intestinal enzymes by aspiration has been performed.Metabolism at membranic level has been studied by enzymatic activity of amylase and lipase in the small intestine. Production of enzymes (monoglyceride lipase, lactase, saccharase, maltase, glycyl-l-leucine dipeptidase) promoting metabolism in enterocytes has been estimated as to their activity in homogenates of jejunum mucosa samples. Participation of mucosa in intestinal digestion has been assessed by alkaline phosphatase activity in a secretory chyme from proximal portion of jejunum. Absorptive capacity of jejunum was evaluated by D-xylose test results. DNA, lysozyme, immunoglobulin contents of chyme have also been calculated and bacteriological study of chyme has been also performed.Secondary enteritis, accompanied by moderate dystrophic changes of mucous membrane, thinning of limbus, and decrease of Paneth cell mitotic index, was found to occur in chronic pancreatitis patients. Enteritis is followed by changes in enzymatic processes in the sphere of membrane and intestinal digestion, decrease of absorption, accelerated desquamation of epithelium, fall in local immunity and development of bacterial overgrowth syndrome.Existence of secondary enteritis and bacterial overgrowth syndrome validates lack of enzyme replacement therapy efficacy in some chronic pancreatitis patients with pancreatic insufficiency. To optimize treatment in such cases it is important to perform small intestine decontamination and escalate enzyme preparation dosage.

Terapia de reemplazo enzimático en la forma infantil de la enfermedad de Pompe: experiencia de un caso con 7 años de seguimiento en Argentina

The infantile form of Pompe disease drives children to death before the first year of life due to cardiomyopathy and respiratory insufficiency. We present the seven-year follow-up experience with enzyme replacement therapy on a child with Pompe disease, being the longest follow-up in the country. The treatment was well tolerated without adverse reactions. The echocardiographic and electrocardiographic parameters clearly improved during the first year and remain stable. Motor milestones (like rolling over or sitting down without support) were initially achieved, but, after the third year were getting lost. The average age of ventilator dependence was also delayed (16 months). The 7-year old patient remains alive with severe generalized muscle weakness. The child notably overcame the average age of survival and onset of ventilator dependence. Although the cardiovascular improvement was clear, enzyme replacement therapy efficacy on skeletal muscle was limited in this patient.

Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks

Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981).

Pharmacokinetics of Factor VII

Abstract 2259 Introduction:In Congenital Bleeding Disorders (CBD), efficacy of Replacement Therapy (RT) can be indirectly measured on the basis of pharmacokinetic (PK) methods. Therapeutic concentrations of clotting factors in the blood-stream at a given time depend on the dose and frequency of RT and the fall off patterns specific for each clotting factor (i.e. PK properties). The issue of the frequency of RT administration is particularly relevant in Factor VII (FVII) deficiency, a CBD characterized by the lack of a rare protein with a very short half-life. Recombinant FVIIa (rFVIIa), plasma-derived FVII (pdFVII) concentrates and Fresh Frozen Plasma (FFP) are used for on-demand or prophylaxis replacement despite reported half-lives in the range of 2–5 hours. Very limited information is available with reference to the pharmacokinetic parameters of infused FVII in FVII deficiency. The same holds for the In Vivo Recovery (IVR). In this study, we evaluated the PK of rFVIIa in 11 severe (FVIIc <2%) FVII deficient patients. Further, evaluation of “incremental” IVR was performed in 116 patients with a FVII deficiency (90 for rFVIIa, 19 for pdFVII concentrates and 7 for FFP). Methods & Results:Eleven severe FVII-deficient individuals in the non-bleeding state were given rFVIIa doses ranging from 16 to 24 μg/Kg/bw (mean 19.7, median 20). Pharmacokinetic parameters of rFVIIa were analyzed with reference to FVIIc post-infusion levels. Analyses of the PK parameters are detailed in Tab. 1. In Tab. 2 results regarding the IVR analyses of rFVIIa, pdFVII and FFP are reported, on the basis of FVIIc 15' after replacement. IVR data were also evaluated with reference to the baseline FVIIc, age and FVII mutation zygosity.Tab. 1Pharmacokinetic parameters of rFVIIa in 11 patients with severe FVII deficiencyCorr_XYTerminal HL (h)AUC (U*h/ml)Vz (ml/Kg)CL (ml/h/Kg)MRT (h)T1/2 (h)Vss (ml/Kg)Mean0.994.5190378.8215.623.282.7351.77Median0.993.581,9882.670.512.862.081.56SD0.0262.472,055124.6626.362.041.4283.59Min. value−12.0813.90.410.132.782.010.66Max value0.9011.157,197331679.886.86225Tab. 2In Vivo Recovery of FFP, pdFVII concentrates and rFVIa.ProductIncremental IVR (U/dl/U/Kg)Cases(n)Mean (SD)Median (range)Kruskal-wallis test (ordinal Anova)1. FFP70,62 (0,28)0,58 (0,33–1,13)P<0.0001 POST hoc analysis: (1) FFP differs from pdFVII (2) rFVIIa differs from pdFVII (3) pdFVII differs from FFP and pdFVII2. pdFVII192,5 (1,28)2,27 (0,56–6)3. rFVIIa900,59 (0,54)0,46 (0,02–3,03)All1160,91 (0,99)0,57 (0,02–6) Conclusions:PK data are characterized by an optimal correspondence between FVIIc levels and time; data variability is ample considering that all individuals were adults or teen-agers. Terminal half-life appeared longer than the Mean Residence Time (MRT) or T1/2, a data that can be interpreted as a reduction of the factor flow from the plasma pool to the extravascular space at the end of the fall off curve; this is confirmed by the Apparent volume of distribution based on the terminal phase (Vz) that is higher than the Apparent Volume of distribution at equilibrium (Vss). MRT and T1/2 are in keeping with previous studies and appear lower than those already reported for the pdFVII concentrates. Quite variable is also the Clearance (CL) showing that metabolic degradation and/or FVIIa vascular uptake greatly differ among patients. The latter aspect points towards the need for a CL individualized evaluation for patients who are eligible for continuous infusion protocols. Incremental IVRs of rFVIIa and FFP were lower (p< 0.001) than those calculated for the pdFVII concentrates. The difference between the recoveries of rFVIIa and pdFVII can either be ascribed to the FVIIc assay (only FVIIa assayed in the case of rFVIIa administration, FVII zymogen and FVIIa assayed in the case of pdFVII concentrates), to a more rapid disappearance rate of FVIIa from the vascular compartment or, finally, to a more rapid uptake by the FVIIa receptors (TF on the pericytes and the PC receptor on the endothelial cells). No difference was found between IVRs in children and adults nor between individuals with baseline FVIIc <2% or ≥ 2%. Also, no differences were found between patients homozygous or compound heterozygous for FVII gene lesions. Disclosures:No relevant conflicts of interest to declare.