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PubMed1995

A monoclonal antibody that blocks the complement regulatory activity of guinea pig erythrocytes and characterization of the antigen involved as guinea pig decay-accelerating factor.

MCA44 is a mAb with the capacity to sensitize neuraminidase-treated guinea pig E for hemolysis by homologous guinea pig C, and the Fab fragments of this mAb could also sensitize guinea pig E interfering with the function of a membrane inhibitor of C on guinea pig E. Using an immunosorbent column to which MCA44 was coupled, the antigenic molecule termed 44Ag was purified from the glycoprotein fraction extracted from E membranes. C intermediate sheep E treated with guinea pig C1 and C4 after sensitization with Ab (EAC14b cells) lost the ability to generate C3 convertase with C2 after incubation with 44Ag. Treatment of guinea pig E and PBL with phosphatidyl-inositol specific phospholipase C (PIPLC) partially removed 44Ag, as determined by flow cytometric analysis after immunofluorescence staining with MCA44. However, 125I-labeled 44Ag adsorbed to human E was efficiently removed by PIPLC treatment with a slight reduction in M(r). The 44Ag purified on an immunosorbent column showed three bands on SDS-PAGE. However, partial N-terminal amino acid sequences of the 55-kDa, 70-kDa, and 88-kDa bands under nonreducing conditions were identical and the sequence was 55% homologous to the N-terminal sequence of human decay accelerating factor (CD55). Intracutaneous administration of MCA44 or its F(ab')2 fragment resulted in increased capillary permeability, even after 3 days, as determined by the appearance of Evans blue spots after i.v. administration of the dye. Because control Abs including anti-class I-MHC did not cause such increased capillary permeability, the increase in permeability caused by MCA44 was likely induced by blocking the function of 44Ag in vivo, indicating a crucial role for these molecules in preventing over-activation of C at the site.

Amino Acid Sequence↗
PubMed1984

Selective determination of alpha 2-plasmin inhibitor activity in plasma using chromogenic substrate.

In determination of antiplasmin activity of alpha 2-plasmin inhibitor (alpha 2 PI) using an amidolytic method, alpha 2-macroglobulin (alpha 2 M) in concentrations present in normal plasma inhibits the cleavage of chromogenic substrates by plasmin even if the reaction time between alpha 2M and plasmin is shortened as much as possible. The purpose of this study was to develop a new method to assay alpha 2 PI selectively with the chromogenic substrate S-2251 using an end-point method. The antiplasmin activity of alpha 2 M was destroyed by the addition of methylamine hydrochloride. In a case of congenital alpha 2 PI deficiency, antiplasmin activity determined with the previous method without the addition of methylamine was 20% of normal plasma, whereas the results obtained using this newly developed method was 5%. A statistically significant correlation between alpha 2 PI levels determined with this method and with a single radial immunodiffusion method was observed in plasma samples collected from 40 healthy subjects and 11 patients with disseminated intravascular coagulation (DIC). In two cases of DIC, in which markedly depleted levels of alpha 2 PI and normal concentrations of alpha 2 M were observed, antiplasmin activities measured without the addition of methylamine were higher than the ones measured immunologically, whereas the results obtained with the method described here were in accordance with the antigenicities of alpha 2 PI.

Aged↗
PubMed2001

Expression of C1 esterase inhibitor by the baculovirus expression vector system: preparation, purification, and characterization.

C1 esterase inhibitor (C1INH) is an important regulator of the classical complement pathway. Hereditary deficiency of C1INH causes angioedema of the skin, gut, and respiratory tissues that may be fatal. C1INH replacement therapy may be lifesaving for patients with this disorder. The objective of this study was to evaluate the use of the baculovirus expression vector system for mass producing biologically active human recombinant (rC1INH). A recombinant baculovirus was constructed coding the human native (nC1INH) sequence under control of the polyhedrin promoter. Spodoptera frugiperda Sf-9 insect cells were infected with this recombinant baculovirus in a medium-scale (10-L) bioreactor to produce rC1INH with a specific activity of 45 U/mg. Purification of rC1INH from the culture harvested at 60 h postinfection yielded 5.9 microg rC1INH/mL supernatant of a 75-kDa product with a specific activity of 31,000 U/mg purified rC1INH compared to 71,000 U/mg purified nC1INH from human serum using the same procedure. This rC1INH was about 25 kDa smaller than nC1INH, suggesting that Sf-9 cells express underglycosylated rC1INH. Glycan analysis showed that both N-glycan and O-glycan chains were present in rC1INH. The N-glycan chains, released using PNGaseF and fluorescently labeled, were analyzed using exoglycosidase treatment and capillary electrophoresis. Their high-mannose structure was consistent with the known failure of the insect cell glycosylation pathway to afford the fully elaborated biantennary structures found on human native nC1INH.

Animals↗
PubMed1989

Regulation of C1-inhibitor synthesis by interferons and other agents.

C1-inhibitor (C1-inh) is synthesised and secreted by at least four cell types: hepatocytes, mononuclear phagocytes, fibroblasts and umbilical vein endothelial cells. The production of this protein by monocytes/macrophages and Hep G2 cells has been studied in great detail. Environmental factors alter C1-inh synthesis by these cells. A number of agents which inhibit monocyte C1-inh production (such as histamine, PGE2 C5a des arg and serum treated immune complexes) bind to membrane receptors, activate adenylate cyclase, elevate intracellular cAMP and activate cAMP-dependent protein kinase. Elevation of monocyte cAMP levels is associated with decreased C1-inh secretion by these cells and reduced C1-inh mRNA levels. These changes can be seen within 8 hours of exposure. Stimulation of monocyte C1-inh synthesis occurs after the addition of agents which induce the formation of sodium ion and calcium ion channels, activate the phosphatidyl inositol cycle and activate protein kinase C (immune-complexes, carbamylcholine and phenylephrine). Agents which act directly on protein kinase C (phorbol myristate acetate) also stimulate C1-inh synthesis. Amongst the most potent stimulators of monocyte and Hep G2 C1-inh synthesis are the interferons (Ifns) Ifn alpha, Ifn beta and Ifn gamma. These are known to bind to specific receptors on cells (Ifn alpha and beta binding to Type I Ifn receptors and Ifn-gamma binding to type II Ifn receptors). At least two mechanisms by which Ifn receptor-ligand interaction elicit their effects exist. These are: 1) binding of an activated receptor transducer/regulatory component to specific DNA sequences on Ifn sensitive genes; 2) the activation of protein kinase C and binding of its regulatory components to specific DNA sequences. Ifn alpha, beta and gamma cause a dose related increase in monocyte and Hep G2 cell C1-inh mRNA abundance and protein synthesis. Ifn-gamma is the most potent of the interferons on monocyte C1-inh synthesis. Ifn alpha and beta being less effective but equipotent. These cytokines elicit their maximum effect on monocyte C1-inh synthesis after 1-2 hours treatment. This rapid stimulation of monocyte C1-inh synthesis suggests that this increases the transcription of the C1-inh gene. After removal of Ifns from monocytes the elevated C1-inh mRNA levels subside towards control levels of expression in Ifn alpha and beta-treated cells but remain elevated in Ifn-gamma-treated monocytes. This binding suggests that Ifn-gamma alters the stability of C1-inh mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Hepatocellular↗
PubMed1994

Transcriptional regulation of the C1 inhibitor gene by gamma-interferon.

Treatment of the hepatoma cell line, Hep3B, with gamma-interferon (IFN) enhanced expression of C1 inhibitor (C1INH) mRNA, primarily due to an enhanced transcription rate. Hep3B cells transfected with reporter constructs containing various regions of the C1INH gene between positions -1182 and +587, and stimulated with gamma-IFN, expressed increased levels of chloramphenicol acetyltransferase in the presence of the first intron and as few as 12 bases of the 5'-flanking region. However, a 66% reduction in the inducibility of the constructs was observed when the upstream region between -582 and -252 was eliminated. Successive deletions mapped the first intron IFN-responsive elements to a region between +368 and +410. The data indicate that both the upstream and the first intron sequences can independently enhance induction of C1INH gene expression. Examination of the immediate upstream sequence of the C1INH gene reveals the absence of a TATA box. The promoter of the C1INH gene was mapped to a region within 81 bases of the upstream sequence and the first exon. Further examination indicated two regions that were potentially important for promoter activity as follows: 1) a G-C-rich region from -81 to -49, and 2) an initiator element at -3 to +5. The results indicate that the upstream sequences including -81 to -49 and the H-DNA region between -48 and -17 are not necessary for promotor activity. The initiator element from -3 to +5 is sufficient and necessary for promoter function.

Base Sequence↗
PubMed1993

Acquired angioedema as the presenting feature of lymphoproliferative disorders of mature B-lymphocytes.

BACKGROUND: Acquired complement component 1 (C1) inhibitor deficiency with consequent angioedema is a rare condition that may indicate an underlying neoplasm of B-lymphocytes or plasma cells. METHODS: Three patients with C1 inhibitor deficiency and late-onset angioedema were studied to establish the presence and to characterize the nature of any underlying lymphoproliferative disorder. RESULTS: Each of the patients was found to have a low-grade B-lineage lymphoma. In one patient, the underlying disorder, best characterized as splenic lymphoma with villous lymphocytes, was occult initially. The other two patients had splenic lymphoma with villous lymphocytes and small lymphocytic lymphoma, respectively. Two of the patients had an immunoglobulin M (IgM) serum paraprotein with cold agglutinin activity; the third patient had no paraprotein, but his cells expressed monoclonal membrane IgM. Two of the patients initially did not require specific anti-lymphoma therapy and responded to therapy with an attenuated androgen; in the third patient, splenectomy and cytotoxic chemotherapy led to resolution of the acquired angioedema. In all three patient, there was considerable delay in diagnosis consequent to lack of awareness of this syndrome. CONCLUSIONS: The presence of a neoplasm of B-lymphocytes was established eventually in all three patients, although in one patient it was occult initially. In each case, the lymphocytes were mature B-lymphocytes that either showed cytologic evidence of plasma cell differentiation or secreted a paraprotein. Underlying lymphoma is common in patients who are seen initially with late-onset angioedema. Angioedema is an important, potentially life-threatening complication of lymphoma. Optimal patient management requires that both angioedema and the underlying lymphoma are recognized.

Aged↗
PubMed2003

N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits.

Human C1 inhibitor (hC1INH) is a therapeutic N, O-glycoprotein with a growing number of clinical applications, but the current natural supplies are not likely to meet the clinical demands. Therefore, recombinant approaches are of interest, whereby specific attention has to be paid to the generated glycosylation patterns. Here, the N,O-glycoprotein was expressed in the mammary gland of transgenic rabbits and subjected to glycan analysis. After release of the N-glycans of recombinant-rabbit human C1 inhibitor (rhC1INH) by peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase F, the oligosaccharides were separated from the O-glycoprotein by centrifugal filtration, then fractionated by a combination of anion-exchange, normal-phase, and high-pH anion-exchange liquid chromatography. The O-glycans, released from the O-glycoprotein by alkaline borohydride treatment, were fractionated by anion-exchange high-performance liquid chromatography (HPLC). The structures of individual components were analysed by 500 MHz 1H NMR spectroscopy, in most cases combined with MALDI-TOF MS. In contrast to the structural data reported for native serum hC1INH, rhC1INH contained a broad array of different N-glycans, made up of oligomannose-, hybrid-, and complex-type structures. In the case of complex-type N-glycans (partially) (alpha2-6)-sialylated (N-acetylneuraminic acid only), mono- and diantennary chains were found; part of the diantennary structures were (alpha1-6)-core-fucosylated or (alpha1-3)-fucosylated in the lower or upper antenna (Lewis x). The manno-oligosaccharide pattern of part of the hybrid- and oligomannose-type structures indicates that besides the usual N-glycan processing route, also the alternative endo-mannosidase pathway is followed. The small core 1-type O-glycans showed the usual (alpha2-3)- and (alpha2-6)-sialylation pattern of O-glycoproteins of nonmucinous origin.

Animals↗
PubMed2006

Administration of C1-esterase inhibitor during emergency coronary artery bypass surgery in acute ST-elevation myocardial infarction.

OBJECTIVE: Myocardial inflammatory response including complement activation was demonstrated as an important mechanism of ischemia-reperfusion injury and complement inhibition by C1-esterase inhibitor (C1-INH) has recently shown to have cardioprotective effects in experimental and clinical settings. METHODS: The effects of C1-INH on complement activation, myocardial cell injury, and clinical outcome were studied in patients undergoing emergency CABG due to acute ST-elevation myocardial infarction (STEMI) with (group 1, CABG+STEMI+C1-INH, n=28) and without (group 2, CABG+STEMI, n=29) bolus administration of C1-INH (40 IU kg(-1)) during reperfusion and 6 h postoperatively (20 IU kg(-1)) besides the same study protocol. C1-INH activity, C3c and C4 complement activation fragments, and cardiac troponin I (cTnI) were measured preoperatively and up to 48 h postoperatively and compared to another elective set of CABG patients without STEMI as controls (group 3, CABG-STEMI, n=10). Clinical data, adverse events, and patient outcome were recorded prospectively. RESULTS: Patient characteristics were not different between groups 1 and 2. No drug-related adverse events were observed. Constant plasma levels of C1-INH were found in group 1, but not in groups 2 and 3. Plasma levels of C3c and C4 complement fragments were reduced in all three groups after surgery throughout the observation time, but tended to be lower in groups 1 and 2 compared with group 3. Preoperative cTnI levels were elevated but not different between the groups 1 and 2. The area under curve (AUC), as well as the postoperative cTnI serum levels, was significantly lower (P<0.05) in group 1 with a treatment delay < or = 6 h between reperfusion and symptom onset compared to group 2 at 36 h (47.9+/-11.1 ng/ml vs 97.7+/-17.2 ng/ml; mean+/-SEM), and 48 h (33.5+/-5.8 ng/ml vs 86.5+/-19.2 ng/ml) after surgery, but remained unchanged between groups among patients with a treatment delay of more than 6-24 h. In-hospital adverse events and postoperative complications, ICU and hospital stay, as well as in-hospital mortality (14.3% vs 13.8%; P=NS) were not different between groups 1 and 2. CONCLUSIONS: C1-INH administration in emergency CABG with acute STEMI is safe and effective to inhibit complement activation and may reduce myocardial ischemia-reperfusion injury as measured by cTnI.

Aged↗
PubMed1988

Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis.

Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(-)-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(-4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.

Adolescent↗
PubMed1999

The promoter of the C1 inhibitor gene contains a polypurine.polypyrimidine segment that enhances transcriptional activity.

The C1 inhibitor (C1INH) promoter is unusual in two respects: 1) It contains no TATA sequence, but instead contains a TdT-like initiator element (Inr) at nucleotides -3 to +5; 2) it contains a polypurine.polypyrimidine tract between nucleotides -17 and -45. Disruption of the Inr by the introduction of point mutations reduced promoter activity by 40%. A TATA element inserted at nucleotide -30 in the wild-type promoter and in promoter constructs containing the mutated Inr led to a 2-fold increase in basal promoter activity. Previous studies suggested that the potential hinged DNA-forming polypurine.polypyrimidine tract might be important in the regulation of C1INH promoter activity. The present studies indicate that this region is capable of such intramolecular triple helix formation. Disruption of the polypurine.polypyrimidine sequence by substitution of 5 of the 23 cytosine residues with adenine prevented triple helix formation. Site-directed mutagenesis experiments demonstrate that the regulation of promoter activity is independent of hinged DNA-forming capacity but requires an intact AC box (ACCCTNNNNNACCCT) or the overlapping PuF binding site (GGGTGGG). The C1INH gene also contains a number of potential regulatory elements, including an Sp-1 and an hepatocyte nuclear factor-1 binding site and a CAAT box. The role of these elements in regulation of the C1INH promoter was examined. Elimination of the hepatocyte nuclear factor-1 site at nucleotides -94 to -81 by truncation reduced the activity of the promoter by approximately 50%. Similarly, site-directed mutations that disrupt this site reduce promoter activity by 70%.

5' Untranslated Regions↗
PubMed1994

Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium.

Activation of the complement (C) system has been documented in both experimental and clinical studies of myocardial infarction, but the exact time course and mechanisms leading to C activation have remained unclear. Our earlier postmortem study on human beings showed that formation of the membrane attack complex (MAC) of C was associated with loss of CD59 (protectin), an important sarcolemmal regulator of MAC, from the infarcted area. The recent discovery of a rat analogue of CD59 has now allowed the first experimental evaluation of the temporal and spatial relationship between C component deposition and loss of CD59 in acute myocardial infarction (AMI). After ligating the left coronary artery in rats the earliest sign of C activation, focal deposition of C3, was observed at 2 hours. Deposition of the early (C1, C3) and late pathway (C8, C9) components in the AMI lesions occurred at 3 hours. Glycophosphoinositol-anchored rat CD59 was expressed in the sarcolemmal membranes of normal cardiomyocytes. In Western blot analysis extracts of normal rat heart CD59 appeared as a band of 21 kd of molecular weight under nonreducing conditions. Loss of CD59 in the AMI lesions was observed in association with deposits of MAC from day one onward. Our results show that C activation universally accompanies AMI in vivo. It is initiated within 2 hours after coronary artery obstruction via deposition of C3, which may be due to generation of the alternative pathway C3 convertase in the ischemic area. Deposition of C1 and late C components also starts during the early hours (2 to 4 hours) after ischemia. Subsequent loss of the protective CD59 antigen may initiate postinjury clearance of the irreversibly damaged tissue.

Animals↗
PubMed2002

Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90.

Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyper-reactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of Factor XII, prekallikrein and high molecular weight kininogen (HK). The mechanism by which initiation occurs is uncertain. Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of Factor XII. We demonstrate herein that during a 2-h incubation time, plasma deficient in either Factor XII or high molecular weight kininogen (HK) fail to activate kinin-forming cascade as compared to normal plasma. With more prolonged incubation, Factor XII deficient plasma gradually activates and HK deficient plasma does not. Our data support both Factor XII-dependent (rapid) and Factor XII-independent (slow) mechanisms; the latter may require a cell-derived protein (possibly protease) to activate prekallikrein in the presence of zinc ion and HK. To further define this cellular factor, we demonstrated that both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein in the presence of HK and zinc ion. We purified this factor from cytosol by affinity chromatography employing corn trypsin inhibitor (CTI) as ligand. The fractions with peak activity were subjected to SDS-PAGE analysis, ligand blotted with biotinylated CTI, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as one of the proteins. Zinc-dependent activation of the prekallikrein-HK complex on endothelial cells was inhibited upon the addition of polyclonal antibody to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not yet clear, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.

Amino Acid Sequence↗
PubMed1987

Detection of activation of the contact system of coagulation in vitro and in vivo: quantitation of activated Hageman factor-C-1-inhibitor and kallikrein-C-1-inhibitor complexes by specific radioimmunoassays.

Radioimmunoassays (RIAs) for the detection of C-1-inhibitor (C-1-Inh) complexed to either kallikrein or activated Hageman factor (factor XIIa) are described. Kallikrein-C-1-Inh or factor XIIa-C-1-Inh complexes were bound to Sepharose to which monospecific antibodies against (pre)kallikrein or factor XII, respectively, were coupled. Bound complexes were subsequently detected by an incubation with affinity purified 125I-labeled antibodies against C-1-Inh. These RIAs were used to detect activation of the contact system of coagulation in vitro and in vivo. Addition of dextran sulfate (DXS) (20 micrograms/ml) to fresh plasma resulted at 37 degrees C in the rapid generation of amidolytic kallikrein activity, which was maximal after 1 to 2 min of incubation and subsequently decreased within a few minutes. The generation of kallikrein activity coincided with the appearance of both kallikrein-C-1-Inh and factor XIIa-C-1-Inh complexes. However, in contrast to kallikrein activity, both types of complexes remained detectable in the incubation mixtures during the incubation period. Experiments with purified kallikrein. C-1-Inh and partly purified beta-factor XIIa, and activation experiments in plasmas deficient in either factor XII or prekallikrein, demonstrated the specificity of both RIAs. The minimal amount of DXS that resulted in the generation of measurable amounts of both types of complexes in plasma was 2-3 micrograms per ml. Similar experiments with kaolin showed that with limiting amounts of activator (1-2 mg/ml), only kallikrein-C-1-Inh complexes were detected in plasma. When larger amounts of kaolin were added to plasma, factor XIIa-C-1-Inh complexes were additionally detected in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed2003

Novel complement C1 inhibitor BSF468248 does not improve brain damage after cortical vein occlusion.

BSF468248 is a novel potent complement C1 inhibitor. To determine whether BSF468248 is effective against focal cerebral ischemia, we evaluated the change of cerebral blood flow (CBF) and infarction volume using a photochemically-induced cortical vein occlusion model in rats in blind studies. In 22 Wistar rats, two adjacent cortical veins were occluded by photochemical thrombosis and fiberoptic illumination under controlled anesthesia and ventilation. Just after the occlusion, BSF468248 or physiological saline was administrated. In the low-dose study, a treatment group (n = 7) was administered BSF468248 1 mg/kg bolus and 1 mg/kg continuously for 30 min. The same volume of saline was given to a vehicle group (n = 5). In the high-dose study, a treatment group (n = 5) was administrated BSF468248 1 mg/kg bolus and 12 mg/kg continuously for 180 min. The same volume of saline was given to a vehicle group (n = 5). During the experiment, regional cerebral blood flow (rCBF) was measured in both the low-dose study (120 min) and the high-dose study (180 min). Seven days after the experiment, the animals were killed in order to evaluate the infarct volume. The rCBF at the end of the experiment showed a similar decrease in both the low-dose study (at 120 min: treatment group: 66.5 +/- 10.2%; vehicle group: 69.3 +/- 10.2%) and the high-dose study (at 180 min: treatment group: 62.1 +/- 7.5%; vehicle group: 65.1 +/- 12.3%), with no significant differences (t-test). The infarct volume also showed no significant difference in either group of the low-dose study (treatment group: 3.46 +/- 0.84 mm3; vehicle group: 3.56 +/- 1.40 mm3) or the high-dose study (treatment group: 2.27 +/- 0.43 mm3; vehicle group: 1.76 +/- 0.31 mm3). Our study found that BSF468248 is not effective in improving the rCBF and the infarct volume following focal cerebral ischemia.

Animals↗
PubMed2002

Does heparin prophylaxis prevent exacerbations of hereditary angioedema?

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by episodes of angioedema of the skin, mucous membranes, and gastrointestinal tract resulting from a defect in the gene that produces C1 esterase inhibitor. Although in vitro laboratory data and past reports suggested that heparin might be efficacious in preventing HAE attacks, no controlled study has been reported to examine heparin's efficacy in this regard. OBJECTIVES: We sought to determine the safety and efficacy of inhaled and subcutaneous heparin versus that of placebo in the prevention of HAE attacks. METHODS: We performed a double-blind, double-dummy, saline placebo-controlled, randomized, 3-way crossover study with 11 visits. RESULTS: The study was designed to enroll 24 patients. Twenty-two patients were randomized and received the study drug. Patients did not have a significant decrease in average flare intensity after they received injected or inhaled heparin compared with that seen after placebo, the primary endpoint. However, when patients received injected heparin, they had a statistically significant decrease in average flare intensity compared with that seen with inhaled heparin after a normalizing transformation was applied. When the means are back transformed, this translates into median flare intensities of 9.2, 8.0, and 5.1 in the patients treated with inhaled heparin, placebo, and injected heparin, respectively. There were no significant differences when individual symptoms were examined, when total numbers of flares over a 6-week observation period were examined, or when global evaluations by the patients and investigators were evaluated. Adverse event severity was fairly uniform across treatments, with the majority of events classified as moderate and the remainder split between mild and severe. Injected heparin treatment was associated with higher rates of relatedness than other treatments, which was partially explained by 17 adverse events specifically related to the injection process itself (tenderness, bruising, redness, pain, and itching at the injection site). The injection treatment was also associated with a larger overall number of reported adverse events (70 vs 48 in the placebo treatment). Tenderness and bruising at the injection site were entirely confined to the injected heparin treatment. CONCLUSIONS: Injected and inhaled heparin failed to attenuate average flare intensity, the primary endpoint, compared with placebo. Interestingly, after patients injected heparin, they had a significant decrease in average flare intensity compared with that seen after inhalation of heparin. There were no differences among groups in other efficacy parameters. Taken together, these data indicate that commercial heparin was ineffective in preventing exacerbations of HAE.

Acute Disease↗