Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys.

CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor of all three pathways of the complement system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys. Recovery from any effects was evaluated during a four-week recovery period.

Treatment with recombinant ADAMTS13, alleviates hypoxia/reoxygenation-induced pathologies in a mouse model of human sickle cell disease.

Background: Sickle cell disease (SCD) is an inherited red blood cell disorder with a causative substitution in the beta-globin gene that encodes beta-globin in hemoglobin. Furthermore, the ensuing vasculopathy in the microvasculature involves heightened endothelial cell adhesion, inflammation, and coagulopathy, all of which contribute to vaso-occlusive crisis (VOC) and the sequelae of SCD. In particular, dysregulation of the von Willebrand factor (VWF) and a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in human SCD pathology.

Sialylation-dependent pharmacokinetics and differential complement pathway inhibition are hallmarks of CR1 activity in vivo.

Human Complement Receptor 1 (HuCR1) is a potent membrane-bound regulator of complement both in vitro and in vivo, acting via interaction with its ligands C3b and C4b. Soluble versions of HuCR1 have been described such as TP10, the recombinant full-length extracellular domain, and more recently CSL040, a truncated version lacking the C-terminal long homologous repeat domain D (LHR-D). However, the role of N-linked glycosylation in determining its pharmacokinetic (PK) and pharmacodynamic (PD) properties is only partly understood.

Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques.

Background: 3F7 is a monoclonal antibody targeting the enzymatic pocket of activated factor XII (FXIIa), thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thromboinflammation, along with its apparent redundancy for hemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases.

Methods: The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease-angiotensin II-induced abdominal aortic aneurysm (AAA), an ApoE model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability.

Relapse of Anterior Open Bite: A Case Report.

The aim and objective of this study is to report the recurrence of the treatment of the anterior open bite after 5 years of treatment. A female patient aged 8 years 6 months old had a negative vertical crossing of -4.7 mm.

Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey.

Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD.

Clinical complications during early treatment of anterior open bite.

The object of this study was to compare the clinical complications of 4 different appliances used in the early treatment of anterior open bite (AOB), and to test the null hypothesis that there is no difference in the number of complications among the appliances. Records from 99 Class I malocclusion patients with AOB treated using bonded spurs, BS, n = 25; chin cup, CC, n = 25; fixed palatal crib, FPC, n = 25; and removable palatal crib, RPC, n = 24) were examined. The total number and frequency of clinical complications that occurred over 12 months were described and compared by using chi-square and Kruskal-Wallis tests (Dunn's post-test) (α = 5%, CI = 95%).

Do fluorescent agents alter the mechanical strength of orthodontic adhesives? An in vitro and clinical study.

Background: Fluorescent agents are added to orthodontic adhesives with the aim of making them visible under ultraviolet (UV) light, which ensures the complete, safe removal of remnants after orthodontic treatment. However, it is necessary to evaluate if the mechanical strength of these materials is maintained. Therefore, this study evaluated whether the addition of fluorescent agents influences the shear bond strength and clinical performance of a UV light-sensitive adhesive system.

Dentoalveolar effects produced by different appliances on early treatment of anterior open bite: A randomized clinical trial.

Objectives:: To compare different appliances for early anterior open bite (AOB) correction.

Materials And Methods:: This was a parallel, randomized clinical trial. A prospective sample of patients with AOB was recruited consecutively.

Expression and distribution of CYP3A genes, CYP2B22, and MDR1, MRP1, MRP2, LRP efflux transporters in brain of control and rifampicin-treated pigs.

The in vivo effect of rifampicin, a potent ligand of PXR, on gene expression of CYP2B22, 3A22, 3A29, 3A46, CAR, PXR and MDR1, MRP1, MRP2, LRP transporters in liver and cortex, cerebellum, midbrain, hippocampus, meninges and brain capillaries of pig was investigated. Animals were treated i.p.

Effect of beta-naphthoflavone on AhR-regulated genes (CYP1A1, 1A2, 1B1, 2S1, Nrf2, and GST) and antioxidant enzymes in various brain regions of pig.

The constitutive and inducible expression of aryl hydrocarbon receptor (AhR) and of the AhR-regulated genes coding for CYP1A1, CYP1A2, CYP1B1, CYP2S1, and Nrf2 was investigated by real-time or traditional PCR in cerebral areas (cortex, cerebellum, midbrain, and hippocampus), blood-brain interfaces (meninges and brain microvessels) and liver obtained from control pigs and from pigs treated with beta-naphthoflavone (betaNF), a potent AhR agonist. The enzymatic activities of ethoxyresorufin-O-deethylase (EROD), and methoxyresorufin-O-deethylase (MEROD), marker for CYP1A1 and CYP1A2, the GST and various antioxidant enzymes (catalase, superoxide dismutase, GSSG-reductase, and GSH-peroxidase) were also determined in the same CNS regions. The AhR, CYP1A1, CYP1A2, CYP1B1, Nrf2 mRNAs were detected, although at different extent, in all the CNS regions, while CYP2S1 mRNA was detected only in midbrain.

Antioxidant activity of different dihydropyridines.

Lacidipine, a dihydropyridine-based calcium antagonist (DHP), has already been demonstrated to possess antioxidant activity and to reduce the intracellular production of reactive oxygen species (ROS). To verify if this effect is a peculiarity of this molecule, or belongs to other DHPs, the activity of lacidipine was compared with those of amlodipine, lercanidipine, nimodipine, and nifedipine. The DHPs were incorporated in bovine aortic endothelial cells (BAECs).

Comparative effects of different dihydropyridines on the expression of adhesion molecules induced by TNF-alpha on endothelial cells.

Objective: Lacidipine has already been demonstrated to reduce the expression of some adhesion molecules induced by pro-oxidant signals on endothelial cells. In order to verify if this effect is a peculiarity of this molecule, or belongs to other dihydropyridinic compounds (DHPs), the activity of lacidipine was compared with that of lercanidipine, amlodipine, nimodipine and nifedipine.

Design And Methods: The compounds were incorporated in human umbilical vein endothelial cells (HUVECs) using native low-density lipoprotein as a carrier.

Growth hormone response to clonidine in anovulatory infertile women resistant to clomiphene citrate stimulation.

Objective: To evaluate the GH response to the clonidine test in a group of infertile women and to determine their ovulatory response to clomiphene citrate (CC) stimulation.

Design: Prospective study.

Setting: Reproductive endocrinology unit.

Metabolism of a novel CCK-B antagonist in rat, dog and human liver microsomes.

1. The in vitro metabolism of a novel CCK-B antagonist ((+)-N-[1-adamantane-1-methyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H- 1, 5-benzodiazepin-3-yl]N'-phenyl-urea; GV150013X) was investigated using rat, dog and human liver microsomes. 2.

In vitro metabolism of GV150013X by using liver microsomes and liver tissue slices from different species.

The metabolism of GV150013X was studied in vitro using washed liver microsomes and liver tissue slices from different species. This work was carried out in order to compare the metabolite profiles resulting from incubation of GV150013X with human, rat, dog and rabbit liver microsomes and those from rat, rabbit and human liver tissue slices. This compound was found to be converted to at least 8 metabolites by rat and human liver microsomes.

Analysis of plasma cholesterol oxidation products using gas- and high-performance liquid chromatography/mass spectrometry.

The application of gas chromatography and high-pressure liquid chromatography/mass spectrometry techniques for analysis of plasma cholesterol oxidation products is described. Cholesterol oxides that are widely identified in biological samples were subjected to gas (GC) and high-pressure liquid chromatographic (HPLC) separations, and their detection and characterization by mass spectrometry (MS) were compared. Analysis of cholesterol oxides from plasma samples revealed distinct advantages for each method according to the specific cholesterol oxide in question.

Effectiveness of norethisterone enantate in the treatment of the climacteic syndrome.

The Authors have studied the effects of Norethisterone enantate given i.m. every one or two months to 75 patients complaining of climacteric syndrome either spontaneous or induced surgically.

Effect of lisuride on inhibition of lactation and serum prolactin.

Lisuride, a new semisynthetic ergot derivative, was given to 53 women to inhibit lactation; 26 women had 300 micrograms daily and 27 had 600 micrograms daily for seven days. Eight lactating women acted as controls. Lisuride effectively inhibited lactation and also suppressed the serum prolactin levels; the latter effect was dose related.

Effect of Lisuride on serum prolactin levels during puerperium.

A new semisynthetic ergot derivative, Lisuride, has been administered to 40 women who wanted to have lactation inhibited. Purpose of the study was to evaluate the drug's effect on serum PRL levels. Treatment was carried out for 7 days with daily doses of 300 or 600 microgram.

Estradiol and estetrol plasma levels before and after intravenous administration of dehydroepiandrosterone sulfate in normal and pathologic pregnancies.

Intravenous injections of 50 mg dehydroepiandrosterone sulfate (DHEAS) were given to 7 women with normal pregnancies and 5 with pathologic pregnancies and the serum levels of 17 beta-estradiol and estetrol were assayed before and at 15 or 30-minute intervals for three hours after the injection. All tests were carried out during the 25th to 36th week of amenorrhea. Serum estradiol rose rapidly in normal subjects and remained high to the end of the test.

Trazodone intravenously administered and plasma prolactin levels.

Plasma prolactin levels during intravenous Trazodone infusion have been evaluated. Although the modifications were not statistically significant, a slight decrease of plasma prolactin levels was noted. This result suggests that Trazodone has no remarkable effect on hypothalamic function.

The effect of lisuride hydrogen maleate in the hyperprolactinaemia-amenorrhoea syndrome: clinical and hormonal responses.

Eleven women with secondary amenorrhoea and hyperprolactinaemia were treated with lisuride, a new semisynthetic ergot derivative. Acute administration of lisuride (100 microgram orally) significantly suppressed serum prolactin (PRL) levels in nine out of eleven subjects. In these nine patients, prolonged treatment with lisuride (50--200 microgram daily) lowered PRL levels into the normal range, menstrual cycles were resumed and eight patients ovulated.

Demonstration of human chorionic gonadotropin during the second half of the menstrual cycle in plasma of regularly menstruating women users of copper IUds.

An attempt has been made of demonstrating the beta subunit of HCG in the plasma of 13 regularly menstruating women wearing a copper IUD. Eighteen menstrual cycles were explored with a total of 94 specimens obtained at 3-day intervals starting from the 16th day of the cycle. A cross reaction with LH was excluded by simultaneous assay of this hormone.