Explore chapters and articles related to this topic
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Other syndromes with metaphyseal dysplasia: Shwachman-Diamond syndrome: also shows exocrine pancreatic insufficiency, haematologic abnormalities, including increased risk of malignant transformation (myelodysplasia and acute myeloid leukaemia), short stature, narrow thorax with prominent anterior rib ends in infancy. Caused by recessive mutations in SBDS. Omenn syndrome: severe disorder characterised by reticuloendotheliosis with eosinophilia, generalised erythrodermia, diarrhoea, failure to thrive, and hepatosplenomegaly. Jansen syndrome: marked expansion of metaphyses with a flocculent appearance; short stature, bowing of radius, ulna, tibia and fibula, osteopaenia, choanal stenosis or atresia, prominent hyperteloric eyes, hypercalcaemia with very low parathormone levels. Caused by gain of function of PTHR (parathyroid hormone receptor).
A Meta-Analysis of Calcium Intake and Risk of Glioma
Published in Nutrition and Cancer, 2022
There are many explanations for the mechanism by which calcium reduces the risk of glioma. This may be related to the involvement of calcium in cell apoptosis. Juin et al. discovered that glutamate-induced apoptosis in cerebellar granule neurons is characterized by intracellular calcium increase (33). Intracellular calcium may affect DNA repair through calmodulin (34). Besides, higher levels of calcium will lead to down-regulation of parathyroid hormone production (35). Parathyroid hormone has been considered as a tumor promoter and can act as a mitogen and anti-apoptotic factor. De Miguel et al. detected parathyroid hormone-related protein in human astrocytomas and proposed that the parathyroid hormonerelated protein, via the parathyroid hormone receptor, is associated with astrocytoma cell proliferation and dedifferentiation (36). Our results support the evidence that calcium intake is negatively correlated with the risk of brain tumors, but the relationship between calcium intake and astrocytoma risk and serum parathyroid hormone levels needs further research to explore.
Formulation optimization and pharmacokinetics evaluation of oral self-microemulsifying drug delivery system for poorly water soluble drug cinacalcet and no food effect
Published in Drug Development and Industrial Pharmacy, 2018
Mengyuan Cao, Xu Xue, Xixi Pei, Yiwen Qian, Lan Liu, Lili Ren, Guoguang Chen
Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) [1]. Cinacalcet, N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine, was FDA-approved first calcimimetic for the treatment of SHPT in patients with CKD on dialysis [2]. Cinacalcet mimiced calcium at the parathyroid hormone receptor. The calcium outside the cells had become sensitized to the calcium-sensing receptors in the parathyroid gland because of this binding, and reducing the secretion of parathyroid hormone directly [3]. At the same time, cinacalcet overcome the side effect of traditional agents such as phosphate binders and vitamin D sterols in the risk of hypercalcemia and hyperphosphatemia [4]. Cinacalcet had poor aqueous solubility. Therefore, cinacalcet was designed as nonconventional formulations to promote the absorption and enhance bioavailability of oral administration.
Discovery and design of G protein-coupled receptor targeting antibodies
Published in Expert Opinion on Drug Discovery, 2023
Sean M. Peterson, Catherine J. Hutchings, Cameron F. Hu, Melina Mathur, Janelle W. Salameh, Fumiko Axelrod, Aaron K. Sato
The secretin family of Class B1 GPCRs has been targeted for agonist antibodies to treat diabetes and obesity. The clinically approved glucagon-like peptide 1 receptor (GLP-1 R) agonist dulaglutide (Trulicity) was engineered by Eli Lilly as a fusion of the GLP-1 peptide to the Fc (fragment crystallizable region) of IgG4 [11]. IgG4 is known to engage with FcRn receptors to enhance antibody half-life via recycling [12] and indeed, dulaglutide has a serum half-life of over 12 hours in humans, compared with less than 2–5 hours for exenatide and other GLP-1 peptide mimetics [13]. Importantly, IgG4 does not activate the complement cascade which leads to antibody-dependent complement-dependent cytoxicity (ADCC) [5]. Furthermore, the F234A and L235A mutations were introduced into dulaglutide’s IgG4 Fc region to reduce any possibility of ADCC [11]. In summary, dulaglutide is a unique peptide agonist fused to an inert Fc region to activate GLP-1 R. In addition, Gmax Biopharm has developed glutazumab, a fusion of the GLP-1 peptide to the light chain of an anti-GLP-1 R antibody [14]. Glutazumab is currently in clinical trials for the treatment of diabetes. Another such anti-GLP-1 R antibody fused to GLP-1 peptide to produce agonism, everestmab, has been described [15]. Everestmab is a bispecific nanobody between an albumin-binding domain and a mutated GLP-1 peptide. Similarly, we recently described a GLP-1 peptide light-chain fusion to a GLP-1 R antibody called TB-059-002 [16]. Amgen has recently reported positive data for a GLP-1 peptide fused to a glucose-dependent insulinotropic polypeptide receptor (GIPR) antibody, AMG-133, that functions as a dual GLP-1 R agonist/GIPR antagonist [17,18]. Tethering the GLP-1 peptide to the anti-GIPR antibody has the advantage of extending the half-life of the GLP-1 peptide and was shown to enhance localization of the molecule to the pancreas [17]. AMG-133 is derived from a series of dual GLP-1 R agonists/GIPR antagonists and has recently been reported to show strong Phase 1 data in obesity. Ligand tethering with antibody delivery was also recently described for another Class B1 GPCR parathyroid hormone receptor (PTHR1) [19].