The HEAVEN criteria predict laryngoscopic view and intubation success for both direct and video laryngoscopy: a cohort analysis.

BACKGROUND: Existing difficult airway prediction tools are not practical for emergency intubation and do not incorporate physiological data. The HEAVEN criteria (Hypoxaemia, Extremes of size, Anatomic challenges, Vomit/blood/fluid, Exsanguination, Neck mobility) may be more relevant for emergency rapid sequence intubation (RSI). METHODS: A retrospective analysis included air medical RSI patients. A checklist was used to assess HEAVEN criteria prior to RSI, and Cormack-Lehane (CL) laryngoscopic view was recorded for the first intubation attempt. The incidence of a difficult (CL III/IV) laryngoscopic view as well as failure to intubate on first attempt with and without oxygen desaturation were determined for each of the HEAVEN criteria and total number of HEAVEN criteria. In addition, the association between HEAVEN criteria and both laryngoscopic view and intubation performance were quantified using multivariate logistic regression for direct laryngoscopy (DL) and video laryngoscopy (VL) configured with a Macintosh #4 non-hyperangulated blade. RESULTS: A total of 5137 RSI patients over 24 months were included. Overall intubation success was 97%. A CL III/IV laryngoscopic view was reported in 25% of DL attempts and 15% of VL attempts. Each of the HEAVEN criteria and total number of HEAVEN criteria were associated with both CL III/IV laryngoscopic view and failure to intubate on the first attempt with and without oxygen desaturation for both DL and VL. These associations persisted after adjustment for multiple co-variables including the other HEAVEN criteria. CONCLUSION: The HEAVEN criteria may be useful to predict laryngoscopic view and intubation performance for DL and VL during emergency RSI.

Use of QSPR Modeling to Characterize In Vitro Binding of Drugs to a Gut-Restricted Polymer.

PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2 = 0.7, Q 2 = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs.

Critical Cysteine Residues in Both the Calcium-Sensing Receptor and the Allosteric Activator AMG 416 Underlie the Mechanism of Action.

AMG 416 is a novel D-amino acid-containing peptide agonist of the calcium-sensing receptor (CaSR) that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis. The principal amino acid residues and their location in the CaSR that accommodate AMG 416 binding and mode of action have not previously been reported. Herein we establish the importance of a pair of cysteine residues, one from AMG 416 and the other from the CaSR at position 482 (Cys482), and correlate the degree of disulfide bond formation between these residues with the pharmacological activity of AMG 416. KP-2067, a form of the CaSR agonist peptide, was included to establish the role of cysteine in vivo and in disulfide exchange. Studies conducted with AMG 416 in pigs showed a complete lack of pharmacodynamic effect and provided a foundation for determining the peptide agonist interaction site within the human CaSR. Inactivity of AMG 416 on the pig CaSR resulted from a naturally occurring mutation encoding tyrosine for cysteine (Cys) at position 482 in the pig CaSR. Replacing Cys482 in the human CaSR with serine or tyrosine ablated AMG 416 activity. Decidedly, a single substitution of cysteine for tyrosine at position 482 in the native pig CaSR provided a complete gain of activity by the peptide agonist. Direct evidence for this disulfide bond formation between the peptide and receptor was demonstrated using a mass spectrometry assay. The extent of disulfide bond formation was found to correlate with the extent of receptor activation. Notwithstanding the covalent basis of this disulfide bond, the observed in vivo pharmacology of AMG 416 showed readily reversible pharmacodynamics.

Comparison of AMG 416 and cinacalcet in rodent models of uremia.

BACKGROUND: AMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis. METHODS: AMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the "1K1C" model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively). RESULTS: Administration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals. CONCLUSIONS: As a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.

Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients.

A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.

Therapeutic applications of cell-penetrating peptides.

Since the discovery over 15 years ago of a protein transcription factor that possessed the ability to cross the plasma membrane, cell-penetrating peptides (CPPs) have been evaluated for the ability to transport diverse cargoes into cells, tissues, and organs. Certain CPPs have been used for the intracellular delivery of information-rich molecules to modulate protein-protein interactions and thereby inhibit key cellular mechanisms of disease. The ability to introduce drugs into cells allows the conventional biodistribution of drugs to be altered in order to favorably impact toxicity, patient compliance, and other treatment factors. In this monograph, we present the current status and future prospects for the application of CPPs to the development of human therapeutics. We discuss some of the advantages and disadvantages of using CPPs in the in vivo setting, and review the current status of a number of preclinical and human clinical studies of CPP-mediated delivery of therapeutics. These include CPP-conjugated moieties directed against a growing variety of targets and disease areas, including cancer, cardiology, pain, and stroke. Our discussion focuses on those therapeutics that have been tested in humans, including a CPP conjugate for the treatment of acute myocardial infarction. The promising results obtained in a number of these studies indicate that CPPs may have an important role in the development of novel therapeutics.

Non-ATP-competitive kinase inhibitors - enhancing selectivity through new inhibition strategies.

BACKGROUND: ATP-competitive inhibitors of protein kinases have been successfully developed for life-threatening indications such as cancer. However, owing to the similarity of the ATP binding sites between kinases, it has been challenging to identify specific inhibitors. The progress towards the generation of kinase inhibiting drugs for more chronic indications has been slowed by the concern that low specificity kinase inhibitors will have undesired toxicities. OBJECTIVE AND METHODS: We have reviewed the scientific and patent literature to summarize alternative strategies that are being used to develop non-ATP-competitive kinase inhibitors with greater selectivity. RESULTS/CONCLUSION: Several new approaches are being taken to achieve selectivity. Among these, the use of small peptide therapeutics is particularly promising and is already yielding drugs that are demonstrating promise in human clinical trials.

Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, nonpeptide agonists.

The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC50's = 20 microm) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC50 = 2 nm) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC50 = 980 nm) and estradiol production from primary rat ovarian granulosa cells (EC50 = 10.5 nm). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy.

Agonists of the follicle stimulating hormone receptor from an encoded thiazolidinone library.

The design, synthesis, characterization, and screening of a large, encoded thiazolidinone library are described. Three sets of 35 building blocks were combined by encoded split-pool synthesis to give a library containing more than 42 000 members. Building block selection was based in part on a novel small molecule follicle stimulating hormone receptor agonist hit and in part for diversity. HPLC/MS techniques were applied at the single-bead level to build confidence in the reliability of library construction. Application of two distinct screening strategies resulted in the identification of compounds with significantly improved potency over the initial hit. This work demonstrates the versatility of encoded libraries for preparing a large number of analogues of a given hit while simultaneously generating a large collection of compounds for screening against other targets.

Drugs and probes: the symbiotic relationship between pharmaceutical discovery and imaging science.

Pharmaceutical research and imaging science are becoming increasingly intertwined. Positron emission tomography (PET) is a molecular imaging technique with particularly broad application in drug discovery and development. At the same time, modern techniques of drug discovery are helping accelerate the development of new PET probes. This article describes the relationship between the two fields, with particular consideration of practical and strategic limitations to full utilization of available technology.

Safety-catch linker strategies for the production of radiopharmaceuticals labeled with positron-emitting isotopes.

A novel synthetic stratetegy for compounds labeled with the positron-emitting isotope carbon-11 is described. The use of precursors attached to a solid support via safety-catch linkers allows selective release of radiolabeled material, leaving unreacted precursor attached to the support. Two different linkers demonstrate the application to the preparation of radiolabeled N-alkyl tertiary amines and N-alkylsulfonamides. This technique is expected to lead to more widespread use of positron emission tomography for the in vivo analysis of compound behavior.