CAL-130 Hydrochloride

Class I phosphoinositide 3-kinase (PI3K) activate fundamental pathways controlling cell survival, metabolism, proliferation and and therefore play crucial role in cancer development. It is reported that p110γ is mainly expressed in leukocytes, whose role in cancer development is recently starting to be studied. CAL-130 is a specific dual inhibitor of p110γ and p110δ.
In vitro: To demonstrate that CAL-130 can block the activities of both PI3Kγ and PI3Kδ in thymocytes, previous autors evaluated its ability of preventing phosphorylation of Akt (Ser473) and calcium flux in response to T cell receptor (TCR). Consistently, CAL-130 treated thymocytes from 6-week-old WT animals prevented TCR-induced Akt phosphorylation and attenuated calcium flux to levels observed for their Pik3cγ-/-; Pik3cδ-/- counterparts [1].
In vivo: To assess the in vivo efficacy, previous study determined its effects on 6-week-old WT mice thymi. Mice orally received 10 mg/kg of the inhibitor, which was sufficient to maintain plasma concentrations of 0.33 μM at the end of 8 hrs. Moreover, such dose did not affect either plasma glucose or insulin levels. In contrast, CAL-130 treatment (10 mg/kg every 8 hrs) for a period of 7 days greatly affected the size, cellularity, and overall architecture of the thymus. Notely there was a 18-fold reduction in total thymocyte number when comparred to controls, which was mainly due to the DP population loss [1].
Clinical trial: CAL-130 is currently in the preclinical developlent stage and no clinical data are available.
Reference:
[1] Subramaniam PS, Whye DW, Efimenko E, Chen J, Tosello V, De Keersmaecker K, Kashishian A, Thompson MA, Castillo M, Cordon-Cardo C, Davé UP, Ferrando A, Lannutti BJ, Diacovo TG. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell. 2012;21(4):459-72.

Identification of pyrolysis products of the new psychoactive substance 2-amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) and its iodo analogue bk-2C-I.[Pubmed:28371351]

Drug Test Anal. 2018 Jan;10(1):229-236.

2-Amino-1-(4-bromo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-B) has recently emerged as a new psychoactive substance (NPS). It is most commonly consumed orally, although there are indications that it might also be ingested by inhalation or 'smoking'. Information about the stability of bk-2C-B when exposed to heat is unavailable and the potential for pyrolytic degradation and formation of unknown substances available for inhalation prompted an investigation using a simulated 'meth pipe' scenario. Twelve products following pyrolysis of bk-2C-B were detected and verified by organic synthesis of the corresponding standards. In addition, 2-amino-1-(4-iodo-2,5-dimethoxyphenyl)ethanone hydrochloride (bk-2C-I) was characterized for the first time and subjected to pyrolysis as well. Similar products were formed, which indicated that the replacement of the bromo with the iodo substituent did not affect the pyrolysis pattern under the conditions used. Two additional products were detected in the bk-2C-I pyrolates, namely 1-(2,5-dimethoxyphenyl)-ethanone and 1-iodo-4-ethenyl-5-methoxyphenol. The potential ingestion of pyrolysis products with unknown toxicity adds an element of concern. Copyright (c) 2017 John Wiley & Sons, Ltd.

Compatibility and Stability of Rolapitant Injectable Emulsion Admixed with Intravenous Palonosetron Hydrochloride.[Pubmed:28346200]

Int J Pharm Compd. 2017 Jan-Feb;21(1):76-82.

Neurokinin-1 receptor antagonist, 5-hydroxytryptamine-3 RA, and dexamethasone combination therapy is standard of care for the prevention of chemotherapy-induced nausea and vomiting. Herein we describe the physical and chemical stability of rolapitant injectable emulsion 166.5 mg in 92.5 mL (185 mg hydrochloride salt) admixed with palonosetron injection 0.25 mg in 5 mL (0.28 mg hydrochloride salt). Admixtures were prepared and stored in two types of container closures (110-mL Crystal Zenith plastic and glass bottles) and four types of intravenous administration sets (or intravenous tubing sets). Assessment of the physical and chemical stability was conducted on the admixtures in the ready-to-use container closure systems as supplied by the manufacturer, stored at room temperature (20 degrees C to 25 degrees C under fluorescent light), and evaluated at 0, 1, and 6 hours; 1 and 2 days; and under refrigeration (2 degrees C to 8 degrees C protected from light) after 1, 3, and 7 days. For admixtures in intravenous tubing sets, the assessment of physicochemical stability was performed after 0 and 7 hours of storage at 20 degrees C to 25 degrees C initially, and then after 20 hours (total 27 hours) at 2 degrees C to 8 degrees C protected from light. Physical stability was assessed by visual examination of the container contents under normal room light, and measuring turbidity and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations and impurity levels with high-performance liquid chromatographic analysis. The results indicated that all samples were physically compatible throughout the duration of the study. The pH, turbidity, and particulate matter of the admixture stayed within narrow and acceptable ranges. Rolapitant admixed with palonosetron was chemically stable when admixed in glass and Crystal Zenith bottles for at least 48 hours at room temperature and for 7 days under refrigeration, as well as in the four selected intravenous tubing sets for 7 hours at 20 degrees C to 25 degrees C and then for 20 hours at 2 degrees C to 8 degrees C. No loss of potency of any admixed components occurred in the samples stored at the two temperature ranges and time period studied.

[The Discovery, Research and Development of Etelcalcetide Hydrochloride, the World 1st Intravenous Calcimimetics.][Pubmed:28336830]

Clin Calcium. 2017;27(4):537-545.

Etelcalcetide hydrochloride is the first intravenous calcimimetics agent for secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is to be administered through dialysis circuit by physician or medical staff upon completion of dialysis and such administration is expected to reduce the burden of medication in patients. From the nonclinical study results, etelcalcetide functions as an allosteric activator of calcium-sensing receptor(CaSR). Etelcalcetide suppressed PTH secretion both in vitro and in vivo. In a rat model of chronic renal insufficiency, etelcalcetide suppressed SHPT disorders, such as parathyroid gland hypertrophy, bone disorder, and ectopic calcification. In conclusion, etelcalcetide hydrochloride is expected to exhibit therapeutic effect against each SHPT condition by decreasing blood PTH concentrations via CaSR-agonist activity in the clinical situation.

Study on the interaction of 6-(2-morpholin-4-yl-ethyl)-6H-indolo [2,3-b]quinoxaline hydrochloride with human serum albumin by fluorescence spectroscopy.[Pubmed:28355158]

Methods Appl Fluoresc. 2016 Sep 14;4(3):034012.

Under physiological conditions, in vitro interaction between the bio-active substance 6-(2-morpholin-4-yl-ethyl)-6H-indolo[2,3-b]quinoxaline hydrochloride (MIQ) and human serum albumin (HSA) was investigated at an excitation wavelength 260 nm and at different temperatures (298 K, 308 K and 313 K) by fluorescence emission spectroscopy. From spectral analysis, MIQ showed a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure. The binding constant is estimated asK A = 2.55 x 10(-4) l . mol(-1) at 298 K. Based on the thermodynamic parameters evaluated from the van 't Hoff equation, the enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ) were derived to be negative values. A value of 2.37 nm for the average distance r between MIQ (acceptor) and tryptophan residues of HSA (donor) was derived from the fluorescence resonance energy transfer. UV/vis absorption spectra were used to confirm the quenching mechanism.