Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life

: Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup (n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) (p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA (p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA (p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features

Aggregation Properties of Aminoalkylsulfanyl Polythiophenes

The aggregation properties of an aminoalkylsulfanyl polythiophenes cayying a tromethylammonium group were characterized through a combined AFM, DOSY NMR and DLS study

Organic- and Water-Soluble Aminoalkylsulfanyl Polythiophenes

Six new aminoalkylsulfanyl polythiophenes (PTs), namely PTNHBoc, PTNMeBoc, PTNH2,PTNHMe, PTNMe2, and PTN+Me3, were synthesized. Four of them were obtained through Stille coupling, whereasPTNH2 and PTNHMe were obtained through deprotection via N-Boc precursors. The solubility changes goingfrom the protected amines to the quaternary ammonium salt. All the polymers are soluble in DMSO and DMF.PTNHBoc and PTNMeBoc are also soluble in CHCl3, CH2Cl2, THF, and DMPU; PTNH2 and PTNHMe aresoluble in CH3OH, whereas PTNMe2 and PTN+Me3 are soluble both in CH3OH and in H2O. These PTs show atendency toward microaggregation in solution that does not represent an obstacle to their solubility. NMR, UV-vis,and XRD results prove that they are able to reach very high conjugation lengths and ordered conformations, notonly in the solid state but also in solutions of good solvents

Octithiophenes via One-Pot Oxidative Coupling of 4-(\u3c9-Functionalized Alkylsulfanyl)-2,2\u2032-Bithiophenes

The oxidative coupling reaction with FeCl3 on nitrile, methyl ester and amino functionalized 4-(alkylsulfanyl)-2,2\u2019-bitiophenes afforded symmetric octithiophenes (OTs). These new OTs have solvatochromic properties similar to those reported for poly(\u3c9-functionalized alkylsulfanyl)thiophenes and have a potential use in optoelectronic devices. The carboxy (obtained through hydrolysis from nitrile and methyl ester functionalized OTs) and the amino functionalized OTs are also water soluble as salts. From this and our previous results, the oxidative coupling with FeCl3 can be proposed as a general method for the synthesis of OTs when the starting materials are 4-(alkylsulfanyl)-, 4-(\u3c9-functionalized alkylsulfanyl)-, and 4-alkylsulfanyl-4\u2019-halo-2,2\u2019-bithiophenes

Aminoalkylsulfanyl Substituted Polythiophene: an Aggregation Study

The aggregation behaviour of poly{trimethyl-[7-(3-thienylsulfanyl)heptyl]ammonium iodide-co-thiophene} (PTN+Me3) was investigated through NMR, atomic force microscopy (AFM), dynamic light scattering (DLS), UV-Vis and fluorescence spectroscopy. The interaction with sodium ursodesoxycholate (NaUDC) causes a marked enhancement of fluorescence emission

7-Oxo-[1,4]oxazino[2,3,4-<i>ij</i>]quinoline-6-carboxamides as Selective CB₂ Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists

Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]­oxazino­[2,3,4-<i>ij</i>]­quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB₂ receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (<b>20</b>, hCB₂ <i>K</i>_i = 2.5 nM, SI = 166; <b>21</b>, hCB₂ <i>K</i>_i = 0.81 nM, SI = 383; <b>38</b>, hCB₂ <i>K</i>_i = 15.8 nM, SI > 633; <b>56</b>, hCB₂ <i>K</i>_i = 8.12 nM, SI > 1231; (<i>R</i>)-<b>58</b>, hCB₂ <i>K</i>_i = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (<i>R</i>)-enantiomers exhibited greater affinity at the CB₂ receptor than the (<i>S</i>)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB₂ receptor

Discovery of 7‑Oxopyrazolo[1,5‑<i>a</i>]pyrimidine-6-carboxamides as Potent and Selective CB₂ Cannabinoid Receptor Inverse Agonists

We recently described the medicinal chemistry of a new series of heteroaryl-4-oxopyridine/7-oxopyrimidines as CB₂ receptor partial agonists, showing that the functionality of these ligands is controlled by the nature of the heteroaryl function condensed with the pyridine ring. We describe herein the design and synthesis of the 7-oxopyrazolo­[1,5-<i>a</i>]­pyrimidine-6-carboxamides, structural isomers of our previously reported pyrazolo­[3,4-<i>b</i>]­pyridines. All of the new compounds showed high affinity and selectivity for the CB₂ receptor in the nanomolar range. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series shows stimulatory effects on forskolin-induced cAMP production acting as inverse agonists

Venous thromboembolism and COVID-19: a single center experience from an academic tertiary referral hospital of Northern Italy

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in d-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE