A Study of the Influence of Operating Conditions on the Degradation of the Structure of Steel 14MoV63

Приведены результаты исследования микроструктуры и свойств образцов, выполненных из фрагментов труб паропроводов из стали 12Х1МФ. Рассмотрена деградация структуры стали в процессе эксплуатации и изменения механических свойствThe results of the study of the microstructure and properties of the manufactured pipe fragments of steel pipe lines 14MoV63 are given. The deterioration of the structure of the steel during operation and changes in mechanical properties are considere

Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig

1. Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to possess antiaddictive properties in several models of drug dependence. We have examined their effect at μ-opioid receptors regulating neurogenic contractions of several smooth muscle preparations and also against spontaneous contractions of the rat isolated portal vein. 2. Ibogaine (pIC(50) 5.28) and 18-methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of cholinergic contractions of the guinea-pig ileum which was not affected by the opioid receptor antagonist naloxone (1 μM). 3. In the rat isolated vas deferens ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement of purinergic contractions. Both agents (30 μM) caused a 3–5 fold rightward displacement of DAMGO-induced inhibition of purinergic contractions, but similar effects were observed for ibogaine against α(2)-adrenoceptor-mediated inhibition of neurogenic responses. 4. In the guinea-pig isolated bladder both ibogaine (10 μM) and 18-methoxycoronaridine (10 μM) caused a 2 fold increase in the purinergic component of neurogenic contractions without significantly altering cholinergic contractions or responses to exogenous ATP. In contrast, ibogaine (1–30 μM), but not 18-methoxycoronaridine, caused a concentration-dependent enhancement of spontaneous contractions of the rat isolated portal vein. 5. In summary, while ibogaine and 18-methoxycoronaridine modulated electrically-evoked contractions in the three preparations examined, we have no evidence for a selective interaction with pre-junctional μ-opioid receptors. The pronounced enhancement of purinergic contractions produced by both agents is a novel finding and worthy of further investigation

An ex Vivo

Transurothelial drug delivery continues to be an attractive treatment option for a range of urological conditions; however, dosing regimens remain largely empirical. Recently, intravesical delivery of the nonsteroidal anti-inflammatory ketorolac has been shown to significantly reduce ureteral stent-related pain. While this latest development provides an opportunity for advancing the management of stent-related pain, clinical translation will undoubtedly require an understanding of the rate and extent of delivery of ketorolac into the bladder wall. Using an ex vivo porcine model, we evaluate the urothelial permeability and bladder wall distribution of ketorolac. The subsequent application of a pharmacokinetic (PK) model enables prediction of concentrations achieved in vivo. Ketorolac was applied to the urothelium and a transurothelial permeability coefficient (Kp) calculated. Relative drug distribution into the bladder wall after 90 min was determined. Ketorolac was able to permeate the urothelium (Kp = 2.63 × 10–6 cm s–1), and after 90 min average concentrations of 400, 141 and 21 μg g–1 were achieved in the urothelium, lamina propria and detrusor respectively. An average concentration of 87 μg g–1 was achieved across the whole bladder wall. PK simulations (STELLA) were then carried out, using ex vivo values for Kp and muscle/saline partition coefficient (providing an estimation of vascular clearance), to predict 90 min in vivo ketorolac tissue concentrations. When dilution of the drug solution with urine and vascular clearance were taken into account, a reduced ketorolac concentration of 37 μg g–1 across the whole bladder wall was predicted. These studies reveal crucial information about the urothelium’s permeability to agents such as ketorolac and the concentrations achievable in the bladder wall. It would appear that levels of ketorolac delivered to the bladder wall intravesically would be sufficient to provide an anti-inflammatory effect. The combination of such ex vivo data and PK modeling provides an insight into the likelihood of achieving clinically relevant concentrations of drug following intravesical administration

NOP-Targeted Peptide Ligands

The nociceptin/orphanin FQ (N/OFQ)-N/OFQ peptide (NOP) receptor system is widely distributed at both the peripheral and central level where it modulates important biological functions with increasing therapeutic implications. This chapter wants to provide a comprehensive and updated overview focused on the available structure-activity relationship studies on NOP receptor peptide ligands developed through different rational approaches. Punctual modifications and cyclizations of the N/OFQ sequence have been properly combined furnishing potent NOP selective ligands with different pharmacological activities (full and partial agonists, pure antagonists) and enhanced metabolic stability in vivo. The screening of peptide libraries provided a second family of NOP ligands that have been successfully optimized. Moreover, recent findings suggest the possibility to apply different multimerization strategies for the realization of multi-target NOP/opioid receptor ligands or tetrabranched N/OFQ derivatives with extraordinarily prolonged duration of action in vivo. The diverse approaches led to the identification of important pharmacological tools along with drug candidates currently in clinical development such as Rec 0438 (aka UFP-112) for the treatment of overactive bladder and SER 100 (aka ZP120) for the clinical management of systolic hypertension