Effectiveness and safety of two different antithymocyte globulins used in induction therapy in kidney transplant recipients: A single-center experience.

BACKGROUND: Antithymocyte globulin (ATG) is widely used as an induction therapy after kidney transplantation. The present study aimed to compare the effectiveness and safety of induction therapy between two ATG formulations, Grafalon (Fresenius® ) and Thymoglobulin (Sanofi® ), in kidney transplant patients. METHODS: This study included 140 consecutive kidney transplant recipients, 71 treated with Grafalon and 69 treated with Thymoglobulin, in the period between February 2010 and January 2018. To optimize therapy costs, considering the periodically limited drug availability and the substantial drug waste in the case of Grafalon, Thymoglobulin induction was introduced into the immunosuppressive protocol. RESULTS: The ATG total dose in mg/kg of body mass [median: 5.3 (3.7-7.1) vs 8.6 (4.3-17.3); P < .001] was significantly lower in the Thymoglobulin subgroup. There were 7 (5%) graft losses and 15 (10.7%) deaths during the first 12 months, with 66.7% of deaths due to infection complications. Patients treated with Thymoglobulin were characterized by a lower absolute lymphocyte count at day 7 and during the 12 months of follow-up, compared with the Grafalon group [236 (205-267) vs 483 (372-594), respectively; P < .001]. Logistic regression analysis showed that a lymphocyte count < 200/µL at day 7 (OR = 10.5; 95%CI, 1.6-69.0; P = .01) and age >50 years (OR = 14.6; 95%CI, 1.4-155.0; P = .03), but not type of ATG, independently increased the risk of death due to infection. The 12-month acute rejection rate was higher in the Grafalon group (25.3% vs 10.1%, P = .02). CONCLUSION: Treatment with Thymoglobulin in kidney transplant recipients resulted in more pronounced lymphopenia and a lower 12-month rate of acute rejection.

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H3 receptor ligands.

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H3 receptor (hH3R) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hH3R affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hH3R Ki = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at H3R, as well as drug-like properties of selected ligands were evaluated using in vitro methods.

Optimization and preclinical evaluation of novel histamine H3receptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives.

As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Ki = 5.2-115 nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Ki = 5.2 and 15.4 nM vs. 10.2 and 115 nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.

The Pre-Transplant Drop in Panel-Reactive Antibodies Titer Evaluated Using Complement-Dependent Cytotoxicity (PRA-CDC) and the Risk of Early Acute Rejection in Sensitized Kidney Transplant Recipients.

Background: The panel-reactive antibodies that use the complement-dependent cytotoxicity test (PRA-CDC) are still a standard method for monitoring the degree of immunization in kidney transplant candidates on active waiting lists in some countries, including Poland. The aim of this study was to analyze the relationship between the maximum and the last pre-transplant PRA titer on the percentage of positive cross-matches and rate of early acute rejection episodes. Material and methods: The retrospective analysis included 528 patients from two transplant centers. All patients were divided into three groups, depending on their peak and last pre-transplant PRA titers. There were 437 (82.8%) patients with peak PRA <20% (non-sensitized group, non-ST) and 91 (17.2%) patients with peak PRA >20%. Among the latter group, 38 had maintained PRA level >20% at the time of transplantation (sensitized patients, ST), whereas 53 had pre-transplant PRA ≤20% (previously sensitized patients, prev-ST). Results: The percentages of positive crossmatches were 76.9% in ST and 53.7% in prev-ST groups versus 18.4 in non-ST group (both p < 0.001). The acute rejection rates were 18.9, 17.6 and 6.8%, respectively (p < 0.001 for ST or prev-ST versus non-ST). The pre-transplant PRA titer drop did not decrease the risk of early acute rejection [OR = 1.09 (95% CI: 0.31⁻3.85)] in a multiple logistic regression analysis. The occurrences of primary graft non-function and delayed graft function were similar in all study groups. Conclusions: Previously immunized kidney transplant candidates even with substantial decrease in pre-transplant PRA-CDC levels are still at high immunological risk when compared with non-immunized patients, and they should receive lymphocyte-depleting induction therapy.