nling Li

Effect of CYP3A5 Genotype on Renal Allograft Recipients Treated With Tacrolimus

OBJECTIVE Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months. METHODS Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy. RESULTS There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group. CONCLUSION CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.

Glass Transitions of Poly(methyl methacrylate) Confined in Nanopores: Conversion of Three- and Two-Layer Models

The glass transitions of poly(methyl methacrylate) (PMMA) oligomer confined in alumina nanopores with diameters much larger than the polymer chain dimension were investigated. Compared with the case of 80 nm nanopores, PMMA oligomer confined in 300 nm nanopores shows three glass transition temperatures (from from low to high, denoted as Tg,lo, Tg,inter, and Tg,hi). Such phenomenon can be interpreted by a three-layer model: there exists an interphase between the adsorbed layer and core volume called the interlayer, which has an intermediate Tg. The behavior of multi-Tg parameters is ascribed to the propagation of the interfacial interaction during vitrifaction process. Besides, because of the nonequilibrium effect in the adsorbed layer, the cooling rate plays an important role in the glass transitions: the fast cooling rate generates a single Tg; the intermediate cooling rate induces three Tg values, while the ultraslow cooling rate results in two Tg values. With decreasing the cooling rate, the thickness of interlayer would continually decrease, while those of the adsorbed layer and core volume gradually increase; meanwhile, the Tg,lo gradually increases, Tg,inter almost stays constant, and the Tg,hi value keeps decreasing. In such a process, the dynamic exchanges between the interlayer and adsorbed layer, core volume should be dominant.

Therapeutic effect of Tripterygium wilfordii on proteinuria associated with sirolimus in renal transplant recipients.

Sirolimus (SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after renal transplantation. Nevertheless, the occurrence of proteinuria has recently been recognized among patients on SRL-based therapy. The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii Hook F. (T II) on proteinuria associated with SRL in renal transplant recipients. According to accepting T II, 36 recipients were divided into 2 groups: T II group (n = 21) and valsartan group (n = 15). The T II group was administered 1 mg/kg/d, and the valsartan group, 80 mg twice per day for 12 months. Efficiency was then evaluated. Complete remission: proteinuria decreased by >50%; partial remission: proteinuria decreased by 20% to 50%; ineffective: proteinuria decreased by <20%. Upon 12-month follow-up, the total effective rates in the T II group and the valsartan group were 95.2% and 86.7% (P < .05), respectively. Twenty of 21 patients with proteinuria in the T II group were negative at 3-month follow-up with disappearance of edema. There were some adverse events that had greater incidence rates in the valsartan group compared with the T II group, such as hyperkalemia (26.7% vs 4.8%). We concluded that the application of T II markedly reduced proteinuria associated with SRL in renal transplant patients.

Observation of Efficacy and Safety of Converting the Calcineurin Inhibitor to Sirolimus in Renal Transplant Recipients With Chronic Allograft Nephropathy

OBJECTIVE The objective of this study was to evaluate the efficacy and safety of converting from a calcineurin inhibitor (CNI) to sirolimus among renal transplant recipients with chronic allograft nephropathy (CAN). METHODS In 16 patients with CAN, substituted sirolimus for CsA or FK506 and observed the incidence of acute rejection and changes in serum creatinine, triglycerides, cholesterol, blood uric acid, and peripheral blood leukocyte/platelet counts within 12 months. All recipients underwent an allograft biopsy before conversion. The targeted sirolimus level was 4-8 ug/L. RESULTS After conversion to sirolimus, the creatinine level of 7 cases decreased and the efficacy rate was (43.8%). No acute rejection occurred during the follow-up. The cases with hypercholesteremia increased from 3 to 7 after conversion; hypertriglyceridemia increased from 3 to 5; leukopenia occurred in 2; subnormal platelet counts increased from 2 to 3; and hyperuricemia increased from 6 to 7. Meanwhile, the average level of peripheral blood leukocytes obviously decreased in the first month, the average peripheral blood cholesterol increased over 12 months, but the average content of peripheral blood platelets, triglyceride and blood uric acid failed to display as statistic difference. Eight patients showed C4d deposition in peritubular capillary in graft tissue before conversion, 7 cases of whom showed no improvement in renal function. In 6 cases there was no C4d deposition in peritubular capillary in graft tissue. Only 2 of 6 cases showed no improvement in renal function. There were 6 patients whose creatinine level was <2.48 mg/dL before conversion, and renal function in 5 of them improved in a year after conversion. In contrast, among 10 patients whose blood creatinine level was >2.48 mg/dL, only 2 cases improved. CONCLUSION It is safe for patients with CAN to use substitute sirolimus for CNI; the incidence of acute rejection did not increase. In this study, 43.8% of patients showed improved renal function. The main adverse reactions after conversion to sirolimus were hypercholesteremia and decreased peripheral blood leukocytes. The serum creatinine level and the deposition of C4d in peritubular capillary were important factors influencing therapeutic efficacy.

Synthesis, characterization and thermal properties of polystyrene–poly(lactic acid)–polystyrene triblock copolymer via atom transfer radical polymerization

Polystyrene (PS)–poly(lactic acid) (PLA)–PS triblock copolymer is prepared with PLA and styrene (St) via atom transfer radical polymerization (ATRP). The structure and thermal properties of the copolymer are analyzed by infrared spectroscopy, gel permeation chromatography, nuclear magnetic resonance, thermogravimetry, differential scanning calorimetry and alcoholysis. The ATRP of St using bromine-terminated PLA as the initiator exhibits first-order kinetics and a low-molecular-weight distribution (M w/M n ≈ 1.5). The thermal stability of PLA is improved by copolymerization. Both the initial temperature of thermal decomposition and glass transition temperature are increased with an increasing length of PS block.

Successful Renal Transplantation in a Patient With Antineutrophil Cytoplasmic Autoantibody-Associated Microscopic Polyangiitis: Effect of Early Plasma Exchange and Mycophenolate Mofetil

Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis readily relapses after renal transplantation; the recurrence often causes graft losts. We have reported herein a 53-year-old cadaveric renal allograft recipient. His original disease was ANCA-associated microscopic polyangiitis (MPA), which was proven by renal biopsy. On postoperative day 4, the patient developed dyspnea, hemoptysis, and gross hematuria; the serum p-ANCA titer increased from 1:40 to 1:80. The patient was immediately treated with 5 sessions of plasma exchange. Five days later, the hemoptysis and gross hematuria both disappeared. Serum p-ANCA titer recovered to 1:40. The patient showed stable graft function for 2 months, until mycophenolate mofetil (MMF) was converted to mizoribine (150 mg/d). Seven days after the conversion, the serum creatinine increased from 1.27 to 1.7 mg/dL. Serum p-ANCA increased to 1:160. When mizoribine was converted to MMF, 2 days later the renal function and p-ANCA titer recovered. This case report suggested that early use of plasma exchange combined with MMF was effective to prevent the relapse of ANCA-associated systemic vasculitis after transplantation, and may be helpful to improve transplant outcomes.

How thermal stress alters the confinement of polymers vitrificated in nanopores

Understanding and controlling the glass transition temperature (Tg) and dynamics of polymers in confined geometries are of significance in both academia and industry. Here, we investigate how the thermal stress induced by a mismatch in the coefficient of thermal expansion affects the Tg behavior of polystyrene (PS) nanorods located inside cylindrical alumina nanopores. The size effects and molecular weight dependence of the Tg are also studied. A multi-step relaxation process was employed to study the relationship between thermal stress and cooling rate. At fast cooling rates, the imparted thermal stress would overcome the yield stress of PS and peel chains off the pore walls, while at slow cooling rates, chains are kept in contact with the pore walls due to timely dissipation of the produced thermal stress during vitrification. In smaller nanopores, more PS chains closely contact with pore walls, then stronger internal thermal stress would be generated between core and shell of PS nanorod, which results in a larger deviation between two Tgs. The core part of PS shows lower Tg than bulk value, which can induce faster dynamics in the center region. A complex and important role stress plays is supposed in complex confinement condition, e.g., in nanopores, during vitrification.

Tripterygium Wilfordii Hook F Increase the Blood Concentration of Tacrolimus

OBJECTIVE To observe the influence of the Tripterygium wilfordii Hook F (T II) on the blood concentration of tacrolimus and analyze the impact of this effect. METHOD Twenty-two renal transplant receipts taking tacrolimus combined with the T II were selected for this study. We analyzed the blood concentrations and the rate of concentration compared with dosage (C/D rate) pre- and postcombination over 6 months. All cases underwent the CYP3A5 genotype test. RESULT The concentrations of tacrolimus were raised to a certain degree after the combination in all the cases. The first-time elevation differed from 1 week to 4 months. The C/D rate increased by 1.7 to 7.2 times with most evaluated C/D rates ranging from 1.8 to 3.8. The elevated C/D rate of the subgroup of CYP3A5 1/1 and 1/3 (n = 10) contrasted with the 3/3 genotype subgroup (n = 12: 2.99 +/- 1.71 vs 2.55 +/- 1.07; P = .472). The mycophenolate mofetil subgroup (n = 17) was not contrasted to the mizoribine subgroup (n = 5: 2.85 +/- 1.51 vs 2.31 +/- 0.26; P = .498). CONCLUSION T II considerably increased the blood concentration and the C/D rate of tacrolimus. The degree of increase was probably not related to the CYP3A5 genotype and the combination of immunosuppressive agents.

Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial, and Intermolecular Interactions

The production and stabilization of amorphous drugs by the nanoconfinement effect has recently become a research hotspot in pharmaceutical sciences. Herein, two guest/host systems, indomethacin (IMC) and griseofulvin (GSF) confined in anodic aluminum oxide (AAO) templates with different pore diameters (25-250 nm) are investigated by differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). The crystallization of the confined drugs is suppressed, and their glass transition temperatures show an evident pore-size dependency. Moreover, a combination of dielectric and calorimetric results demonstrates that the significant change in the temperature dependence of the structural relaxation time during the cooling process is attributed to the vitrification of the interfacial molecules and the local density heterogeneity under isochoric confinement. Interestingly, compared with the case of IMC/AAO, which can be described by a typical two-layer model, GSF/AAO presents an rare scenario of three glass transition temperatures under fast cooling (40-10 K/min), indicating that there exists a thermodynamic nonequilibrium interlayer between the bulk-like core and interfacial layer. In contrast, the slow cooling process (0.5 K/min) would lead confined GSF into the stable core-shell nanostructure. Using surface modification, the interfacial effect is confirmed to be an important reason for the different phenomena between these two guest/host systems, and intermolecular hydrogen bonding is also suggested to be emphasized considering the long-range effect of interfacial interactions. Our results not only provide insight into the glass transition behavior of geometrically confined supercooled liquids, but also offer a means of adjusting and stabilizing the nanostructure of amorphous drugs under two-dimensional confinement.

Crowding-Induced Crystallization of Poly(Ethylene Terephthalate)

Samples of poly(ethylene terephthalate) (PET) extracted from three-component systems with different ratios among PET, phenol, and poly(ethylene glycol) (PEG) were prepared. As a crowding agent, PEG can greatly increase PET crystallinity. The crystal and thermal behaviors were characterized by wide-angle x-ray scattering and differential scanning calorimetry. There were two endothermic maxima of the crowding-induced crystallization process as molecular weight and concentration of PEG increased. The theory of crowding can interpret the phenomena well.