Tacrolimus Combined with Two Different Dosages of Sirolimus in Kidney Transplantation: Results of a Multicenter Study

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.     

Electrical coupling can prevent expression of adult-like properties in an embryonic neural circuit.

Electrical coupling is widespread in developing nervous systems and plays a major role in circuit formation and patterning of activity. In most reported cases, such coupling between rhythmogenic neurons tends to synchronize and enhance their oscillatory behavior, thereby producing monophasic rhythmic output. However, in many adult networks, such as those responsible for rhythmic motor behavior, oscillatory neurons are linked by synaptic inhibition to produce rhythmic output with multiple phases. The question then arises whether such networks are still able to generate multiphasic output in the early stage of development when electrical coupling is abundant. A suitable model for addressing this issue is the lobster stomatogastric nervous system (STNS). In the adult animal, the STNS consists of three discrete neural networks that are comprised of oscillatory neurons interconnected by reciprocal inhibition. These networks generate three distinct rhythmic motor patterns with large amplitude neuronal oscillations. By contrast, in the embryo the same neuronal population expresses a single multiphasic rhythm with small-amplitude oscillations. Recent findings have revealed that adult-like network properties are already present early in the embryonic system but are masked by an as yet unknown mechanism. Here we use computer simulation to test whether extensive electrical coupling may be involved in masking adult-like properties in the embryonic STNS. Our basic model consists of three different adult-like STNS networks that are built of relaxation oscillators interconnected by reciprocal synaptic inhibition. Individual model cells generate slow membrane potential oscillations without action potentials. The introduction of widespread electrical coupling between members of these networks dampens oscillation amplitudes and, at moderate coupling strengths, may coordinate neuronal activity into a single rhythm with different phases, which is strongly reminiscent of embryonic STNS output. With a further increase in coupling strength, the system reaches one of two final states depending on the relative contribution of inhibition and inherent oscillatory properties within the networks: either fully synchronized and dampened oscillations, or a complete collapse of activity. Our simulations indicate that, beginning from either of these two states, the emergence of distinct adult networks during maturation may arise from a developmental decrease in electrical coupling that unmasks preexisting adult-like network properties.     

MISE AU POINT D'UNE TECHNIQUE D'ADMINISTRATION IN VIVO DES VECTEURS GENETIQUES DANS LEMUSCLE CARDIAQUE

Objective In order to improve the in vivo gene transfer into the heart muscle, we have designed a ECG-synchronized microinjection system that allows sequential gene delivery to the myocardium.Methods A cannula was introduced into the right carotid artery of the Wistar rat under general anesthesia.With the ECG-synchronized injection during diastole, the genetic vector (Ad CMV lacZ ) infusion was performed with various concentrations( l07 ～ l010pfu ) and different frequency ( the ratio of heart beats per injection from 1: 1 to 4: 1 ). The hearts of the rats were removed after 7 days for histological examination. Results Best results were obtained with a total vector amount of l09 pfu and a good ratio 3: 1 between heart frequency and injection frequency. The transfection efficiency was increased by use of vasodilators and by an increase of vascular permeability. No signs of myocardial ischemia or ventricular arrythmia were observed. Conclusion We have established a novel and safe method for in vivo gene transfer into the heart. Transgene expression suggests that this method may be useful technique to study cardiac function of treat cardiac diseases by means of gene theratpy.     

Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.     

Comparison of the detection of subtle changes in myocardial regional systolic function using qualitative and semi-quantitative techniques.

PURPOSE: To evaluate qualitative wall motion assessment vs. quantitative wall thickening for the assessment of subtle changes in myocardial systolic function using cine MRI. METHODS: Cine MR images were obtained in 5 canines with a significant coronary artery stenosis and in 2 controls on a 1.5T scanner. Qualitative results were obtained using a numerical scoring system; quantitative analysis was performed using a semi-automatic segmentation program. The techniques were matched and compared using Spearman correlations. RESULTS: All correlations in the experimental group revealed significant but weak to moderate relationships between the qualitative and quantitative results (e.g., at-risk tissue rho = 0.363, p < 0.0001; remote tissue rho = 0.275, p = 0.0002), with each identifying changes in regional function that ensued following creation of the stenosis. Intra-observer variability was reasonable in both methods when repeat analysis on a subset of the data was performed, with both techniques showing a significant correlation between the repeated measurements (quantitative - rho = 0.52, p < 0.0001; qualitative - rho = 0.54, p < 0.0001). CONCLUSION: Both methods were able to detect very limited wall motion abnormalities present in the canines with significant stenosis and either method gives comparable results.