Tacrolimus-related adverse effects in liver transplant recipients: Its association with trough concentrations

Background

Tacrolimus is an important immunosuppressant administered to patients following liver transplantation (LT), with a recommended trough concentration of 8 to 11 ng/mL to prevent allograft rejection. We retrospectively examined our data to identify the tacrolimus trough concentration that combined efficacy with minimal adverse effects.

Methods

The case records of LT recipients, who were nondiabetic, nonhypertensive, and with normal renal parameters prior to LT were retrospectively examined for acute cellular rejection (ACR) episodes and three major adverse effects of tacrolimus, i.e. neurotoxicity, nephrotoxicity, and new onset diabetes mellitus (NODM).

Results

Thirty-two LT recipients fulfilled the criteria for the study. The mean (±SD) tacrolimus level for the 290 troughs (after 10 days) was 8.5?±?3.8 ng/mL. At 10 days, 1 month, 3 months, and 6 months, the trough values were 7.3?±?2.9, 9.7?±?3.4, 7.9?±?3.3, and 7.6?±?2.6 ng/mL, respectively. The mean time taken for stabilization of the blood pressure and biochemical parameters was 7?±?2 days. Overall, a trough window with the least adverse effect was 7 to 7.9 ng/mL. Neurotoxicity was least in the trough range 5 to <8 ng/mL. Symptoms included headache in four, tremors in three, seizure in one, confusion and psychosis in two, and combination in three. Nephrotoxicity was least in trough 8 to <11 ng/mL. One patient progressed to chronic kidney disease at 6 months. NODM was present in 11 % to 18 % across the various trough range, including the extremes (mean trough level, 8.4?±?4.4 ng/dL). At 6 months, five recipients were on treatment for NODM. Three recipients developed ACR, two within the first month and one at 7 weeks. The trough levels were 8.5, 9, 15.2 ng/mL, respectively. All recovered with three pulse doses of methylprednisolone.

Conclusion

Tacrolimus concentration of 5 to <8 ng/mL was associated with least overall toxicity, neurotoxicity, and ACR.     

Sex differences in the prevalence of peripheral artery disease in patients undergoing coronary catheterization

To determine whether there are sex differences in the prevalence of peripheral artery disease, we performed an observational study of 1014 men and 547 women, aged ≥ 40 years, referred for elective coronary angiography. Women were slightly older, more obese, had higher low-density lipoprotein cholesterol (LDL-C) levels and systolic blood pressure (BP), and were more likely to be African American. Women had higher high-density lipoprotein cholesterol (HDL-C) levels, lower diastolic BP, and were less likely to smoke or to have a history of cardiovascular disease. Women had less prevalent (62% vs 81%) and less severe coronary artery disease (CAD) (p < 0.001 for both) by coronary angiography, but more prevalent peripheral artery disease (PAD) as determined by the ankle-brachial index (ABI) than men (23.6% versus 17.2%). Independent predictors of lower ABI were female sex, black race, older age, tobacco use, CAD, diabetes, and triglyceride level. In a full multivariable logistic regression model, women had a risk-adjusted odds ratio for PAD of 1.78 (95% CI 1.25-2.54) relative to men. Among patients referred for coronary angiography, women have less prevalent and less severe CAD, but more prevalent PAD, a sex difference that is not explained by traditional cardiovascular disease risk factors or CAD severity. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00380185.     

Value of high-density endocardial and epicardial mapping for catheter ablation of hemodynamically unstable ventricular tachycardia

BACKGROUND: Percutaneous epicardial mapping has been used for ablation of recurrent ventricular tachycardia (VT). OBJECTIVES: The purpose of this study was to use a combined epicardial and endocardial mapping strategy to delineate the myocardial substrate for recurrent VT in both ischemic (n = 12) and nonischemic cardiomyopathy (n = 8), and to define the role of epicardial ablation. METHODS: Electroanatomic mapping was performed in 20 patients. High-density voltage maps were obtained by acquiring both endocardial and epicardial electrograms. Electrograms derived from six patients with structurally normal hearts were used as controls. A total of 26 VTs were targeted in the 20 patients. RESULTS: Most VTs (23/26 [88.5%]) were hemodynamically unstable. In patients with ischemic cardiomyopathy, the extent of endocardial scar was greater than epicardial scar. A definable pattern of scar could not be demonstrated in nonischemic cardiomyopathy. Pathologic examination of explanted hearts in two patients with nonischemic cardiomyopathy demonstrated that low-voltage areas were not always predictive of scarred myocardium. A substrate-based approach was used for catheter ablation. Catheter ablation was performed on the endocardium in all patients; additional epicardial delivery of radiofrequency energy was required in 8 (40%) of 20 patients for successful ablation. During follow-up (12 +/- 4 months), 15 (75%) of 20 patients have been arrhythmia-free. CONCLUSION: Patients with ischemic cardiomyopathy tend to have a larger endocardial than epicardial scar. Use of epicardial and endocardial electroanatomic mapping to define the full extent of myocardial scars allows successful catheter ablation in patients with hemodynamically unstable VTs.     

Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery

The fabrication, morphological characterization, and drug release kinetics from microspheres of three bioerodible polyanhydrides, poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)), poly(sebacic anhydride) (poly(SA)), and the copolymer poly(CPH-co-SA) 50:50 (CPH:SA 50:50) is reported. The fabrication technique yields microspheres with different morphologies for each of the three polymers studied, ranging from very smooth exterior surfaces for poly(CPH) to coarse surface roughness with large pores for poly(SA). Release profiles for the model drug, p-nitroaniline are also different for each polymer. The release profile from poly(CPH) has a large initial burst and shows little additional release after 2 days. The release from poly(SA) is nearly zero-order and lasts for about 8 days. The release profile from CPH:SA 50:50 shows a relatively small burst and then exhibits zero-order release for about I month. The different release profiles are attributed to both polymer erosion rates and drug distribution characteristics of the microspheres. Tailored release profiles of a burst followed by zero-order release are obtained by appropriately combining the microspheres. This technique enables independent modulation of both the burst and the zero-order release rate by varying the number of poly(CPH) and poly(SA) microspheres respectively. Additionally, the zero-order release can be extended from about a week to a month by including CPH:SA 50:50 microspheres.     

Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter,Factorial, Randomized,Controlled Pilot Trial

Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of ≥2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 × 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of ≥80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47–1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90–1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries.Clinical trial number: NCT02240199PerspectiveThis article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.     

Management of radial clubhand with gradual distraction followed by centralization

Background:

Treatment of radial clubhand has progressed over the years from no treatment to aggressive surgical correction. Various surgical methods of correction have been described; Centralization of the carpus over the distal end of the ulna has become the method of choice. Corrective casting prior to centralization is an easy and effective method of obtaining soft tissue stretching before any definitive procedure is undertaken. Moreover, it helps put the limb in a correct position. The outcome of deformity correction by serial casting / JESS distractor followed by centralization is discussed.

Materials and Methods:

In a prospective study, of 17 cases with 18 radial clubhands of Heikel''s Grade III and IV (with average age 11 months (range 20 days – 24 months) with M:F of 2.6:1, were treated by gradual soft tissue stretching using corrective cast (14 cases) and JESS distraction (4 cases), followed by centralization (16 cases) or radialization (2 cases) and tendon transfers.

Results:

The average correction attained during the study was 71° of radial deviation and 31° of volar flexion. The average third metacarpal to distal ulna angle in anteroposterior and lateral view at final follow-up was 7° in both views. Angle of movement at elbow showed a small increase from 99° to 101° during the follow-up period. However, the range of movement at fingers showed increase in stiffness during the follow-up. No injury occurred to the distal ulnar epiphysis during the operative intervention. The results at the final follow-up, at the end of 2 years were graded on the basis of the criteria of F.W. Bora, and of Bayne and Klug. Considering the criteria of F.W. Bora, satisfactory result was shown by nine of the 18 hands (50%) while 16 out of 18 hands (89%) showed good or satisfactory result based on deformity criteria of Bayne and Klug.

Conclusion:

The management of radial clubhand by gradual corrective cast or JESS distractor followed by centralization and tendon transfers in children is an acceptable method of treatment with consistently satisfactory results, both functional and cosmetic.     

Thermostable variants of cocaine esterase for long-time protection against cocaine toxicity

Enhancing cocaine metabolism by administration of cocaine esterase (CocE) has been recognized as a promising treatment strategy for cocaine overdose and addiction, because CocE is the most efficient native enzyme for metabolizing the naturally occurring cocaine yet identified. A major obstacle to the clinical application of CocE is the thermoinstability of native CocE with a half-life of only a few minutes at physiological temperature (37 degrees C). Here we report thermostable variants of CocE developed through rational design using a novel computational approach followed by in vitro and in vivo studies. This integrated computational-experimental effort has yielded a CocE variant with a approximately 30-fold increase in plasma half-life both in vitro and in vivo. The novel design strategy can be used to develop thermostable mutants of any protein.