Anti-Thymocyte Gamma-Globulin May Prevent Antibody Production After Heart Transplantation

BackgroundRabbit anti-thymocyte globulin (RATG) has been used as induction therapy in heart transplantation. RATG is polyclonal and has been postulated to have anti-humoral properties by preventing the production of circulating antibodies after heart transplant. Thus, we reviewed our patients who received RATG induction therapy and compared them with those who did not receive therapy for post-transplant de novo antibody production.MethodsBetween January 1, 2006, and January 1, 2013, we assessed 196 non-sensitized heart transplant recipients and divided them into those who received 3 to 5 days of RATG induction therapy mostly due to renal insufficiency (n = 35) versus patients who did not receive therapy (n = 161). All patients were given tacrolimus, mycophenolate mofetil, and corticosteroids. Post-transplant circulating antibodies were routinely monitored at 1, 3, 6, and 12 months after heart transplantation; 1-year and 3-year end points were assessed.ResultsThe RATG-treated group had a significantly higher 12-month freedom from de novo antibody production compared with the patients who did not receive RATG induction (89% vs 71%, log-rank P = .043); however there was no significant difference for 12-month freedom from de novo donor-specific antibody production (91% vs 88%, log-rank P = .541). Treated rejection rates in the first-year were comparable in both groups; 3-year actuarial survival, freedom from cardiac allograft vasculopathy, and freedom from non-fatal major adverse cardiac events were also similar between both groups.ConclusionsRATG induction therapy appears to reduce the production of de novo circulating antibodies in non-sensitized patients during the first year after heart transplantation. Although there were no short-term clinical differences between groups, there were imbalances in group characteristics and relatively short follow-up, which are limitations to this study. A randomized, clinical trial with longer follow-up in a larger cohort of patients is warranted.     

Chronic meningitis in systemic lupus erythematosus: An unusual etiology

Chronic aseptic meningitis is a rare manifestation of systemic lupus erythematosus (SLE). Apart from immunological causes and drugs, the aseptic meningitis group can include some unidentified viral infections that cannot be detected by routine microbiological testing. It is imperative to do complete cerebrospinal fluid (CSF) workup before implicating the symptoms to disease activity or drugs, as untreated infections cause significant mortality in SLE. We present a case of young female with SLE who presented with chronic meningitis of an uncommon etiology.     

Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery

Urinary biomarkers of AKI provide prognostic value for in-hospital outcomes, but little is known about their association with longer-term mortality after surgery. We sought to assess the association between kidney injury biomarkers and all-cause mortality in an international, multicenter, prospective long-term follow-up study from six clinical centers in the United States and Canada composed of 1199 adults who underwent cardiac surgery between 2007 and 2009 and were enrolled in the Translational Research in Biomarker Endpoints in AKI cohort. On postoperative days 1–3, we measured the following five urinary biomarkers: neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1 (KIM-1), liver fatty acid binding protein, and albumin. During a median follow-up of 3.0 years (interquartile range, 2.2–3.6 years), 139 participants died (55 deaths per 1000 person-years). Among patients with clinical AKI, the highest tertiles of peak urinary neutrophil gelatinase-associated lipocalin, IL-18, KIM-1, liver fatty acid binding protein, and albumin associated independently with a 2.0- to 3.2-fold increased risk for mortality compared with the lowest tertiles. In patients without clinical AKI, the highest tertiles of peak IL-18 and KIM-1 also associated independently with long-term mortality (adjusted hazard ratios [95% confidence intervals] of 1.2 [1.0 to 1.5] and 1.8 [1.4 to 2.3] for IL-18 and KIM-1, respectively), and yielded continuous net reclassification improvements of 0.26 and 0.37, respectively, for the prediction of 3-year mortality. In conclusion, urinary biomarkers of kidney injury, particularly IL-18 and KIM-1, in the immediate postoperative period provide additional prognostic information for 3-year mortality risk in patients with and without clinical AKI.In many studies, the development of AKI, defined by acute changes in serum creatinine, associates with a higher risk of long-term mortality.^1,2 Acute changes in serum creatinine, however, may not fully reflect the severity of kidney injury due to the influence of age, sex, muscle mass, changes in hydration, nutritional status, and medications on creatinine kinetics. Moreover, serum creatinine may abruptly rise in hospitalized settings due to functional processes such as altered hemodynamics, without any true nephron damage. Several urinary biomarkers of structural kidney injury have been investigated in human cohorts in an effort to identify AKI earlier, improve the diagnosis of AKI, and to aid in risk stratification.³ It is largely unknown, however, whether kidney injury biomarkers associate with long-term outcomes, including mortality, and whether these biomarkers add useful prognostic information beyond the standard measure to detect AKI (e.g., peak change in serum creatinine). Some data suggest that “subclinical AKI,” as evidenced by elevations in urinary kidney injury biomarkers in the absence of a rise in serum creatinine, associates with worse in-hospital clinical outcomes.⁴ Few studies have examined whether kidney injury biomarkers associate with long-term mortality after hospital discharge.⁵To address the current knowledge gaps, we conducted this study to characterize the association between kidney injury biomarkers and long-term mortality and to assess whether these biomarkers provide any incremental prognostic information for long-term mortality beyond that of serum creatinine changes and other clinical variables.     

Surgical Operative Time Increases the Risk of Deep Venous Thrombosis and Pulmonary Embolism in Robotic Prostatectomy

Background and Objectives:

To evaluate the effect of operative time on the risk of symptomatic venous thromboembolic events (VTEs) in patients undergoing robot-assisted radical prostatectomy (RARP).

Methods:

We reviewed the records of all patients at our institution who underwent RARP by a single surgeon from January 2007 until April 2011. Clinical and pathologic information and VTE incidence were recorded for each patient and analyzed by use of logistic regression to evaluate for association with VTE risk. All patients had mechanical prophylaxis, and beginning in February 2008, a single dose of unfractionated heparin, 5000 U, was administered before surgery.

Results:

A total of 549 consecutive patients were identified, with a median follow-up period of 8 months. During the initial 30 days postoperatively, 10 patients (1.8%) had a VTE (deep venous thrombosis in 7 and pulmonary embolism in 3). The median operative time was 177 minutes (range, 121–360 minutes). An increase in operative time of 30 or 60 minutes was associated with 1.6 and 2.8 times increased VTE risks. A 5-point increase in body mass index and need for blood transfusion were also associated with increased risk of VTEs (odds ratios of 2.0 and 11.8, respectively). Heparin prophylaxis was not associated with a significant VTE risk reduction but also was not associated with a significant increase in estimated blood loss (P = .23) or transfusion rate (P = .37).

Conclusion:

A prolonged operative time increases the risk of symptomatic VTEs after RARP. Future studies are needed to evaluate the best VTE prophylactic approach in patients at risk.     

Synergistic Effect of Hydrotrope and Surfactant on Solubility and Dissolution of Atorvastatin Calcium: Screening Factorial Design Followed by Ratio Optimization

The present study was aimed at investigating the effect of hydrotrope and surfactant on poor solubility of atorvastatin calcium. Excipients screening followed by factorial design was performed to study effect of excipients and manufacturing methods on solubility of drug. Three independent factors (carrier, surfactant and manufacturing method) were evaluated at two levels using solubility as a dependant variable. Solid-state characterisation was performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimised complex were incorporated into orally disintegrating micro tablets and in vitro dissolution test was performed. Nicotinamide, Plasdone and sodium dodecyl sulphate were emerged as promising excipients from excipient screening. General regression analysis revealed only the type of carrier has significantly enhanced (P<0.05) the solubility of drug while other factors were found to be nonsignificant. Ratio optimisation trial revealed that drug to nicotinamide ratio is more critical in enhancing the solubility of drug (40 fold increases in solubility compared to pure drug) in comparison to drug-surfactant ratio; however the presence of surfactant deemed essential. Significantly higher rate and extent of dissolution was observed from solid dispersion complex and tablets compared to dissolution of pure drug (P<0.05). Study revealed hydrotrope and surfactant have synergistic effect on solubility and dissolution of atorvastatin calcium and this can be explored further.     

Development and Validation of Stability-indicating HPLC Method for Simultaneous Estimation of Cefixime and Linezolid

A stability-indicating reverse phase high performance liquid chromatography method was developed and validated for cefixime and linezolid. The wavelength selected for quantitation was 276 nm. The method has been validated for linearity, accuracy, precision, robustness, limit of detection and limit of quantitation. Linearity was observed in the concentration range of 2-12 μg/ml for cefixime and 6-36 μg/ml for linezolid. For RP-HPLC, the separation was achieved by Phenomenex Luna C₁₈ (250×4.6 mm) 5 μm column using phosphate buffer (pH 7):methanol (60:40 v/v) as mobile phase with flow rate 1 ml/min. The retention time of cefixime and linezolid were found to be 3.127 min and 11.986 min, respectively. During force degradation, drug product was exposed to hydrolysis (acid and base hydrolysis), H₂O₂, thermal degradation and photo degradation. The % degradation was found to be 10 to 20% for both cefixime and linezolid in the given condition. The method specifically estimates both the drugs in presence of all the degradants generated during forced degradation study. The developed methods were simple, specific and economic, which can be used for simultaneous estimation of cefixime and linezolid in tablet dosage form.