Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy

For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug–drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population.     

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3?Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3?Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10⁹/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.     

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61‐year‐old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis. Diagn. Cytopathol. 2011;39:278–282. © 2010 Wiley‐Liss, Inc.     

Interference with Ca2+ release activated Ca2+ (CRAC) channel function delays T‐cell arrest in vivo

Entry of lymphocytes into secondary lymphoid organs (SLOs) involves intravascular arrest and intracellular calcium ion ([Ca²⁺]_i) elevation. TCR activation triggers increased [Ca²⁺]_i and can arrest T‐cell motility in vitro. However, the requirement for [Ca²⁺]_i elevation in arresting T cells in vivo has not been tested. Here, we have manipulated the Ca²⁺ release‐activated Ca²⁺ (CRAC) channel pathway required for [Ca²⁺]_i elevation in T cells through genetic deletion of stromal interaction molecule (STIM) 1 or by expression of a dominant‐negative ORAI1 channel subunit (ORAI1‐DN). Interestingly, the absence of CRAC did not interfere with homing of naïve CD4⁺ T cells to SLOs and only moderately reduced crawling speeds in vivo. T cells expressing ORAI1‐DN lacked TCR activation induced [Ca²⁺]_i elevation, yet arrested motility similar to control T cells in vitro. In contrast, antigen‐specific ORAI1‐DN T cells had a twofold delayed onset of arrest following injection of OVA peptide in vivo. CRAC channel function is not required for homing to SLOs, but enhances spatiotemporal coordination of TCR signaling and motility arrest.     

12-month efficacy and safety of OROS® MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH

PURPOSE: The aim of this study was to evaluate long-term clinical treatment with OROS methylphenidate (MPH) (Concerta) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had been previously treated with immediate release (IR) MPH. METHODS: Subjects aged 6-16 years (n=105) who were stable on IR MPH (10-60 mg/day) were switched to 18, 36 or 54 mg OROS MPH once daily for 21 days, depending on prestudy MPH dose. Subjects who benefited from OROS MPH could continue in a 12-month extension period. ADHD symptoms and treatment response were assessed by parents/caregivers and investigators. RESULTS: Out of 105 enrolled children, 101 completed the 21-day treatment phase. In all, 89 parents/caregivers (88.1%) wanted their child to continue with the study treatment into the extension phase, and 56 children (63 %) completed the 1-year trial. The parent/caregiver global assessment of satisfaction ranged from 49 to 69% during the extension phase, and 49 to 71% of investigators rated the treatment as adequate. Efficacy and satisfaction were found more commonly in patients in the older age group (10-16 years), those on a higher dose (36 mg or 54 mg) and with the predominantly inattentive ADHD subtype. OROS MPH was well tolerated. CONCLUSIONS: Children and adolescents can effectively and safely be switched from IR MPH to OROS MPH with improved symptom control and compliance.     

Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation

Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the alpha7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor-kappaB nuclear entry in an inhibitor kappaB (IkappaB)alpha- and IkappaBepsilon-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.     

Auxotrophic mutant of the cyanobacterium Nostoc muscorum showing absolute requirement of Cs+ or Rb+ for diazotrophy and autotrophy

Caesium-resistant (Cs(+)-R) mutant clones of the cyanobacterium Nostoc muscorum were characterized for diazotrophic growth in a medium devoid of Cs(+) or Rb(+) or both. Cs(+)-R phenotype suffered severe genetic damage of a pleiotropic nature affecting diazotrophic growth, chlorophyll a content, nitrogenase activity and photosynthetic O(2) evolution. Mutation leading to development of Cs(+)-R phenotype could be overcome by availability of Cs(+)/Rb(+). Parent and mutant strains were similar with respect to their Cs(+)/Rb(+) uptake. Available data suggests operation of an efficient coupling of the two incompatible reactions viz. oxygenic photosynthesis and oxygen sensitive N(2) fixation in this cyanobacterium.