Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis.

Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.

Evolution of Minimally Invasive Coronary Artery Bypass Grafting: Learning Curve.

OBJECTIVE: Minimally invasive coronary surgery approach for coronary artery bypass grafting is a safe and reproducible procedure for multivessel revascularization. This study reviewed a single surgeon's experience with minimally invasive coronary surgery coronary artery bypass grafting, including operative time, number of bypasses, and conversion to sternotomy. METHODS: A prospective database of consecutive minimally invasive coronary surgery coronary artery bypass grafting procedures from 2005 to 2013 was reviewed. A small anterolateral left thoracotomy allowed left internal mammary artery harvest, proximal anastomoses on the ascending aorta, and distal coronary anastomoses. Early cases were compared with the later cases, focusing on grafting strategies that led to a standardized approach with Propensity Score Matching analysis. RESULTS: Seven hundred consecutive cases were divided into early (1-200) and late (201-700) groups. In the late group, the number of triple-vessel disease patients trended higher (50% vs. 57%, P = 0.0674) and the number of bypasses increased (2.3 ± 0.8 vs. 2.7 ± 1.0, P < 0.0001). Conversion to sternotomy significantly decreased between the groups (6% vs. 0.6%, P < 0.0001). There was no difference in rate of postoperative complications between the groups except for prolonged intubation (10% vs. 5%, P = 0.0236) and shortened length of stay (5.9 ± 6.7 vs. 5.5 ± 6.0, P = 0.0268). Propensity score matching analysis (n = 177) was significant for total bypass performed and time per bypass (P < 0.05). The late group was further divided into subgroups of one hundred each (subgroup 1 through 5). Operative times differed significantly (subgroup 1: 249 ± 71.2, subgroup 2: 259 ± 85.8, subgroup 3: 244 ± 71.0, subgroup 4: 270 ± 58.4, and subgroup 5: 246 ± 47.9, P < 0.005). CONCLUSIONS: As experience with minimally invasive coronary surgery coronary artery bypass grafting increased, the ideal sequence of steps to optimize surgical outcome was defined. The number of bypassed vessels increased and the operative time and conversion to sternotomy decreased.

Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4].

Copper(2)(II)(3,5-ditertiarybutylsalicylate)(4)(ethanol)(4), Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), was synthesized and characterized for evaluation as an anti-apoptotic superoxide dismutase (SOD)-mimetic in an in vitro 50 microM cis-diamminedichloroplatinum(II), [Pt(II)(NH(3))(2)(Cl)(2)]-treated kidney proximal tubule epithelial cell (LLC-PK) preparation. Synthesized Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) was characterized by elemental analysis, FTIR spectrophotometry, and X-ray crystallography. The IC(50) for SOD-mimetic reactivity of Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), determined with the xanthine/xanthine oxidase/nitroblue tetrazolium (NBT) system, was found to be 2.69 microM for the binuclear chelate. Pretreatment of LLC-PK cells with 20 microM Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) prevented 50 microM Pt(II)(NH(3))(2)(Cl)(2)-induced and superoxide-mediated apoptosis. This SOD-mimetic significantly suppressed Pt(II)(NH(3))(2)(Cl)(2)-induced translocation of pro-apoptotic Bax from the cytosol to the inner mitochondrial membrane, prevented Pt(II)(NH(3))(2)(Cl)(2)-induced release of cytochrome c from the inner mitochondrial membrane and the appearance of cytochrome c in the cytosol, and prevented conversion of procaspase-3 to active caspase-3. Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) treatment inhibited Pt(II)(NH(3))(2)(Cl)(2)-mediated tubular cell injury by preventing activation of cellular mechanisms that lead to proximal tubule kidney cell death. Based on these observations, Pt(II)(NH(3))(2)(Cl)(2)- induced O(2)(-)-mediated apoptosis can be mechanistically overcome with a small molecular mass SOD-mimetic, Cu(2)(II)(3,5-DTBS)(4)(Eth)(4). Prior treatment of patients who are to undergo treatment with Pt(II)(NH(3))(2)(Cl)(2) for their neoplastic disease with Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) may be beneficial to these patients.