The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative

HRP 913 {1-[3-(6-fluoro-1,2-benzisoxazole-3-yl)propyl]-4-(2-oxo-1-benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED₅₀ = 0.4 mg/kg, i.p.), amphetamine circling in SN-lesioned rats (ED₅₀ = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED₅₀ = 0.8 mg/kg, i.p.), but not apomorphine circling in SN-lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED₅₀ = 0.17 mg/kg, i.p.) and monkeys (ED₅₀ = 0.2 mg/kg, p.o.) and blocked intracranial self-stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced ³H-spiroperidol from rat striatal sites (IC₅₀ = 6.0 × 10^?9 M) and inhibited WB-4101 binding (IC₅₀ = 2.6 × 10^?8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α-blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.     

Optimization of recombinant human erythropoietin therapy after allogeneic hematopoietic stem cell transplantation

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with prolonged anemia caused by defective erythropoietin (Epo) production. We enrolled 34 recipients of an allogeneic HSCT in three consecutive trials to determine the optimal utilization of recombinant human erythropoietin (rhEpo) therapy in this setting. MATERIALS AND METHODS: In the first trial (n = 7), rhEpo 1400 U/kg/week was given from day 1 until a hemoglobin (Hb) level of 10 g/dL was achieved, for a maximum of 60 days. In the second trial, rhEpo 500 U/kg/week was given to achieve Hb levels of 13 to 14 g/dL in 13 anemic patients with fatigue 56 to 1440 days after transplant. In the third trial, rhEpo was scheduled to start on day 35 in 14 patients at a dose of 500 U/kg/week with the aim of achieving Hb levels of 13 to 14 g/dL. RESULTS: In trial 1, erythroid recovery to 1% reticulocytes and red blood cell transfusion independence were faster, but the number of transfusions was not reduced compared to 10 controls. Responses were brisk in trial 2, with transfusion independence achieved after a median of 1 week in 12 of 13 patients, and 2-g Hb increments or Hb values of 11, 12, and 13 g/dL after 6, 7, 10, and 10 weeks, respectively. Transfusions were significantly reduced in the first month of rhEpo therapy. In trial 3, transfusion independence was obtained after a median of 1 week in 13 of 14 patients, and 2-g Hb increments or Hb values of 11, 12, and 13 g/dL after 3, 4, 6, and 8 weeks, respectively. Transfusions rates were considerably reduced compared to the previous month in the same patients or compared to controls undergoing peripheral blood or marrow transplant without rhEpo. CONCLUSIONS: Anemia after allogeneic HSCT is exquisitely sensitive to rhEpo. The benefit is minimal when it is given early post-transplant, as used in all trials to date. However, the rate of major response is greater than 90% when rhEpo is started after day 35. These data provide the basis on which to conduct a prospective, randomized, placebo-controlled trial of rhEpo therapy after allogeneic HSCT.     

Differential expression of distinct microtubule-associated proteins during brain development.

The levels of three different microtubule-associated proteins (MAP1, -2, and -3) in brain were found to undergo large changes during postnatal development. MAP1 was barely detectable at birth but thereafter steadily increased, reaching adult levels by postnatal day 20 (P20). Both MAP2 and MAP3 showed differential expression patterns of their component peptides. At birth, MAP2 was represented by the smaller of two Mr 280,000 peptides (MAP2b) and three antigenically related Mr 70,000 peptides. The larger of the Mr 280,000 peptides (MAP2a) first appeared between P10 and P20, and the Mr 70,000 components disappeared at the same time. Of the two MAP3 peptides, the larger (MAP3a) was present in the late embryo, several days before MAP3b appeared. Between P10 and P20, both MAP3 components underwent a striking decrease in abundance (a factor of 10), which correlated with their disappearance from all neuronal compartments except neurofilament-containing axons. These developmental changes in expression are different and characteristic for each of the three MAPs, yet in each case they are detectable in brain homogenates, indicating that they occur concurrently throughout the brain.     

Measuring brain oxygenation in humans using a multiparametric quantitative blood oxygenation level dependent MRI approach

Quantitative blood oxygenation level dependent approaches have been designed to obtain quantitative oxygenation information using MRI. A mathematical model is usually fitted to the time signal decay of a gradient‐echo and spin‐echo measurements to derive hemodynamic parameters such as the blood oxygen saturation or the cerebral blood volume. Although the results in rats and human brain have been encouraging, recent studies have pointed out the need for independent estimation of one or more variables to increase the accuracy of the method. In this study, a multiparametric quantitative blood oxygenation level dependent approach is proposed. A combination of arterial spin labeling and dynamic susceptibility contrast methods were used to obtain quantitative estimates of cerebral blood volume and cerebral blood flow. These results were combined with T and T₂ measurements to derive maps of blood oxygen saturation or cerebral metabolic rate of oxygen. In 12 normal subjects, a mean cerebral blood volume of 4.33 ± 0.7%, cerebral blood flow of 43.8 ± 5.7 mL/min/100 g, blood oxygen saturation of 60 ± 6% and cerebral metabolic rate of oxygen 157 ± 23 μmol/100 g/min were found, which are in agreement with literature values. The results obtained in this study suggest that this methodology could be applied to study brain hypoxia in the setting of pathology. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Computed tomography angiographic parameters of pulmonary artery as prognostic factors of residual pulmonary hypertension after pulmonary endarterectomy

ObjectivesThis study aimed to retrospectively assess using computed tomography pulmonary angiography (CTPA) for predicting residual pulmonary hypertension (RPH) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA).MethodsWe retrospectively analyzed data of 131 patients with CTEPH who underwent PEA in our center (2008–2015). We measured several diameters of the pulmonary artery and thoracic aorta preoperatively. We evaluated the relationship between these measurements (and their indices) and signs of RPH represented by pulmonary artery systolic pressure (PASP) estimated by echocardiography.ResultsSignificant correlations were observed between the aortopulmonary index and prediction of any residual hypertension and moderate/severe hypertension 1 year after PEA, and any residual hypertension and severe hypertension 2 years after PEA. The aortopulmonary index was significantly related to a reduction in PASP 1 year after the operation. A lower aortopulmonary index (≤0.88 for the ascending aorta and ≤0.64 for the descending aorta) predicted lower RPH.ConclusionsPreoperative CTPA parameters can be used to assess the risk of RPH after PEA. The aortopulmonary index has significant predictive value for RPH and a reduction in PASP after PEA. Lower values of the aortopulmonary index suggest a better outcome after PEA.     

Involvement of serum retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers in Hungary

AIM: To analyze the serum levels of retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers. METHODS: The changes in serum levels of retinoids (vitamin A, α-and β-carotene, α-and β-cryptoxanthin, zeaxanthin, lutein) and Leiden mutation were measured by high liquid performance chromatography (HPLC) and polymerase chain reaction (PCR) in 107 patients (70 males/37 females) with esophageal (0/8), gastric (16/5), liver (8/7), pancreatic (6/4), and colorectal (30/21 including 9 patients suffering from in situ colon cancer) cancer. Fifty-seven healthy subjects (in matched groups) for controls of serum retinoids and 600 healthy blood donors for Leiden mutation were used. RESULTS: The serum levels of vitamin A and zeaxanthin were decreased significantly in all groups of patients with gastrointestinal (GI) tumors except for vitamin A in patients with pancreatic cancer. No changes were obtained in the serum levels of α-and β-carotene, α-and β-cryptoxanthin, zeaxanthin, lutein in patients with GI cancer. The prevalence of Leiden mutation significantly increased in all groups of patients with GI cancer. CONCLUSION: Retinoids (as environmental factors) are decreased significantly with increased prevalence of Leiden mutation (as a genetic factor) in patients before the clinical manifestation of histologically different (planocellular and hepatocellular carcinoma, and adenocarcinoma) GI cancer.     

Mesenchymal Stem Cells in Cancer: Tumor-Associated Fibroblasts and Cell-Based Delivery Vehicles

Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.