Clinical and Metabolic Correlates of Pure Stone Subtypes.

Background: There are multiple stone types, with each forming under different urinary conditions. We compared clinical and metabolic findings in pure stone formers (SFs) to understand whether there are consistent factors that differentiate these groups in terms of underlying etiology and potential for empiric treatment. Materials and Methods: Pure SFs based on infrared spectroscopic analysis of stones obtained at our institution between January 2002 and July 2018 with a corresponding 24-hour urinalysis were retrospectively evaluated. Results: One hundred twenty-one apatite (AP), 54 brushite (BRU), 50 calcium oxalate (CaOx) dihydrate, 104 CaOx monohydrate, and 82 uric acid (UA) patients were analyzed. AP, BRU, and CaOx dihydrate patients were younger than CaOx monohydrate and UA patients. The UA patients had the highest male predominance (76.8%), whereas AP patients were predominantly female (80.2%). UA was most associated with diabetes mellitus (45.3%), and CaOx monohydrate with cardiovascular disease (27.2%) and malabsorptive gastrointestinal conditions (19.2%). BRU patients had the highest prevalence of primary hyperparathyroidism (17%). AP, BRU, and CaOx dihydrate patients demonstrated high rates of hypercalciuria (66.1%, 79.6%, 82%). AP and BRU patients had the highest urinary pH. AP patients exhibited the highest rate of hypocitraturia, whereas CaOx dihydrate patients exhibited the lowest (55.4%, 30%). CaOx monohydrate patients had the highest rate of hyperoxaluria (51.9%). UA patients had the lowest urinary pH. There were no observable differences in the rates of hyperuricosuria or hypernatriuria. Conclusions: These results demonstrate that pure stone composition correlates with certain urinary and clinical characteristics. These data can help guide empiric clinical decision making.

The effects of blood pressure on rebleeding when using ExcelArrest™ in a porcine model of lethal femoral injury.

BACKGROUND: Uncontrolled hemorrhage is one of the leading causes of death in both combat and civilian trauma. This study was designed to compare the arterial blood pressures at which rebleeding occurred when a hemostatic agent, ExcelArrest™, was used compared with a standard pressure dressing. MATERIALS AND METHODS: This study was a prospective, experimental, and mixed research design. Swine were assigned to one of two groups: ExcelArrest™ (n=5) or a control consisting of standard pressure dressings (n=5). Investigators generated a complex groin injury. The femoral artery and vein were transected and allowed to bleed for 60 s in each pig. After 60 s, ExcelArrest™ was poured into the wound. The control group underwent the same procedures, but without treatment with the hemostatic agent. After 5 min of direct pressure, a standard pressure dressing was applied. After 30 min, dressings were removed and the systolic blood pressure (SBP) was increased incrementally using intravenous phenylephrine until rebleeding occurred. STATISTICAL ANALYSIS: A multivariate ANOVA and a least significant difference were used to analyze the data. RESULTS: ExcelArrest™ was more effective in preventing rebleeding compared to a standard pressure dressing (P<0.05). The means and standard deviations in mmHg for SBP and mean arterial pressure (MAP) for rebleeding were as follows: ExcelArrest™ (SBP=206.4, SD±11.6; MAP=171.4, SD±12.5); for the control group (SBP=89.40±3.58, MAP=58.60±12.86). CONCLUSIONS: ExcelArrest™ was more effective in preventing rebleeding compared to the standard dressing with elevated blood pressures. There may be protective benefits in using this hemostatic agent against elevated blood pressures provided by ExcelArrest™.

Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity.

The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.

4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.

7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.

Neuropsychological measures and single photon emission computed tomography in the differentiation and classification of cerebral perfusion deficits in Alzheimer's dementia.

The accurate diagnosis of Dementia of the Alzheimer's Type (DAT) continues to be an area of difficulty for the fields of neuropsychology and neurology. The introduction of new medications that appear to mediate the insidious progression of the disorder increases the need for timely differentiation of DAT from other dementia-related disorders. The present study examined the relationship between hemispheric differences in regional cerebral blood flow with corresponding lateral neuropsychological processing deficits in patients with DAT. Eighty patients with a diagnosis of DAT were administered Single Photon Emission Computerized Tomography (SPECT) scans and a battery of left and right hemisphere neuropsychological-based tasks. The results of ANOVA indicated that patients with DAT who were not suffering from perfusion deficits exhibited significantly fewer neuropsychological deficits than did patients with DAT who had perfusion deficits. The neuropsychological tests that measured verbal ability, logical memory, word-pair learning, reading, arithmetic, and visual-perceptual organization were all significantly lower in the group with perfusion deficits. Further analysis indicated that patients with left hemisphere perfusion deficits tended to have poorer neuropsychological skills than did individuals with right hemisphere perfusion deficits, diffuse perfusion deficits, and no perfusion deficits. A Stepwise Discriminant Analysis was unable to use the neuropsychological variables to classify patients accurately into perfusion deficit groups.

1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties.

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.

1-[2-[(5-Cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties.

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. We report the first use of solid-phase synthesis in the discovery of a new DPP-IV inhibitor class and a solution-phase synthesis that is practical up to the multikilogram scale. One compound, NVP-DPP728 (2), is profiled as a potent, selective, and short-acting DPP-IV inhibitor that has excellent oral bioavailability and potent antihyperglycemic activity.