Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists.

Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.

Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective alpha1a-receptor antagonists.

Several 1,3-diaminocyclopentane linked alpha1a-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on alpha1-receptor binding.

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Transient abnormalities in serum bilirubin and lactate dehydrogenase levels following red blood cell transfusions in adults.

BACKGROUND: The effect of transfusion of small amounts of packed red blood cells (PRBC) on serum chemistry values is not known. METHODS: We studied 73 adult patients without evidence of bleeding who received 2-unit PRBC transfusions. In study 1 (n=39), we examined multiple laboratory values pretransfusion and 15 minutes, 1 hour, 2 hours, and 24 hours posttransfusion. In study 2 (n=34), we examined changes in fractionated bilirubin, lactate dehydrogenase, and haptoglobin prior to and 1 hour following the transfusion. RESULTS: Total bilirubin increased from a median pretransfusion baseline of 0.7 mg/dL to 1.4 mg/dL shortly after transfusion (P <0.0005), and then returned to normal 24 hours later. Of the 36 patients with normal pretreatment total bilirubin levels, 17 (47%) became transiently abnormal. The lactate dehydrogenase level increased similarly 15 minutes after transfusion, but returned to baseline 24 hours later. The unconjugated bilirubin level increased from a median baseline pretransfusion value of 0.3 mg/dL to 1.1 mg/dL at 1 hour posttransfusion (P <0.0005). No significant changes were noted in conjugated bilirubin levels or haptoglobin concentration following transfusion. CONCLUSIONS: Transient increases in serum bilirubin and lactate dehydrogenase are seen following transfusion of PRBC. These data should be considered when interpreting laboratory values during the first few hours after a transfusion.

Pulse oximetry correction for smoking exposure.

Pulse oximetry oxygen saturation (SpO2) does not distinguish carboxyhemoglobin (COHb) from oxyhemoglobin (O2Hb), giving a false impression of the apparent degree of oxyhemoglobin saturation in smokers who have elevated levels of COHb. We questioned whether accounting for smoking exposure history could improve description of pulse oximetry by correcting for COHb levels. We evaluated smoking history and %SpO2 as predictors of %O2Hb and %COHb by CO-oximetry of arterial blood in 18 actively smoking and 18 age-matched nonsmoking patients in a clinical pilot study. The difference between %SpO2 and %O2Hb was significantly greater (p < 0.001) in the smokers (5.6 +/- 3.1) than the nonsmokers (2.1 +/- 2.1). This difference correlated with %COHb (rp = 0.789; p < 0.001) and the smoking exposure score (SES, rp = 0.621; p < 0.001), a six-point index we developed based on whether patients were active smokers, refrained from smoking prior to testing, or were exposed to passive smoking in the home or workplace. The following formula summarizes the correction: %O2Hb = 0.882[%SpO2] - 0.968[SES] + 9.245 (rp = 0.841; SES = 2.478; p < 0.001). This pilot study suggests that smoking exposure history correlates with COHb levels and that correction for smoking exposure improves the accuracy of pulse oximetry.

Pyogenic arthritis complicating varicella infection.

Arthritis has not previously been reported as a complication in adult patients with chickenpox. In pediatric patients, the arthritis that complicates chickenpox is most commonly aseptic but does rarely result from bacterial infection. We report the case of a 21-year-old man who developed acute monoarticular septic arthritis due to Lancefield Group A beta-hemolytic streptococci. Despite the more common viral cause of arthritis in pediatric patients, physicians should not attribute arthritis associated with varicella in adults to a viral cause without diagnostic arthrocentesis.