Cumulative effects of quinidine and aspirin on bleeding time and platelet alpha 2-adrenoceptors: potential mechanism of bleeding diathesis in patients receiving this combination

We observed quinidine-induced prolongation of bleeding time without thrombocytopenia in three subjects. In addition, we noticed a cumulative prolongation of bleeding time by a combination of quinidine and aspirin. We postulated that because both quinidine and aspirin inhibit epinephrine-induced platelet aggregation, a cumulative effect of the two drugs might be responsible for the hemostatic defect. In studies using normal human platelets, we confirmed a marked reduction in epinephrine-induced platelet aggregation by the combination of these two agents. To further study the potential mechanism of this cumulative effect, platelet lysates were incubated with the alpha 2-adrenoceptor antagonist tritiated yohimbine in the presence of quinidine and aspirin. On the basis of the radioligand binding data, the dissociation constant (KD) of alpha 2-adrenoceptors was observed to increase in the presence of quinidine as well as aspirin. The combination of these two agents caused a marked increase in the KD of platelet alpha 2-adrenoceptors without alteration in the number of receptor sites. These data suggest that the cumulative effects of quinidine and aspirin on platelet alpha 2-adrenoceptor KD may relate to the significant reduction in epinephrine-induced platelet aggregation. This phenomenon, coupled with other well-known effects of aspirin on the platelet release reaction and arachidonate metabolism, may lead to bleeding problems in some patients receiving this combination.     

Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry

The pain tolerance latencies of 10 chronic pain patients were evaluated by heat beam dolorimetry (stimulus intensity 15.33 mW.cm-2.sec-1) prior to and following administration of morphine by intrathecal (n = 5) or intravenous (n = 5) routes. Patients not undergoing opiate withdrawal evinced increased baseline pain tolerance latencies prior to drug administration compared with normal volunteers. Two patients undergoing the opiate withdrawal syndrome at the time of test experienced reduced pain tolerance latencies compared with normal volunteers, most probably corresponding to the hyperesthesia symptom of the syndrome. Intravenous morphine infusion (30 mg) induced a time-dependent increase in cutaneous pain tolerance with peak effect occurring 1-2 h after administration. This persisted for up to 4 h and thereafter declined. The time course of subjective pain self-report by visual pain analog scale (VPAS) measurements corresponded to the time course of increasing cutaneous pain tolerance latency assessed by dolorimetry. Pain self-reports following intrathecal morphine infusion (2.25 or 1 mg) followed a similar though slower onset to that reported by patients receiving intravenous morphine and was of lesser degree. In contrast, heat beam dolorimetric evidence of increased cutaneous pain tolerance (which was of lesser degree than following i.v. morphine) did not reach its maximum during the 4 h measuring period. A dissociation was noted therefore between the self-reported relief of endogenous pain and dolorimetrically measured cutaneous analgesia following intrathecal morphine administration. Linear regression correlation analysis characterized this phenomenon as a positive correlation between cutaneous pain tolerance and pain relief self-report following intravenous morphine infusion and a negative correlation following intrathecal administration. We propose that the phenomenon may be due to intrathecal morphine acting via two separate compartments: one spinal and one supraspinal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic, psychological, and health correlates of dietary restraint in healthy postmenopausal women

BACKGROUND: Dietary restraint, a term used to describe the intentional control of food intake to prevent weight gain or promote weight loss, is commonly practiced by older adults, but little is known about its effects on physiology and metabolism. METHODS: We therefore compared a wide range of parameters between groups of healthy non-obese postmenopausal women classified psychometrically as unrestrained eaters (body mass index [BMI] 23.8 +/- 0.6 [SEM] kg/m(2), n = 28) or restrained eaters (BMI 24.5 +/- 0.5, n = 39). Measurements were made of reported micronutrient intakes, cardiopulmonary function, hematology, body temperature, skin thickness, bone mass, and immune function; in addition, self-perceived health, mood, and some dimensions of eating behavior were assessed by questionnaire. RESULTS: Macronutrient and micronutrient intakes were not significantly different between restrained and unrestrained eaters reporting energy intake to within 30% of predicted total energy expenditure. Restrained eaters had significantly lower hemoglobin (12.9 +/- 0.1 [SEM] vs 13.2 +/- 0.1 g/dl; p <.05), but values were within the normal range in both groups. In addition, restrained eaters scored significantly higher on the Eating Attitudes Test (p <.01) and drive-for-thinness (p <.001) and maturity fears (p <.05) subscores of the Eating Disorders Inventory, but values were again within the normal range. No other parameter differed significantly between groups. CONCLUSIONS: In this normal-weight population, restrained eating was not associated with detrimental effects in a wide range of physiological, metabolic, and health characteristics. Further work is needed to determine the relevance of these results to the general population.     

Rates and predictors of exposure to Legionella pneumophila in the United States among dental practitioners: 2002 through 2012

Background

In this study, the authors compared the odds of exposure to Legionella pneumophila among currently active dental practitioners with that of nonpractitioners and evaluated demographic and clinical practice predictors of exposure.

Foundations of medical decision-making for older adults with cardiovascu-lar disease

In order to help older adults with cardiovascular disease navigate complex decisions, clinicians must know tenets of medical ethics and have good communication skills. The elements of decision making capacity and informed consent are reviewed, using relevant clinical examples to illustrate the basic concepts. The shared decision making model, by which clinician and patient work together to determine the plan of care, is described. Useful communication techniques to implement shared decision making are suggested.     

Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds

Introduction

The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds.

Methods

This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration <120 μmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption.

Results

Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r =0.70, P <0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired.

Conclusions

In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs.