James V. Winkler

A NOVEL ASSAY FOR COBALT-ALBUMIN BINDING AND ITS POTENTIAL AS A MARKER FOR MYOCARDIAL ISCHEMIA—A PRELIMINARY REPORT

We initially observed a phenomenon of reduced in vitro binding of exogenous cobalt [Co(II)] to the N-terminus of human serum albumin (HSA) in emergency chest pain patients with early onset unstable angina and myocardial infarction. We then developed a colorimetric assay to measure cobalt-HSA binding and record the results in absorbance units (ABSU). In a preliminary clinical study of 139 emergency patients with acute chest pain, 99 patients with evidence of myocardial ischemia (Group 1) had elevated assay levels (mean ABSU +/- SD; 0.519 +/- 0.086) compared to 40 patients (Group 2) with no evidence of ischemia (0.316 +/- 0.092) (p < 0.00001). In Group 1, 95 of 99 (96.0%) patients had levels higher than a decision threshold of 0.400 ABSU and in Group 2, 37 of 40 (92.5%) samples had higher cobalt binding capacity (ABSU </= 0.400). Further studies are warranted to determine if an assay measuring altered cobalt-HSA binding is a clinically useful diagnostic test to rule out myocardial ischemia.

A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes.

BACKGROUND Premature ejaculation (PE) is a widely observed male sexual dysfunction with a major impact on quality of life for many men and their sexual partners. OBJECTIVE To assess the safety of tramadol orally disintegrating tablet (ODT) (Zertane) and its efficacy in prolonging intravaginal ejaculation latency time (IELT) and improving Premature Ejaculation Profile (PEP) scores. DESIGN, SETTING, AND PARTICIPANTS We conducted an integrated analysis of two identical 12-wk randomized double-blind, placebo-controlled phase 3 trials across 62 sites in Europe. Healthy men 18-65 yr of age with a history of lifelong PE according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, and an IELT ≤ 120 s were included. There were 604 intent-to-treat subjects included in the analysis. INTERVENTION Subjects were randomized to receive 1:1:1 placebo (n=200), 62 mg tramadol ODT (n=206), or 89 mg tramadol ODT (n=198). MEASUREMENTS We measured overall change and fold increase in median IELT and the mean change in all four measures of the PEP. Differences across treatment groups were analyzed using Wilcoxon rank-sum tests, analysis of variance, and chi-square analyses. RESULTS AND LIMITATIONS Tramadol ODT resulted in significant increases in median IELT compared with placebo; increases were 0.6 min (1.6 fold), 1.2 min (2.4 fold), and 1.5 min (2.5 fold) for placebo, 62 mg tramadol ODT, and 89 mg tramadol ODT, respectively (p<0.001 for all comparisons). Men saw significantly greater improvement in all four measures of the PEP in both doses compared with placebo (p<0.05 for all comparisons). Tramadol ODT was well tolerated; study discontinuation occurred in 0%, 1.0%, and 1.6% of subjects in placebo, 62 mg, and 89 mg tramadol ODT groups, respectively. Limitations include study inclusion for men with IELT up to 120 s. CONCLUSIONS On-demand 62mg tramadol ODT is an effective treatment for PE in a low and safe therapeutic dose and provides a new option for managing mild to severe PE.

Prehospital use of the glasgow coma scale in severe head injury

To determine the prognostic value of prehospital Glasgow Coma Scale (GCS) scores in severe blunt head injuries, the GCS at the scene of injury (INGCS) and the GCS in the emergency department (EDGCS) were compared with neurologic outcomes in 33 consecutive head-injured patients. Patients were categorized according to final outcome: Group I (n = 7) had no neurologic deficits, group II (n = 3) had only minor neurologic deficits, group III (n = 11) had major neurologic deficits, and group IV (n = 12) died. Mean INGCS was not significantly different for any of the four groups (range 4.14 to 4.67). However, mean EDGCS was significantly higher (P less than .05) for group I (9.43 +/- 4.08) than for group IV (5.17 +/- 3.13), and mean EDGCS for groups I and II (8.8 +/- 3.99) were significantly higher (P less than .05) than that of groups III and IV (5.7 +/- 2.88). The net change in GCS (EDGCS--INGCS) was significantly higher (P less than .05) for groups I and II (4.5 +/- 4.4) than for groups III and IV (1.3 +/- 2.91). We conclude that INGCS alone has no prognostic value, but that EDGCS and any prehospital change in GCS may have prognostic value for severely head-injured patients.

Copper stimulates the synthesis and release of interleukin-8 in human endothelial cells: A possible early role in systemic inflammatory responses

Endogenous copper can play an important role in postischemic reperfusion injury, a condition associated with endothelial cell activation and increased interleukin 8 (IL-8) production. Excessive endothelial IL-8 secreted during trauma, major surgery, and sepsis may contribute to the development of systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS), and multiple organ failure (MOF). No previous reports have indicated that copper has a direct role in stimulating human endothelial IL-8 secretion. Increased IL-8 in the culture medium of human umbilical vein (HUVEC), lung microvascular, and iliac artery endothelial cells was observed 24 h after the addition of 10 to 50 &mgr;M CuCl2 (cupric ions). HUVEC IL-8 induction by copper was higher than by 50 pg/mL tumor necrosis factor-&agr;, whereas 50 pg/mL IL-1&bgr; and 1 ng/mL platelet-activating factor did not stimulate IL-8 production or release. HUVEC IL-8 mRNA increased 3 h after CuCl2 stimulation and remained elevated after 24 h, implying sustained transcriptional activation. Copper did not stimulate HUVECs to secrete other cytokines. Cu(II) appeared to be the primary copper ion responsible for the observed increase in IL-8 because a specific high-affinity Cu(II)-binding peptide, d-Asp-d-Ala-d-His-d-Lys (d-DAHK), completely abolished this effect in a dose-dependent manner. These results suggest that Cu(II) may induce endothelial IL-8 by a mechanism independent of known Cu(I) generation of reactive oxygen species. Furthermore, in vivo studies are warranted to determine if copper is involved in the pathogenesis of systemic inflammation and if Cu(II) chelation can reduce this IL-8-induced endothelial inflammatory response.

Low albumin level in the emergency department: a potential independent predictor of delayed mortality in blunt trauma.

Albumin is an abundant plasma protein with multiple physiologic functions, and low serum albumin levels have been associated with increased mortality in hospitalized patients. In a retrospective matched-pair study, we investigated whether emergency department (ED) albumin levels predict delayed mortality for patients initially stabilized after blunt trauma. Fifty-one hospital non-survivors who died more than 24 h after admission to a trauma center ED were matched by Injury Severity Score, type and location of injury, age, and gender with 51 survivors. All patients had serum albumin levels determined upon arrival in the ED. The non-survivors had a significantly lower admission albumin of 3.1 g/dL compared to 3.5 g/dL for survivors. Patients with albumin levels < 3.4 g/dL were 2.5 times more likely to die compared to patients with normal albumin levels. These preliminary results indicate that initial hypoalbuminemia in blunt trauma patients is an independent predictor of delayed mortality, suggesting that these patients require continued clinical vigilance and an aggressive search for evolving complications.

Copper-induced oxidation of epinephrine: protective effect of D-DAHK, a synthetic analogue of the high affinity copper binding site of human albumin.

Epinephrine is known to be rapidly oxidized during sepsis. Ischemia and acidosis, which often accompany sepsis, are associated with the release of weakly bound cupric ions from plasma proteins. We investigated whether copper promotes oxidation of epinephrine at both physiological and acidic pH and whether D-Asp-D-Ala-D-His-D-Lys (D-DAHK), a human albumin (HSA) N-terminus synthetic peptide with a high affinity for cupric ions, attenuates this oxidation. Epinephrine alone [100 microM] or with CuCl(2) [10 microM], and with CuCl(2) [10 microM] and D-DAHK [20 microM] at pH 7.4, 7.0, 6.5, and 6.0 were incubated for 1h at 37 degrees C. Epinephrine oxidation was measured by the spectrophotometric quantification of its oxidation product, adrenochrome. We found that adrenochrome increased, suggesting copper-induced oxidation of epinephrine. At pH 7.4, 7.0, 6.5, and 6.0, adrenochrome increased by 47%, 53%, 24%, and 6% above baseline, respectively. D-DAHK attenuated the copper-induced oxidation of epinephrine to baseline levels. These in vitro results indicate that copper-induced epinephrine oxidation is greatest at the physiological pH 7.4 as well as in severe acidosis, pH 7.0, and that D-DAHK completely inhibits this oxidation.

PROTRACTED METABOLIC ACIDOSIS: THE IMPACT OF ACUTE ETHANOL IN HEMORRHAGIC SHOCK

The effects of acute ethanol administration on acid-base balance and hemodynamic parameters were studied in a canine model. Ten mongrel dogs, anesthetized and maintained on a volume ventilator, underwent splenic artery ligation 30 minutes prior to study. Group A (N = 5) served as controls. Thirty minutes after drug administration, the animals underwent a 20-cc/kg hemorrhage over 15 minutes. Thirty minutes postphlebotomy, resuscitation was performed with the same volume of homologous blood. Acid-base and hemodynamic parameters were monitored over 3.5 hours. Ethanol levels peaked 60 minutes following administration at 207 +/- 13 mg%. During the entire study, no differences were observed in heart rate, pulmonary capillary wedge pressure, systemic vascular resistance index, pO2, or pCO2, between the two groups. Following hemorrhage, statistically significant decreases in pH, mean arterial pressure (MAP), cardiac index (CI), and left ventricular stroke work index (LVSWI) developed in group A compared to controls. Maximal disparity developed in pH (7.21 +/- 0.05 to 7.33 +/- 0.02, P < 0.01), MAP (67 +/- 11 v 110 +/- 9 torr, P < 0.01), CI (1.69 +/- 0.24 compared to 2.72 +/- 0.19 L/min/M2, and LVSWI (18.7 +/- 1.2 compared to 44.9 +/- 4.8 gr-meter/M2/beat, P < 0.01) at 60, 45, 30, and 75 minutes postphlebotomy. In this study, ethanol directly or indirectly caused an increased metabolic acidosis and myocardial depression in the post-hemorrhage period.

Mothball differentiation: Naphthalene from paradichlorobenzene

In order to develop a rapid, simple test to differentiate toxic naphthalene from the less toxic mothball ingredient paradichlorobenzene, both types of mothballs were dissolved in isopropyl alcohol, ethanol, methanol, and turpentine. Twenty-five naphthalene and 25 paradichlorobenzene mothballs were weighed, randomly grouped, and then dissolved in the solvents. After 30 minutes, the mothballs were reweighed. Isopropyl alcohol, ethanol, and methanol did not differentially dissolve the mothballs fast enough to provide a useful test. Turpentine, however, dissolved paradichlorobenzene at a much more rapid rate than naphthalene (P less than .001). After 60 minutes, all of the paradichlorobenzene mothballs had dissolved, while at least 25% of the naphthalene remained. Thus, when confronted with an ingestion of unlabeled mothballs, the physician could gain preliminary information regarding possible toxicity by dissolving a remaining mothball in turpentine for 60 minutes.

Naloxone: Effects on hypoxic pulmonary vasoconstriction

To determine the effect of naloxone on the hypoxic pulmonary vasoconstrictive response, six mongrel dogs were rendered hypoxic with 10% oxygen and were given either saline or naloxone. Following hypoxia all dogs had significant increases in mean pulmonary artery pressure (PAP) and pulmonary arterial resistance index (PARI) without changes in cardiac output or systemic blood pressure. Beta endorphins did not change at any time following hypoxia. Dogs receiving naloxone had significant lowering of PAP and PARI without changes in plasma beta endorphin levels. We conclude that naloxone attenuates hypoxic pulmonary vasoconstriction without measurable alterations of plasma beta endorphin levels.