Venous oxygen embolism produced by injection of hydrogen peroxide into an enterocutaneous fistula

We report a venous oxygen embolism that occurred in a 66-yr-old man after 60 mL of 3% hydrogen peroxide was injected into a perianal fistula intraoperatively to locate its internal opening. The diagnosis was made after detecting hypoxemia, decreased end-tidal carbon dioxide tension, systemic hypotension, increased central venous pressure, and a new heart murmur. The patient recovered quickly and had no long-term sequelae. Oxygen embolism is a potentially fatal complication that can develop when hydrogen peroxide is used near venous spaces, and clinicians should be aware of the potential dangers when using this seemingly innocuous chemical.     

Enflurane and halothane in status asthmaticus

A patient with status asthmaticus deteriorated while receiving conventional therapy including mechanical ventilation. She failed to respond to the inhalation of enflurane but had a beneficial response to halothane. Her subsequent course was complicated by a prolonged metabolic encephalopathy which was associated with an elevated plasma bromide level from the metabolism of halothane.     

A trial of vitamin A therapy to facilitate ductal closure in premature infants

OBJECTIVE: To determine whether postnatal vitamin A therapy increased ductal closure rate in premature infants. STUDY DESIGN: This was a prospective, double-blind, placebo-controlled trial. Subjects (n=40) were recruited on day of life 1. Inclusion criteria were premature neonates weighing 500 to 1500 g with an indwelling umbilical line. Vitamin A was administered intramuscularly on days 1, 3, and 7. Blood vitamin A and retinol binding protein levels were obtained on days 1 and 3. Echocardiography was performed on days 1, 3, 7, and 14. Failure of ductal closure was defined as the presence of a moderate to large patent ductus arteriosus on day 14, indomethacin therapy, or surgical ligation. RESULTS: Comparison between the treatment and placebo groups revealed no differences in gestational age, weight, or oxygenation index. Vitamin A and retinol binding protein levels did not differ between the groups at entry but increased significantly after vitamin A treatment. Failure of ductal closure occurred in 22 of 40 babies without any difference between the groups (12/22 vs 10/18, P=NS). Four infants required surgical ligation, all in the treatment group (P=.04). Clinical outcome did not vary between groups. CONCLUSION: Postnatal vitamin A therapy did not improve ductal closure rates in premature infants.     

The effect of hypothermia on the expression of the apoptosis-regulating protein Bax after incomplete cerebral ischemia and reperfusion in rats

This study investigated the effects of hypothermia on apoptosis-regulating proteins in a rat model of incomplete cerebral ischemia. Twenty-seven fasted male Sprague-Dawley rats (300-420 g) were anesthetized, intubated, and mechanically ventilated with 2.0% isoflurane and N(2)O/O(2) (FiO(2) = 0.33). Catheters were inserted and cerebral blood flow velocity was measured using bilateral laser Doppler flowmetry. At the end of preparation, the administration of isoflurane was replaced by fentanyl (25 microg. kg(-1). h(-1)). Animals were randomly assigned to one of the following groups: group 1 (n = 9, normothermia), normothermia (37.5 degrees C) during ischemia; group 2 (n = 9, hypothermia), 34 degrees C pericranial temperature during ischemia; and group 3 (n = 9, sham-operated animals), normothermia, no cerebral ischemia. Ischemia (30 minutes) was produced by unilateral common carotid artery occlusion plus hemorrhagic hypotension (mean arterial blood pressure 30-35 mm Hg). Arterial blood gas tensions and pH were maintained constant. Four hours after 30 minutes of incomplete cerebral ischemia, the brains were removed for determination of the expression of the apoptosis-regulating proteins Bax, Bcl-2, p53, and Mdm-2 using immunofluorescence and Western blot analysis. Four hours after cerebral ischemia there was a significant increase in the expression of the pro-apoptotic protein Bax in normothermic animals compared with hypothermic (85-260%) and sham-operated animals (60-190%). The proteins Bcl-2, p53, and Mdm-2 showed no statistically significant differences between the groups or between the hemispheres. In conclusion, hypothermia during ischemia decreased Bax protein expression that is associated with programed cell death. This suggests that neuroprotection seen with hypothermia may be related to a reduction of pro-apoptotic events.     

The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease

Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.     

Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design

In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH's provided details of how the adenosyl moiety of NAD(+) interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH's. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N(6)-(1-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (6e), N(6)-(substituted-naphthalenemethyl)-2'-deoxy-2'-(substituted-benzamido)adenosine analogues were investigated. N(6)-(1-Naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (6m), N(6)-[1-(3-hydroxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (7m), N(6)-[1-(3-methoxynaphthalene)methyl]-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (9m), N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3-methoxybenzamido)adenosine (11e), and N(6)-(2-naphthalenemethyl)-2'-deoxy-2'-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC(50)'s of these compounds were in the range 2-12 microM for T. brucei, T. cruzi, and L. mexicana GAPDH's, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure-activity relationships of this class of compounds, a library of 240 N(6)-(substituted)-2'-deoxy-2'-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N(6) and C2' substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH's in the low micromolar range. We also explored adenosine analogues containing 5'-amido substituents and found that 2',5'-dideoxy-2'-(3,5-dimethoxybenzamido)-5'-(diphenylacetamido)adenosine (49) displays an IC(50) of 60-100 microM against the three parasite GAPDH's.