Current evidence for pharmacologic therapy following stage 1 palliation for single ventricle congenital heart disease.

INTRODUCTION: Infants with single ventricle congenital heart disease are vulnerable to complications between stage 1 and stage 2 of palliation. Pharmaceutical treatment during this period is varied and often dependent on institutional practices as there is little evidence supporting a particular treatment path. AREAS COVERED: This review focuses on medical management of patients following stage I palliation. We performed a scoping review of the current literature regarding angiotensin converting enzyme inhibitors and digoxin treatment in the interstage period. In addition, we discuss other medication classes frequently used in these patients. EXPERT OPINION: Due to significant heterogeneity of anatomy, rarity of disease, and other confounding factors, there is limited evidence to support most commonly used medications within the interstage period. Digoxin is associated with improved mortality within the interstage period and should be considered; however, no large randomized controlled trial exists supporting its use. Prevention of thrombotic complication with aspirin is also associated with improved outcomes and should be considered unless a contraindication exists. The addition of other prescriptions in this patient population should be considered only after an evaluation of the risks and benefits of each medication, recognizing the burden and risk of polypharmacy in this fragile patient population.

The Relationship Between Estimated Median Household Income and Critical Care Length of Stay in Children With Diabetic Ketoacidosis.

Diabetic ketoacidosis (DKA) is an important diagnosis in the pediatric intensive care unit (PICU) and is associated with significant morbidity. We hypothesized children with DKA living in poorer communities would have unfavorable outcomes while critically ill. This single-center retrospective study included children with DKA admitted to a PICU over a 27-month period. Patients were classified as low-income if they lived in a ZIP code where the median household income was estimated to be less than 200% of the federal poverty threshold, or $48 016 for a family of 4. In this study, living in a low-income ZIP code was not associated with increased severity of illness, longer PICU length of stay (LOS), or readmission.

SLIME: robust, high-speed 3D microvascular mapping.

Three dimensional (3D) microvascular imaging of cubic millimeter to centimeter size volumes often requires much time and expensive instruments. By combining optical clearing with a novel scatter-based optical coherence tomography (OCT) contrast agent, we have greatly extended OCT imaging depth in excised tissues while maintaining a simple and low cost approach that does not require in-depth OCT knowledge. The new method enables fast 3D microvascular mapping in large tissue volumes, providing a promising tool for investigating organ level microvascular abnormalities in large cohorts.

Outcomes of Children With Critical Bronchiolitis Living in Poor Communities.

There are established associations between adverse health outcomes and poverty, but little is known regarding these associations in critically ill children. We hypothesized that living in poorer communities would be associated with unfavorable outcomes in children with critical bronchiolitis. This retrospective study included children with bronchiolitis admitted to a pediatric intensive care unit (PICU) over a 2-year period. Median household income was estimated from patient ZIP codes and 2014 US Census Bureau data. The 2014 Federal Poverty Threshold (FPT) for a family of 4 was $24 008. Patients were classified as living in ZIP codes below or above the 150% FPT (150FPT). Living <150FPT was associated with longer PICU length of stay (LOS), longer hospital LOS, higher odds of needing mechanical ventilation, and increased hospital charges. In this cohort of critically ill children with bronchiolitis, living in a poorer community was associated with more unfavorable clinical outcomes.

Hepatic oxidative drug metabolism and the microsomal milieu in a rat model of congenital hyperbilirubinemia.

The aims of this study were to evaluate the hypothesis that impaired glucuronidation of bilirubin and possibly of drug oxidation in the liver of homozygous (jj) Gunn rats may be due to an altered microsomal milieu. Accordingly, we investigated and compared in vivo and in vitro demethylation of aminopyrine, hepatic cytochrome P-450 levels, microsomal lipid composition, and microsomal membrane fluidity in icteric, homozygous (jj) Gunn rats and in their anicteric heterozygous (jJ) littermates. In both males and females, [14C]aminopyrine demethylation in vivo, using the 14CO2 breath test, was unimpaired in the icteric animals. Likewise, cytochrome P-450 levels in the icteric and nonicteric groups were similar, and aminopyrine kinetics in vitro in the females were comparable in icteric and nonicteric littermates. The main lipid classes were also similar in the homozygous and heterozygous female Gunn rats, whereas only minor changes were seen in the phospholipid fatty acyl composition with a small, but significant, increase in the unsaturated index in the icteric group. Despite this, there was no apparent effect on hepatic microsomal membrane fluidity as measured by the order parameter of I[12,3] and the rotational correlation time of I[1,14] in either female or male sets of homozygous and heterozygous Gunn rats. Our data, therefore, do not support an alteration of composition or fluidity of the microsomal milieu as a mechanism of impaired bilirubin glucuronidation and possibly of oxidation in these animals. They also absolve long-term unconjugated hyperbilirubinemia as a mechanism of hepatic microsomal dysfunction. Our study, therefore, indirectly suggests that abnormal glucuronidation of bilirubin and some other aglycones in homozygous Gunn rats is due to genetic abnormalities involving the enzyme(s) itself.

The concentration in brain of octopamine and tyramine after portal-systemic bypass in rats: neuroamine concentrations determined simultaneously by methane chemical ionization gas chromatography mass spectrometry.

The concentration in brain of both octopamine (OCT) and tyramine (TYR) was significantly increased in rats 8 weeks after portal-systemic bypass. This suggests that the increase in OCT is secondary to increased decarboxylation of tyrosine to TYR. However, the role these neuroamines, particularly OCT, play in the development of hepatic encephalopathy remains controversial.

Lack of effect of nizatidine on hepatic drug metabolism in man.

The effect of nizatidine, a new H2-receptor antagonist, on the hepatic metabolism of three probe drugs was studied in normal volunteers. The drugs studied were chlordiazepoxide and theophylline which are metabolized in part by N-demethylation by the hepatic microsomal cytochrome P-450 system and lorazepam which is conjugated to lorazepam glucuronide. A 7 day course of nizatidine did not interfere with the disposition of any of these therapeutic agents in man.

Effects of influenza virus vaccine on hepatic drug metabolism.

Experimental and more limited clinical studies have suggested that influenza vaccination may depress the oxidative hepatic metabolism of various drugs and lead to drug toxicity. The alleged mechanism is the formation of interferon and the resulting decrease in cytochrome P-450 available for drug oxidation. Because of the clinical and basic science implications of these reports, we undertook to study the effects of influenza vaccine on the metabolism of three commonly used drugs: chlordiazepoxide, theophylline, and lorazepam. Our healthy male subjects were studied just before and 1 and 7 days after vaccination. As expected, lorazepam metabolism, which proceeds by glucuronidation and not oxidation, was not altered by vaccination. Surprisingly, however, the oxidation of chlordiazepoxide was also not depressed by the vaccine. Theophylline oxidation, which proceeds primarily by microsomal oxidation (demethylation), was significantly decreased 1 day, but not 7 days, after vaccination. Serum alpha-interferon levels rose after vaccination for only about 8 hours, and levels of gamma-interferon rose to about 500 IU/ml at 24 hours, peaked at 72 hours, and returned to normal by 100 hours after dosing. It appeared that the higher the theophylline clearance before vaccination, the greater the degree of clearance depression after vaccination. Thus the inhibition of drug oxidation after influenza vaccination is selective and each drug should be studied individually. The degree of depression of theophylline clearance is small and transient and appears to be greater in subjects with higher prevaccination clearance.

Effect of ketoconazole on hepatic oxidative drug metabolism.

Several clinical reports have suggested (but not demonstrated) that ketoconazole, a broad-spectrum antifungal drug, may inhibit hepatic oxidative drug metabolism in man. We recently demonstrated that ketoconazole inhibits caffeine and aminopyrine oxidation in the rat; we now study the influence of ketoconazole on theophylline and chlordiazepoxide kinetics in man. These studies were performed before and after varying doses of ketoconazole within the currently accepted therapeutic range. Ketoconazole had no effect on theophylline clearance, whereas the drug impaired chlordiazepoxide clearance from plasma. After a single dose of ketoconazole, there was a 20% decrease in clearance and a 26% decrease in volume of distribution without evidence of inhibition of drug metabolism. These changes apparently were not related to ketoconazole dose. After repetitive dosing with ketoconazole, chlordiazepoxide clearance decreased by 38% and was associated with reduced concentrations of its first oxidative metabolite, N-desmethylchlordiazepoxide. We conclude that ketoconazole inhibits at least one subset of the hepatic mixed-function oxidase system, but is not as general an inhibitor of hepatic oxidative drug metabolism as cimetidine appears to be. For some coadministered drugs, ketoconazole may also have an effect on other kinetic parameters such as volume of distribution. Therefore, we caution that clinically important drug interactions may occur with the concurrent use of ketoconazole.

The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro.

Ketoconazole is a new antifungal drug which has increasing clinical application due to its wide spectrum of activity and oral availability. Since substituted imidazoles may be potent inhibitors of cytochrome-mediated drug oxidation, we have examined the effect of ketoconazole on aminopyrine and caffeine metabolism in the rat. The 14C breath test was used to determine the elimination rate of aminopyrine and caffeine in vivo after single and chronic (7 day) treatment with ketoconazole. Acutely, ketoconazole (50 mg/kg) impaired markedly both aminopyrine (56% inhibition) and caffeine demethylation (83% inhibition). Inhibition of aminopyrine and caffeine demethylation as studied with the breath tests was related to ketoconazole dose. The decreased rate of aminopyrine demethylation measured by breath test correlated with decreased aminopyrine clearance from plasma after iv dosage. Chronic treatment with ketoconazole further increased the inhibition of aminopyrine demethylation while chronic treatment was associated with less inhibition of caffeine demethylation than found with a single dose. Breath tests repeated up to 72 hr after ketoconazole treatment revealed differences in aminopyrine and caffeine demethylation. At 24 hr after ketoconazole, aminopyrine demethylation was still inhibited at 78% of controls whereas caffeine demethylation was enhanced to 146% of control. Binding of ketoconazole to microsomal P-450 was determined by spectral analysis. A type II difference spectrum was found with absorbance maximum at 430 nm and minimum at 390 nm. Scatchard analysis revealed a biphasic interaction with estimated dissociation constants of 0.6 and 3.69 microM. Aminopyrine N-demethylation in vitro was markedly impaired with an I50 for ketoconazole of 27 microM and Ki of 8.5 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Nizatidine, a new histamine H2-receptor antagonist, and hepatic oxidative drug metabolism in the rat: a comparison with structurally related compounds.

The effects of nizatidine (a new H2-receptor antagonist) and of related compounds were studied on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H2-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [14C]aminopyrine (ABT) or [14C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mM) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (Ki = 92 mM). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H2-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.

Cimetidine inhibits renal procainamide clearance.

Procainamide and cimetidine are eliminated in large part by the kidneys. Both are secreted by an active transport mechanism in the proximal tubule and each inhibits secretion of the other in the isolated, perfused rabbit tubule. In this study in man, cimetidine inhibited renal clearance of oral procainamide by 36%. This was associated with a 28% decrease in the ratio of systemic clearance of procainamide to bioavailability, an 18% decrease in the elimination rate constant, and a 24% prolongation of elimination t1/2. These results suggest that cimetidine increases plasma t1/2 and decreases systemic clearance of procainamide in part by inhibiting its active secretion by the kidneys.

Diphenhydramine disposition in chronic liver disease.

Diphenhydramine (DPHM) disposition was examined in nine patients with chronic alcohol-related liver disease and in eight normal subjects. Sleep of 1 to 2 hr duration was induced in all subjects by a 0.8 mg/kg iv dose without an apparent increase in cerebral sensitivity in the patients with cirrhosis. Protein binding as determined by equilibrium dialysis (3H-DPHM) revealed a 15% decrease in the cirrhotic patients, while recovery of unchanged DPHM in urine (2%) was of the same order in the two groups. Computerized biexponential curve analysis was used to compare the plasma profiles for five of the patients and six of the normal subjects. Monoexponential curve analysis of the terminal beta-phase, including all subjects, was also used to compare the two groups. The means of plasma clearance and apparent volume of distribution in cirrhotic patients were respectively less and greater than in normal subjects, but these differences were not significant. The t1/2 for the beta-phase (t1/2 beta), which reflects this reciprocal trend, was increased in the patients (15.2 +/- 1.5 and 9.3 +/- 0.9 hr). This correlated in part with severity of disease, with r = 0.723 between t1/2 beta and the serum bilirubin levels. In conclusion, a single intravenous dose of DPHM provided safe and effective sedation in patients with cirrhosis.

The pharmacokinetic interaction of diethyl ether with aminopyrine in the rat.

Our studies in rats clearly demonstrate a significant depression of aminopyrine metabolism in vivo by ether anesthesia. The depression of aminopyrine elimination was shown both by measurements of plasma aminopyrine clearance and by depression of the [14C]aminopyrine breath test. No apparent effect of ether was seen on aminopyrine volume of distribution. The effect of ether was prolonged, as judged by its persistence in the aminopyrine breath test for 3 hr after stopping ether anesthesia. In addition, when ether was administered in combination with a single dose of ethanol, aminopyrine clearance was inhibited significantly more than with ethanol alone. These data not only have a bearing on proper methodologic design of drug clearance studies but also may relate to the effects of some anesthetics on hepatic function.

Effects of oral contraceptive steroids on acetaminophen metabolism and elimination.

Plasma acetaminophen elimination was examined in women taking low-dose estrogen oral contraceptive (OC) steroids and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +/- 13 ml/min to 470 +/- 51 ml/min in women taking OC steroids, whereas elimination t1/2 decreased from 2.40 +/- 0.14 hr to 1.67 +/- 0.16 hr. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OC steroids, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OC steroids results from increased glucuronidation of the drug, although the mechanism is not known.

PIP: Plasma acetaminophen elimination was examined in women taking low-dose oral contraceptives (OCs) and in age-matched control women. Fractional rates of elimination and fractional clearances were calculated for each of the metabolic pathways, including oxidation, sulfation, and glucuronidation. The cysteine adduct and mercapturic acid derivative of acetaminophen were used as an index of oxidative biotransformation, a potentially toxic route of metabolism for acetaminophen. Plasma acetaminophen clearance rose from 287 +or- 13 ml/minute to 470 +or- 51 ml/minute in women taking OCs, whereas elimination t1/2 decreased from 2.40 +or- 0.14 hours to 1.67 +or- 0.16 hours. The fractional clearance and rate of elimination of acetaminophen by glucuronidation increased in women taking OCs, whereas the clearance and elimination by sulfation did not differ significantly from values in control subjects. Fractional clearance of the cysteine adduct also increased significantly, but clearance of acetaminophen mercapturic acid did not change. These data suggest that the increased clearance of acetaminophen from plasma in women taking OCs results from increased glucuronidation of the drug, although the mechanism is not known.

Cimetidine and acute upper gastrointestinal bleeding: a double-blind controlled trial.

Patients presenting with acute upper gastrointestinal bleeding from a variety of lesions were admitted to a prospective double-blind controlled trial to determine if cimetidine reduces the severity of bleeding and/or the incidence of rebleeding. During the first 48 hours, the patients received intravenous cimetidine (200 mg four-hourly) or placebo, and for the following ten days, oral cimetidine (1 g/24 hr) or placebo. Eight-eight patients entered the trial of whom 45 (51%) were in the cimetidine-treated group. Six of the seven patients requiring surgery for life-threatening bleeding and four of the six patients who rebled were in the cimetidine-treated group. This study failed to demonstrate any advantage of using cimetidine routinely in the treatment of acute upper gastrointestinal bleeding.

Macrodosage of phenytoin.

Large doses (up to 1200 mg) of phenytoin were required to achieve therapeutic plasma concentrations and to control post-traumatic seizures in a 62-year-old woman. The elimination half-life of phenytoin was calculated to be 3.5 hours. Frequent monitoring of the plasma concentration was essential to optimize the therapeutic control and to avoid systemic toxicity.

Successful removal of retained bile duct stones by endoscopic sphincterotomy.

Two cases are reported in which endoscopic sphincterotomy was successful in allowing passage of stones retained in the common bile duct after cholecystectomy, performed in one case three weeks and in the other 14 years before.