Saul Lowitt

Factors influencing acquired subgottic stenosis in infants

A prospective study of factors that might contribute to the development of acquired subglottic stenosis was undertaken in newborn infants with endotracheal tubes in place for 7 days or more. Duration of intubation, the number of endotracheal tubes inserted, the duration of mechanical ventilation, the presence of post-extubation stridor, and the size of the endotracheal tube in relation to gestational age significantly correlated with the development of subglottic stenosis. Patients at risk for significant subglottic stenosis were those with post-extubation stridor and those with tubes in place for 25 days or longer. On the basis of these findings, it is recommended that endotracheal tubes be chosen such that the ratio of nominal tube size divided by the patients gestational age in weeks is less than 0.1.

Effects of phenobarbital and 3-methylcholanthrene pretreatment on the plasma half-life and urinary excretion profile of theophylline and its metabolites in rats

Abstract The effects of the inducers of the hepatic microsomal enzyme system, phenobarbital and 3-methylcholanthrene, on theophylline plasma half-life and on the elimination of theophylline and its metabolites in urine and feces have been examined. The results indicate that induction of the hepatic microsomal drug-metabolizing enzyme system significantly decreases plasma theophylline half-life. In this respect, 3-methylcholanthrene was more effective than phenobarbital. Control theophylline half-life was 3.5 hr. After phenobarbital or 3-methylcholanthrene pretreatment, the theophylline half-life was 2.6 and 0.8 hr respectively. Thin-layer Chromatographie analysis of the urine showed three radioactive peaks corresponding to 1,3-dimethyluric acid, 1-methyluric acid and unchanged theophylline. Both inducing agents significantly increased the urinary elimination of 1,3-dimethyluric acid above that seen in control animals throughout the 24-hr collection period, but only 3-methylcholanthrene increased the total amounts of 1-methyluric acid excreted. Urinary elimination of unchanged theophylline was decreased from control values by both agents. A small, but not statistically significant, increase in the fecal elimination of radioactive material was also noted in the animals pretreated with phenobarbital. The results indicate that alteration in hepatic drug-metabolizing activity may markedly affect the in vivo biotransformation of theophylline.

Nonosmotic diabetic cataracts.

ABSTRACT: It has been suggested that sugar cataracts associated with diabetes mellitus result from the accumulation of excess sorbitol within lens fibrils. Swelling of lens fibrils occurs when water moves in to maintain osmotic balance; the excess water causes disruption of fibrils and cataract formation. Other studies have indicated that more than sorbitol-induced osmotic stress is involved. Our study used lenses collected from rats after 21 or 44 d of streptozotocin diabetes. Cataracts formed in untreated 44-d streptozotocin diabetic rats, but were not apparent in the 21-d untreated diabetic animals. Lens sorbitol increased in the diabetic animals both before and after cataract formation. Lens taurine varied inversely with the sorbitol content in a fashion that resulted in no net change in total lens osmoles. Lens water did not increase in the diabetic animals with or without cataracts. The aldose reductase inhibitor Sorbinil prevented the increase in lens sorbitol in both the 21− and 44-d streptozotocin diabetic rats; cataract formation was prevented in the 44-d diabetic animals. The lens water in untreated diabetic animals with cataracts did not differ from lens water in the Sorbinil-treated diabetic animals that did not develop cataracts. Sorbinil treatment of diabetic animals was associated with normalization of both lens sorbitol and taurine levels. Taurine has been shown to serve both as an osmoregulator and as an antioxidant. The apparent increase in lens osmolality attributed to sorbitol was counterbalanced by an equimolar reduction in taurine concentration. The reciprocal relationship between taurine and sorbitol reduces the likelihood of an osmotic mechanism for sugar cataractogenesis; the reduced lens taurine, however, may increase the risk of lens protein oxidation and subsequent cataract formation. Thus in vivo sugar cataract formation may be an oxidative process rather than an osmotic phenomenon.

The Effect of Hyperglycemia on Nerve Conduction and Structure Is Age Dependent

The nerve conduction velocity (NCV) of nondiabetic male Wistar rats continues to increase until ∼ 26 weeks of age. Rats made hyperglycemic at 6 weeks of age manifest reduced NCV by 10 weeks of age and show morphological differences in the sciatic tibial nerve after 5 months of hyperglycemia when compared with age-matched controls. Fiber diameter, myelin width, and the number of large myelinated fibers were decreased in the tibial nerves of the hyperglycemic animals. Rats made hyperglycemic at 26 weeks of age had elevated glycosylated hemoglobin and sciatic nerve sorbitol levels but maintained normal NCVs and had little change in morphology after 7 months of hyperglycemia. Thus, animals with maturing peripheral nerve structure and function exposed to chronic hyperglycemia manifest greater pathological alterations than those that occur when more matured nerves are exposed to similarly elevated glucose concentrations for an even greater duration. We suggest that immature animal models commonly used to study diabetic peripheral neuropathy may not be appropriate for understanding a process that commonly develops in humans who become hyperglycemic after maturation of the peripheral nerves.

Acetyl-L-carnitine corrects electroretinographic deficits in experimental diabetes.

Acetyl-L-carnitine reduces the latencies of electroretinogram oscillatory potentials in healthy humans. The effect of acetyl-L-carnitine (50 mg · kg−1 · day−1) on the increased electroretinogram latencies found in rats with STZ-induced hyperglycemia of 3-wk duration was evaluated. The aldose reductase inhibitor sorbinil, which has been shown to normalize abnormal electroretinogram tracings associated with STZ-induced diabetes, was used as a positive control. Aldose reductase inhibitors are thought to lower tissue sorbitol while increasing myo-inositol. The electroretinograms of the STZ-induced diabetic rats in this study were abnormal; treatment with acetyl-L-carnitine as well as sorbinil significantly improved electroretinogram b-wave amplitude and decreased the latencies of oscillatory potentials 2 and 3. Acetyl-L-carnitine treatment of STZ-induced diabetic rats did not affect hyperglycemia or erythrocyte polyol pathway activity as reflected by erythrocyte sorbitol levels. In contrast, sorbinil did reduce elevated erythrocyte sorbitol levels. This suggests that the impaired electroretinograms associated with STZ-induced diabetes may not be caused solely by increased polyol pathway activity.

Pharmacological and biochemical activities of some monomethylxanthine and methyluric acid derivatives of theophylline and caffeine

Abstract Some monomethylxanthine and methyluric acid derivatives of theophylline and caffeine have been studied to explore whether they possess pharmacological and biochemical activities similar to those of their parent compounds. Both 3-methylxanthine and 1-methylxanthine, but not 1,3-dimethyluric acid or 3-methyluric acid, produced the same maximal relaxation of guinea pig tracheal muscle as did theophylline. The EC 50 values for theophylline and 3-methylxanthine were not significantly different, whereas those for 1-methylxanthine, 1,3-dimethyluric acid and 3-methyluric acid were significantly higher than that if theophylline. In the Langendorff guinea pig heart, theophylline and 3-methylxanthine caused essentially identical increases in cardiac contractile force. Although less effective than theophylline, 1-methylxanthine and caffeine produced equivalent increases in cardiac contractility. At concentrations higher than those effective for the methylxanthines, 1,3-dimethyluric acid markedly increased contractile force. 3-Methylxanthine inhibited cyclic AMP phosphodiesterase to a lesser extent than did theophylline at both 1.4 and 400 μM cyclic nucleotide concentrations. However, at the higher substrate concentration, cyclic GMP phosphodiesterase activity was inhibited by 3-methylxanthine more than by theophylline. Thus, it appears that the monomethylxanthine and methyluric acid derivatives of theophylline and caffeine possess a spectrum of pharmacological activity similar to that of their parent compounds, a finding which raises important questions about various aspects of the current therapeutic use of methylxanthines.

Involvement of a heat-stable and heat-labile component of Bordetella pertussis in the depression of the murine hepatic mixed-function oxidase system

Abstract Experiments were conducted to determine whether the decrease in ethylmorphine N -demethylase and aniline hydroxylase activities and in the levels of cytochrome P-450 observed after injection of Bordetella pertussis to mice was related to an activity of the well-characterized 80°-heatlabile bacterial component (HSF) which causes an increased sensitivity to histamine. Temporal studies over 10–15 days following B. pertussis inoculation of mice suggested a possible correlation between the development of histamine sensitivity and the decrease in both in vivo and in vitro activities of the hepatic mixed-function oxidase system. Treatment of mice with unheated or 56°-heated vaccine produced a decrease in microsomal drug-metabolizing enzyme activity and an increased sensitivity to histamine at both 24 hr and 5 days after injection. In contrast, mice injected with an 80°-heated vaccine did not show an increased sensitivity to histamine at either time point or a decrease in drug-metabolizing activity at 5 days. There was, however, a significant loss of microsomal enzyme activity determined at 24 hr post-injection of the 80°-heated vaccine. Injection of B. pertussis into a strain of mice insensitive to HSF activity was shown to produce a decrease in the drug-metabolizing activity at both 24 hr and 5 days without the concomitant increase in histamine sensitivity. On the other hand, injection of partially purified HSF into a susceptible strain of mice produced histamine sensitization without the loss of hepatic enzyme activity. These studies suggest that HSF per se is not the bacterial component responsible for the reduction in the hepatic microsomal enzyme activity. The results would indicate that two separate bacterial components may be involved. One is stable to heat of 80° and may cause the acute (24 hr) loss of activity. The second is labile to heat between 56 and 80° and may be responsible for the prolonged (5–10 days) loss of enzyme activity. The identity of the heat-labile component is unknown but the former, heat-stable component may be bacterial endotoxin. This conclusion is based on the similarity between the transient reduction in drug-metabolizing activity produced by injection of 500 μmg/kg of endotoxin and that produced by the 80°-heated vaccine.

Endotoxin depression of hepatic mixed function oxidase system in c3h/hej and c3h/hen mice.

The effect of endotoxin to depress the hepatic drug-metabolizing enzyme activity has been studied in the C3H/HeJ and C3H/HeN strains of mice. The C3H/HeJ mouse strain is generally considered to be unresponsive to the biological effects of endotoxin. However, injection of these mice with 0.5 mg/kg body weight of E.coli endotoxin (Westphal extracted) produced a decrease in the rate of N-demethylation of ethylmorphine and in the levels of cytochrome P-450 and cytochrome b5 comparable to that observed in the endotoxin-sensitive C3H/HeJ mouse strain. Although the mechanism of endotoxin action to decrease hepatic microsomal drug-metabolizing activity is presently unknown, the results suggest that: 1) the C3H/HeJ mouse stain is responsive to this endotoxin effect, and 2)that cellular constituents other than B-cells or macrophages are probably involved in eliciting the response, since these cells of the C3H/HeJ mouse are unresponsive to endotoxin.

Measurements of tissue sorbitol in diabetes mellitus : enzyme method versus gas-liquid chromatography

Two methods are commonly used to measure sorbitol in mammalian tissues. The first uses sorbitol dehydrogenase for a coupled enzymatic reaction; unfortunately, other polyols are also substrates for this enzyme. The second uses gas-liquid chromatography (GLC) for separation of polyols and mass quantitation of sorbitol. A comparison of these two methods for the measurement of sorbitol in duplicate samples of lens, nerve, and erythrocytes indicates that GLC of polyol acetates consistently finds less sorbitol than measured by sorbitol dehydrogenase. Erythritol, threitol, ribitol, arabitol, and galactitol are polyols found in variable quantities in these tissues, which have a variable influence on the activity of sorbitol dehydrogenase and therefore alter sorbitol quantitation with this enzyme. Moreover, there is an unidentified substance(s) that reacts with sorbitol dehydrogenase which seems to increase in association with hyperglycemia in the lens and nerve, but not in erythrocytes. The quantity of this unknown substance(s) seems to be reduced by the aldose reductase inhibitor sorbinil in erythrocytes and to a lesser extent sciatic nerve and lens. Since enzymatic sorbitol quantitation in the lens, nerve, and erythrocytes is influenced by many known and unknown factors other than sorbitol, we recommend that GLC of polyol acetates be used to measure sorbitol in biologic tissues.

Endotoxin inhibition of dexamethasone induction of tryptophan oxygenase in suspension culture of isolated rat parenchymal cells: Involvement of the hepatic nonparenchymal cell fraction

Abstract The effect of endotoxin on the induction of tryptophan oxygenase activity by dexamethasone has been studied in suspension cultures of isolated rat hepatic parenchymal cells incubated alone or mixed with hepatic nonparenchymal cells. Hepatic cellular fractions were isolated from untreated rats and from animals injected 2 hr prior to killing with 2 mg/kg of endotoxin. Endotoxin (400 μg/ml) added to suspensions of parenchymal cells from untreated animals did not decrease the induction of tryptophan oxygenase by dexamethasone. Endotoxin addition to cell suspension containing parenchymal and nonparenchymal cells from untreated rats caused a significant diminution in the induction of enzyme activity elicited by 0.1 μM, but not by 20 μM, dexamethasone. The nonparenchymal cell fraction from untreated animals had no effect on enzyme induction in the absence of added endotoxin. However, nonparenchymal cells isolated from rats pretreated in vivo with endotoxin diminished the induction of tryptophan oxygenase activity elicited by 0.1 and 20 μM dexamethasone even in the absence of added endotoxin. The inhibitory effect of nonparenchymal cells from endotoxin-pretreated rats was related to cell concentration and was accentuated by the in vitro addition of endotoxin. Parenchymal cells from the endotoxin-pretreated animals had an altered sensitivity to dexamethasone. The ec 50 concentration for dexamethasone induction of tryptophan oxygenase was 40 and 500 μm for parenchymal cells from untreated and endotoxin-pretreated animals respectively. Parenchymal cells from the pretreated animals were more sensitive to the inhibitory effect of the nonparenchymal cells from the pretreated animals. These results are interpreted as indicating that endotoxin does not directly antagonize the induction of tryptophan oxygenase. The results suggest that this inhibition of tryptophan oxygenase induction is a mediated event involving an interaction of endotoxin with cellular constituents of the hepatic nonparenchymal cell fraction.