[Noonan syndrome with atrial septal defect and hypertrophic cardiomyopathy].

Noonan syndrome is one of the most common nonchromosomal syndromes seen in children with congenital heart disease. The major cause of death is congestive heart failure. We report a case of Noonan syndrome with hypertrophic cardiomyopathy and arterial septal defect (ASD). Since 10 years old he had been suffering from congestive heart failure. ASD patch closure with a fenestrated flap valve patch was performed at 12 years of age. After operation, left-to-right shunt flow through the patch gradually decreased and he was discharged at 19 postoperative day in good condition.

[Ventricular septal defect with aortic valvular regurgitation complicated with infective endocarditis; report of a case].

We report a case of ventricular septal defect (VSD) associated with infective endocarditis complication of aortic and pulmonary valvular regurgitation. He received treatment for pyelonephritis and after 2 months he was suffering from congestive heart failure. Echocardiography showed vegetation on the aortic valve and the anterior semilunar cusp of the pulmonary valve. He was referred to our department for surgical repair. Aortic valvular replacement, pulmonary valvular repair and direct closure of VSD were performed. The postoperative course was uneventful and the patient discharged at 28 postoperative day.

[A low birth weight infant (904 g) associated with ventricular septal defect].

Published data has suggested that low body weight is risk factor for surgical intervention in congenital heart disease. We report a case of a low birth weight infant with ventricular septal defect (VSD) and pulmonary hypertension (PH). A female infant was born at 31 weeks' gestation. The birth weight was 904 g. At birth she was suffering from congestive heart failure. We diagnosed VSD and PH. We performed pulmonary artery banding at 23 days of age. She accepted the band at a circumference of 15.5 mm. And we performed VSD patch closure and de-banding at 175 days of age. After operation she was on good course and discharged at 19 postoperative day.

Kinetics and mechanism of in vitro uptake of amino-beta-lactam antibiotics by rat small intestine and relation to the intact-peptide transport system.

By utilizing the everted jejunum of rats, the initial uptake rates of several antibiotics were measured over a wide range of concentrations. The uptakes followed mixed-type kinetics involving saturable and non-saturable processes in parallel. The pertinent kinetic parameters for the uptake of each antibiotic were determined. The effect of cephalexin on the uptake of cyclacillin obeyed competitive inhibition kinetics, and the inhibition constant Ki was found to be equal to the Michaelis constant Kt for the uptake of cephalexin itself. In a similar way, the uptake of cephalexin was inhibited by cyclacillin. Uptakes of both cyclacillin and cephalexin were reduced significantly by several metabolic inhibitors. From the effect of temperature on the uptakes of cyclacillin and cephalexin, activation energies of 24.8 and 23.1 kcal/mole were obtained respectively. These results indicate the involvement of an active transport mechanism for cyclacillin and cephalexin. It was found that several dipeptides markedly inhibited the uptakes of cyclacillin and cefadroxil. Furthermore, the uptake of glycylglycine, a typical dipeptide, was inhibited by cyclacillin, cefadroxil, cephalexin, and cephradine. The kinetics of mutual inhibition of the uptakes of cyclacillin and glycylglycine were consistent with competitive-type inhibition. This is the first report which establishes, from a kinetic point of view, the involvement of a common transport system in the in vitro uptakes of the dipeptides and the antibiotics.

Avascular zone in the macula in cicatricial retinopathy of prematurity.

Avascular zones in the maculas of 49 eyes of 33 patients aged 5 to 15 years with cicatricial retinopathy of prematurity were examined by fluorescein angiography. Twenty-three eyes of 18 subjects under 15 years of age who had been born at full term served as controls. The mean diameter of the avascular zones in the patients was 0.22 +/- 0.09 disk diameter, which was smaller than the diameter of 0.32 +/- 0.05 disk diameter in the controls (P less than .001). The patient group was divided into those with avascular zones of 0.2 disk diameter or less, regarded as underdeveloped avascular zones, and those with zones of 0.21 disk diameter or more, considered well-developed avascular zones. In the first group, ocular manifestations in the active stage were statistically more severe than in the second group. Visual acuity was good in most patients in each group.

Quantitative assessment of macular edema with retinal vein occlusion.

PURPOSE: To evaluate the retinal thickness analyzer, a new image analyzer involving laser-slit biomicroscopy, for quantitative assessment of retinal thickness in patients with macular edema secondary to retinal vein occlusion. METHODS: Fifty-eight patients (central retinal vein occlusion, 22 eyes; branch retinal vein occlusion, 36 eyes) with a clinical diagnosis of macular edema associated with retinal vein occlusion were evaluated. Retinal thickness analysis was performed with the retinal thickness analyzer. A green helium-neon laser slit directed into the eye was scanned to generate optical cross-sections of the retina. Images were analyzed by an automated software algorithm, and a detailed map of the retinal thickness was obtained. RESULTS: Laser-slit images obtained with the retinal thickness analyzer in patients with macular edema associated with retinal vein occlusion disclosed intraretinal changes such as retinal edema, cystoid spaces, and hemorrhages. Linear regression analysis showed a significant relationship between the macular thickness in the central fovea and corrected visual acuity reported on a logMAR scale (P = .002, adjusted R2 = 0.40 in central retinal vein occlusion; P = .002, adjusted R2 = 0.34 in branch retinal vein occlusion). CONCLUSION: We confirmed the capability of the retinal thickness analyzer to provide rapid and precise evaluation of macular thickening in patients with retinal vein occlusion.

Comparative stability of cephalosporins in aqueous solution: kinetics and mechanisms of degradation.

The acidic, neutral, and alkaline degradations of six therapeutically useful cephalosporins (cephalothin, cephaloridine, cephaloglycin, cephalexin, cephradine, and cefazolin), 7-amino-cephalosporanic acid, 7-aminodeacetoxycephalosporanic acid, and some 7-substituted derivatives were followed by high-pressure liquid chromatographic, UV spectrometric, iodometric, and hydroxamic acid assays. The pH-rate profiles were determined at 35 degrees and mu = 0.5. The acidic degradation pathway for the 3-acetoxymethyl and 3-pyridinylmethyl derivatives was the specific hydrogen-ion-catalyzed hydrolysis of the beta-lactam bonds. The beta-lactam hydrolyses of these antibiotics exhibited half-lives of about 25 hr at pH 1.0 and 35 degrees. The acetyl functions of 3-acetoxymethylcephalosporins were hydrolyzed eight times faster than their beta-lactam moieties to yield the corresponding deacetyl intermediates, which were rapidly converted to the lactones. Deacetoxycephalosporins were fairly acid stable; e.g., cephalexin and cephradine were about 25 times more stable than cephalothin, cephaloridine, and cephaloglycin and about 180 times more stable than ampicillin at pH 1.0. In the neutral degradation of 3-acetoxymethyl compounds, the competitive reactions of the direct water attack and intramolecular catalysis by the side-chain amido upon the beta-lactams were proposed. The pH-rate profiles near pH 8 for cephaloglycin, cephalexin, and cephradine could be explained by the intramolecular-nucleophilic attack of the side-chain alpha-amino group upon the beta-lactam carbonyls to produce diketopiperazine-type compounds. The reactivity of the cephalosporins in the hydroxideion-catalyzed degradation was influenced significantly by the C-3 methylene substituents.

Hydrolysis and epimerization kinetics of hetacillin in aqueous solution.

Methods were developed for quantitating epimerization to epihetacillin and hydrolysis to ampicillin in the alkaline degradation of hetacillin, and both rates in deuterium oxide at 35 degrees and in water at various temperatures were determined. In each case, plots of log k for the epimerization against pH or pD yielded straight lines with a positive slope, which verified the first-order dependence on the hydroxide ion or deuteroxide ion. The activation energy of the epimerization process was 21.2 kcal/mole. In aqueous solution at high pH, epimerization rather than conversion to ampicillin represents a major pathway of hetacillin degradation, although the beta-lactam ring of the hetacillin molecule is highly resistant to attack by the hydroxide ion.

Effects of surfactants on the GI absorption of beta-lactam antibiotics in rats.

The effects of various nonionic and ionic surfactants and two bile salts (sodium cholate and sodium taurocholate) on the GI absorption of beta-lactam antibiotics were investigated using the in situ rat GI perfusion technique. Addition of 10 mM polyoxyethylene-23-lauryl ether in the perfusion solution reduced the absorption of propicillin by the stomach and markedly increased the absorption of propicillin and cefazolin by the small intestine. Ester-type nonionic surfactants and bile salts exerted no significant influence on the intestinal absorption of these antibiotics.

Chemical reactions in cephalosporin allergy: high-pressure liquid chromatographic analysis of cephalosporin aminolysis kinetics.

Cephalosporin reaction with protein amino groups is fundamental to cephalosporin allergy. Cephalothin and cefazolin reaction kinetics with epsilon-aminocaproic acid, B-alanine, and glycine in aqueous solution were investigated. All reactions were conducted at 35 degrees and 0.5 ionic strength and were followed by ion-exchange high-pressure liquid chromatography. The aminolysis rate constants can be expressed as terms representing uncatlyzed or water-catalyzed amine reaction, self-assited nucleophilic reaction, and hydroxide-ion-catalayzed nucleophilic amine attack on the beta-lactam moiety. Cephalothin and cefazolin react with amines as readily as penicillin G. The UV spectra of several cephalothin-glycine reaction products were recorded, and their possible structures are discussed.

Physicochemical properties of amphoteric beta-lactam antibiotics. II: Solubility and dissolution behavior of aminocephalosporins as a function of pH.

The solubility of aminocephalosporins in aqueous solution at 37 degrees and an ionic strength of 0.5 exhibited U-shaped curves against pH. At their isoelectric pH, cephradine monohydrate was the most soluble, followed by cephalexin monohydrate and cephaloglycin dihydrate, with intrinsic solubilities of 26.0, 17.2, and 14.8 mg/ml, respectively. The dissolution rate constants from the rotating disk were also determined as a function of the pH of the dissolution medium and interpreted reasonably by the simultaneous dissociation equilibrium reaction and the diffusion kinetics model. Energies for the solubility and dissolution were determined for these three aminocephalosporins.

Carbenicillin prodrugs: stability kinetics of alpha-phenyl and alpha-indanyl esters in aqueous solution.

Both ester and beta-lactam degradations of alpha-esters of carbenicillin disodium, carbenicillin indanyl sodium, and carbenicillin phenyl sodium in aqueous solution at 35 degrees and at 0.5 ionic strength were investigated. The reactions were followed by spectrophotometric assay, reversed-phase high-pressure liquid chromatography, and colorimetric assay. The degradation pathways were established, and the rate-pH profiles for ester and beta-lactam cleavage reactions are given for pH 1-11. Below pH 3, the beta-lactam degradation of the prodrugs proceeded exclusively. Above pH 7, the degradation was superseded by the ester hydrolysis to carbenicillin, beta-Lactams of both prodrugs are around three times more stable than carbenicillin disodium at pH 1, six times at PH 2, and 17 times at pH 3. The half-lives for carbenicillin production were predicted to be 17 hr for carbenicillin indanyl sodium and 8.5 hr for carbenicillin phenyl sodium at pH 7.0 and 37 degrees.

Physicochemical properties of beta-lactam antibacterials: deuterium solvent isotope effect on penicillin G degradation rate.

To obtain kinetic evidence on the degradation mechanism of penicillin in aqueous solution, degradation rates of penicillin G in water and deuterium oxide were measured in the pH (pD) range of 4-10. The solvent isotope effect (kH2O/kD2O) of 1.53 below pH (pD) 6 supports the mechanism of water-catalyzed rearrangement of undissociated penicillin G to benzylpenicillenic acid. The spontaneous degradation at neutral pH (pD) and the hydroxide-ion-catalyzed degradation in the alkaline pH (pD) range progress with a deuterium solvent isotope effect (kH2O/kD2O) of 4.5 and 0.59, respectively. This finding indicates the mechanisms of general base-catalyzed hydrolysis by water in the neutral pH range and of nucleophilic attack of the hydroxide ion on the beta-lactam in the alkaline pH range. No significant side-chain dependency was observed in the reaction of penicillins with bases. The solvent isotope studies led to the conclusion that penicillin degradation is catalyzed by a series of bases via general base-catalyzed and nucleophilic mechanisms, depending on their basicity.

Physicochemical properties of beta-lactam antibiotics: oil-water distribution.

Apparent partition coefficients Papp, of beta-lactam antibiotics were determined in octanol-water and 2-methylpropanol-water systems at various pH values. The pKa values also were determined by potentiometry under the conditions of partition experiments. The intrinsic partition coefficients for the unionized form, Pu, and the ionized form, Pi, of beta-lactam antibiotics were calculated from the equation Papp = Pu[aH+/(Ka + aH+)] + Pi[Ka/(Ka + aH+)]. The correlation between Pu and Pi values and lipophilic parameters of penicillins measured in other systems was examined.

Physicochemical properties of amphoteric beta-lactam antibiotics I: Stability, solubility, and dissolution behavior of amino penicillins as a function of pH.

The degradation rate, solubility, and dissolution rate of amino penicillins, amoxicillin, ampicillin, epicillin, and cyclacillin, were determined quantitatively as a function of pH. In the pH range studied, 0.30-10.50, the degradation of amoxicillin and epicillin followed pseudo-first-order kinetics to give the same type of pH-rate profiles as those of ampicillin and cyclacillin. Cyclacillin anhydrate was the most soluble, followed in order by ampicillin anhydrate, ampicillin trihydrate, amoxicillin trihydrate, and epicillin anhydrate. These pH-solubility profiles showed showed U-shaped curves. The dissolution rate constants from the rotating disk were analyzed by the simultaneous chemical reaction and diffusion models. Their relative bioavailability after a single oral administration was assessed from their physicochemical properties determined in vitro.

GI absorption of beta-lactam antibiotics II: deviation from pH--partition hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers.

The absorption of propicillin from the rat stomach and small intestine in situ was examined as a function of recirculating solution pH. The in vitro interphase transport from an aqueous buffer of various pH values to the octanol phase was also studied for several penicillins by the use of a two-phase rolling cell. The rate--pH profiles obtained from both in situ and in vitro experiments deviated significantly from the dissociation curves. The degrees of the shifts were approximately 2 pH units for the in situ intestinal absorption of propicillin and in vitro transport of propicillin and cloxacillin, approximately 1.5 pH units for the in vitro transport of penicillin V, and 0.8 pH unit for the in situ stomach absorption of propicillin. These discrepancies from the classical pH--partition hypothesis can be interpreted by the permeation through the lipoidal barrier of the undissociated species of penicillins transported through the aqueous diffusion layer adjacent to the lipoidal surface. All in situ and in vitro experiments tend to support this theory.

Novel method for determination of partition coefficients of penicillins and cephalosporins by high-pressure liquid chromatography.

Newly defined lipophilic indexes, log k', of a series of penicillins and cephalosporins were rapidly and reliably determined by reversed-phase high-pressure liquid chromatography (HPLC) on bonded octadecylsilane supports. The log k' values obtained from their retention times exhibited a linear relationship with methanol concentration (v/v%) in the mobile phase. The extrapolated log k' values to zero and those at 30% correlated well with the partition coefficients, log P, in 1-octanol-water and with Rm values from TLC. This HPLC technique provided some new log P and Rm values for highly ionizable beta-lactam antibiotics. The HPLC method for the determination of partition coefficients of drugs has some advantages and is a useful alternative for the determination of log P and Rm.

Carbenicillin prodrugs: kinetics of intestinal absorption competing degradation of the alpha-esters of carbenicillin and prediction of prodrug absorbability from quantitative structure-absorption rate relationship.

The intestinal absorption of alpha-esters of carbenicillin disodium, carbenicillin phenyl sodium, and carbenicillin indanyl sodium was investigated using the in situ rat intestinal recirculating method. In the in situ intestinal lumen at pH 7, two prodrugs were rapidly converted to poorly absorbable carbenicillin, possibly by the action of intestinal nonspecific esterase in competition with the slow absorption of prodrugs. At pH 5, the reduced action of esterase and the increased absorption rate after 3 hr resulted in 50 and 60% absorption of carbenicillin phenyl sodium and carbenicillin indanyl sodium, respectively. The absorption rate constants determined for both prodrugs were in good agreement with the prediction from the quantitative structure-absorption rate relationship derived from the two-compartment aqueous diffusion model.

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics I: Comparative absorption and evidence for saturable transport of amino-beta-lactam antibiotics by in situ rat small intestine.

The disappearance of various beta-lactam antibiotics from in situ rat small intestinal loops was studied at pH 7.4. For monobasic penicillins, despite the wide variety of apparent partition coefficients in isobutyl alcohol-water, the disappearance from the jejunal loops was almost 30% (+/- 5% SD). On the other hand, the disappearance of amphoteric derivatives of penicillins and cephalosporins having very low lipid solubility varied widely between 12 and 80%. The peak blood levels after intraduodenal administration to the rats correlated well with the extent of disappearance of amphoteric penicillins from the intestinal loops. Absorption studies utilizing in situ intestinal loops were performed at variable dose ranges to yield a clear dose-dependent disappearance. It is suggested that certain carrier-mediated transport systems underlie the absorption mechanism of amphoteric beta-lactam antibiotics.

Intestinal absorption mechanism of amphoteric beta-lactam antibiotics II: Michaelis-Menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats.

The absorption of cyclacillin at pH 7.0 by the rat small intestine was investigated using in situ perfusion. At the lowest dose of 95 microgram/ml, the antibiotic disappearance was rapid and followed first-order kinetics, with the disappearance being 85% at 100 min. At the intermediate concentrations of 770 and 1200 microgram/ml, the disappearance after 100 min was 69 and 54%, respectively, and semilogarithmic plots clearly showed convex curvatures. At the highest concentration of 30 mg/ml, cyclacillin disappeared slowly from the perfusate, in an apparent first-order fashion. The disappearance was 26% after 100 min of perfusion and was similar in extent at 5.2 mg/ml. This concentration-time profile was satisfactorily fitted to the simultaneous Michaelis-Menten and first-order kinetic equations. The area under the blood concentration versus time curve (AUC) after a single intraduodenal dose of cyclacillin was almost consistent with the AUC after the equivalent intravenous dose (10 mg/kg). Additional evidence from a pharmacokinetic analysis of steady-state blood concentrations after constant infusion of cyclacillin through the portal vein and the small intestinal lumen indicated that cyclacillin absorption by the rat intestinal tissue at relatively low concentrations (less than 1 mg/ml) followed solely Michaelis-Menten kinetics. Cyclacillin may be transported by certain types of carrier-mediated mechanisms.