Cytotoxic benzylidene hydrazides of terephthalic acid and related compounds.

The present investigation involved the synthesis of a number of novel benzylidene hydrazides as candidate cytotoxic agents. The preparation of these compounds from terephthalic acid and isophthalic acid proceeded satisfactorily. However, the reaction of phthalic acid hydrazide with various aryl aldehydes was unsuccessful in general. Some of the unexpected products were identified. The shapes and also the distances between the centers of the aryl rings designated B and C of three representative compounds 1b, 2b and 3b were determined. The compounds designated 1a-e, 2a-e and 3b were screened against human HCT116 and HT29 colon cancer cells as well as human CRL1790 non-malignant colon cells which revealed the tumor-selective toxicity displayed by these compounds.

General pediatric emergencies. Malignant hyperthermia syndrome.

Anesthesiologists always undertake the challenge of keeping themselves informed about advances in medical knowledge aggressively; however, they have not been particularly active in the areas of patient education and advocacy. Malignant hyperthermia syndrome is a unique condition that anesthesiologists as clinicians understand well--in most cases, better than other specialists. They are positioned best to inform patients initially about the significance of malignant hyperthermia syndrome susceptibility and to provide an ongoing resource for counseling. The physician-patient relationship, according to the American Society of Anesthesiologists' Guidelines for the Ethical Practice of Anesthesiology, "involves special obligations for the physician that include placing the patient's interest foremost, faithfully caring for the patient, and being truthful." The care, counseling, and support that anesthesiologists bring to the patient susceptible to malignant hyperthermia syndrome truly fulfills this relationship.

Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations.

BACKGROUND: Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. METHODS: Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. RESULTS: All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. CONCLUSIONS: A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.

Effect of peptide concentration and temperature on leuprolide stability in dimethyl sulfoxide.

The effects of temperature and concentration on leuprolide degradation in dimethyl sulfoxide (DMSO) were explored. Leuprolide degradation products were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC), size exclusion chromatography (SEC) and structurally characterized by mass spectrometry. Leuprolide solution stability in DMSO was characterized at 50, 100, 200, 400 mg/ml at 37-80 degrees C for 2 months to 3 years. Leuprolide degradation products were identified by mass spectrometry and could generally be attributed to isomerization, hydrolysis, oxidation, or aggregation. The hydrolytic degradation products consisted primarily of backbone cleavage C-terminal to Trp(3), Ser(4), Tyr(5), Leu(6) and Leu(7), and oxidation of Trp(3) and beta-elimination of Ser(4) were identified. Leuprolide degradation at 50 degrees C, 65 degrees C and 80 degrees C proceeded in an exponential fashion (E(a)=22. 6+/-1.2 kcal/mol); however, leuprolide degradation plateau'd after approximately 6 months at 37 degrees C. Upon closer examination, degradation product peak areas were seen to vary with temperature. For example, aggregation products did not increase with time at 37 degrees C, but aggregation peak intensities increased sharply with time at 80 degrees C. Increasing the temperature also increased the proportion of leuprolide degrading via isomerization/hydrolytic pathways, and decreased the proportion degrading via oxidation. These variations suggested that solvent dielectric, free H(+) in an aprotic solvent, oxygen solubility, impurities and residual moisture may play a role. Leuprolide solubilized in DMSO yields adequate stabililty for a 1 year implantable osmotic delivery system, where use of a dry aprotic solvent results in conditions similar to solid state stability.

Pressure-limited ventilation of infants with low-compliance lungs: the efficacy of an adult circle system versus two free-standing intensive care unit ventilator systems using an in vitro model.

UNLABELLED: We compared the efficacy of a Drager Narkomed GS (North American Drager, Telford, PA) equipped with an adult circle system with two free-standing infant ventilator systems (Servo 300; Siemens Medical Systems, Danvers, MA and Babylog 8000; North American Drager) to deliver minute ventilation (VE) using pressure-limited ventilation to a test lung set to low compliance. To simulate a wide variety of potential patterns of ventilation, VE was measured at peak inspiratory pressures (PIP) of 20, 30, 40, and 50 cm H2O and at respiratory rates (RR) of 20, 30, 40, and 50 breaths/min. Each measurement was made three times; the average was used for data analysis using the multiple regression technique. Delivered V(E) was positively correlated with both PIP (P = 0.001) and RR (P = 0.001). Only minimal differences in VE were observed between the circle and the two free-standing systems. At lower RR and PIP, the Babylog 8000 system delivered slightly higher VE than the circle system, whereas at higher RR and PIP, the Babylog 8000 delivered slightly lower VE than the circle system; these differences in VE were not statistically significant (P = 0.45). The Servo 300 delivered slightly higher VE than the circle system in all test conditions, but these differences were not statistically significant (P = 0.09). None of the differences in delivered VE between the Servo 300 and the circle system are of clinical importance. IMPLICATIONS: Our laboratory investigation suggests that pressure-limited ventilation delivered by a standard adult circle system compares favorably with that of freestanding infant ventilators used in pressure-limited mode. Changing from an adult circle system to a free-standing pressure-limited ventilator may not substantially improve ventilation of a low-compliance infant lung; the efficacy of such a practice should be investigated.

Characterization and comparison of leuprolide degradation profiles in water and dimethyl sulfoxide.

The effect of solvent on the rate of leuprolide degradation and on the structure of the degradation products was explored. Leuprolide solutions (370 mg/mL) were prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROS osmotic implants. Both solvent systems demonstrated better than 90% stability after 1 year at 37 degrees C, where the DMSO formulation afforded better stability than the aqueous formulation and was used in subsequent clinical trials. The rate of leuprolide degradation in DMSO was also observed to accelerate with increasing moisture content, indicating that the aprotic solvent minimized chemical degradation. Interestingly, leuprolide degradation products varied with formulation vehicle. The proportions of leuprolide degradation products observed to form in water and DMSO at 37 degrees C were hydrolysis > aggregation > isomerization > oxidation and aggregation > oxidation > hydrolysis > isomerization, respectively. Specifically, more N-terminal hydrolysis and acetylation were observed under aqueous conditions, and increased Trp oxidation and Ser beta-elimination were seen under non-aqueous conditions. Furthermore, the major chemical degradation pathway changed with temperature in the DMSO formulation (decreasing oxidation with increasing temperature), but not in the aqueous formulation.

An adult system versus a Bain system: comparative ability to deliver minute ventilation to an infant lung model with pressure-limited ventilation.

UNLABELLED: We compared the efficacy of an adult circle system versus a Bain system to deliver minute ventilation (V(E)) to an infant test lung model using pressure-limited ventilation. To simulate a wide variety of potential infant clinical states, V(E) was measured with two compliances: at peak inspiratory pressures (PIP) of 20, 30, 40, and 50 cm H2O and at respiratory rates (RR) of 20, 30, 40, and 50 breaths/min. Each measurement was made three times, and their average was used for analysis. Data were analyzed using the multiple regression technique. In both normal and low-compliance lung models, V(E) was nearly identical between adult circle and Bain systems (P = 0.67 for normal compliance model, P = 0.89 for low-compliance model). V(E) positively correlated with RR (P < 0.001), PIP (P < 0.001), and lung compliance (P < 0.001). Very high PIP or RR were required to deliver V(E) to the low-compliance lung model. The adult circle system is equivalent to the Bain system in its ability to ventilate an infant test lung over a wide range of RR, PIP, and two compliances during pressure-limited ventilation. V(E) is dependent of PIP, RR, and lung compliance. With low-compliance lungs, both systems require a high PIP. We conclude that both anesthetic systems deliver ventilation over a wide range of respiratory variables during pressure-limited ventilation in infants. IMPLICATIONS: We obtained results from this infant test lung study that indicate that either an adult circle breathing system or the Bain system can reliably deliver ventilation over a wide range of respiratory variables during pressure-limited ventilation in infants.

A comparison of three modes of ventilation with the use of an adult circle system in an infant lung model.

UNLABELLED: We examined the efficiency of an adult circle system with adult bellows to deliver minute ventilation (VE) to an infant test lung model. A Narkomed 2B system (North American Drager, Telford, PA) using three modes of ventilator setup were used: A = time-cycled, volume-controlled using bellows excursion to control delivered volume; B = time-cycled, pressure-controlled using inspiratory pressure limit adjustment to control delivered volume; C = time-cycled, pressure-controlled using the inspiratory flow adjustment to control delivered volume. VE was measured with two compliances (normal and low) and four endotracheal tube (ETT) sizes (2.5-, 3.0-, 3.5-, and 4.0-mm inner diameter). VE was measured at peak inspiratory pressures (PIP) of 20, 30, 40 or 50 cm H2O while respiratory rate (RR) was held constant at 20 breaths/min. VE was measured as RR was set at 20, 30, 40, or 50 breaths/min while target PIP was held constant at 20 cm H2O. Data were analyzed using the multiple regression technique. With the low compliance model, VE was nearly identical regardless of the ventilator setup. With the normal compliance model, minor differences in VE were observed, especially at the highest RR and PIP. VE was dependent on RR, PIP, and lung compliance. Overall, the ventilator setup resulted in minor changes in VE. Very high PIPs were required to deliver VE to the low compliance model. ETT size did not affect VE when lung compliance was low; however, smaller ETT size was a factor when test lung compliance was normal, decreasing delivered VE at higher PIP and RR. We conclude that with a Narkomed 2B adult circle system VE is dependent on PIP, RR, and lung compliance, but not on mode of ventilator setup. IMPLICATIONS: The results of this laboratory investigation indicate that when an adult circle system is used during infant anesthesia, the ventilation delivered depends primarily on the respiratory rate, peak inspiratory pressure, and the compliance of the lung being ventilated, rather than on the specific mode of ventilator setup.

The effect of circuit compliance on delivered ventilation with use of an adult circle system for time cycled volume controlled ventilation using an infant lung model.

This in vitro study examined the effect of circuit compliance on delivered ventilation (VE) using a time-cycled, volume controlled circle system in an infant lung model. A Bio-Tek ventilator tester set to simulate normal and abnormal lung compliance measured VE delivered by the Narkomed 2B system. Circle circuits of varied compliance (2.75, 1.22 and 0.73 microliters.cm H2O-1) were tested. Tidal volume was adjusted to peak inflation pressures (PIP) of 20, 30, 40, and 50 cm H2O with three circuits, two lung compliances, and four different size tracheal tubes (TT) (2.5, 3.5, 4, 4.5 mm ID). Data were analysed using the multiple regression technique. Delivered VE was directly related to PIP and lung compliance. Delivered VE was not affected by the choice of circuit. TT size had minimal effects on VE when lung compliance was low; TT size was a more important factor when test lung compliance was normal. Extrapolating this data to the clinical setting, adequate ventilation of infants can be achieved with an adult circle system if an appropriate PIP is chosen, regardless of the compliance of the circuit used. Infants with poor lung compliance may require very high PIP for adequate ventilation.

Calcium channel types mediating synaptic transmission during aging.

The effects of omega-conotoxin (CTX) GVIA, omega-agatoxin (Aga) IVA, and the dihydropyridine nicardipine were studied on synaptic transmission in the hippocampus during aging. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region in slices from young and aged Fischer 344 rats. Peptide toxins reduced synaptic transmissions similarly in both age groups while nicardipine showed no effect. These results suggests that the well documented age-related changes in synaptic transmissions in the hippocampus cannot be explained by changes in the types of Ca2+ channel mediating synaptic transmission.

Pediatric sedation in radiology: the practice of safe sleep.

Children will probably always need to be sedated for some radiologic procedures, and controlling the state of consciousness of a child involves more than selecting an agent. The safe and effective sedation process emanates from a carefully designed sedation program. This program begins even before it is determined that sedation is necessary to properly perform a radiologic examination or procedure. Although several issues, controversies, and choices are involved, the context and dialogue of sedation must originate from the principle of protecting the health and safety of children.

Do latex precautions in children with myelodysplasia reduce intraoperative allergic reactions?

Children with myelodysplasia have an increased incidence of latex allergy, which can lead to severe intraoperative allergic reactions. Despite widespread recommendations to avoid intraoperative latex exposure, little evidence exists to support the efficacy of this practice. We examined the incidence of intraoperative allergic reactions in children with myelodysplasia who underwent 1,025 operations in a 36-month period before and after institution of a standardized latex-avoidance protocol. Risk factors for an intraoperative reaction were found to be a history of latex allergy (p = 0.001) and surgery performed before institution of the latex-avoidance protocol (p = 0.01). The estimate of increased risk for allergic reaction was 3.09 times higher in cases performed without latex avoidance. Recognized violation of the protocol after its institution led to severe allergic reactions in three patients. Our experience suggests that a latex-avoidance protocol reduces intraoperative allergic reactions in children with myelodysplasia. Development of severe allergic reactions with violation of the protocol reinforces the importance of vigilance on the part of all operating room personnel in its implementation.

Retrograde fibreoptic intubation in a child with Nager's syndrome.

PURPOSE: The authors describe a retrograde fibreoptic technique for tracheal intubation in a micrognathic child with a tracheo-cutaneous fistula. CLINICAL FEATURES: A four-year-old child with Nager's syndrome presented for surgical closure of a tracheocutaneous fistula. A tracheostomy tube had been placed in the neonatal period for management of upper airway obstruction due to severe micrognathia. At 2 1/2 yr of age, after a successful mandibular advancement procedure, the tracheostomy was removed and the child allowed to breathe through the natural airway. Preoperative physical examination revealed an uncooperative child, unable to open her mouth due to limited temporo-mandibular motion. The child was first anaesthetized with ketamine, 70 mg im, then halothane by mask. The authors were unable to open the child's mouth sufficiently to allow rigid laryngoscopy. Attempts at oral and nasal fibreoptic intubation were unsuccessful. Ultimately, the authors were able to intubate nasally by passing an ultrathin Olympus LF-P laryngoscope under direct vision through the tracheocutaneous fistula in a cephalad direction, through the larynx and nasopharynx, then out the nares. An endotracheal tube was then advanced over the fibreoptic scope and positioned distal to the tracheocutaneous fistula. The surgical procedure was successfully accomplished and the trachea was extubated postoperatively without difficulty. CONCLUSION: Retrograde fibreoptic intubation may be an option for airway management of a select group of children who cannot be intubated by traditional techniques.

Micronucleus induction in human lymphocytes: comparative effects of X rays, alpha particles, beta particles and neutrons and implications for biological dosimetry.

The cytokinesis-block micronucleus assay in peripheral blood lymphocytes has the potential for being a simple and rapid method of biological dosimetry. This technique has been used to study the induction of micronuclei in the blood from 12 donors after exposure to a range of radiations with track-averaged LET values ranging from 0.26 to 44 keV microns -1. Data based on the average response of the 12 individuals for 250 kVp X rays were found to agree well with results published previously from other laboratories using similar techniques. Low dose-limiting RBE values relative to 250 kVp X rays for the radiations studied were found to be 0.50 for strontium/yttrium-90 beta particles, 6.9 for 20-23 keV microns -1 alpha particles and 17 for 24 keV neutrons. The pattern of the variation of individual radiosensitivity was found to be complex and dependent on dose, and the evaluation of individual radiosensitivity based on the response at one dose only can be misleading. It is concluded that, although the cytokinesis-block micronucleus assay in blood lymphocytes is a radiobiologically appropriate technique to use for biological dosimetry, its practical implementation may be limited by a need to perform individual pre-exposure calibrations.