Solution conformations of the peptide backbone for DPDPE and its β-MePhe4-substituted analogs

The solution structures of DPDPE, a conformationally restricted pentapeptide with the sequence H-Tyr¹-d -Pen²-Gly³-Phe⁴-d -Pen⁵-OH, and its four β-MePhe⁴-substituted analogs were examined by a combined approach including the NMR measurements in DMSO and water as well as independent energy calculations. It was concluded that several low energy conformers of DPDPE backbone satisfy the NMR data obtained in this study as well as in previous studies by other authors. These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly³ residue in a conformation close to a γ-turn, and the Phe⁴ residue in a conformation close to α-helical torsion angles. They differ in the space arrangements of the flexible Tyr¹ moiety. The solution structures of the β-MePhe⁴-substituted analogs of DPDPE are interesting. For analogs with an S-configuration at the C^α atom in the Phe⁴ residue, the cyclic backbone conformations resemble those of DPDPE itself, whereas for analogs with an R-configuration at the C^α atom, the backbone conformation is somewhat different. This observation is in line with the high biological potencies and selectivities displayed by the former compounds but not by the latter ones. It was noted also that as far as the peptide backbone conformers are concerned, some of the possible DPDPE conformers in water are similar to the previously suggested model for the δ-receptor-bound conformation of DPDPE, becoming virtually identical to this conformation by rotating the side chains of the Tyr¹ and the Phe⁴ residues.     

Prechronic Inhalation Toxicity Studies of 2-Mercaptobenzimidazole (2-MBI)in F344/N Rats

2-Mercaptobenzimidazole (2-MBI), used in rubber processing,is a suspect carcinogen structurally related to ethylene thiourea.The inhalation toxicity of 2-MBI was evaluated in male and femaleF344/N rats exposed 6 hr/day, 5 days/week to respirable aerosolsgenerated by spray atomization of aqueous suspensions of the2-MBI powder and subsequent drying of the resulting aerosols.Twelve exposures at target concentrations of 0, 6.3, 12.5, 25.0,50.0, or 100 mg/m³ of 2-MBI produced a dose-related reductionin body weight gains, thyroid follicular cell hyperplasia, adrenalcortex fatty change, and pituitary atrophy. Sub-chronic exposureswere conducted at target concentrations of 0, 3.1, 6.2, 12.5,25.0, and 50.0 mg/m³ of 2-MBI. Rats at 25 mg/m³ displayed hunchedposture, hypoactivity, and reduced body weight gain, with compoundrelated mortality at the highest exposure level. Anemia; increasedSGPT, SGOT, alkaline phosphatase, sorbitol dehydrogenase, BUN,and cholesterol; and reduced free fatty acid were seen in ratsat 25 mg/m³. Increased thyroid weight and thyroid follicularcell hyperplasia were noted in both sexes at 6.2 mg/m³, withreduced triiodothyronine and thyroxine levels in both sexesat > 12.5 mg/m³. Thyroid follicular cell hyperplasia wasalso seen in rats at 3.1 mg/m³. Thymus weights were significantlyreduced in both sexes at all exposure levels with liver weightincreases at 6.2 mg/m³. Exposure-related histopathologic changesincluded pituitary cytoplasmic vacuolization, adrenal cortexnecrosis, lymphoid depletion, thymic atrophy, liver cell hypertrophy,renal mineralization and tubular atrophy, and hypocellularityof the bone marrow.     

Comparison of salbutamol powder with terbutaline aerosol administered with a tube spacer in asthmatic children

ABSTRACT. The bronchodilator effect of 400 μ of salbutamol powder (2 capsules) administered by a rota-haler was compared with that of 500 μg of terbutaline (2 mete red doses) administered as an aerosol via a tube-spacer in a group of ten stable asthmatic children (mean age 12 years). The salbutamol powder produced significantly greater bronchodilatation compared with the terbutaline. Forty-five minutes after the administration of each preparation, nebulised salbutamol was given to determine if further bronchodilatation was possible. Additional bronchodilatation was seen in both groups, the greater additional change being after terbutaline. It is concluded that 400 μg of salbutamol powder was more effective than 500 μg of terbutaline via tube-spacer but following both preparations, nebulised salbutamol produced significant additional bronchodilatation.     

Clinical and psychosocial service needs of children and families affected by human immunodeficiency virus in Europe

Background: Although human immunodeficiency virus (HIV)-infectedchildren have specific service needs, uninfected children bornto HIV-infected mothers are also likely to be profoundly affectedby HIV. However, there has been little systematic documentationof services available for families with HIV infection in Europeor any investigation into service use by families and theirsatisfaction with current provision. Methods: A two-part surveywas carried out: interviews with service-providers in 15 paediatricHIV centres in Europe were carried out to obtain informationon current provision of clinical and psychosocial services.This was followed by an anonymous, self-completed questionnairesurvey of parents and carers of children attending ten of these15 centres. Results: Most (nine out of 15) centres had weeklycase-loads of more than ten HIV-infected and -affected children.Three-quarters (138 out of 182) of the families surveyed includedat least one HIV-infected child. In most (13 out of 15) clinicsa psychosocial professional was routinely available, in additionto paediatricians. Service users reported general satisfactionwith clinic organization, such as medical appointment schedules,continuity of in-and out-patient care and coordination of adultand child appointments. The level of information provided wasconsidered satisfactory by most service users, although parentstended to be less satisfied than alternative carers. Sick parentsand unemployed respondents had the highest level of serviceuse and three-quarters of service users reported unmet serviceneeds. Conclusion: The range of services provided was remarkablysimilar across countries, which may reflect the fact that allcentres were referral centres. However, the challenge of meetingthe outstanding service needs of certain families remains.     

Codeine: Developmental Toxicity in Hamsters and Mice

Codeine: Developmental Toxicity in Hamsters and Mice. Williams,J., PRICE, C. J., SLEET, R. B., GEORGE, J. D., MARR, M. C, KIMMEL,C. A., AND MORRISSEY, R. E. (1991). Fundam. Appl. Toxicol. 16,401–413. Timed-pregnant LVG Syrian hamsters and SwissCD-I mice were dosed orally twice daily (b.i.d.) with codeinein water on Gestational Days (gd) 5–13 (0, 10, 50, or150 mg/kg, b.i.d.—hamsters) or 6–15 (0, 37.5, 75,150, or 300 mg/kg, b.i.d.—mice). Dams were necropsiedon gd 14 (hamsters) or 17 (mice), and fetuses were weighed,sexed, and examined for external, visceral, and skeletal malformations.No maternal deaths were observed in hamsters, while 19% of thepregnant mice in the high-dose group died. Maternal weight gain(gestational and treatment periods) and gravid uterine weightswere significantly depressed in hamsters (150 mg/kg, b.i.d.)and in mice (300 mg/kg, b.i.d.). However, the corrected weightgain for both species, although decreased, was not significantlydifferent from that of the controls. In both species, maternalliver weights (relative) were significantly increased in thehigh-dose groups. There were increases in the percentage resorptionsper pregnant dam and in the proportion of litters with 100%resorptions in the high-dose groups of both species. Consideringonly live litters, the number of live fetuses per litter andthe sex ratio were unaffected in both species. Mean fetal bodyweights were also significantly decreased in the 50 and 150mg/kg, b.i.d. (hamsters), and the 150 and 300 mg/kg, b.i.d.(mice), groups. The no-observed-adverse-effect levels (NOAELs)for developmental toxicity were 10 (hamsters) and 75 (mice)mg/kg, b.i.d., whereas the NOAELs for maternal toxicity were50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structuralmalformation in hamsters was meningoencephalocele (high-dosegroup only), affecting 3% of fetuses and 19% of litters (neitherstatistically significant). Codeine did not induce any increasein structural malformations in mice. Thus, codeine produceddevelopmental toxicity (as indicated by decreased fetal bodyweight) at doses below those producing maternal toxicity inboth hamsters and mice. In the hamster, the more sensitive speciesto codeine developmental toxicity, effects were observed ata total daily dose of 100 mg/kg, which is only 11 times themaximum human therapeutic oral dose.     

Inhibition of melatonin secretion onset by low levels of illumination

Melatonin is a hormone released during darkness under the control of the hypothalamic circadian pacemaker. It has been shown that melatonin is suppressed by light as a function of intensity, with low levels of illumination producing small effects and more intense light greater, but not complete inhibition. The studies which lead to these conclusions administered light subsequent to the secretion pattern being well established. Light as low as 250 lux administered during the normal onset of secretion can reduce melatonin to below detectable levels. The onset of melatonin secretion was delayed for at least an hour during 250 lux exposure and did not rise until termination of light exposure (two hours after control melatonin onset) with higher illumination (500, 1000 and 2500 lux). This tentatively indicates that duration of the inhibition is intensity dependent. It is suggested that the experimental paradigm used in the present study may be a more realistic representation of the effect of normal light exposure (both natural and artificial) on the circadian system, and that findings may be pertinent to the aetiology of certain sleep onset insomnias, which would include delayed sleep phase syndrome (DSPS) and adaptation to shift work.     

Midtrimester Amniotic Fluid Tumor Necrosis Factor-Alpha Does Not Predict Small-for-Gestational-Age Infants

PROBLEM: To evaluate the independent ability of midtrimester amniotic fluid tumor necrosis factor-alpha (TNF-α) in the prediction of small-for-gestational-age (SGA) infants. METHOD OF STUDY: In this case-control study, patients delivering a SGA infant were matched with controls based on GA at delivery, maternal age, race, and parity. Patients with immune disease, chronic hypertension, diabetes, asthma, congenital hearts disease, multiple gestation, and fetal anomalies were excluded. Amniotic fluid samples were immunoassayed for TNF-α. Potential confounding variables evaluated were maternal serum alpha-fetoprotein level, smoking history, pregnancy induced hypertension, and neonatal gender. Statistical analysis included Fisher's exact test and ANOVA after log transformation with P < 0.05 considered significant. RESULTS: Eighteen patients delivered SGA neonates and were matched with 41 controls. No significant differences were identified in the confounding variables between patients with SGA neonates and controls. Amniotic fluid TNF-α levels were not significantly different between patients subsequently delivering SGA neonates and controls [median 7.63 (range 0.25-16.1) pg/mL versus 9.39 (0.25–66.9) pg/mL, P = 0.8]. CONCLUSIONS: Midtrimester amniotic fluid TNF-α levels are not predictive of SGA neonates when compared with controls matched for gestational age at delivery.