Thiol Reduction of 3′-Azidothymidine to 3′-Aminothymidine: Kinetics and Biomedical Implications

The ability of thiols to reduce 3-azidothymidine (AZT) to 3-aminothymidine has been investigated. Incubation with glutathione, dithiothreitol (DTT), or mercaptoethanol at pH 7.2 and 37°C leads to quantitative reduction of the azido moiety to an amine. The reaction is first order in AZT and first order in reducing agent (mono- or dithiol). The second-order rate constants are 2.77 × 10^–3, 6.55 × 10^–5, and 6.35 × 10^–6 M ^–l sec^–1 for the dithiothreitol, glutathione, and mercaptoethanol reductions, respectively. The thiol reduction of alkyl azide to amine under mild conditions is a synthetic method particularly suitable for water-soluble azido compounds that are sensitive to catalytic hydrogenation. The potential for the mono- or dithiol-mediated reduction of alkyl azides under biological conditions must be considered when conducting studies of azido drugs.     

Suggested approaches for research protocols involving the potential for life-threatening reactions

These guidelines are intended to reduce the potential for serious or life-threatening reactions when clinical research is conducted. The following issues were addressed: identifying the risks involved in the research, providing adequate safeguards in the protocol design and during withholding of medication, anticipating risks, minimizing the chances for human error, providing resuscitative equipment sufficient to deal with the most serious anticipated life-threatening reactions, planning for medical support in case of a life-threatening emergency, and optimizing the use of medical personnel and expertise to handle emergency situations. The guidelines also discuss important general issues about protocol design and implementation and the human subject consent form, which should facilitate the approval of protocols by the governing institutional review board.The guidelines are not meant to be inflexible or applicable to all research situations. However, it is our hope that they will allow for clinical research to be conducted in a manner that affords the research subjects a high degree of protection from unnecessary and possibly fatal injuries.     

Association of ambient air‐pollution levels with acute asthma exacerbation among children in Singapore

BACKGROUND: Air-pollution levels have been shown to be associated with increased morbidity of respiratory diseases. METHODS: Data for ambient air-pollutant levels, meteorologic factors, and hospitalization or emergency room (ER) visits for acute asthma in Singapore children over a 5-year period (1990-4) were obtained and analyzed for associations by time-series methods. RESULTS: Throughout this period, the annual mean and 24-h mean levels for sulfur dioxide (SO2), nitrogen dioxide (NO2), and total suspended particles (TSP) and maximum 1-h daily average for ozone were generally within the air-quality guidelines established by the World Health Organization (WHO). However, positive correlation between levels of each of these pollutants and daily ER visits for asthma was observed in children aged 3-12 years, but not among adolescents and young adults (13-21 years old). The association with SO2 and TSP persisted after standardization for meteorologic and temporal variables. An adjusted increase in 2.9 ER visits for every 20 microg/m3 increase in atmospheric SO2 levels, lagged by 1 day, was observed on days when levels were above 68 microg/m3. With TSP, an adjusted increase of 5.80 ER visits for every 20 microg/m3 increase in its daily atmospheric levels, lagged by 1 day, was observed on days with levels above 73 microg/m3. Similar results were also obtained after controlling for autocorrelation by time-series analysis. CONCLUSIONS: These associations were observed even though the overall levels of all pollutants were generally within the air-quality guidelines established by the WHO. These findings suggest that asthmatic children are susceptible to increased levels of air pollutants, particularly SO2 and TSP, although the ambient levels are generally within "acceptable" ranges.     

Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994

OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.