Inhalation toxicity of Cyclosarin (GF) vapor in rats as a function of exposure concentration and duration: potency comparison to sarin (GB).

The inhalation toxicity of cyclohexyl methylphosphonofluoridate (GF) was examined in male and female Sprague-Dawley rats exposed by whole body in a dynamic 750-L chamber. The objectives of this study were to (1) generate GF vapor in a dynamic inhalation chamber system, starting in the lethal to near-lethal concentration range, (2) examine dose-response effects of inhaled GF vapor and analyze the relationship between concentration (C) and exposure duration (T) in determining probability of lethality, and (3) establish a lethal potency ratio between GF and the more volatile agent Sarin (GB). Using a syringe pump, GF vapor concentrations were generated for exposure times of 10, 60, and 240 min. Dose-response curves with associated slopes were determined for each exposure duration by the Bliss probit method. GF vapor exposures were associated with sublethal clinical signs such as tremors, convulsions, salivation, and miosis. Concentration-exposure time values for lethality in 50% of the exposed population (LCT(50)) were calculated for 24-h and 14-day postexposure periods for 10-, 60-, and 240-min exposures. In general, LCT(50) values were lower in female rats than males and increased with exposure duration; that is, CT was not constant over time. The GF LCT(50) values for female rats were 253 mg min/m(3) at 10 min, 334 mg min/m(3) at 60 min, and 533 mg min/m(3) at 240 min, while the values for males were 371, 396, and 585 mg min/m(3), respectively. The GB LCT(50) values for female rats were 235 mg min/m(3) at 10 min, 355 mg min/m(3) at 60 min, and 840 mg min/m(3) at 240 min, while the values for males were 316, 433, and 1296 mg min/m(3), respectively. At longer exposure durations, the LCT(50) for GF was less than that found for GB but at shorter exposure durations, the LCT(50) for GF was more than that found for GB. Empirical models, consisting of the toxic load model plus higher order terms, were developed and successfully fit to the data.

Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats.

Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.

Pulmonary oxygen consumption: a hypothesis to explain the increase in oxygen consumption of low birth weight infants with lung disease.

OBJECTIVE: We determined pulmonary oxygen consumption (VO2lung) in low-birthweight infants with acute lung disease to help explain the greater whole-body oxygen consumption (VO2wb) in these infants with than in those without lung disease. METHODS AND MATERIALS: Eleven infants (birth weight 1,076+/-364 g; gestational age 28+/-3 weeks) undergoing mechanical ventilation for respiratory distress syndrome were studied in their first week of life. We measured VO2wb by indirect calorimetry and simultaneously determined systemic oxygen uptake (VO2Fick) as the product of cardiac output (echocardiography) and the arterial-mixed venous oxygen content difference (cooximetry) assuming that VO2wb-VO2Fick accounts for VO2lung. Right atrial blood samples were used to determine mixed venous oxygenation, and infants were excluded if samples returned saturations greater than 89%. RESULTS: VO2lung was 1.92+/-1.74 ml x kg(-1) x min(-1), representing 25% of their VO2wb (7.58+/-1.48 ml x kg(-1) x min(-1)). VO2lung was not correlated with clinical measures of acute disease severity. However, infants with the most severe changes on follow-up radiography (Edwards score 5 as assessed by radiologist blinded for VO2 data) all had a VO2lung level greater than 2.0 ml x kg(-1) x min(-1). CONCLUSION: VO2lung can account for the elevated metabolic rate in low-birthweight infants with lung injury. We speculate that this reflects in part inflammatory pulmonary processes and may herald chronic lung disease.

Mass spectrometric and NMR characterization of metabolites of roxifiban, a potent and selective antagonist of the platelet glycoprotein IIb/IIIa receptor.

1. The methyl ester prodrug roxifiban is an orally active, potent and selective antagonist of the platelet glycoprotein GPIIb/IIIa receptor and is being developed for the prevention and treatment of arterial thrombosis. 2. Roxifiban was rapidly hydrolyzed to the zwitterion XV459 in vivo and by liver slices from the rat, mouse and human and by intestinal cores from dog. XV459 was metabolized to only a small extent in vitro and in vivo. 3. Studies with rat and dog given radiolabelled roxifiban showed limited oral absorption with the majority of the radiolabel being excreted in faeces. After i.v. doses of 14C-roxifiban, most of the radioactivity was recovered in the urine of rat whereas the dog excreted significant amounts of radioactivity in bile and urine. 4. XV459 could be metabolized extrahepatically by dog gut flora to produce an isoxazoline ring-opened metabolite. In vitro hepatic metabolism of XV459 was mainly by hydroxylation at the prochiral and chiral centres of the isoxazoline ring. These hydroxylated metabolites were not detected in the urine and plasma of human volunteers administered roxifiban. 5. Initial LC/MS identification of metabolites was achieved by dosing the rat with an equimolar mixture of d0:d4 roxifiban and detecting isotopic clusters of pseudomolecular ions. Unequivocal characterization of these metabolites was achieved by LC/MS, LC/NMR and high-field NMR techniques using synthetic standards of the metabolites. 6. The synthesis of one hydroxylated metabolite enabled the assignment of the correct stereochemistry of the substituted hydroxyl group on the isoxazoline ring.

Characterization of sulfur mustard vapor-induced cutaneous lesions on haired guinea pigs.

BACKGROUND/AIMS: Sulfur mustard (2,2'-dichlorodiethyl sulfide, HD) is a potent vesicating (blistering) agent. In this report, we describe the time-course and the dose-dependent response following cutaneous exposure to sulfur mustard (HD) in the haired guinea pig model. The purpose of this study was to evaluate the usefulness of the haired guinea pig as a vesicant research model. METHODS: Seventy-two animals were divided into nine groups of eight animals each. Hair on the dorsal side of each animal was removed by clipping with an electric clipper followed by application of a chemical depilating agent (MAGIC Shaving Powder). Six dorsal skin sites on each animal of a given group were exposed to saturated HD vapor (1.4 mg/l) for one of nine exposure times between 0-8 min. Lesions were evaluated for erythema (reflectance colorimeter) and edema (ultrasound imaging) at 4, 6, 12, and 24 h postexposure. Damage at the dermal-epidermal junction (DEJ) was evaluated by histopathology at 24 h postexposure. RESULTS: We observed that the hair removal process was time-consuming, produced significant initial erythema, and resulted in increased dorsal skin sensitivity to low HD exposure levels. The time-course of exposure response to HD was observed to be dose-dependent and similar to the hairless guinea pig model. CONCLUSIONS: The haired guinea pig is inferior to the hairless guinea pig as a vesicant model due to the complications resulting from the hair removal process. However, the haired guinea pig is a useful model for evaluating the cutaneous effects of HD vapor and can be developed into a routine screening tool for the evaluation of topical barriers against HD vapor exposure.

Nikolsky's sign: a novel way to evaluate damage at the dermal-epidermal junction.

BACKGROUND/AIMS: Sulfur mustard (2,2'-dichlorodiethyl sulfide, HD) is a potent vesicating (blistering) agent. Cutaneous exposure causes the destruction of basal cells and leads to a separation at the dermal-epidermal junction. To evaluate the efficacy of candidate antivesicant compounds, suitable animal models are needed. A tape stripping method and the Dermal Torque Meter (DTM) have been used in novel applications to evaluate for the Nikolsky's sign in the hairless guinea pig. The Nikolsky's sign is the separation and loss of the epidermis from the dermis when the skin is pressed with a sliding or twisting motion. The purpose of this study was to find an objective, reproducible, and quantitative method that could be used as an end-point to evaluate the degree of damage at the dermal-epidermal junction following cutaneous HD vapor exposure. METHODS: Hairless guinea pigs were exposed to saturated HD vapor (1.4 mg/l) for time intervals between 2 and 9 min using 14-mm vapor cups. At 24 h post-exposure, both tape stripping (fabric carpet tape) and a DTM were used to produce the Nikolsky's sign in animals under anesthesia. Using the tape stripping method, 15-mm disks of tape were applied to each skin site. After 5 s the tape was peeled off. The D T M was used to apply a horizontal twisting motion to the skin. The parameters included a 15-mm center disk, a ring gap of 1 mm, a torque of 30 mNm, and a 5-s cycle time. A cyanoacrylate adhesive was used to secure the center disk and guard ring to the skin. The loss of the epidermis was determined by visual observation and confirmed by histopathological examination. The standard D T M unit was modified to use multiple center disk/guard ring assemblies so that several sites on each animal could be evaluated at the same time. RESULTS: The mean (±S E M) percent incidence of positive Nikolsky's sign observations using the tape stripping method for HD vapor exposures of 3,5,7, and 9 min was 0,50 (±16), 94 (±6.2), and 100, respectively. The mean (±S E M) percent incidence of positive Nikolsky's sign observations using the D T M method for HD vapor exposures of 2, 3, 4, and 5 min was 0, 25 (±7.1), 91 (±2.9), and 96 (±2.3), respectively. CONCLUSIONS: The Nikolsky's sign produced by the tape stripping method and the D T M were useful in evaluating damage at the dermal-epidermal junction following cutaneous HD vapor exposures. These methods have the potential to replace histopathology as an end-point for routine screening procedures designed to evaluate the efficacy of antivesicant compounds.

Beam flatness perturbation effects of a perforated thermoplastic immobilization device on 6 and 12 MeV electron beams.

PURPOSE: Perforated thermoplastic masks are widely used in radiotherapy of head and neck malignancies. They provide for patient immobilization and increase setup reproducibility. Some oncology treatment centers cut mask portals (windows) for the beam to pass through; for those centers that do not, the mask affects beam fluence. The extent to which beam flatness is altered by such a mask is investigated. MATERIALS AND METHODS: The effects of perforated thermoplastic on 6 MeV and 12 MeV electron beams was described in terms of optical density differences in a comparative film study. RESULTS: Variations of beam flatness were documented of up to 11.8% at 5 mm depth for 6 MeV, and 8.1% for 12 MeV electrons. The depth at which this effect may be considered insignificant (mean optical density differences < 2%) is approximately 10 mm for both beam energies. CONCLUSIONS: For clinical situations where the target volume is superficial, some consideration should be given to beam inhomogeneity caused by the mask.

Effect of the arterial oxygenation level on cardiac output, oxygen extraction, and oxygen consumption in low birth weight infants receiving mechanical ventilation.

OBJECTIVE: To investigate the effects on oxygenation of targeting the higher versus the lower end of the currently recommended range for pulse oximetry (Spo2). DESIGN: Nonrandomized crossover trial with the use of within-subject comparisons (two-tailed paired t test). SETTING: Level III neonatal intensive care unit of a university hospital. PATIENTS: Twenty infants whose lungs were mechanically ventilated (mean +/- SD: birth weight, 1192 +/- 396 gm; gestational age, 28.7 +/- 2.7 weeks; age at time of study, 42 +/- 26 hours). INTERVENTIONS: The inspired oxygen concentration was adjusted to achieve Spo2 readings of 93% to 96% versus 89% to 92% (Ohmeda pulse oximeter) or 95% to 98% versus 91% to 94% (Nellcor oximeter). MEASUREMENTS: Cardiac output was measured by echocardiography, oxygen content of arterial blood samples by cooximetry, and oxygen consumption by indirect calorimetry. RESULTS: The inspired oxygen concentrations required to achieve the Spo2 target ranges were 39.8% +/- 8.3% versus 28.7% +/- 6.1% (p < 0.001). The respective arterial oxygen contents were 18.0 +/- 2.6 ml/dl versus 16.9 +/- 2.5 ml/dl (p < 0.001). Oxygen consumption was unchanged. In the lower-oxygen condition no compensatory increase in cardiac output was detected; thus the estimated mixed venous oxygen tension decreased and the oxygen extraction ratio increased. Venous admixture increased from 15% +/- 6% to 31% +/- 9% in the lower-oxygen condition (p < 0.001). CONCLUSIONS: The "low normal" Spo2 target range allowed for less oxygen exposure. No signs of mismatch between systemic oxygen delivery and demand could be detected.

Initial experiences with clozapine at Kenmore Psychiatric Hospital.

OBJECTIVE: To replicate overseas experience with clozapine, a new antipsychotic drug reputed to be effective in producing major improvement in a high proportion of patients with treatment-resistant schizophrenia. DESIGN AND SETTING: A prospective clinical trial at Kenmore Psychiatric Hospital, Goulburn, NSW. This paper is a preliminary communication covering 14 to 18 weeks after commencement of clozapine. PATIENTS: Twelve patients with treatment-refractory chronic schizophrenia, chosen on the basis of the severity of their disability. INTERVENTION: After existing medication was changed to be compatible with clozapine, it was reduced to the minimum level acceptable for staff and patient safety. Clozapine was then introduced gradually while other medication was withdrawn. OUTCOME MEASURES: Progress was monitored in terms of clinical presentation, side effects, use of supplementary medication and assessments by means of three standardised scaling systems. RESULTS: None of the patients deteriorated. Of six patients aged 35 years or less, three showed dramatic improvement and three showed clinically significant improvement. None of the six older patients showed major improvement, except that extrapyramidal symptoms were reduced in all cases. Drowsiness and hypersalivation were the only common side effects. CONCLUSIONS: These preliminary findings are consistent with results reported overseas.

Cardiopulmonary function during long-term central venous catheterization.

A prospective study was performed in an ambulatory group of infants, children, and young adults with neoplastic disorders to determine the prevalence of significant cardiopulmonary complications during long-term central venous catheterization. A cohort of 20 consecutive patients who had central venous catheters in situ for a mean of 13.5 months underwent pulmonary function testing, chest radiography, ventilation perfusion lung scintigraphy, electrocardiography, and echocardiography. No significant complications were seen. Specifically, there was no evidence of localized thrombus formation or pulmonary emboli, and no indirect evidence of pulmonary hypertension. In addition, we reviewed retrospectively the autopsy reports of 15 patients who died with central venous catheters in place. Three of these patients had superficial endocardial reactions. One patient had a right atrial mural thrombus related to the catheter, but two other patients were noted to have left atrial mural thrombi. This study demonstrates that central venous catheters can be used safely on a long-term basis in ambulatory patients requiring frequent venous access for treatment of their neoplastic disorders.

Burmese culture, personality and mental health.

As Australia, shaped by new policies of immigration and multiculturalism, grows more cosmopolitan, the challenge for psychiatry is to gain greater familiarity with the new ethnic minority groups, including their cultural personalities and backgrounds. The problem faced by the Burmese group in Australia is distinctive and poignant. Some 20,000 Burmese immigrated following World War II, chiefly to Western Australia in the first place, uniting and consolidating their families. Following the military coup and the Revolutionary Council Government of the early 60s, further emigration from Burma was cut off. This meant that the Burmese in Australia, already under stress arising from cultural differences, were prevented from developing the extensive internal social support systems that characterise other major ethnic groups. The author, a Burmese doctor working in a psychiatric setting in Sydney, draws attention to aspects of his country and its people which should be helpful for psychiatric and related professions.