Safety pharmacology of the respiratory system: Techniques and study design

The known effects of drugs from a variety of pharmacologic/therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. The objective of these studies is to evaluate the potential for drugs to cause secondary pharmacologic or toxicologic effects that influence respiratory function. Changes in respiratory function can result either from alterations in the pumping apparatus that controls the pattern of pulmonary ventilation or from changes in the mechanical properties of the lung that determine the transpulmonary pressures (work) required for lung inflation and deflation. Defects in the pumping apparatus are classified as hypo- or hyperventilation syndromes and are evaluated by examining ventilatory parameters in a conscious animal model. The ventilatory parameters include respiratory rate, tidal volume, minute volume, peak (or mean) inspiratory flow, peak (or mean) expiratory flow, and fractional inspiratory time. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow-volume and pressure-volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes post-dose). The species used in the safety pharmacology studies conducted in our laboratory are the same as those used in toxicology studies since pharmacokinetic and toxicologic/pathologic data are available in these species. These data can be used to help select test measurement intervals and doses and to aid in the interpretation of functional change. The techniques and procedures for measuring respiratory function parameters are well established in guinea pigs, rats, and dogs.     

PRETERM BIRTH PREVENTION PROGRAMS: A Critique of Current Literature

Published reports of the effectiveness of preterm birth prevention programs have produced mixed results. Many larger observational studies suggest benefit. The randomized trials, however, suggest no effect on reducing rates of preterm birth in high-risk populations. This article reviews and critiques these reports and suggests areas for further research.     

Effects of niacin source on epinephrine stimulation of plasma nonesterified fatty acid and glucose concentrations, on diet digestibility and on rumen protozoal numbers in lactating dairy cows

Effects of niacin (nicotinic acid or nicotinamide) supplementation of dairy cow diets on apparent total tract nutrient digestibility, milk yield and milk composition were determined using six mid-lactation Holstein cows in a replicated 3 x 3 Latin square design arranged to test for residual treatment effects. Treatments were control, 12 g/d of nicotinic acid or 12 g/d of nicotinamide. Periods were 14 d long; d 1 to 4 served as an adaptation period before treatment administration commenced (d 5 to 14). Effects of supplemental niacin on plasma nonesterified fatty acid (NEFA) concentrations and plasma glucose concentrations were tested following saline injection on d 10. Blood was then sampled for 5.5 h at 15-min intervals. On d 13, cows were treated similarly except that epinephrine replaced saline. The area below d-10 curves was subtracted from the area below d-13 curves to serve as an indicator of niacin's effect on plasma NEFA and glucose concentration responses to epinephrine injection. Niacin treatments did not change the area differences for plasma glucose compared to the control treatment; however, there was a trend for niacin to reduce the area difference compared to the control treatment for plasma NEFA. Niacin treatments did not alter dry matter intake, nutrient digestibility, milk yield or composition. Niacin supplementation increased the number of entodinia protozoa in rumen fluid.     

Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics.

BACKGROUND: A subgroup of children with obsessive-compulsive and tic disorders are proposed to have an infectious trigger. The purpose of this study was to investigate the relationship between group A streptococcal titers and symptom fluctuations in children with a clinical course resembling that described for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. METHODS: Twenty-five children with obsessive-compulsive disorder and/or tic disorder were evaluated for neuropsychiatric severity and group A streptococcal antibody titers (streptolysin O, deoxyribonuclease B, and carbohydrate A) at 6-week intervals for > or = six consecutive evaluations (total visits=277). RESULTS: Children with large symptom fluctuations (n=15) were compared with children without dramatic fluctuations (n=10). Co-movements of obsessive-compulsive/tic severity and group A streptococcal antibodies were assessed. In subjects with large symptom changes, positive correlations were found between streptococcal titers and obsessive-compulsive severity rating changes (p=.0130). These subjects were also more likely to have elevated group A streptococcal titers during the majority of observations (p=.001). Tic symptom exacerbations occurred more often in the fall/winter months than spring/summer months (p=.03). CONCLUSIONS: Patients with marked obsessive-compulsive/tic symptom changes may be characterized by streptococcal titer elevations and exhibit evidence of seasonal tic exacerbations.     

Transfer of 45Ca and 36Cl at the blood-nerve barrier of the sciatic nerve in rats fed low or high calcium diets

Unidirectional fluxes of 45Ca, 36Cl, and of [3H]mannitol from blood into the sciatic nerve and cerebral cortex were determined from 5- and 15-min uptakes of these tracers after an intravenous (i.v.) bolus injection in awake rats. Rats were fed diets for 8 wk, that had either a low (0.01% wt/wt), normal (0.67%), or high (3%) Ca content. Plasma [Ca] was 32% less and 11% more in rats fed low (LOCA) and high Ca diets (HICA), respectively, than in rats fed a normal Ca diet (CONT). The mean permeability-surface area product (PA) of 45Ca at the blood-nerve barrier was about eightfold higher than at the blood-brain barrier in the same animals and did not differ significantly between groups (greater than 0.05). Mean PA ratios of 45Ca/36Cl for the blood-nerve and blood-brain barriers in CONT rats, 0.52 +/- 0.04 and 0.40 +/- 0.02, respectively, were not significantly different from corresponding ratios in LOCA and HICA groups, and corresponded to the aqueous limiting diffusion ratio (0.45). Our results show no evidence for concentration-dependent transport of Ca over a plasma [Ca] range of 0.8-1.4 mmol/liter at the blood-nerve barrier of the rat peripheral nerve, and suggest that Ca and Cl exchange slowly between nerve and blood via paracellular pathways.     

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.     

Combined prostacyclin and thromboxane synthetase inhibitor UK 38485 in flap survival

Thromboxane, a prostanoid derivative, is a central mediator of the progressive dermal ischemia seen in the distal dying flap. Prostacyclin; a vasoactive prostanoid derivative, has been found to enhance ischemic flap survival. This study examines the effects of prostacyclin and UK 38485 (specific thromboxane synthetase inhibitor), separately and combined, in axial flap survival in the pig. Each increased flap survival over control flaps; their combined use demonstrated an even greater flap survival (p less than 0.005).