The role of 5-lipoxygenase products in preclinical models of asthma.

BACKGROUND: The action of 5-lipoxygenase on arachidonic acid generates potent inflammatory mediators that may contribute to the pathophysiology of asthma. METHODS: Using the potent and selective 5-lipoxygenase inhibitor BI-L-239, we have examined the role of 5-lipoxygenase products in three animal models of asthma. RESULTS: In vitro BI-L-239 inhibited 5-lipoxygenase product generation from human lung mast cells, alveolar macrophages, and peripheral blood leukocytes with a concentration that would provide 50% inhibition values of 28 to 340 nmol/L. A 36-fold selectivity for immunoreactive leukotriene C4 versus immunoreactive prostaglandin D2 inhibition was demonstrated in mast cells. In anesthetized cynomolgus monkeys, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced immunoreactive leukotriene C4 release (maximum, 73%; bronchoalveolar lavage [BAL], 20 minutes), late-phase bronchoconstriction (maximum, 41%; +6 to 8 hours), and neutrophil infiltration (maximum, 63%; BAL, +8 hours). In conscious sheep, inhaled BI-L-239 provided dose-dependent inhibition of the inhaled Ascaris-induced late-phase bronchoconstriction (maximum, 66%; +6 to 8 hours) and increase in airway responsiveness (maximum, 82%; carbachol, +24 hours). The acute bronchoconstriction was shortened, and neutrophil infiltration diminished (maximum, 61%; BAL, +8 hours) in this model. Finally in conscious actively sensitized guinea pigs pretreated with pyrilamine and indomethacin, inhaled BI-L-239 attenuated acute bronchoconstriction (maximum, 80%; +5 to 15 minutes), leukocyte infiltration (58%; BAL, +3 days) and increase in airway responsiveness (100%; methacholine, +3 days) induced by three alternate-day ovalbumin inhalations. CONCLUSIONS: In conclusion, results in these three animal models indicate that 5-lipoxygenase products may be major contributors to the bronchoconstriction (especially late phase), leukocyte infiltration, and airway hyperresponsiveness that characterize asthma.

Issues surrounding MDI formulation development with non-CFC propellants.

Reformulation of metered-dose inhalers (MDIs) without the use of chlorofluorocarbon (CFC) propellants presents numerous obstacles because there are no alternative propellants that can serve as immediate replacements for pharmaceutical use. Hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs) and hydrocarbons (HCs) are all under consideration as possible alternatives for CFC propellants. However, no single propellant or combination of propellants has been identified with all of the physical-chemical properties of CFCs. Based on their zero ozone depletion potentials, relatively low global warming potentials, non-flammabilities, densities, and vapor pressures, HFA-134a and HFA-227 are the most attractive replacement propellants identified to date. Yet, their use in MDIs will still require: (1) identification of a metering valve with propellant and formulation-compatible gaskets, (2) use of current suspending agents at levels much lower than in present MDIs or identification (and characterization) of new suspending agents, and (3) modification of existing manufacturing technologies. Demonstration of acceptable final product stability, safety and efficacy will be necessary prior to submission to worldwide registration authorities.

Water vapor sorption of water-soluble substances: studies of crystalline solids below their critical relative humidities.

Water vapor sorption on unground and ground samples of sodium chloride and sodium salicylate at relative humidities below RHo, that at which deliquescence is initiated, has been measured. Sorption isotherms, expressed as the amount sorbed per unit area of solid surface, were different for unground and ground samples. Measurement of specific surface area for samples previously exposed to various relative humidities revealed no change with unground samples but a significant reduction with ground samples beyond about 20% relative humidity. Correcting isotherms for this change in area brings the results with ground and unground samples into closer agreement. These studies reveal that relatively low levels of water vapor sorption on crystalline water-soluble solids, below RHo, can give rise to some form of "surface dissolution" when the solid had been subjected to various forms of mechanical disturbance.

The interactions of water with cellulose- and starch-derived pharmaceutical excipients.

Water associated with polymeric pharmaceutical excipients derived from cellulose and starch can have a profound effect on the properties of the excipient and on the other ingredients making up a solid dosage form. Important questions which need to be addressed include How much water will be sorbed or desorbed at various relative humidities and temperatures? and What is the thermodynamic state of water associated with the solid as a function of moisture content? A critical review of the literature is presented to demonstrate the most likely answers to these questions. It appears that water exists in at least three thermodynamic states in starch, cellulose, and their derivatives: (1) water directly and tightly bound, with a stoichiometry of one water molecule per anhydroglucose unit; (2) water in a relatively unrestricted form, approaching the properties of bulk or pure liquid water; and (3) water in an intermediate state or states, with properties reflecting a much higher level of structure than bulk water but less than that of tightly bound water. Some implications of such behavior for pharmaceutical systems are discussed.

Moisture sorption kinetics for water-soluble substances. IV: Studies with mixtures of solids.

This paper extends earlier work from this laboratory concerning the sorption kinetics of water vapor on deliquescent water-soluble substances to mixtures of these solids. A theoretical model, based on heat transport control, excellently predicted a priori the rate of water uptake by a variety of binary mixtures of alkali halides and sugars. The rates for mixtures containing highly water-soluble quaternary ammonium salts, as either one or both of the components, were less successfully predicted as the combined water solubilities of the two components increased. It is concluded that water-soluble deliquescent substances, normally encountered in pharmaceutical dosage forms, rapidly form saturated aqueous solutions in the aqueous film formed as water vapor uptake proceeds, and that the water uptake rate can be predicted a priori from known and experimentally determinable parameters using the heat transport model.