Pharmacology & therapeutics. Part B: General & systematic pharmacology最新文献

The nose plays an important part in the normal physiological function of the body and is a key defense against airborne noxious influences. The ability of the nose to play these roles is dependent upon a normal nasal airway and healthy nasal mucosa. Most nasal diseases run a self-limited course, and injury resulting therefrom is quickly followed by a restoration of normal function. In the treatment of nasal symptoms the physician must carefully weigh the desire to alleviate the patient's discomfort against the possibility of acutely or chronically impairing nasal function.

Even a cursory examination of the literature reveals the paucity of reliable information not only on the relative effectiveness of most pharmacological agents employed in nasal disease, but also on their adverse effects upon nasal function. We now have a better understanding of nasal function which can serve as a guide to those seeking the discovery of improved nasal medications. We also have readily available tools for measuring some of the desired effects of drugs upon nasal function and some of the functions which might be injured. Rhinomanometry (Brown, 1967; Bridger and Proctor, 1970) and measurement of mucociliary function (Hill, 1957; Gosselin, 1961; Quinlan et al., 1969; Dadaian, 1971; Sakakura et al., 1973) can be carried out by intelligent investigators in most first class clinical environments. Climate chambers are available for testing the effects of environmental influences and for measuring the effect of therapeutic agents under controlled conditions (Proctor et al., 1973a). We urge that appropriate studies be employed for weighing the relative usefulness of currently used drugs and for testing new ones prior to their release for public consumption. Clinical impression, upon which we must now to a large degree rely, should not be accepted in the future as adequate evidence supporting pharmacological therapy of nasal disease.

The glucocorticoid hormones have glucose-regulating properties (for which they) were named) and also influence many other metabolic functions in a number of tissues. These actions are coordinated in many respects. The pharmacological effects of these hormones form the basis for steroid use in therapy of numerous disorders. The molecular basis for most physiological and pharmacological actions of glucocorticoids (both catabolic and anabolic) and of other classes of steroid hormones are probably very similar. The steroid readily penetrates the cell membrane (and probably does not require transport mechanisms) and reversibly binds to specific proteins—termed cytoplasmic receptors. Associated with this interaction are conformational changes in the receptor which result in receptor-glucocorticoid steroid complex binding to DNA-containing sites in the cell nucleus. The latter reaction results in influences on the synthesis of specific messenger RNAs which code for proteins that are ultimately responsible for the glucocorticoid response.

Catabolism is observed in muscle, adipose tissue, connective tissue, skin and lymphoid tissue. In general, this involves increased degradation and decreased synthesis of proteins, fat, DNA and RNA and decreased uptake of glucose, and amino and nucleic acids. These catabolic actions are probably responsible for certain deleterious effects of pharmacological dosages such as the inhibition of growth observed in children, osteoporosis, bruising, impaired wound healing and enhanced susceptibility to infections. Conversely, these same actions also provide the rationale for glucocorticoid employment in immunosuppression as in treatment of transplant rejection and of the autoimmune diseases. A number of tissues, particularly brain, heart and red blood cells, are in general spared the catabolic actions, but in some of these, there are glucocorticoid-induced alterations in certain functions. In liver there is a general increase in protein and RNA synthesis with a general enhancement in the gluconeogenic capacity. The later, combined with an elevated plasma level of gluconeogenic precursors, results in an increased glucose production which, combined with decreased uptake of glucose in peripheral tissues, results in an enhanced tendency to hyperglycemia. This is ordinarily countered by secondary hyperinsulinism. The latter combined with enhanced enzyme capacity in the liver also leads to glycogen deposition. The tendency to make glucose available for tissues such as heart, brain and blood cells at the expense of other tissues could be considered in terms of a hormonal preparation of the host for nutritional deprivation. In many respects, this ‘stress response’ parallels the responses to stimuli which activate adenyl cyclase, and the ‘permissive’ actions of glucocorticoids facilitate actions of other hormones which are frequently those which stimulate adenyl cyclase. Other glucocorticoid actions, e.g. on vascular and o