THE trophic factors responsible for initiating and guiding the outgrowth of axons have proven to be elusive throughout most of this century. Entorhinal cortex injury, which denervates the hippocampal formation of rats, induces axonal sprouting by several surviving hippocampal afferents and results in a significant elevation of growth factors, one of which is basic fibroblast growth factor (bFGF). The possibility that bFGF may regulate lesion-induced hippocampal sprouting was examined by making i.v. bFGF infusions into rats with unilateral entorhinal lesions. Basic FGF treatment significantly increased sprouting by the cholinergic septodentate pathway. Thus, the increase in bFGF following central nervous system injury may signal its role in the regulation of injury-related axonal remodeling of a cholinergic pathway.
Clinical pharmacologists are often asked to conduct special studies on mechanism of action, drug-drug interactions, bioequivalence, disposition, and other such investigations, the nature of Phase I and II studies and special clinical pharmacology investigations determine the education, experience, and specific skills required by an industrial clinical pharmacology staff. Since clinical pharmacology studies are characteristically small in size and intensive in design, it is essential that statisticians participate in the planning as well as the analysis to ensure that appropriate measurements and numbers of subjects are employed to give meaningful results. To summarize the principal role of clinical pharmacology in the pharmaceutical industry is to conduct Phase I and II investigations which are adequate in design and execution to permit a decision on the future course of new drug candidates. Planning includes careful attention to animal pharmacology, toxicology, drug disposition information, as well as to experimental design to minimize the study population and avoid the need for repetition of studies.
This symposium reviewed the fundamental principles, pharmacology, and clinical pharmacology of central alpha-adrenergic blood pressure regulating mechanisms. Fundamental principles Arterial baro- and chemoreceptor signals reach the nucleus of the tractus solitarius (NTS) via vagal and glossopharyngeal afferents. The NTS communicates with sympathetic preganglionic neurons in the spinal cord via centers and tracts in the medulla, pons, and hypothalamus that include an alpha-adrenergic inhibitory network. Descending tracts emphasized in this symposium originate in the C-1 epinephrine cells of the medulla, B-1 and B-3 serotonin cells of the medulla, and A-5 norepinephrine cells of the pons. Transmitters involved are norepinephrine, epinephrine, serotonin, glutamate, and gamma-aminobutyric acid (GABA). Catecholamine enzymes share protein domains in their primary structures and may be coded by linked or single genes. New methods of purifying and locating alpha- and beta-receptors have been developed. Pharmacology Methyldopa, clonidine, and clonidine-like drugs lower blood pressure by stimulating postsynaptic alpha 2-receptors in a brain stem inhibitory network, which down-regulates these receptors. Alpha 1-receptors were found to be higher in normotensive than in hypertensive rats and were increased in the latter by methyldopa administration. Alpha 2-receptors were found to differ in various tissues, which permits the development of highly selective agonists and antagonists. Although alpha-methylnorepinephrine is probably the principal metabolite of methyldopa, alpha-methylepinephrine and alpha-methyldopamine may also contribute. The site of action usually is identified as the NTS. Possible roles for the descending tracts were suggested. Clinical pharmacology Methyldopa, clonidine, guanfacine, and related drugs lower blood pressure principally by CNS mechanisms but peripheral actions may also contribute.(ABSTRACT TRUNCATED AT 250 WORDS)
The Heidelberg capsule is an indigestible indicator of gastrointestinal pH, which was used to evaluate the relationship between gastric residence time (GRT) and variability in aspirin absorption from enteric-coated tablets. In a crossover study, eight healthy subjects (four men and four women) received an enteric-coated aspirin (648 mg) together with a Heidelberg capsule while fasting or with food (breakfast, followed 4 hours later by lunch). Salicylic acid and salicyluric acid concentrations in plasma and urine were measured by HPLC. The mean (±SD) GRT was significantly delayed by food (0.8 ± 0.5 vs. 5.9 ± 3.3 hours; P < 0.005). The mean (±SD) lag time (TL) and time to peak concentration (expressed as salicylic acid equivalents) were markedly prolonged after the fed regimen (2.7 ± 0.8 vs. 8.9 ± 3.7 hours [P < 0.005] and 8.3 ± 2.9 vs. 13.8 ± 4.5 hours [P < 0.025]). For the combined data from the fasting and fed evaluations, an excellent correlation existed between TL and GRT of the capsule (TL = 1.0 GRT + 1.95; n = 16; r = 0.94; P < 0.0001). Women demonstrated greater delays in GRT and TL than did men. The delay in aspirin absorption from an enteric-coated tablet is directly related to its GRT, which is gender related and greatly affected by food. Clinical Pharmacology and Therapeutics (1987) 41, 11–17; doi:10.1038/clpt.1987.3
Human blood platelets incubated for one hour at 37° C. with dopamine‐l‐ 14 C (DA) accumulated the amine against a gradient. Such accumulation was markedly reduced by cold and by various metabolic inhibitors including iodoacetate, dinitrophenol, and sodium cyanide. Increasing the concentration of DA caused a decrease in the steady‐state distribution ratio which suggests that the uptake process is saturable. Various compounds which inhibit or compete for the amine pump in the platelet membrane, including desmethylimpromine (DMI), diphenhydramine, serotonin, debrisoquin, and guanethidine, depress the accumulation of DA. Uptake of DA was also reduced by benztropine, trihexyphenidyl, and haloperidol. Less than 10 per cent of the DA which accumulates in the platelet during one hour is metabolized. DA is a relatively poor substrate for platelet MAO and in addition the cell does not appear to contain dopamine β‐hydroxylase.
