Cyclooxygenase (COX) is the enzyme that catalyzes the conversion of arachidonic acid to prostaglandin endoperoxides. In addition to constitutive COX-1, inducible COX-2 has been discovered. COX-2 is induced not only in acute exudative rat carrageenin-induced pleurisy, but in granuloma formation/proliferative inflammation for the acceleration of angiogenesis. This means that COX-2 is induced in the healing process of wounds such as in granuloma of gastric ulcer and the proliferative stage of endometrium. COX-2 is also introduced in ovulation and parturition. Osteoblasts induce COX-2 to accelerate bone absorption. Induction of COX-2 in colon carcinoma is a recent, very exciting topic of investigation. We can learn about many unknown roles of COX-2 from its knockout mouse, but the results must be interpreted cautiously. Development of selective COX-2 inhibitors, such as NS-398, opened a new era in which the side effects of gastric and renal lesions by NSAIDs could be ignored. However, prolongation of wound healing by the inhibitors and transient expression of COX-2 must be considered in medical intervention with selective COX-2 inhibitors. Nevertheless, acute exudative inflammation, granuloma formation and bone absorption in rheumatoid arthritis are good targets for these inhibitors and application of these inhibitors will be extended to dysmenorrhea, interruption of abortion and increasing survival rate of patients with colon carcinoma

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Various techniques have been developed to image human brain function in the past decade. X-ray computerized tomography and magnetic resonance imaging (MR) are used to evaluate brain structure. Recently, positron emission tomography (PET) and MR are often utilized to perform human brain mapping such as attention, cognition, language comprehension, and so on. PET also makes it possible to evaluate the states of various types of neurotransmission. These techniques cannot only be used to map “brain neurochemistry” in normal human brains, but they will also increase our knowledge by demonstrating neurochemical abnormalities in a wide range of neurological and psychiatric disorders or those that occur during normal aging. The PET techniques are applicable to the development of new drugs in the pharmaceutical industry. Using PET techniques of imaging neurotransmission, it is feasible to measure the release of neurotransmitter after activation of the CNS by various methods (ligand activation study). We have developed the methodology of using ¹¹C-labeled antagonists for mapping functional histamine H₁-receptors in human brain directly and noninvasively by PET. The present review article provides an outline of the conceptual and methodological progress over the past several years that has made it possible to visualize neurotransmission in human brains by PET.

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⁴⁵Ca kinetics and calcium balance studies allow for the simultaneous determination of calcium movement in the intestines, kidneys and bones. Since the flow of minerals in each of these organs depends on those in other organs, it is important to evaluate calcium movement as a whole throughout the entire body. Morphological methods can be used to evaluate local bone formation and resorption microscopically within defined windows. However, bone remodeling does not proceed equally in every part of the skeleton, and local events tend to be misread as general phenomena. Although variables such as bone formation and resorption obtained in ⁴⁵Ca kinetics and calcium balance studies tell nothing about the location of these events, and the concept of compartments can be somewhat difficult to understand, this method is still useful for obtaining quite reliable results compared to those obtained by other methods. Our review describes the concept of the compartment model and explains the pertinent methods in comparison with other methods.

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The antihypertensive effects of oral or intravenous administration of AE0047, a novel 1, 4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj), one kidney-one clip renal hypertensive rats (RHR), deoxycorticosterone acetate (DOCA)-salt hypertensive rats (DHR) and two kidney-one clip renal hypertensive dogs (RHD). AE0047 (1, 3, 10 mg/kg, p.o.) caused a dose-related reduction of systolic blood pressure (SBP) with low reflex tachycardia in SHR/crj and RHR. The effect reached its maximum at 2-4 hr after administration and was sustained for a long time. In DHR, AE0047 (0.3, 1, 3 mg/kg, p.o.) similarly showed the antihypertensive effects at 2-7 hr with no significant changes in heart rates (HR). The doses (ED₃₀) of AE0047 required to decrease SBP by 30% were 2.6, 3.4 and 0.68 mg/kg in SHR/crj, RHR and DHR, respectively. In RHD, an AE0047 capsule (GJ-0956: 4, 8, 16, 32 mg/body, p.o.) produced dose-dependent and long-lasting effects with a transient and slight increase in HR. Furthermore, the intravenous administration of AE0047 (10, 30, 100 μg/kg) produced the antihypertensive action slowly, reached a plateau 10 min later and then maintained for many hours. In contrast, nitrendipine (3-100 mg/kg, p.o., 3-30 μg/kg, i.v.) and nicardipine (1-30 mg/kg, p.o., 3-30 μg/kg, i.v.) exhibited a similar potency to AE0047, but these maximal effects were produced at 1-2 hr and 0.5-1 min in the case of oral and intravenous administration, respectively, with a rapid recovery in the above hypertensive rats. These results indicate that AE0047 exhibits an antihypertensive effect with a slow onset and long-lasting profile.

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The antihypertensive effects of AE0047, a novel 1, 4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/ kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, an AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.

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