Prostaglandin E₂ (PGE₂) is widely distributed in various tissues, and exhibits various biologically important activities. PGE₂ synthase (PGES) catalyzes conversion of COX-derived PGH₂ to PGE₂. It now appears that there are at least three distinct types of PGES in mammals. We identified two distinct glutathione-dependent PGESs. Cytosolic PGES (cPGES), known as p23, is constitutively and ubiquitously expressed and predominantly converts COX-1-derived PGH₂ to PGE₂. We find that the regulation of cPGES/p23 activity in cells depends on its association with hsp90. Microsomal PGES-1 (mPGES-1), identical to MGST1-L1, is an inducible perinuclear enzyme that is functionally linked with COX-2 in marked preference to COX-1. COX-2 and mPGES-1 are essential components for delayed PGE₂ synthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer. Most recently, glutathione-nonspecific mPGES-2, homologous to glutaredoxin and thioredoxin, was identified. These PGESs seem to be a potential novel target for drug development.

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Osteoporosis with increased risk of bone fracture is a disabling syndrome that naturally occurs as long as one ages and moves on two legs. Recent progress in bone cell biology has shed light on the mechanisms underlying the anti-osteoporotic properties of drugs that have been in use for a long time, providing a fresh stage for novel pharmacotherapies. In addition, large scale clinical trials developed in the past decade appear not only to rationalize the clinical utilities of these drugs but also to provide new concepts for the development of new therapeutic modalities. Progress in the fields of basic and clinical research field is briefly reviewed herein.

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Meloxicam (Mobic) is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid, exhibiting selectivity for cyclooxygenase (COX)-2 over COX-1. Meloxicam has shown potent anti-inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models. It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat, but also of bone and cartilage destruction. The therapeutic range of meloxicam in the rat, with regard to inhibition of adjuvant arthritis, was several times greater than that of other NSAIDs. Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers. In clinical studies, meloxicam has shown reliable efficacy against rheumatoid arthritis, osteoarthritis, lumbago (low back pain), scapulohumeral periarthritis, and neck-shoulder-arm syndrome with low gastrointestinal toxicity.

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Ribavirin (Rebetol^®) is an antiviral agent used in combination with interferon α-2b (IFN α-2b) for the treatment of chronic hepatitis C. Ribavirin has been reported to have a broad-spectrum antiviral activity mainly against RNA viruses. The effect of ribavirin was potentiated when administered in combination with IFN α-2b in an antiviral assay using bovine viral diarrhea virus as a surrogate for hepatitis C virus (HCV). Inhibition of host inosine monophosphate dehydrogenase and inhibition of RNA-dependent RNA polymerase (RdRp) of RNA viruses have been reported as the modes of action of ribavirin. Recently, ribavirin has been shown to induce mutation as template for newly generated RNA after uptake in RNA by RdRp of poliovirus, which is an RNA virus as in the case of HCV. It has also been shown that the infectivity of viruses is drastically reduced by the very slight increase in mutations induced by ribavirin. This effect as a mutagen on RNA viruses is a novel mode of ribavirin, and it is thought necessary to classify ribavirin into a new antiviral drug class.

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Alendronate (alendronate sodium hydrate; Bonalon^® Tablet, 5 mg) is a nitrogen-containing bisphosphonate, which combines with the bone surface and reduces osteoclast-mediated bone resorption. It is a third-generation bisphosphonate compound, specifically distributed on the surface of bone resorption and taken into osteoclasts. Under the closed circumstances which is formed with osteoclast and the bone surface, alendronate becomes detached from the bone surface and taken into osteoclast since acid released from osteoclast leads to pH decrease (acidified). The uptaken alendronate blocks the pathway of mevalonic acid synthesis, which is cholesteric synthesis, inhibits the prenylation of GTP binding protein, and decreases the osteoclast's function by influencing the cytoskeleton. This restraint of alendronate in bone resorption against osteoclast is reversible, showing no cytotoxicity at more than hundredfold concentration level at which action occurs. Alendronate is an agent for the treatment of osteoporosis that has established safety with regards to bone quality since it neither inhibits bone calcification nor influences fracture healing in chronic administration. The most serious morbidity in osteoporosis is developing fractures. The efficacy of alendronate on restraining fracture, as well as on increase in BMD, is evidenced in Japan. Recently, in addition to senile or postmenopausal osteoporosis, drug-induced osteoporosis, such as steroid-induced osteoporosis, has attracted attention. In this regard, alendronate has been found to be an effective agent for the treatment of osteoporosis overseas, being approved in over 90 countries and used by more than 4.5 million patients. This review will give an outline of alendronate, the preparation to have introduced a concept of Evidence Based Medicine earlier, from pharmacodynamic action to clinical efficacy.

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Interferon alfacon-1 (Advaferon^®, also referred to as consensus interferon) is a novel synthetic recombinant type-I interferon (IFN) developed by comparing the amino acid sequences of several natural IFN-α subtypes and assigning the most frequently observed amino acid in each corresponding position to generate a consensus molecule. Interferon alfacon-1 binds with high affinity to type-I IFN receptors and has greater biological activity than naturally occurring IFN-α as assessed by its increased antiviral, anti-proliferative, and natural killer cell activities, as well as its stronger IFN-stimulated gene induction. In a multicenter, randomized, controlled study, the safety and efficacy of interferon alfacon-1 in comparison with lymphoblastoid interferon-α[IFN-α(NAMALWA)] was evaluated in patients infected with high-titer chronic hepatitis C virus (HCV). Interferon alfacon-1 (18 MIU) was superior in efficacy without additional toxicity to IFN-α (NAMALWA) (9 MIU) in high-titer chronic HCV patients, particularly those infected with genotype 1b. A multicenter open-label study showed that treatment with interferon alfacon-1 (12 MIU) was an effective and tolerable therapy in chronic HCV patients with low viral titers. Another multicenter open-label study showed that re-treatment with interferon alfacon-1 (18 MIU) was an effective and tolerable therapy in chronic HCV patients who relapsed after traditional IFN therapy. Collectively, these clinical studies indicate that interferon alfacon-1, as a novel synthetic interferon, may be a useful therapeutic alternative for the effective treatment of hepatitis C.

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Much effort has been made to create highly potentiated active vitamin D for better clinical applications and falecalcitriol was successfully synthesized as one of such candidates with highly potent and long-lasting effects. Its chemical structure has a calcitriol side chain modification in which both methyls at positions C-26 and C-27 are substituted by tri-fluoromethyls. The mechanism for its strong and long-lasting effects is probably due to altered side chain metabolism and decreased inactivation. Although C-24 position hydroxylation catalyzed by Cyp24 inactivates calcitriol, falecarcitriol is metabolized to C-23S hydroxylated metabolite by the same enzyme Cyp24 and this metabolite still has strong activity. Stronger action of falecalcitriol has been shown in target organs or cells of active vitamin D such as bone, parathyroid cells, and keratinocytes, when compared with calcitriol, the endogenous active form of vitamin D. Daily oral administration of falecalcitriol at doses lower than those required for calcitriol has been shown to have clinical effects for the treatment of diseases such as hyperparathyroidism due to chronic renal failure (2°HPT), rickets, osteomalacia and hypoparathyroidism. The comparative study with alfacalcidol showed its specific action on parathyroid hormone suppression and better improvement of bone metabolism markers in 2°HPT patients.

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