Current Pharmaceutical Design - Volume 11, Issue 14, 2005

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used medications worldwide to inhibit cyclooxygenase (COX) activity for the treatment of pain and inflammation. Although they are effective in the treatment of pain and inflammation, their routine and long-term administration is limited due to their gastrointestinal and renal side effects. COX isozymes are of great interest to the researchers and drug designers, because they are the main targets of NSAIDs. While the inhibition of COX-2 is related to anti-inflammatory effects, that of COX-1 is associated with the adverse effects. Therefore, new generation selective COX-2 inhibitors (coxibs) have been developed for reducing adverse effects of NSAIDs. Recently, these new anti-inflammatory drugs are being preferred for the treatment of various inflammatory diseases. At the same time, in dentistry, coxibs are prescribed to control dental pain and in the treatment of periodontal diseases, which are still among the major causes of tooth loss, and in the chemoprevention and treatment of oral precancerous and cancerous lesions. This issue of Current Pharmaceutical Design contains five invited review articles. In this issue, the role of COX enzymes and prostaglandins in the pathogenesis of pain, periodontal diseases and oral cancer are reviewed, and the administration of coxibs in dentistry is discussed and compared with that of conventional NSAIDs. Drs. Lee and Dionne from National Institutes of Health and Dr. Rodriquez from Boston University provide an overview on the therapeutic use of selective COX-2 inhibitors for relief of acute pain, largely based on clinical trials in patients undergoing the surgical removal of impacted third molars, with focus on analgesic efficacy and the potential safety associated with their use compared to dual COX-1/COX-2 inhibitors. Dr Lee and co-authors suggest that the design of COX-inhibiting analgesics that suppresses COX-1 activity at early time points at site of injury, suppresses COX-2 expression or its enzymatic activity both in the periphery and in the spinal cord, and also gains access to the spinal cord to suppress COX-1 activity. Drs. Salvi and Lang from University of Berne review the experimental and clinical evidence concerning the role of arachidonic acid metabolites in the pathogenesis of periodontal tissue destruction and the effects of adjunctive systemic or topical administration of selective and non-selective NSAIDs in the treatment of periodontal diseases. According to the authors, the development of topical NSAIDs formulations with an appropriate carrier, an optimal concentration, and in the absence of adverse systemic effects seems to be of particular interest. Compared to systemic administration, this approach would help to improve patient's compliance in long-term NSAIDs administration. In his article, Dr Wang from Boston University focuses on a comprehensive examination and discussion of the potential role of COX-2 in oral cancer development, and the use of COX-2 inhibitors for oral cancer chemoprevention or treatment. The author suggests that the COX-2 inhibitors should be investigated as a new treatment, particularly new chemoprevention agents, for patients who are at high risk for developing oral cancer. Dr. Akarca from Ege University reviews the pathogenesis of gastrointestinal adverse effects of coxibs comparatively with the conventional NSAIDs, and the management and prevention of gastrointestinal adverse effects of coxibs and NSAIDs. Dr Akarca states that patients at high risk or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors. Drs. Cheng and Harris from Vanderbielt University provide an overview on the expression of COX-1 and -2 in the kidney, the interaction of COX-2 and renin-angiotensin system, and the influence of COX-2 inhibiton on renal hemodynamics. Renal adverse effects of coxibs and NSAIDs have contraindicated the long-term administration of these drugs in patients with some systemic diseases. The authors recommend the administration of agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor to reduce adverse renal effects. I appreciate the contributions of the authors in preparation of this issue of Current Pharmaceutical Design. All authors are experts in their fields, and have dedicated their valuable time and knowledge to the production of these reviews. I believe that this issue would provide new insights to the researchers in the design and discovery of the new generation coxibs and new formulations with increased analgesic and anti-inflammatory effects, but reduced systemic adverse effects of NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain. Cyclooxygenase (COX) enzyme is of particular interest because it is the major target of NSAIDs. Although NSAIDs are remarkably effective in the management of pain and inflammation, their use is limited by several adverse effects including gastrointestinal bleeding and ulceration, impaired renal function, and inhibition of platelet aggregation. Discovery of a second cyclooxygenase, COX-2, led to the hypothesis that NSAID side effects could be decreased, as the inhibition of COX-2 is more directly implicated in ameliorating inflammation while the inhibition of COX-1 is related to adverse effects in the GI tract. This stimulated the development of selective COX-2 inhibitors (coxibs) that are better tolerated than nonselective NSAIDs but comparable in analgesic efficacy. This article provides an overview on the therapeutic use of selective COX-2 inhibitors for relief of acute pain, largely based on clinical trials in patients undergoing the surgical removal of impacted third molars, with focus on analgesic efficacy and the potential safety associated with their use compared to dual COX-1/COX-2 inhibitors.

The objective was to review the literature on the effects of selective and non-selective non-steroidal antiinflammatory drugs (NSAIDs) on the treatment of periodontal diseases. A search of MEDLINE was conducted and articles published in English until December 2003 were included. The results from in vitro and animal experiments as well as from human clinical trials are presented. Non-selective cyclooxygenase-1 (COX-1) inhibitors used in periodontal research include compounds such as aspirin, flurbiprofen, ibuprofen, naproxen and piroxicam. Selective cyclooxygenase- 2 (COX-2) inhibitors represent a new group of pharmaceutical products termed “coxibs” that include meloxicam, nimesulide, etodolac and celecoxib. Evidence from animal experiments and clinical trials documents that selective and non-selective NSAIDs are mainly responsible for the stabilization of periodontal conditions by reducing the rate of alveolar bone resorption. This is achieved through local inhibition of both enzymes (e.g. COX-1 and COX-2) responsible for the synthesis of arachidonic acid metabolites. Evidence shows that the effects of NSAIDs drop off rapidly after drugwithdrawal. One of the major advantages of selective COX-2 inhibition is the reduction of adverse systemic effects. Although some studies present promising results, no data from long-term, multicenter prospective clinical trials are yet available for determining whether these therapeutic effects can be retained on a long-term basis. Many of these compounds, such as flurbiprofen, are readily absorbed through the gingival tissues. Therefore, the development of topical NSAIDs formulations (e.g. gels, toothpastes, rinses) with a daily application seems to be of particular interest. This may help to further reduce adverse systemic effects of non-selective NSAIDs in the long-term host modulation of periodontitis-susceptible patients.

Oral cancer is challenging for clinicians due to its high mortality and increasing incidence rate. Cyclooxygenase-2 (COX-2) is extensively expressed in oral cancer and oral premalignant lesions and seems to be enhanced specifically in high-risk oral lesions. Mounting evidence suggests that these inhibitors may represent a promising approach for chemoprevention or treatment of oral cancer. This review reports on Medline and PubMed literature searches of published articles from 1995 to 2003. Our purpose is to provide a comprehensive examination and discussion of the potential role of COX-2 in oral cancer development and the use of COX-2 inhibitors for oral cancer chemoprevention or treatment. The data in the literature strongly indicate that COX-2 is significantly upregulated in oral cancer and premalignant lesions, and we believe that inhibition of COX-2 would suppress development of oral lesions by affecting several pathways of oral carcinogenesis. Therefore, the COX-2 inhibitors should be investigated as a new treatment, particularly new chemoprevention agents, for patients who are at high risk for developing oral cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed group of drugs. Patients receiving NSAIDs often experience abdominal discomfort, and some of them develop serious gastrointestinal complications, such as ulceration, bleeding, perforation, or obstruction. Gastrointestinal side effects of NSAIDs are mostly attributed to cyclooxygenase (COX) inhibition resulting in reduction of prostaglandin in gastric mucosa. Topical irritant effects are also contributed to their systemic effect of prostaglandin inhibition. Anti-inflammatory effects of NSAIDs are mediated by COX-2 inhibition, while COX-1 inhibition is responsible for gastric prostaglandin inhibition. Management of gastrointestinal complications of NSAIDs is costly. In order to prevent or treat the gastrointestinal complications of NSAIDs, anti-ulcer drugs can be used concomitantly. Other alternative is the application or substitution of COX-2 selective inhibitors, which spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Application of COX-2 selective inhibitors as a first line treatment for arthritic disorders may not be cost-effective, if patients do not have any risk factors including advanced age, history of complicating peptic ulcer, concomitant anticoagulant and corticosteroid medication. Patients with risk factors or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors if necessary.

Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used medications worldwide to inhibiting COX activity for the treatment of pain and inflammation. Their nephrotoxicity has been well documented. With the development and clinical implementation of new COX-2 inhibitors, the safety, including the effects on renal function and blood pressure, is attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion and maintenance of renal blood flow. Similar to conventional NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in highrisk patients (including elderly and patients with volume depletion). Recently, agents with combined lipooxygenase/COX inhibition and agents that combine NSAIDs with a nitric oxide (NO) donor have been reported to reduce adverse renal effects.

Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120 - CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process - with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.

The characterisation of the human kinome in recent years has resulted in the emergence of numerous kinase drug targets in a variety of therapeutic areas. Through the elucidation of the sequence and structural composition of kinase active sites, coupled with the solution of numerous ATP competitive ligand complex structures, significant advances have been made in developing inhibitors that are highly selective. This has shown to be the case not only for kinases that are divergent in primary structure, but also for isoforms with highly conserved structure and ATP binding sites. Here we review the methods employed in the generation of selective inhibitors and describe several successful examples of the design of highly potent and selective kinase ATP competitive ligands. We also describe examples where an alternate approach to selectivity was used. These include the use of small molecules to sequester kinases in inactive conformations, and to block phospho-transferase activity by preventing substrate docking and recruitment. Substrate recruitment sites are promising from a structure based design perspective as they contain features unique to individual protein kinases.