Antirheumatic drugs: clinical pharmacological and therapeutic aspects.

There are many current concepts of the pathogenesis of rheumatic diseases which incorporate immunological, infectious and hereditary factors. Rheumatic diseases may sometimes become apparent after trauma, be associated with certain diseases and may be induced by nerve damage and serum sickness. Systemic lupuserythematosus may result from the use of a variety of drugs. At present the body of evidence tends to incriminate immunological factors as well as infectious agents as principal factors in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Just as there is uncertainty regarding the pathogenesis of rheumatic diseases, knowledge of the mechanism of action of the various drugs used to treat these diseases is also incomplete. Recent progress indicates that inhibition of prostaglandin biosynthesis and possibly lysosomal membrane stabilization are primary modes of action of the anti-inflammatory agents. Certain antirheumatic drugs have also been shown to exert some of their therapeutic effect by interfering with the kallikrein-kinin-kininase system...     

Psychoactive agents, seizure production, and sudden death in epilepsy

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.     

Antimalarial drugs in systemic lupus erythematosus: use in pregnancy.

The 4-aminoquinoline radical containing antimalarial drugs are also used in the management of various connective tissue diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis. These agents are particularly useful for the management of inflammatory polyarthritis and skin disease. By raising the pH in intracellular compartments, these drugs interfere with normal phagocytic function which consequently enables them to interfere with antigen processing. Other actions include inhibition of platelet aggregation, this is advantageous in patients with phospholipid antibodies (aPL) which are known to predispose patients to recurrent arterial and venous clinical thrombotic events. Hydroxychloroquine has also been demonstrated to reduce serum lipid levels including cholesterol, triglycerides and low density lipoproteins. As it is now known that patients with SLE are at risk for accelerated artherogenesis and premature heart disease, this action may be an added benefit for these patients. The use of the 4-aminoquinoline radical containing antimalarial drugs during pregnancy is controversial. It is known that these agents can cross the placenta and are deposited in fetal pigmented tissues. These findings have led to the recommendation that these agents should be discontinued in pregnancy for patients with connective tissue diseases even though they have long been recommended for malarial prophylaxis in pregnant women travelling to malarial infested areas. Flares of SLE disease have been documented when these agents are discontinued and as flares of SLE disease activity are known to be detrimental to pregnancy outcome in patients with SLE, it is our opinion that these drugs should not be discontinued during pregnancy in a patient with lupus, particularly when the known terminal elimination half life is 1 to 2 months.     

TNF-alpha antagonists: monoclonal antibodies, soluble receptors, thalidomide and other novel approaches

Tumour necrosis factor-alpha (TNF-alpha) is a pleiotropic molecule produced in response to a variety of stimuli during normal host defence. At low levels, TNF-alpha confers protection against infectious agents, tumours and tissue damage, and plays a role in the development of humoral immunity. However, overproduction of TNF-alpha has been implicated in the pathogenesis of a wide variety of conditions, including autoimmunity, malignancy, inflammatory and immunopathological diseases. Furthermore, TNF-alpha is a key regulator of other pro-inflammatory cytokines; infiltrating mononuclear cells that produce excessive amounts of TNF-alpha at sites of inflammation are, therefore, primary targets for therapeutic intervention. Traditional anti-inflammatory drugs, such as cyclosporin, have widespread immunosuppressive effects and are now being replaced by more specific anti-TNF-alpha compounds. In this report, work presented at the recent Cambridge Symposia meeting on TNF-alpha antagonists in Santa Fe, New Mexico, will be highlighted and discussed.     

Quantitative comparison of the analgesic and anti-inflammatory activities of aspirin, phenacetin and acetaminophen in rodents.

The mild analgesic activities of aspirin, phenacetin and acetaminophen have been compared in the trypsin, kaolin and carrageenan hyperalgesic assays as well as in the acetic acid writhing test. The trypsin and kaolin hyperalgesic assays were designed to be unaffected by drugs with anti-inflammatory activity. Aspirin and acetaminophen were inactive in these two tests at dose levels devoid of side effects. Phenacetin was active in the trypsin and kaolin assays with oral ED50's of 114 +/- 36.2 and 107 +/- 11.5 mg/kg, respectively. Non-steroidal anti-inflammatory drugs as well as phenacetin and acetaminophen were active in the acetic acid writhing and carrageenan hyperalgesic assays. This led to evaluation of phenacetin and acetaminophen as anti-inflammatory agents. Both of these latter drugs were active in the carrageenan pleurisy and adjuvant arthritis models of inflammation. In all studies phenacetin was equipotent to or more potent than acetaminophen. The data suggest that the analgesia produced by aspirin and acetaminophen results from their anti-inflammatory activity whereas the analgesia produced by phenacetin has two components, one dependent on and one independent of anti-inflammatory activity.     

Moxifloxacin: a review of the microbiological, pharmacological, clinical and safety features

Antimicrobial agents are used to treat patients with infectious diseases. Initial antimicrobial compounds originated from natural sources and were generally deemed to be narrow in spectrum. Today, we are in the era of designer drugs that have been specifically developed with current issues in infectious diseases in mind. For example, some new compounds require once daily dosing, have minimal side effects, are active against resistant pathogens and, for some, have a lower propensity for selecting for antimicrobial resistance during patient therapy.     

Moxifloxacin: a review of the microbiological,pharmacological, clinical and safety features

Antimicrobial agents are used to treat patients with infectious diseases. Initial antimicrobial compounds originated from natural sources and were generally deemed to be narrow in spectrum. Today, we are in the era of designer drugs that have been specifically developed with current issues in infectious diseases in mind. For example, some new compounds require once daily dosing, have minimal side effects, are active against resistant pathogens and, for some, have a lower propensity for selecting for antimicrobial resistance during patient therapy.     

Persons and pathogens: Consequences of co-existence

There is considerable evidence that infectious agents may be a cofactor, or even the cause, of a panoply of chronic inflammatory diseases, as well as of some cancers and neurologic diseases. Examples are presented of the evidence for the thesis that infectious antecedents may underlie many inflammatory conditions and some of the diseases in which infections are postulated to be the precipitating factor. Given that infectious agents may give rise to an impressive array of chronic diseases, should we, therefore, consider alternative modes of treatment for such diseases which focus on the infectious antecedent rather than the consequent disease? With regard to therapy, are new classes of antibiotic/anti-inflammatory drugs needed? Or would preventive measures, such as better food handling and water treatment, along with a widespread campaign of prophylactic and therapeutic vaccines against the likely infectious agents, be a more cost effective approach to ameliorate or ablate the onset of a wide range of inflammatory diseases, cancers and neurologic diseases? Since this conference was primarily designed to discuss the safety and efficacy of NSAIDs, it is appropriate to ponder whether chronic/lifelong NSAID/aspirin intake may have value in preventing or treating chronic inflammatory and neurologic diseases as well as some cancers. There are studies that indicate that long term use of some NSAIDs including aspirin may reduce the likelihood of occurrence of some of these chronic diseases. We thus should ponder the potential risks and benefits of lifelong NSAID/aspirin intake. To that end we should ask what kind of a database should be established so that a valid estimate of the benefits versus the risks of extended, perhaps lifelong, use of a present or future NSAID(s) may be considered for the prevention of any given disease?     

The therapeutic potential of synthetic multivalent carbohydrates

Recent progress has been made in constructing synthetic multivalent carbohydrate ligands targeted at known or probable multivalent carbohydrate ligand receptors. Multivalency can dramatically compensate for the weak affinities of individual carbohydrate ligand moieties. Multivalent branched ligand mimetics have been described bearing multiple mannoside, galactoside, lactoside and Sialyl Lewis X (SLe(x)) moieties. New methods for polymeric backbone construction have provided glyco-polymers of defined and controllable size. Promising examples of multivalent ligands giving significant increases in binding potency are being pursued. These types of agents have extensive therapeutic potential in treating infectious diseases or host abnormalities, and also offer exciting potential as drug-conjugate cell-targeting agents.     

Non-anticoagulant effects of heparin: an overview

Heparin has long been known to possess biological effects that are unrelated to its anticoagulant activity. In particular, much emphasis has been placed upon heparin, or novel agents based upon the heparin template, as potential anti-inflammatory agents. Moreover, heparin has been reported to possess clinical benefit in humans, including in chronic inflammatory diseases and cancer, that are over and above the expected effects on blood coagulation and which in many cases are entirely separable from this role. This chapter aims to provide an overview of the non-anticoagulant effects that have been ascribed to heparin, from those involving the binding and inhibition of specific mediators involved in the inflammatory process to effects in whole system models of disease, with reference to the effects of heparin that have been reported to date in human diseases.     

Putative role of proteolysis and inflammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures

Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.     

The therapeutic potential of synthetic multivalent carbohydrates

Recent progress has been made in constructing synthetic multivalent carbohydrate ligands targeted at known or probable multivalent carbohydrate ligand receptors. Multivalency can dramatically compensate for the weak affinities of individual carbohydrate ligand moieties. Multivalent branched ligand mimetics have been described bearing multiple mannoside, galactoside, lactoside and Sialyl Lewis X (SLe^x) moieties. New methods for polymeric backbone construction have provided glyco-polymers of defined and controllable size. Promising examples of multivalent ligands giving significant increases in binding potency are being pursued. These types of agents have extensive therapeutic potential in treating infectious diseases or host abnormalities, and also offer exciting potential as drug-conjugate cell-targeting agents.     

The involvement of VEGF in endothelial permeability: a target for anti-inflammatory therapy

Many inflammatory mediators are known to contribute to increased vascular permeability during various phases of inflammation. Among these mediators, vascular endothelial growth factor (VEGF), also known as vascular permeability factor, plays an important role in vascular hyper-permeability, and several studies have demonstrated that modulation of VEGF function might contribute to a successful therapeutic approach to the treatment of inflammatory diseases. VEGF receptor monoclonal antibodies, glucocorticoids, leukotriene modifiers, cyclooxygenase-2 inhibitors and non-steroidal anti-inflammatory drugs have been studied for many years as VEGF-blocking drugs in inflammatory diseases in vitro and/or in vivo. The molecular and biological understanding of VEGF and preclinical or clinical trials of VEGF-blocking therapies raise hope that they may be useful as adjuncts to existing anti-inflammatory approaches in the regulation of inflammatory diseases.     

Emerging peptide therapeutics for inflammatory diseases

Steroids are the best known anti-inflammatory drugs and have been in use for more than 50 years. Their chronic use however was limited by safety concerns. Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors although devoid of steroid side effects often possess gastrointestinal side effects. In addition recent data suggest that chronic use of some Cox inhibitors is associated with cardiovascular risk. Currently biologics represent the best option for many inflammatory diseases where TNFalpha is the main culprit. These include rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease and psoriasis. A wealth of information is now available on the role of different cytokines and adhesion molecules in the origin and progression of inflammatory diseases. With the success of protein therapeutics such as Etanercept (Enbrel), which binds TNFalpha and inhibits its activity, research has been focused on developing small peptides that can interfere with cytokines or specific cell surface molecules and inhibit the inflammatory reactions. Here we review these peptides that are in discovery and development phases and their potential in the treatment of inflammatory diseases.     

Nitric oxide-modulating agents for gastrointestinal disorders

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO-non-steroidal anti-inflammatory drugs (NO-NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.     

Nitric oxide-modulating agents for gastrointestinal disorders

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO–non-steroidal anti-inflammatory drugs (NO–NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.     

On the measurement in rats of the convulsant effect of drugs and the changes which follow electroconvulsive shock

Three different methods for measuring the convulsant effects of bicuculline, pentylenetetrazol (PTZ) and picrotoxin in rats have been evaluated. Convulsions were assessed following intraperitoneal bolus, intravenous bolus and continuous infusion. Following intraperitoneal injection of all three drugs the latency to various stages of convulsion (first twitch, writhe, generalized myoclonus and tonic extension) was measured. However not all animals convulsed, posing problems of interpretation. After an intravenous bolus of the drugs all animals convulsed and the severity of the convulsion (bicuculline or PTZ) or the latency (picrotoxin) was measured. With intravenous infusion the dose required to produce the first myoclonic jerk was measured. The problems and merits of these methods have been discussed.Rats were given either a single daily electroconvulsive shock (ECS; 125V. 1s) under halothane anaesthesia or anaesthetic only for 10 days. Twenty-four hours after the last treatment the susceptibility of the rats to the convulsant agents listed above was examined. The only consistent effect of ECS was to increase the susceptibility to the convulsant effects of picrotoxin.     

Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks

Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, especially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient s compliance. Also incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Finally, recent data strongly suggest that dual inhibitors may have specific protective activity also in neurodegeneration.     

Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states.

Naproxen is a propionic acid derivative with analgesic and anti-inflammatory activity which has been widely used in the treatment of rheumatic diseases. Naproxen has been well studied in rheumatoid arthritis and is as effective as aspirin but better tolerated, thus enabling more patients to continue with treatment. For this reason some clinicians now prefer to try propionic acid derivatives, such as naproxen, before aspirin in arthritic patients. In comparative studies with other non-steroidal anti-inflammatory drugs, such as indomethacin, ibuprofen, fenoprofen and others, all drugs were usually of similar overall efficacy although naproxen was sometimes preferred: but as with other non-steroidal anti-inflammatory agents, not all patients will respond to naproxen and in such cases other agents should also be tried until the most satisfactory drug is found for each patient. Naproxen is also effective in degenerative joint diseases of the hip and knee, although further well designed studies are needed to more clearly define its relative place compared with newer drugs such as diclofenac or diflunisal. Results of other comparative studies have shown that naproxen is a suitable alternative to phenylbutazone or indomethacin in ankylosing spondylitis and to aspirin in juvenile rheumatoid arthritis. Naproxen appears to be effective in reducing pain and swelling in acute gout and is an effective analgesic in patients with pain following surgery or trauma and in pain of dysmenorrhoea. Naproxen has generally been better tolerated than aspirin or indomethacin at the dosages used. Because of its relatively long plasma half-life, naproxen can with convenieice be given twice daily, and there is some evidence that once daily dosage is as effective in rheumatoid arthritis.     

Current therapeutic uses of lenalidomide in multiple myeloma

Thalidomide has demonstrated a broad spectrum of pharmacological and immunological effects, with potential therapeutic applications that span a wide spectrum of diseases: cancer and related conditions; infectious diseases; autoimmune diseases; dermatological diseases; and other disorders such as sarcoidosis, macular degeneration and diabetic retinopathy. Immunomodulatory derivative lenalidomide has more potent antitumour and anti-inflammatory effects. The molecular mechanisms of antitumour activity of lenalidomide have been extensively studied in multiple myeloma (MM). It directly induces growth arrest and/or apoptosis of even drug-resistant MM cells; inhibits binding of MM cells to bone marrow extracellular matrix proteins and stromal cells; modulates cytokine secretion and inhibits angiogenesis in the bone marrow milieu; and augments host antitumour immunity. Importantly, lenalidomide induces significant clinical responses even in patients with relapsed/refractory MM. Therefore, lenalidomide represents a new class of antitumour agents that is useful in the treatment of MM. Lenalidomide has received fast track designation from the FDA for the treatment of MM and myelodysplastic syndromes.