Identification of selective inhibitors of cyclin dependent kinase 4.

A new structural type of kinase inhibitor, containing a benzocarbazole nucleus, has been identified. Members of the series are selective for inhibition of the cyclin dependent kinase family of enzymes. Although the cdks are highly homologous, representatives of the series showed intra-cdk selectivities, especially for cdk4. SAR studies elucidated the important features of the molecules for inhibition.

Human mdm2 mediates multiple mono-ubiquitination of p53 by a mechanism requiring enzyme isomerization.

The mdm2 gene product is an important regulator of p53 function and stability. mdm2 is an E3 ubiquitin ligase for p53 and the RING finger domain of mdm2 is critical for ligase activity. Ubiquitin (Ub) conjugation is a general targeting modification and poly-ubiquitin chains specifically target proteins to the proteasome for degradation. In this report, we show that the multistep cascade of mdm2-mediated p53 ubiquitination can be reduced to three purified recombinant proteins: ubiquitin-conjugated E2, mdm2, and p53. This simplification allows enzymatic analysis of the isolated ligase reaction. The simplified reaction recapitulates the ubiquitination of p53 observed with individual components and the p53-Ub((n)) is qualitatively similar to p53-Ub((n)) detected in lactacystin-treated cells. Surprisingly, we find that p53 is modified with multiple mono-ubiquitin moieties as opposed to a poly-ubiquitin chain. Finally, kinetic analysis indicates the transfer reaction proceeds either through a modified Ping Pong mechanism involving requisite enzyme isomerization steps, or through a Rapid Equilibrium Random Bi Bi mechanism involving very large anti-cooperative interactions between the two substrate binding pockets on the enzyme, mediated through allosteric changes in enzyme structure.

Quinazolines as cyclin dependent kinase inhibitors.

Quinazolines have been identified as inhibitors of CDK4/D1 and CDK2/E. Aspects of the SAR were investigated using solution-phase, parallel synthesis. An X-ray crystal structure was obtained of quinazoline 51 bound in CDK2 and key interactions within the ATP binding pocket are defined.

SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4.

NF kappa B is an important transcriptional regulator of multiple pro-inflammatory genes. In non-stimulated cells NF kappa B is anchored in the cytoplasm via the inhibitory protein I kappa B alpha. Following exposure to diverse pro-inflammatory signals (e.g. TNF alpha, IL1, LPS) various signal transduction cascades are initiated converging on the I kappa B kinase (IKK). IKK phosphorylates I kappa B alpha on serines 32 and 36 signaling the inhibitory protein for ubiquitin-mediated degradation. The SCF beta-TRCP complex is the ubiquitin ligase responsible for mediating phosphorylation dependent ubiquitination of I kappa B alpha. Here we reconstitute phosphorylation dependent ubiquitination of I kappa B alpha using recombinant components. Our results suggest that the cullin specificity of the SCF complex may reflect its ability to associate with Rbx1. We demonstrate specific ubiquitination of I kappa B alpha by Ubc3 and Ubc4 in a phosphorylation and SCF beta-TRCP dependent manner and that both are capable of associating with the SCF beta-TRCP complex isolated from human cells. Finally, we show that Ubc4 is in excess to Ubc3 in THP.1 cells and 19 times more efficient in catalyzing the reaction, suggesting that Ubc4 is the preferentially used Ubc in this reaction in vivo. Our results also suggest that ubiquitin is transferred directly from the Ubc to phospho-I kappa B alpha in a SCF beta-TRCP dependent reaction. Oncogene (2000) 19, 3529 - 3536

Human carbon catabolite repressor protein (CCR4)-associative factor 1: cloning, expression and characterization of its interaction with the B-cell translocation protein BTG1.

The human BTG1 protein is thought to be a potential tumour suppressor because its overexpression inhibits NIH 3T3 cell proliferation. However, little is known about how BTG1 exerts its anti-proliferative activity. In this study, we used the yeast 'two-hybrid' system to screen for interacting protein partners and identified human carbon catabolite repressor protein (CCR4)-associative factor 1 (hCAF-1), a homologue of mouse CAF-1 (mCAF-1) and Saccharomyces cerevisiae yCAF-1/POP2. In vitro the hCAF-1/BTG1 complex formation was dependent on the phosphorylation of a putative p34cdc2 kinase site on BTG1 (Ser-159). In yeast, the Ala-159 mutant did not interact with hCAF-1. In addition, phosphorylation of Ser-159 in vitro showed specificity for the cell cycle kinases p34CDK2/cyclin E and p34CDK2/cyclin A, but not for p34CDK4/cyclin D1 or p34cdc2/cyclin B. Cell synchrony experiments with primary cultures of rat aortic smooth-muscle cells (RSMCs) demonstrated that message and protein levels of rat CAF-1 (rCAF-1) were up-regulated under conditions of cell contact, as previously reported for BTG1 [Wilcox, Scott, Subramanian, Ross, Adams-Burton, Stoltenborg and Corjay (1995) Circulation 92, I34-I35]. Western blot and immunohistochemical analysis showed that rCAF-1 localizes to the nucleus of contact-inhibited RSMCs, where it was physically associated with BTG1, as determined by co-immunoprecipitation with anti-hCAF-1 antisera. Overexpression of hCAF-1 in NIH 3T3 and osteosarcoma (U-2-OS) cells was itself anti-proliferative with colony formation reduced by 67% and 90% respectively. Taken together, these results indicate that formation of the hCAF-1/BTG1 complex is driven by phosphorylation at BTG1 (Ser-159) and implicates this complex in the signalling events of cell division that lead to changes in cellular proliferation associated with cell-cell contact.

Orlistat.

Orlistat (tetrahydrolipstatin) is an inhibitor of pancreatic and other lipases. As a pancreatic lipase inhibitor, it acts in the gastrointestinal lumen and is indicated for use in obesity. Serum total cholesterol and low density lipoprotein-cholesterol levels were reduced in obese, but otherwise healthy, patients during < or = 2 years' orlistat treatment; serum triglyceride and high density and very low density lipoprotein-cholesterol levels were unchanged in trials of < or = 12 weeks. Obese patients who were maintained on a hypocaloric diet and who received orlistat 360 mg/day for 12 weeks lost a significantly greater percentage of bodyweight than placebo recipients (5 vs 3.5%). In 2-year studies, weight loss was significantly greater in orlistat than in placebo recipients by the end of year 1; weight was further reduced or maintained in the second year, when a eucaloric diet was allowed, in orlistat but not placebo recipients. A greater proportion of orlistat than placebo recipients lost > 5% or > 10% of their initial bodyweight in 1- and 2-year studies.

Tazarotene.

Tazarotene is a topical retinoid that appears to exert its effects via retinoic acid receptors. It normalises differentiation and proliferation of keratinocytes and has an anti-inflammatory effect. Topical tazarotene 0.05% or 0.1% gel was effective in the treatment of plaque psoriasis in clinical trials and its therapeutic effect was maintained for at least 12 weeks after treatment discontinuation in some patients. In one study in patients with psoriasis, tazarotene had similar efficacy to fluocinonide in reducing plaque elevation, but not erythema. In another study, tazarotene was reported to be less effective than fluocinonide. Combination treatment with tazarotene plus a mid- or high-potency corticosteroid was more effective in the treatment of psoriasis than tazarotene alone. Topical tazarotene 0.1% gel significantly reduced lesion counts in patients with mild to moderate facial acne vulgaris. Skin irritation is a common adverse event with topical tazarotene, but it is mainly of mild to moderate severity. Tazarotene is not recommended for use in women who are, or may become, pregnant.

Fluoxetine. A pharmacoeconomic review of its use in depression.

Depressive illness is a common, often unrecognised and untreated condition with substantial associated costs, particularly indirect costs (e.g. lost productivity and absenteeism). The improved tolerability profile of fluoxetine and associated lower discontinuation rates, the relative safety of the drug in overdosage and its similar efficacy compared with tricyclic antidepressants have provided the main rationale for using this agent in depressed patients. Pharmacoeconomic analyses of fluoxetine have mainly sought to determine whether its higher acquisition cost in comparison with tricyclic antidepressants can be offset by reductions in other costs and whether the use of this agent as first-line therapy can be justified. Studies have also attempted to determine whether the selective serotonin reuptake inhibitors (SSRIs) can be distinguished from one another on pharmacoeconomic grounds; overall efficacy and tolerability of these agents appear to be similar, although tolerability data are conflicting. Most analyses have been of a retrospective database or clinical decision analytic model design; two prospective trials (one conducted in a naturalistic setting) have been conducted. These studies have mainly considered direct treatment costs only from the perspective of the healthcare payer. Available evidence suggests that overall total direct healthcare costs for patients who start antidepressant therapy with fluoxetine are similar to, or lower than, those for patients who start therapy with tricyclic agents or other SSRIs. Offsetting of the higher acquisition cost of fluoxetine compared with that of tricyclic agents may be accounted for by lower in- and outpatient costs with fluoxetine, a possible lower risk of absenteeism from work and lower mean total medical costs associated with acute overdosage. Between-treatment differences in drug use patterns may also, in part, explain the observed differences in total healthcare costs between fluoxetine and other antidepressants. In particular, patients beginning therapy with fluoxetine are more likely to receive treatment regimens that meet minimum recommended guidelines for dosage and duration and are less likely to require treatment switching/augmentation than those receiving tricyclic antidepressants or other SSRIs as initial therapy. In addition, fewer fluoxetine than tricyclic antidepressant recipients discontinue therapy early, and fewer fluoxetine recipients require upward dosage titration or concomitant anxiolytic/ hypnotic medications than patients receiving other SSRIs. In conclusion, fluoxetine is a well established antidepressant which possesses tolerability and safety advantages over the tricyclic agents. The available cost analyses show that these benefits can be obtained without additional overall cost to the healthcare provider. Cost advantages observed to date for fluoxetine over other SSRIs require confirmation.

Paroxetine. An update of its pharmacology and therapeutic use in depression and a review of its use in other disorders.

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT), which was previously reviewed as an antidepressant in Drugs in 1991. Since then, more comparative trials with other antidepressants have become available, and its use in the elderly and as long term maintenance therapy has been investigated. Paroxetine has also been studied in several other disorders with a presumed serotonergic component, primarily obsessive compulsive disorder (OCD) and panic disorder. In short term clinical trials in patients with depression, paroxetine produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with other agents including tricyclic antidepressants (TCAs), maprotiline, nefazodone and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline. Long term data suggest that paroxetine is effective in preventing relapse or recurrence of depression in patients treated for up to 1 year. In the elderly, the overall efficacy of paroxetine was at least as good as that of comparator agents. In short term clinical trials involving patients with OCD or panic disorder, paroxetine was significantly more effective than placebo and of similar efficacy to clomipramine. Limited long term data show that paroxetine is effective in maintaining a therapeutic response over periods of 1 year (OCD) and up to 6 months (panic disorder). Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache. Like the other SSRIs, paroxetine is better tolerated than the TCAs, causing few anticholinergic adverse effects. The most commonly reported adverse event associated with paroxetine treatment is nausea, although this is generally mild and subsides with continued use. Fewer withdrawals from treatment due to adverse effects occurred with paroxetine treatment than with TCAs. The adverse events profile of paroxetine appears to be broadly similar to that of other SSRIs, although data from comparative trials are limited. Serious adverse effects associated with paroxetine are very rare. In conclusion, paroxetine is effective and well tolerated, and suitable as first-line therapy for depression. It also appears to be a useful alternative to other available agents for the treatment of patients with OCD or panic disorder.

Topical mometasone. A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders.

Mometasone, a synthetic 16 alpha-methyl analogue of beclomethasone, is classified as a 'potent' glucocorticoid for dermatological use. It is available as 0.1% cream, ointment and lotion formulations for the treatment of patients with inflammatory glucocorticoid-responsive dermatoses. In patients with atopic dermatitis, the effect of mometasone 0.1% applied once daily over 2 to 3 weeks were similar to those of other glucocorticoids of similar potency, such as betamethasone dipropionate 0.05% twice daily and methylprednisolone aceponate 0.1% once daily. Mometasone 0.1% was significantly superior to twice-daily application of less potent glucocorticoids such as clobetasone 0.05%, hydrocortisone 1.0%, hydrocortisone butyrate and hydrocortisone valerate 0.2%. In patients with seborrhoeic dermatitis, mometasone 0.1% was more effective than ketoconazole 2.0% and hydrocortisone 1.0% in trials lasting 4 or 6 weeks. In the management of scalp psoriasis and psoriasis vulgaris, mometasone 0.1% applied once daily for 2 to 8 weeks was generally more effective than other glucocorticoids of similar or weaker potency such as betamethasone valerate 0.1%, fluocinolone acetonide 0.025%, fluticasone propionate 0.005%, triamcinolone acetonide 0.1% and hydrocortisone 1.0% and as effective as diflucortolone valerate 0.1%. Alternate day application of mometasone 0.1% for 2 weeks was as effective as once-daily application in maintaining symptom control in a small number of patients with psoriasis vulgaris. Although mometasone demonstrates greater anti-inflammatory activity and a longer duration of action than betamethasone, it has low potential to cause adverse systemic effects such as suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Moreover, its atrophogenic potential is low and no greater than that of other glucocorticoids in its class, such as betamethasone valerate. Transient, mild to moderate, local adverse effects such as burning, stinging, folliculitis, dryness, acneiform eruptions and signs of skin atrophy have been reported with mometasone. Mometasone has shown a low risk of primary sensitisation and cross-reactions in preliminary patch test studies. Mometasone is a well tolerated topical glucocorticoid effective in the management of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. In addition to its low potential for causing primary sensitisation and cross-reactions with other topical glucocorticoids, mometasone offers the convenience of once-daily administration.

Meropenem. A pharmacoeconomic review of its use in serious infections.

Meropenem is a carbapenem antibiotic which is active against the majority of aerobic and anaerobic bacteria implicated in serious infections. Its therapeutic efficacy in a wide range of serious infections is similar to that of imipenem/cilastatin and standard combination drug regimens. Hence, meropenem is suitable for use as monotherapy. Although the acquisition cost of meropenem is likely to be higher than that of aminoglycoside- and metronidazole-containing combination regimens, the latter incur additional drug administration costs and potentially higher costs for treatment of adverse effects. In addition, aminoglycoside-containing regimens also incur assay and toxicity monitoring costs. Economic analyses are required to compare overall treatment costs with combination therapy and meropenem. Cost analyses indicate that the ability to give meropenem, but not imipenem/cilastatin, by rapid intravenous bolus injection results in lower drug administration costs than with the standard infusion method. More comprehensive pharmacoeconomic data on meropenem are required. However, assuming that meropenem and imipenem/cilastatin have similar acquisition costs, the option of administering meropenem by bolus injection and its lower epileptogenic potential at high dosages (thus permitting its use in meningitis) should be considered potentially important attributes when choosing a carbapenem antibiotic for inclusion in a hospital formulary.

Cefotaxime. A pharmacoeconomic review of its use in the treatment of infections.

Cefotaxime is a parenterally administered third generation cephalosporin with a broad spectrum of antimicrobial activity. After more than a decade of use, cefotaxime continues to play an important role in the treatment of patients with serious infections, particularly those caused by Gram-negative bacteria. Clinical trials of cefotaxime have demonstrated clinical and/or bacteriological success rates usually between 75 and 100% in hospitalised patients with infections such as pneumonia, complicated urinary tract infections and bacteraemia. In general, comparative trials have shown that cefotaxime has equivalent clinical efficacy to ceftriaxone. Although cefotaxime was traditionally administered at 6- or 8-hourly intervals, evaluations of twice daily regimens have demonstrated the feasibility of using this extended dosage interval in selected patients. Like other parenterally administered cephalosporins, cefotaxime is well tolerated. Cefotaxime does not cause a significant incidence of coagulopathies, as observed with some cephalosporins (e.g., cefamandole and cefoperazone), nor is it associated with the development of pseudocholelithiasis as seen with ceftriaxone. Some hospitals have achieved significant cost savings by implementing programmes or policies involving replacement of prescriptions for ceftriaxone with those for cefotaxime; however, other institutions have shown cost savings when cefotaxime is replaced by ceftriaxone. Similarly, conflicting results were seen in studies that assessed only the drug acquisition and administration supply costs (with or without inclusion of labour costs), highlighting the difficulty in applying pharmacoeconomic data from one clinical setting to another. A limited number of detailed pharmacoeconomic analyses of cefotaxime have been conducted. One analysis, in patients with pneumonia or other serious infections, incorporated published clinical trial data as well as published or estimated cost data (from 1992 or earlier) for the US healthcare setting. Total treatment costs per patient-day were $US25.21 for cefotaxime 1 g twice daily and $US37.23 for cefotaxime 1 g 3 times daily, compared with $US69.97 for ceftriaxone 2 g once daily and $US74.57 for ceftriaxone 1 g twice daily. Costs included those associated with drug acquisition, administration and preparation, laboratory monitoring and adverse events. A large retrospective analysis was conducted between 1989 and 1993 in a US hospital. Patients treated with cefotaxime twice daily had similar clinical outcomes, including duration of hospital stay (7.21 vs 7.24 days), to those receiving antimicrobials other than cefotaxime. However, when a model was applied to determine attributable differences, a trend was demonstrated towards reduced length of hospitalisation (mean reduction 0.5 days) and total cost of hospitalisation (mean reduction $US623 per patient) with cefotaxime. In a Canadian clinical decision-analysis model of initial empirical monotherapy for an average infectious disease state (costs for serious lower respiratory tract infection, urinary tract infection, sepsis, skin/soft tissue infection and febrile neutropenia were weighted according to the incidence of each infection and combined to give a single value), the average total cost per patient for cefotaxime was $Can4099 (1994 dollars). This was lower than that for ceftriaxone ($Can4257) but higher than that for cefepime ($Can3945), ciprofloxacin ($Can4008) and ceftazidime ($Can4086). Costs included those related to drug acquisition, preparation and administration, bacterial culture and sensitivity testing, hospitalisation and adverse events. An analysis conducted in France demonstrated that cefotaxime 1 g 3 times daily was associated with total treatment costs equal to or lower than those for ceftriaxone 2 g once daily. The study also evaluated total costs of cefotaxime 1 g twice daily and ceftazidime 1 g 3 times daily; treatment costs associated with cefotaxime were less than on

Fosphenytoin. Pharmacoeconomic implications of therapy.

Advantages and disadvantages of Fosphenytoin. Advantages. More rapid intravenous administration than phenytoin and no need for an in-line filter. May be administered by intramuscular injection. Lower potential for local tissue and cardiac toxicity than phenytoin. Associated with less pain and phlebitis at the injection site, fewer reductions in infusion rate and fewer changes of administration site because of injection site complications than phenytoin. Benefits in terms of ease of administration and improved tolerability vs phenytoin have pharmacoeconomic implications which may translate into an overall cost advantage. Disadvantages. Approximately 10-fold higher acquisition cost vs phenytoin. Fosphenytoin is a parenterally administered prodrug of phenytoin, used in the treatment of patients with seizures. Advantages of fosphenytoin over phenytoin include more rapid intravenous administration, no need for an intravenous filter, and a lower potential for local tissue and cardiac toxicity. Unlike phenytoin, fosphenytoin may also be administered by intramuscular injection. Pharmacoeconomic data from a small study of patients with acute seizures in a US emergency department showed an overall cost advantage of fosphenytoin over phenytoin, despite a considerably greater acquisition cost of fosphenytoin. The main cost drivers for phenytoin therapy were treatment costs associated with adverse events. In view of the limited pharmacoeconomic data currently available, it is in the interests of individual institutions to conduct their own formal pharmacoeconomic studies applying local cost data and patterns of clinical practise to determine whether fosphenytoin should replace phenytoin on their formularly list.

Nelfinavir.

Nelfinavir is a protease inhibitor which shows good inhibitory activity against HIV-1. The pattern of HIV-1 resistance to nelfinavir is different from that seen with other protease inhibitors. In healthy male volunteers, administration of single 400 and 800mg doses of nelfinavir with food resulted in area under the plasma concentration-time curve values that were 27 to 50% higher than those achieved in fasted volunteers who received the same doses of the drug. Reductions in plasma HIV RNA to below detectable levels (detection limit 500 copies/ml) were achieved in some patients (number not reported) after 28 days' treatment with nelfinavir 500, 600 or 750 mg twice daily, or 500, 750 or 1000 mg 3 times daily. Combination therapy with nelfinavir and stavudine produced greater reductions in plasma HIV RNA levels that stavudine monotherapy in patients who had not previously received stavudine treatment; mean increases in CD4+ cell counts were also greater in the combination treatment group than in monotherapy recipients. Plasma HIV RNA decreased to below detectable levels in 11 of 12 patients with early onset HIV infection who received a triple regimen of nelfinavir, zidovudine and lamivudine for 16 weeks.

Intranasal fluticasone propionate. A reappraisal of its pharmacology and clinical efficacy in the treatment of rhinitis.

The intranasal corticosteroid fluticasone propionate is an effective agent for the treatment of rhinitis, demonstrating potent local anti-inflammatory activity and little, if any, systemic activity. Intranasal fluticasone propionate has shown clinical efficacy similar to that of other intranasal corticosteroids, including beclomethasone (administered at up to a 2-fold higher dosage than fluticasone), budesonide, flunisolide and triamcinolone acetonide, and provides greater relief from nasal symptoms (including nasal blockage) than antihistamine agents and intranasal sodium cromoglycate. Its efficacy in the treatment of seasonal allergic rhinitis and perennial allergic and nonallergic rhinitis has been demonstrated in large well-controlled studies in which the drug maintained adequate control of symptoms when administered in a once daily dose of 200 micrograms. In addition, fluticasone propionate has shown similar efficacy to that of beclomethasone in the treatment of nasal polyps; however, its use in the postoperative setting requires further investigation. Intranasal fluticasone propionate is well tolerated in the majority of patients, the incidence of adverse events being similar to that seen with placebo. Pharmacoeconomic analyses indicate that intranasal fluticasone propionate is significantly more cost-effective than the antihistamines terfenadine and loratadine. Overall quality of life was improved to a similar extent by fluticasone propionate and beclomethasone. In conclusion, recent clinical experience has confirmed that intranasal fluticasone propionate is a convenient, effective and well tolerated alternative to other intranasal corticosteroids and antihistamines for the treatment of rhinitis when administered once daily.

Donepezil.

Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment.

[Not Available].

Rimexolone is a locally active nonfluorinated glucocorticoid which has minimal systemic effects and is virtually devoid of any atrophogenic effects on the skin.It has high corticosteroid receptor affinity and remains localised at the injection site for a prolonged period after intra-articular injection. Thus, serum rimexolone concentrations remain low.Rimexolone had the longest mean intra-articular residence time of several intra-articular steroid preparations (25 days, vs 6 days for triamcinolone hexacetonide and 1 to 4 days for the other drugs, which included methylprednisolone acetate).Single intra-articular injections of rimexolone provided long-lasting improvement of clinical efficacy parameters in patients with rheumatoid arthritis or osteoarthritis.In patients with rheumatoid arthritis, rimexolone was superior to placebo for treating knee joints and superior to placebo and similar to methylprednisolone acetate for treating small joints of the hand.In patients with osteoarthritis of the knee joint, rimexolone was superior to placebo, tended to be slightly more effective than methylprednisolone acetate and was similar to triamcinolone acetonide or a depot preparation of betamethasone dipropionate.