Slow-acting Antirheumatic Drugs Research Articles

Synergistically engineered nanotransethosomes for co-delivery of methotrexate and baicalin for enhanced transdermal delivery against rheumatoid arthritis: formulation, characterisation and in vivo pharmacodynamic evaluation

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease that significantly impacts the quality of life of those affected. Owing to the complex pathophysiology of RA, it is not possible for any singular treatment to entirely impede the progression of the disease. Hence, the current study aimed to adopt a holistic and synergistic approach towards the management of RA by means of a co-delivery strategy involving methotrexate (MTH), a conventional slow-acting anti-rheumatic drug, and baicalin (BCN), a bioactive phytochemical using a transethosomal (TRS) gel formulation.Purpose: The present study aims to evaluate the potential benefits of administering MTH and BCN in nanoparticulate form, which may lead to improved stability and solubility, as well as enhanced penetration into the arthritic tissues of interest.Methods and results: The MTH-BCN-TRS that were synthesised exhibited small particle size of 151.3 nm and polydispersity index of 0.125, as well as a favourable zeta potential of −32.22 mV. Additional assessments were conducted, including a pharmacokinetic analysis, TEM, skin permeation analysis and confocal microscopy. According to the Confocal laser scanning microscopy (CLSM) study, the formulated MTH-BCN-TRS gel exhibited superior MTH and BCN permeation through the skin layers when compared to the MTH-BCN suspension gel. The MTT experiment on Raw 264.7 and SW982 cell lines revealed a considerable reduction (p < .05) in the IC50 value of the MTH-BCN-TRS formulation (9.2 mM and 43.2 mM, respectively) in comparison to the drug suspension. According to the findings of the in vivo study, it was found that the MTH-BCN-TRS gel exhibits significantly promising anti-arthritic properties when compared to the conventional diclofenac gel. This was demonstrated through histopathological studies and radiographic analysis. Furthermore, skin irritation investigation on Wistar albino rats confirmed that the formulated MTH-BCN-TRS is a safe option for topical treatment on the skin. The present study has confirmed that the formulated TRS vesicles are a valuable carrier for the transdermal delivery of MTH and BCN, which may be used for the management of rheumatoid arthritis.

Formulation of a dual drug-loaded nanoparticulate co-delivery hydrogel system and its validation in rheumatoid arthritis animal model

Rheumatoid arthritis (RA), a systemic autoimmune disease that dramatically affects patients’ quality of life. Given the intricacy of RA’s pathophysiology, no single treatment can completely halt the disease progression. Here, we attempted to treat RA holistically and synergistically by co-delivering methotrexate (MTX), a standard slow-acting anti-rheumatic drug, and phenethyl isothiocyanate (PEITC), a bioactive phytochemical, using a sodium alginate (SA)-pluronic F127 (PF-127) in situ hydrogel formulation. Therefore, in the current study, the co-delivery of MTX and PEITC in the nanoparticulate form could help enhance stability and solubility and facilitate greater penetration in the target arthritic tissues. The fabricated MTX NP and PEITC NE were found to have a minimum particle size, PDI, and good zeta potential. Results from in vitro release studies showed that MTX and PEITC were simultaneously released from the DD NP HG matrix over 6–7 days through diffusion and erosion mechanisms. An intra-articular (IA) injection of DD NP HG dramatically reduced chronic inflammation in adjuvant-induced arthritis (AIA) rats, delayed the onset of bone erosion, significantly reduced synovitis, and down-regulated the inflammatory cytokine expression. Most notably, the co-delivery strategy almost entirely restored the morphological features of the ankle joints of RA rats. The hepatic and renal function tests indicated good biological safety for DD NP HG in RA conditions. Taken together, these findings indicated that DD NP HG could achieve good anti-inflammatory activity and reverse cartilage disruption through a synergistic effect between two nanoparticulate forms of MTX and PEITC, which can effectively improve the drawbacks of their free forms.

Analytical Methodologies for Determination of Hydroxychloroquine and its Metabolites in Pharmaceutical, Biological and Environmental Samples

Background:Hydroxychloroquine (HCQ) was originally launched as an antimalarial drug, but now it is also used as a slow-acting anti-rheumatic drug. It contains equal proportions of (-)-(R)-hydroxychloroquine and (+)-(S)-hydroxychloroquine.Introduction:Hydroxychloroquine, a synthetic 4-aminoquinoline derivative, possesses antimalarial, anti-rheumatic activity and also exerts beneficial effects on lupus erythematous disease. Substantial levels of three metabolites of HCQ, which are desethylchloroquine (DCQ), bisdesethylhydroxychloroquine (BDCQ), and desethylhydroxychloroquine (DHCQ), have been determined by various analytical techniques from blood and plasma.Methods:Various analytical techniques have been reported for asynchronous and simultaneous estimation of HCQ and their metabolites in pharmaceuticals and biological samples like (serum, whole blood, and urine). The analytical techniques are Square-wave voltammetry employed with the cathodically pretreated boron-doped diamond electrode, fast UHPLC–fluorescent method, UV spectrophotometry, UHPLC-UV analysis, RP-HPLC, mass spectrometry, NMR, and CE.Results:We have complied various analytical methods to detect HCQ with its various metabolites simultaneously or alone in pharmaceutical dosage forms, biological and environmental samples.Conclusion:The authors believe that the above-mentioned studies compiled in this report will give a choice to readers to select the most appropriate and suitable method for the analysis of HCQ. Further, it is also believed that this study will help the researchers to develop a more sensitive, convenient, and rapid method for these based on literature reports.

Hydroxychloroquine as Potent Inhibitor of COVID -19 Main Protease: Grid Based Docking Approach

Objectives: Coronavirus (COVID-19) is an enveloped RNA virus that occurs in various forms in humans and wildlife. A total of six disease-causing species have been identified in humans. Viral infections play a vital role in human diseases, and recent outbreaks have developed globally in the form of novel corona. The SS-RNA virus from the enveloped coronavirus family caused SARS (Severe Acute Respiratory Syndrome), a life-threatening viral infection. In many countries around the world, the spread of infection is rapid. As of March 26, 2020, there were 462.684 confirmed cases globally, and 20.834 deaths were recorded. The World Health Organization (WHO) described COVID-19 as a pandemic on March 11, 2020. There are numerous drug trials going on with some positive results. However, since no vaccine is available, the best way to combat the virus is to use preventive methods. Methods: In this study, an attempt was made to find the new COVID-19 main protease inhibitor with a molecular docking approach. A grid-based docking approach was chosen to find the binding using VLife MDS software. The 2D structure of the compounds was created and then converted into the 3D, and then, it was energetically minimized up to the RMS gradient of 0.01, using the Merck Molecular Force Field (MMFF). By using cavity determination option, the enzyme’s cavities were determined. Cavity no.1 was selected for docking. The active site for docking was defined as all atoms within 5A? radius. Results: Hydroxychloroquine is a slow-acting antirheumatic drug. The value of hydroxychloroquine is analogous to that reported for other disease-modifying anti-rheumatic drugs. The docking score obtained was -4.308880 and the number of receptor atoms was 77, while the number of ligand atoms was 20, which shows that hydroxychloroquine binds effectively with Covid-19 protease. Conclusion: Hydroxychloroquine was taken as drug following Lipinski’s rule of five, so it had a very good drug score and drug-likeness score as well. This study reveals that Hydroxychloroquine has good binding affinity with COVID-19 protease and thus can be used as prophylaxis and therapeutic treatment for corona patients. Keywords: COVID-19, Hydroxychloroquine, Molecular Docking & Prevention measures

How effective is the average therapeutic dose of a nonsteroidal anti-inflammatory drug in osteoarthritis?

The international multicenter PRECISION study evaluating the cardiovascular safety of celecoxib, naproxen, and ibuprofen is under close scrutiny by critics. One of the criticisms about this study was that the use of relatively low dose (on average just above 200 mg/day) may not be effective enough. But is it really so? This review gives data from numerous international studies dealing with the treatment of osteoarthritis (OA), in which celecoxib 200 mg/day is compared with paracetamol 4000 mg/day, diclofenac 100—150 mg/day, naproxen 1000 mg/day, ibuprofen 2400 mg/day and slow-acting antirheumatic drugs (glucosamine, chondroitin, and their combination). Almost all studies demonstrate that celecoxib 200 mg has a good and rapid analgesic effect that is not inferior to or exceed that of the reference drugs. Celecoxib 200 mg/day could relieve pain in OA for many months and prevent disease recurrences. The low risk of gastrointestinal and cardiovascular complications, which has been confirmed by the PRECISION study, makes celecoxib 200 mg/day the drug of choice for long-term OA therapy, including in patients with serious comorbid conditions.

Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR.

Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA. To design novel and highly potent carbazole inhibitors, molecular docking and three dimensional quantitative structure–activity relationship (3D-QSAR) were applied to explore a dataset of 132 new carbazole carboxamide derivatives. The established comparative molecular field analysis (CoMFA) (q2 = 0.761, r2 = 0.933) and comparative molecular similarity indices analysis (CoMSIA) (q2 = 0.891, r2 = 0.988) models obtained high predictive and satisfactory values. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions and hydrogen-bond donors were preferred at R1 and 1-position, respectively, and introducing hydrophilic substitutions at R1 and R4 was important for improving BTK inhibitory activities. These results will contribute to the design of novel and highly potent BTK inhibitors.

A history of the term "DMARD".

The article outlines a history of the concept of “disease-modifying antirheumatic drugs” or DMARDs—from the emergence in the 1970s of the idea of drugs with decisive long-term effects on bone erosion in rheumatoid arthritis (RA), through the consolidation and popularisation in the term DMARD in 1980s and 1990s. It then examines the usage of the terms “remission-inducing drugs” (RIDs) and “slow-acting anti-rheumatic drugs” (SAARDs), which for some years offered competition to the term DMARDs, thus underscoring the contingency of the establishment of DMARD as a word. Finally, it juxtaposes the apparently spontaneous emergence of the three terms DMARD, SAARD and RID, and the disappearance of the latter two, with a failed attempt in the early 1990s to replace these terms with the new term “disease-controlling antirheumatic treatment” (DC-ART). The analysis highlights the paradoxical qualities of the DMARD concept as robust albeit tension ridden, while playing down the role of identified individuals and overarching explanations of purpose.

Treatment of juvenile rheumatoid arthritis

The systematic approach to pharmacologic treatment is typically to begin with the safest, simplest, and most conservative measures. It has been realized that the more rapidly inflammation is under control, the less likely it is that there will be permanent sequelae. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of initial treatment for inflammation. In addition, the slow-acting antirheumatic drugs (SAARDs) and disease-modifying antirheumatic drugs (DMARDs) have efficacy of anti-inflammatory action in children with chronic arthritis. New therapeutic modalities for inflammation, such as etanercept and infliximab, promise even further improvements in the risk/benefit ratio of treatment. It is not typically possible at the onset of the disease to predict which children will recover and which will go on to have unremitting disease with lingering disability or enter adulthood with serious functional impairment. Therefore, the initial therapeutic approach must be vigorous in all children.

Albuminuria and tubular markers in juvenile idiopathic arthritis

This study investigates whether renal damage occurs in children with juvenile idiopathic arthritis (JIA) either secondary to the disease per se or due to the side effects of non-steroidal anti-inflammatory drugs (NSAIDs) and slow-acting anti-rheumatic drugs (SAARDs) used in treatment. In this cross-sectional study, albuminuria, N -acetyl glucosaminidase (NAG), beta(2)-microglobulin (beta(2)M), and creatinine (Cr) levels were measured in urine samples of 45 patients (23 female, 22 male, 9.4+/-3.9 years) with JIA and a sex- and age-matched control group of 33 healthy children. The urinary albumin/Cr, NAG/Cr, and beta(2)M/Cr ratios of children with JIA and of the control group did not differ statistically. No difference was noted between patient groups with different types of JIA (12 systemic, 18 polyarticular, and 15 oligoarticular JIA). JIA patients with active disease (n=16) had higher NAG/Cr values than patients with inactive disease (P=0.002). NAG/Cr levels correlated with erythrocyte sedimentation rate (r=0.66, P<0.001) and platelet count (r=0.61, P<0.001) and showed a slight correlation with the number of joints with active arthritis in children with polyarticular JIA (r=0.45, P=0.055). Neither beta(2)M/Cr nor albumin/Cr ratios were associated with disease activity. No difference was noted between patient groups treated with different NSAIDs and SAARDs. In children with JIA tubular enzymuria increases during the active phase of the disease; however, it seems that permanent renal damage does not occur.

Management of spondyloarthropathy: new pharmacological treatment options.

Spondyloarthropathies (SpA) are a group of inflammatory arthritides classified according to common features of peripheral and spinal arthritis. The conventional anti-inflammatory and disease-modifying or slow-acting anti-rheumatic drugs do appear to be efficacious in treatment of the peripheral arthritis in a comparable fashion to seropositive rheumatoid arthritis, however, their efficacy in axial disease is unproven. This review examines new pharmacological developments in the treatment of SpA including the specific features of sacroiliitis, enthesitis and spondylitis in addition to the peripheral manifestations. The main points that are discussed are new cyclo-oxygenase (COX)-2 specific anti-inflammatories, biological therapies, such as anti-TNF compounds, and novel uses of well-known agents.

Cytokine pathways and joint inflammation in rheumatoid arthritis.

Rheumatoid arthritis is a common chronic inflammatory and destructive arthropathy that cannot be cured and that has substantial personal, social, and economic costs. The long-term prognosis is poor: 80 percent of affected patients are disabled after 20 years,1 and life expectancy is reduced by an average of 3 to 18 years.2 The medical cost of rheumatoid arthritis averages $5,919 per case per year in the United States3 and approximately £2,600 per case per year in the United Kingdom.4 Current slow-acting antirheumatic drugs have limited efficacy and many side effects. Moreover, they do not improve the long-term prognosis of rheumatoid arthritis. . . .

Serum levels of parathyroid hormone and markers of bone metabolism in patients with rheumatoid arthritis. Relationship to disease activity and glucocorticoid treatment

Objective : To evaluate the influence of inflammatory activity and glucocorticoid (GC) treatment on serum parathyroid hormone (s-PTH) and bone metabolism in patients with rheumatoid arthritis (RA). Furthermore, in patients with active RA, to examine the PTH secretion and Ca 2 + set point before and after treatment with GC. Methods : A range of biochemical markers of bone metabolism and calcium homeostasis were measured in 95 patients with definite RA stratified into groups according to disease activity and GC treatment. In a subgroup of 12 patients with active disease, initiating slow-acting-anti-rheumatic-drugs (SAARDs) - GC, the PTH secretion and calcium set point were evaluated by use of the Cica clamp technique before and after 1 month of treatment. Results : S-osteocalcin, s-total alkaline phosphatase (s-TAP) and s-carboxyterminal crosslinked telopeptide of type I collagen (s-ICTP) were elevated in all groups. The levels of urine pyridinoline (Pyr) and s-albumin-corrected calcium (s-AlbCorrCa 2 + ) were elevated in patients with active disease and patients treated with GC. S-PTH and s-phosphate were within normal ranges. S-TAP, s-ICTP, Pyr and s-AlbCorrCa 2 + correlated positively with indices of disease activity. In the subgroups undergoing the Cica clamp technique, no difference in PTH responsiveness of B-Ca 2 + was unveiled. Conclusion : Neither active disease nor GC therapy appears to induce secondary hyperparathyroidism, nor is there an alteration in PTH responsiveness of B-Ca 2 + in patients with RA. The increased levels of markers of type I collagen metabolism (s-ICTP, Pyr) and s-AlbCorrCa 2 + in patients with active disease and patients treated with GC may be a result of increased degradation in synovium, cartilage and bone due to the inflammatory process.

Les anticorps monoclonaux anti-TNF-α dans le traitement de la polyarthrite rhumatoïde

Introduction. – Current slow-acting anti-rheumatic drugs available for rheumatoid arthritis can fail for certain severe cases; some are used empirically. Improvements in our knowledge of its pathogenesis and advances in molecular biology have made it possible to develop partially selective immunotherapy approaches. Current knowledge and key points. – Tumor necrosis factor- α (TNF-α) is a critical inflammatory mediator in rheumatoid arthritis and may therefore be a useful target for specific immunotherapy. This article summarizes clinical studies using anti-TNF-α antibodies. It appears that there is good evidence for both safety and beneficial effects of anti-TNF- α antibodies in short-term treatment of rheumatoid arthritis. Future prospects and projects. – It remains to be determined whether specific blockade of a single inflammatory mediator may be useful in long-term management. Therapeutic strategies aimed at concomitantly interfering with multiple pathogenic pathways are currently under investigation.

Rheumatoid Arthritis: Strategies for Pharmacotherapy

Historically, treatment of rheumatoid arthritis (RA) has been conservative and symptom or patient-complaint oriented. Newer approaches use disease-modifying antirheumatic drugs (DMARDs), sometimes known as slow-acting antirheumatic drugs (SAARDs), to slow the progression of the disease earlier in its course. Some of these drugs may be used as initial therapy and some may be used in combinations to reduce the side effects or adverse reactions.

A 15-year follow-up study on the outcome in patients with early rheumatoid arthritis

This study aimed to investigate the natural course of early rheumatoid arthritis (RA) after treatment for 15 years based on the present data of patients who had been enrolled in a 1 year study of early RA conducted by the Japan Rheumatism Foundation in 1981 and 1982. An examination form was mailed to each doctor who had participated in the previous study requesting them to record the present data of the patients. The patients were requested to fill out the AIMS2 questionnaire. Patients had been randomly assigned into three treatment groups: those treated with gold, with d-penicillamine and without slow acting antirheumatic drugs (SAARDs). Information was obtained concerning 74 of 161 patients who had completed the previous 1 year study. Clinical remission was observed in 20 of 74 patients. The current status of RA by physician’s assessment was reported to be well controlled in 32 of 48 cases (66.7%); however, no remarkable improvement was seen in erythrocyte sedimentation rate (ESR, and the number of painful joints compared with the values at entry 15 years previously. Radiographical stages showed progression and the average score of AIMS2 had deteriorated in most cases. High ESR, progression of joint damage and positive rheumatoid factors at the early stage of RA were suggested to be factors relating to QOL deterioration. These results suggest that it would be difficult to modify the natural course of RA by currently used treatment strategies with SAARDs.

A 15-year follow-up study on the outcome in patients with early rheumatoid arthritis

This study aimed to investigate the natural course of early rheumatoid arthritis (RA) after treatment for 15 years based on the present data of patients who had been enrolled in a 1 year study of early RA conducted by the Japan Rheumatism Foundation in 1981 and 1982. An examination form was mailed to each doctor who had participated in the previous study requesting them to record the present data of the patients. The patients were requested to fill out the AIMS2 questionnaire. Patients had been randomly assigned into three treatment groups: those treated with gold, with d-penicillamine and without slow acting antirheumatic drugs (SAARDs). Information was obtained concerning 74 of 161 patients who had completed the previous 1 year study. Clinical remission was observed in 20 of 74 patients. The current status of RA by physician’s assessment was reported to be well controlled in 32 of 48 cases (66.7%); however, no remarkable improvement was seen in erythrocyte sedimentation rate (ESR, and the number of painful joints compared with the values at entry 15 years previously. Radiographical stages showed progression and the average score of AIMS2 had deteriorated in most cases. High ESR, progression of joint damage and positive rheumatoid factors at the early stage of RA were suggested to be factors relating to QOL deterioration. These results suggest that it would be difficult to modify the natural course of RA by currently used treatment strategies with SAARDs.

7 Juvenile arthritis with oligoarticular onset

Patients with oligoarticular onset of juvenile arthritis form a large group that is heterogeneous with regard to clinical presentation, further evolution and outcome. The three established subgroups do not cover the whole patient population and are not always easily distinguishable at onset. Therefore, the outcome of children with oligoarticular onset is still, on the whole, unpredictable. Treatment has been very conservative, but, as part of it, the use of intra-articular corticosteroids is increasing and should be encouraged. The question of whether to give slow-acting anti-rheumatic drugs is a difficult one, as these have neither been studied nor recommended for use in persistently oligoarticular patients.

Twenty years of experience with intra-articular rifamycin for chronic arthritides.

Rheumatoid arthritis is a chronic progressive disease causing substantial morbidity and mortality for which current treatments are largely unsatisfactory. Over the past 20 years we have developed a novel therapeutic approach based on the intra-articular administration of rifamycin. The published studies on rifamycin therapy of rheumatoid arthritis and other chronic arthritic disorders, mainly from our group, are reviewed. Our results indicate that intra-articular rifamycin is effective against active synovitis and can profitably be combined with any basic therapy with slow-acting antirheumatic drugs. There is good evidence that the development of new erosions can be prevented or delayed by this treatment and that the balance between side-effects (mainly local pain) and antiarthritic activity is very favourable in the long term. Our observations have led us to hypothesize a possible systemic effect of rifamycin injected multilocally in peripheral joints; we believe that the available data deserve further investigation by independent researchers.

Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments.

There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis. The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis. Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.

4 Treatment of early rheumatoid arthritis patients with slow-acting anti-rheumatic drugs (SAARDs)

Treatment with slow-acting anti-rheumatic drugs (SAARDs) is nowadays initiated earlier in the disease course, preferably before any radiographic damage has occurred. SAARDs have the ability to decrease inflammatory synovitis as measured by clinical and laboratory variables, and there is some evidence that they improve physical function and decrease the progression rate of joint damage in patients with early rheumatoid arthritis. There is a clear difference in survival time between the various SAARDs. The efficacy/toxicity profiles of the SAARDs show equal variation. Rank order of prescription or disease duration may have an effect on drug survival, but different treatment strategies are also important sources of variation. Efficacy might be improved by combining different SAARDs (starting with a multiple drug regimen, or adding a drug to the first one), but further research is necessary to prove this hypothesis.