piperidines and Arthritis

Topics: Antirheumatic Agents; Arthritis; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome

Extraintestinal manifestations are common in patients with chronic inflammatory bowel disease (IBD). Peripheral arthritis occurs in ∼10% of patients with IBD. Treatment of both arthritis and the IBD disease is challenging, and involvement of both the rheumatologist and the gastroenterologist is essential. We present a case with concomitant polyarthritis and ulcerative colitis successfully treated with tofacitinib. A 32-year-old woman with ulcerative colitis currently treated with azathioprine and adalimumab was referred to our rheumatology clinic due to pain and swelling in her knees and finger joints. The patient was diagnosed with IBD-related arthritis. Intra-articular injection with steroid was initially effective, but the arthritis was persistent. Treatment attempts with salazopyrine and golimumab were discontinued due to drug-induced pancreatitis and urticaria, respectively. Subsequently treatment with tofacitinib 10 mg twice daily was effective within weeks, and apart from a mild folliculitis, there were no side effects. With this case report, we would like to draw attention to the fact that treatment with tofacitinib may constitute a good treatment option in refractory cases of IBD-related arthritis.

Topics: Adult; Arthritis; Colitis, Ulcerative; Female; Humans; Inflammatory Bowel Diseases; Piperidines; Pyrimidines

Blau syndrome (BS), a rare, autosomal-dominant autoinflammatory syndrome, is characterized by a clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis and associated with mutations of the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Aim of this study was to assess the efficacy of tofacitinib in Chinese paediatric patients with BS.. Tofacitinib was regularly administered to three BS patients (Patient 1, Patient 2, and Patient 3) at different dosages: 1.7 mg/day (0.11 mg/kg), 2.5 mg/day (0.12 mg/kg), and 2.5 mg/day (0.33 mg/kg). The clinical manifestations of the patients, magnetic resonance imaging results, serological diagnoses, therapeutic measures and outcomes of treatments are described in this report.. The clinical characteristics and serological diagnoses of all BS patients were greatly improved after the administration of tofacitinib treatment. All patients reached clinical remission of polyarthritis and improvements in the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and inflammatory cytokines.. Tofacitinib, a Janus kinase (JAK) inhibitor, is a promising agent for BS patients who have unsatisfactory responses to corticosteroids, traditional disease-modifying antirheumatic drugs, and biological agents.

Topics: Arthritis; Biomarkers; Blood Sedimentation; C-Reactive Protein; Child; Child, Preschool; Cytokines; Electrocardiography; Follow-Up Studies; Humans; Infant; Janus Kinase Inhibitors; Joints; Magnetic Resonance Imaging; Male; Piperidines; Pyrimidines; Sarcoidosis; Synovitis; Time Factors; Uveitis

Topics: Antirheumatic Agents; Arthritis; Humans; Piperidines; Pulmonary Arterial Hypertension; Pyrimidines; Pyrroles; Treatment Outcome

Although newer targeted agents improve survival in cancer patients, they have also been linked with unusual side effects. The most common side effects of Bruton tyrosine kinase inhibitors include fatigue, nausea, diarrhea, bruising, and cytopenias. We describe herein a case of an unusually severe articular syndrome with the use of ibrutinib in a patient with 17 p minus chronic lymphocytic leukemia. The severity of this side effect led to permanent discontinuation of this agent. As the causality ibrutinib-arthralgia seems legitimate, we expect further similar cases to surface in patients treated with Bruton tyrosine kinase inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Arthritis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adolescent; Adult; Arthritis; Exanthema; Female; Humans; Lupus Erythematosus, Systemic; Male; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

The main goal of this work was to analyse how treatment intervention with tofacitinib prevents the early disturbances of bone structure and mechanics in the rat model of adjuvant-induced arthritis. This is the first study to access the impact of tofacitinib on the skeletal bone effects of inflammation.. Fifty Wistar rats with adjuvant-induced arthritis were randomly housed in experimental groups, as follows: non-arthritic healthy group (n = 20); arthritic non-treated group (n = 20); and 10 animals undergoing tofacitinib treatment. Rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for comparison. After 22 days of disease progression, rats were killed and bone samples collected for histology, micro-CT, three-point bending and nanoindentation analysis. Blood samples were also collected for quantification of bone turnover markers and systemic cytokines.. At the tissue level, measured by nanoindentation, tofacitinib increased bone cortical and trabecular hardness. However, micro-CT and three-point bending tests revealed that tofacitinib did not reverse the effects of arthritis on the cortical and trabecular bone structure and on mechanical properties.. Possible reasons for these observations might be related to the mechanism of action of tofacitinib, which leads to direct interactions with bone metabolism, and/or to the kinetics of its bone effects, which might need longer exposure.

Topics: Adjuvants, Immunologic; Animals; Arthritis; Bone and Bones; Bone Remodeling; Bone Resorption; Disease Models, Animal; Female; Osteocalcin; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Treatment Outcome; X-Ray Microtomography

Topics: Arthritis; Female; Humans; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Scleroderma, Systemic

Topics: Arthritis; Arthritis, Psoriatic; Humans; Piperidines; Pyrimidines; Pyrroles

Neuroplastic changes in the amygdala account for emotional-affective aspects of pain and involve neuropeptides such as calcitonin gene-related peptide and corticotropin-releasing factor. Another neuropeptide system, central arginine vasopressin, has been implicated in neuropsychiatric disorders, but its role in pain-related emotional expression and neuroplasticity remains to be determined. Here, we tested the hypothesis that arginine vasopressin in the amygdala contributes to pain-related emotional-affective responses, using stereotaxic applications of arginine vasopressin and antagonists for G-protein coupled vasopressin V1A and oxytocin receptors in adult male Sprague-Dawley rats. In normal animals, arginine vasopressin increased audible and ultrasonic vocalizations and anxiety-like behavior (decreased open-arm preference in the elevated plus maze). The facilitatory effects were blocked by a selective V1A antagonist (SR 49059, Relcovaptan) but not by an oxytocin receptor antagonist (L-371,257). L-371,257 had some facilitatory effects on vocalizations. Arginine vasopressin had no effect in arthritic rats (kaolin/carrageenan knee joint pain model). SR 49059 inhibited vocalizations and anxiety-like behavior (elevated plus maze) in arthritic, but not normal, rats and conveyed anxiolytic properties to arginine vasopressin. Arginine vasopressin, SR 49059, and L-371,257 had no significant effects on spinal reflexes. We interpret the data to suggest that arginine vasopressin through V1A in the amygdala contributes to emotional-affective aspects of pain (arthritis model), whereas oxytocin receptors may mediate some inhibitory effects of the vasopressin system.

Topics: Amygdala; Animals; Arthritis; Benzoxazines; Carrageenan; Disease Models, Animal; Hormone Antagonists; Indoles; Kaolin; Male; Maze Learning; Microdialysis; Pain; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Oxytocin; Receptors, Vasopressin; Reflex; Vocalization, Animal

intra-articular co-injection of kaolin with carrageenan (CGN) in rodents is widely used as an experimental model of arthritis. However, the ability of kaolin to cause arthritis and related immune responses when administered alone is unclear. We evaluated the contribution of prostanoids and sensory C-fibres (and their neuropeptide substance P) to kaolin-induced inflammation in the rat knee.. Wistar rats, 8-10 weeks old, received an intra-articular injection of kaolin (1-10 μg/joint) or saline into the knee joint. Knee inflammation, proinflammatory cytokines, pain behaviour and secondary tactile allodynia were assessed over 5 h, when synovial leukocyte counts, histopathological changes and proinflammatory cytokine levels were evaluated.. The intra-articular injection of kaolin caused a dose- and time-dependent knee swelling and impairment of motion that were associated with secondary tactile allodynia, elevated concentrations of IL-1β, IL-6 and TNFα, leukocyte infiltration, and histopathological changes in the ipsilateral hindpaw. The neurokinin-1 (NK1) receptor antagonist SR140333 or neonatal treatment with capsaicin markedly reduced the inflammatory parameters, cytokines and allodynia but failed to significantly inhibit the impaired motion. The cyclo-oxygenase inhibitor indomethacin partially inhibited knee oedema and allodynia but did not affect the leukocyte influx, myeloperoxidase activity or impaired motion in the kaolin-injected rat.. We show the first evidence that intra-articular injection of kaolin without CGN produced severe acute monoarthritis. This was highly dependent on substance P (released from C-fibres) and NK1 receptor activation, which stimulated local production of proinflammatory cytokines. This model may be of critical importance for mechanistic studies and screening new anti-inflammatory/analgesic drugs.

Topics: Animals; Animals, Newborn; Antidiarrheals; Arthritis; Capsaicin; Cytokines; Disease Models, Animal; Edema; Enzyme Inhibitors; Hyperalgesia; Indomethacin; Kaolin; Knee Joint; Male; Pain Measurement; Peroxidase; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Synovial Fluid

The small molecule halofuginone has been shown to inhibit fibrosis, angiogenesis, and tumor progression. This study was undertaken to evaluate the effects of halofuginone in preventing autoimmune arthritis in mice.. The effects of halofuginone on joint diseases were assessed by clinical scoring and histologic analysis. Protein expression levels were confirmed by immunohistochemistry, enzyme-linked immunosorbent assay, flow cytometry, and/or Western blotting. The expression levels of messenger RNA (mRNA) for various molecules were determined by real-time polymerase chain reaction (PCR). Proliferation of osteoclast precursors was assessed by bromodeoxyuridine uptake. Osteoclast differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and area of resorbed bone.. Treatment with halofuginone suppressed the development of autoimmune arthritis and reciprocally regulated Th17 cells and FoxP3+ Treg cells. These effects of halofuginone on Th17 differentiation involved increased signaling of ERK and reduction of STAT-3 and NF-ATc1 expression. Furthermore, halofuginone induced the expression of indoleamine 2,3-dioxygenase (IDO) in dendritic cells, leading to reduced production of Th17 cells. In addition, halofuginone prevented the formation and activity of osteoclasts through suppression of transcription factors, such as activator protein 1 and NF-ATc1, and inhibited cell cycle arrest by the committed osteoclast precursors via expression of Ccnd1 encoding cyclin D1.. Taken together, our results suggest that halofuginone is a promising therapeutic agent for the treatment of Th17 cell-mediated inflammatory diseases and bone diseases.

Topics: Animals; Arthritis; Autoimmune Diseases; Cell Differentiation; Disease Models, Animal; Disease Progression; Forkhead Transcription Factors; Male; Mice; Mice, Inbred DBA; Mice, Knockout; NFATC Transcription Factors; Osteoclasts; Osteoprotegerin; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Signal Transduction; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells

Reactive oxygen species (ROS) scavengers have not been widely used for treatment of local inflammatory reactions such as arthritis and periodontal disease because they are rapidly eliminated from the inflamed site, which results in a low therapeutic effect. Therefore, to enhance the local retention time of ROS scavengers, we developed a redox-active injectable gel (RIG) system by using poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene]-b-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PMNT-PEG-PMNT) triblock copolymer, which possesses ROS scavenging nitroxide radicals as side chains of the PMNT segment. Cationic PMNT segment in PMNT-PEG-PMNT forms polyion complexes with anionic poly(acrylic acid) (PAAc) to form a flower-like micelle (ca. 79 nm), which exhibits in situ thermo-irreversible gelation under physiological conditions. We confirmed the prolonged site-specific retention time of RIG by performing in vivo noninvasive electron spin resonance imaging and quantitative evaluation. In contrast to low-molecular-weight nitroxide radical compounds that disappeared from injection sites in less than 1h after subcutaneous injection, 40% of the RIG remained even at 3 days. We also found that RIG inhibits neutrophil infiltration and cytokine production, which leads to suppression of hyperalgesia. These findings indicate the potential of RIG as an innovative approach for treatment of local inflammation.

Topics: Acrylic Resins; Animals; Antioxidants; Arthritis; Delayed-Action Preparations; Gels; Inflammation; Injections; Ions; Male; Mice; Micelles; Nitrogen Oxides; Oxidation-Reduction; Phase Transition; Piperidines; Polyethylene Glycols; Styrene; Temperature

The proteinase-activated receptor 2 (PAR(2)) is a putative therapeutic target for arthritis. We hypothesized that the early pro-inflammatory effects secondary to its activation in the temporomandibular joint (TMJ) are mediated by neurogenic mechanisms. Immunofluorescence analysis revealed a high degree of neurons expressing PAR(2) in retrogradely labeled trigeminal ganglion neurons. Furthermore, PAR(2) immunoreactivity was observed in the lining layer of the TMJ, co-localizing with the neuronal marker PGP9.5 and substance-P-containing peripheral sensory nerve fibers. The intra-articular injection of PAR(2) agonists into the TMJ triggered a dose-dependent increase in plasma extravasation, neutrophil influx, and induction of mechanical allodynia. The pharmacological blockade of natural killer 1 (NK(1)) receptors abolished PAR(2)-induced plasma extravasation and inhibited neutrophil influx and mechanical allodynia. We conclude that PAR(2) activation is pro-inflammatory in the TMJ, through a neurogenic mechanism involving NK(1) receptors. This suggests that PAR(2) is an important component of innate neuro-immune response in the rat TMJ.

Topics: Animals; Arthritis; Arthropathy, Neurogenic; Immunity, Innate; Injections, Intra-Articular; Male; Nerve Fibers; Neuroimmunomodulation; Neurokinin-1 Receptor Antagonists; Neurons; Neutrophil Infiltration; Neutrophils; Oligopeptides; Pain Measurement; Piperidines; Plasma; Quinuclidines; Rats; Rats, Wistar; Receptor, PAR-2; Sensory Receptor Cells; Substance P; Temporomandibular Joint; Temporomandibular Joint Disorders; Trigeminal Ganglion; Trypsin; Ubiquitin Thiolesterase

Endothelins (ETs) are involved in inflammatory events, including pain, fever, edema, and cell migration. ET-1 levels are increased in plasma and synovial membrane of rheumatoid arthritis (RA) patients, but the evidence that ETs participate in RA physiopathology is limited. The present study investigated the involvement of ETs in neutrophil accumulation and edema formation in the murine model of zymosan-induced arthritis. Intra-articular (i.a.) administration of selective ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 15 pmol/cavity) prior to i.a. zymosan injection (500 microg/cavity) markedly reduced knee-joint edema formation and neutrophil influx to the synovial cavity 6 h and 24 h after stimulation. Histological analysis showed that ET(A) or ET(B) receptor blockade suppressed zymosan-induced neutrophil accumulation in articular tissue at 6 h. Likewise, dual blockade of ET(A)/ET(B) with bosentan (10 mg/kg, i.v.) also reduced edema formation and neutrophil counts 6 h after zymosan stimulation. Pretreatment with BQ-123 or BQ-788 (i.a.; 15 pmol/cavity) also decreased zymosan-induced TNF-alpha production within 6 h, keratinocyte-derived chemokine/CXCL1 production within 24 h, and leukotriene B(4) at both time-points. Consistent with the demonstration that ET receptor antagonists inhibit zymosan-induced inflammation, i.a. injection of ET-1 (1-30 pmol/cavity) or sarafotoxin S6c (0.1-30 pmol/cavity) also triggered edema formation and neutrophil accumulation within 6 h. Moreover, knee-joint synovial tissue expressed ET(A) and ET(B) receptors. These findings suggest that endogenous ETs contribute to knee-joint inflammation, acting through ET(A) and ET(B) receptors and modulating edema formation, neutrophil recruitment, and production of inflammatory mediators.

Topics: Animals; Antihypertensive Agents; Arthritis; Bosentan; Cell Movement; Chemokine CXCL1; Chemokines; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Immunoblotting; Immunologic Factors; Inflammation Mediators; Knee Joint; Leukocytes; Leukotriene B4; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides; Synovial Fluid; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents; Viper Venoms; Zymosan

The endocannabinoid system modulates many pathophysiological functions, including the brain pathways involved in the regulation of body weight and adipose tissue function. The selective cannabinoid CB(1) receptor antagonist, rimonabant, has undergone phase III clinical testing as anti-obesity drug. Obesity is considered a mild inflammatory condition and predisposes individuals to an increased risk of developing many diseases. It has been recently suggested that a successful intervention to treat obesity is a therapy combining weight-reducing drugs with anti-inflammatory ones. In this scenario, rimonabant's anti-obesity action is accompanied by favorable changes in markers for insulin resistance, C-reactive protein, adiponectin, tumor necrosis factor alpha (TNFalpha). The results reported by Croci and Zarini in this issue highlight the anti-inflammatory and anti-hyperalgesic effect of rimonabant in obese animals, so suggesting that it could provide a more general and aggressive strategy to protect obese patients from many pathological risks.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Arthritis; Humans; Hyperalgesia; Inflammation; Obesity; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

Topics: Animals; Arthritis; Chronic Disease; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Freund's Adjuvant; Lactones; Male; Nitric Oxide Synthase Type II; Pain; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Stifle; Sulfides; Sulfones; Time Factors; Weight-Bearing

In spinal cord neurons in anesthetized rats, the role on neurokinin A and neurokinin-2 receptors in the processing of nociceptive information from the knee joint was studied. The specific non-peptide antagonist at the neurokinin-2 receptor, SR48968, its inactive R-enantiomer, SR48965, neurokinin A, substance P and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), were administered ionophoretically close to neurons with input from the knee joint. SR48968 reduced the effects of exogenous neurokinin A, but not those of exogenous substance P and AMPA, indicating selective blockade of neurokinin-2 receptors. In most neurons with input from the normal knee joint, SR48968 reduced dose-dependently the responses to noxious pressure with applied to the knee, and in approximately 50% of the neurons the responses to innocuous pressure. The administration of SR48968 during the induction of an experimental joint inflammation markedly attenuated the development of inflammation-evoked hyperexcitability. In hyperexcitable neurons with input from the inflamed joint, SR48968 reduced the responses to noxious and innocuous pressure. The relative reduction of the responses was more pronounced than in neurons with input from the normal joint. None of the effects of SR48968 was mimicked by SR48965. These data show that neurokinin-2 receptors are involved in the spinal processing of nociceptive information from the normal joint. Furthermore, neurokinin-2 receptors must be coactivated at an early stage of inflammation, to allow the generation of hyperexcitability. Finally, neurokinin-2 receptors are involved in maintenance of hyperexcitability during inflammation. In summary, spinal neurokinin-2 receptors are important in the generation of pain in the normal and inflamed joint.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Arthritis; Benzamides; Carrageenan; Hyperalgesia; Iontophoresis; Kaolin; Knee Joint; Male; Neurokinin A; Nociceptors; Pain; Piperidines; Pressure; Rats; Rats, Wistar; Receptors, Neurokinin-2; Spinal Cord; Substance P

Topics: Administration, Oral; Analgesics; Anaphylaxis; Animals; Anti-Inflammatory Agents; Arthritis; Edema; Fever; Fluorine; Graft Rejection; Humans; Ketones; Mice; Piperidines; Rabbits; Rats

Topics: Analgesics; Arthritis; Aspirin; Codeine; Dioxoles; Drug Synergism; Humans; Neoplasms; Pain; Palliative Care; Piperidines

Topics: Analgesics; Animals; Arthritis; Chemical Phenomena; Chemistry; Electric Stimulation; Injections, Intraperitoneal; Male; Methods; Mice; Piperidines; Rats; Silver Nitrate; Tail

Topics: Adolescent; Adrenal Cortex Hormones; Arthritis; Child; Chlordiazepoxide; Colitis, Ulcerative; Female; Humans; Infant; Male; Methylprednisolone; Parent-Child Relations; Piperidines; Purpura; Pyoderma; Sulfasalazine; Vitamins