kaolinite and Inflammation

Various reports have demonstrated the importance of small airway inflammation in the development of airflow limitation and progression of COPD. This hypothesis proposes that the pathogenesis of COPD mirrors a chronic inhalational dust-induced disease. The putative inorganic dust in cigarette smoke is aluminum silicate or kaolinite, a common component of clay soils. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. The origin of kaolinite in tobacco products remains unknown, and possible potential sources are proposed. On inhalation, kaolinite deposition in the distal lung may promote macrophage accumulation within the terminal airways leading to a respiratory bronchiolitis. In the susceptible smoker, important genetic, environmental, immunologic, and mechanical factors interact and modulate this small airway inflammation, ultimately leading to the pathologic lesion of emphysema. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.

Topics: Bronchiolitis; Dust; Humans; Inflammation; Kaolin; Macrophages, Alveolar; Nicotiana; Pulmonary Disease, Chronic Obstructive; Smoking

Topics: Animals; Anti-Inflammatory Agents; Bradykinin; Carrageenan; Cell Migration Inhibition; Dextrans; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Foot; Formaldehyde; Guinea Pigs; Histamine; Inflammation; Kaolin; Ovalbumin; p-Methoxy-N-methylphenethylamine; Povidone; Rabbits; Rats; Saccharomyces cerevisiae; Serotonin; Species Specificity

Flunixin is marketed in several countries for analgesia in adult swine but little is known about its efficacy in piglets. Thirty-two piglets (6-8 days old) were randomized to receive placebo saline (n = 11, group CONTROL) or flunixin meglumine intravenously at 2.2 (n = 11, group MEDIUM) or 4.4 (n = 10, group HIGH) mg/kg, 10 hr after subcutaneous injection of kaolin in the left metacarpal area. A hand-held algometer was used to determine each piglet's mechanical nociceptive threshold (MNT) from both front feet up to 50 hr after treatment (cut-off value of 24.5 newton). Serial venous blood samples were obtained to quantify flunixin in plasma using LC-MS/MS. A PKPD model describing the effect of flunixin on the mechanical nociceptive threshold was obtained based on an inhibitory indirect response model. A two-compartmental PK model was used. A significant effect of flunixin was observed for both doses compared to control group, with 4.4 mg/kg showing the most relevant (6-10 newton) and long-lasting effect (34 hr). The median IC50 was 6.78 and 2.63 mg/ml in groups MEDIUM and HIGH, respectively. The ED50 in this model was 6.6 mg/kg. Flunixin exhibited marked antinociceptive effect on kaolin-induced inflammatory hyperalgesia in piglets.

Topics: Analgesics; Animals; Animals, Newborn; Anti-Inflammatory Agents; Clonixin; Disease Models, Animal; Dose-Response Relationship, Drug; Inflammation; Injections, Intravenous; Kaolin; Pain Measurement; Swine

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the anti-inflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to be lower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofen-treated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic/pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC(50) for S-ketoprofen of 26.7 μg/mL and an IC(50) for R-ketoprofen of 1.6 μg/mL. This indicates that R-ketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED(50) for racemic ketoprofen was 2.5 mg/kg.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Female; Fever; Inflammation; Kaolin; Ketoprofen; Male; Models, Biological; Pain; Pain Measurement; Swine; Swine Diseases

The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Chromatography, Liquid; Drug Administration Schedule; Female; Fever; Inflammation; Injections, Intramuscular; Kaolin; Male; Meloxicam; Pain Measurement; Swine; Swine Diseases; Tandem Mass Spectrometry; Thiazines; Thiazoles

A pressure analgesiometric device was developed for unrestrained cats. Eleven cats were studied. Stimulation was via three rounded pins within a bracelet on the forearm. The pins were advanced by manual bladder inflation. Bladder pressure was measured using a strain gauge pressure transducer. The threshold was recorded at the behavioural end point. Thresholds were measured at 5 and 15min intervals for 2-4h, after removal/replacement of the cuff, for 120min after SC butorphanol (0.4mg/kg), and with mild skin inflammation at the testing site. Data were analysed using ANOVA. Pressure thresholds in untreated cats were around 150mmHg. The minimum interval for testing was established as 15min. Data were reproducible over 4h and beyond 24h. Thresholds in 5 cats increased (P<0.05) above baseline for 45min after butorphanol with a maximum increase of 270+/-182mmHg at 10min. Thresholds decreased with inflammation. The method appears suitable for feline analgesia investigations.

Topics: Analgesics; Animals; Butorphanol; Cat Diseases; Cats; Female; Inflammation; Kaolin; Male; Pain; Pain Measurement

Xiaobanxia Decoction (XBXD), a traditional antiemetic formula, is effective in preventing chemotherapy-induced nausea and vomiting (CINV), but its underlying mechanism has not been fully clarified.. To investigate whether the antiemetic mechanisms of XBXD against CINV is associated with the reduction of GSDME-mediated pyroptosis and the alleviation of gastrointestinal inflammation induced by cisplatin.. We established the in vivo pica rat model and the in vitro small intestinal epithelial cell (IEC-6 cell) injury model by cisplatin challenge. The levels of ROS, IL-1β, IL-18, HMGB1 were measured by ELISA. The histopathological changes of gastrointestinal (GI) tissues were examined by HE staining. The expression and localization of GSDME in GI tissues were determined by IHC. The GSDME mRNA expression in GI tissues was determined by RT-PCR. The IEC-6 cell viability was detected by CCK-8. The morphology of IEC-6 cells was observed by optical microscope and scanning electron microscopy. Pyroptosis was examined using Hoechst33342/PI staining. The intracellular ROS levels were measured with the fluorescent probe DCFH-DA. The expression levels of JNK, p-JNK, Bax, Bcl-2, caspase-9, caspase-3 and GSDME in GI tissues and IEC-6 cells were determined by WB.. We found that the cumulative kaolin intake (pica behavior, analogous to emesis) significantly increased in cisplatin-treated rats, accompanied by significant inflammatory pathological changes of GI tissues. XBXD decreased the cumulative kaolin intake and alleviated GI inflammation in cisplatin-treated rats by inhibiting the activation of the ROS/JNK/Bax signaling pathway and by reducing GSDME-mediated pyroptosis. Additionally, cisplatin damaged IEC-6 cells by activating GSDME-dependent pyroptosis. XBXD reduced GSDME-mediated IEC-6 cell pyroptotic death by regulating the ROS/JNK/Bax signaling pathway.. This study suggested that GSDME-mediated pyroptosis greatly contributes to the occurrence of CINV, and suppressing GSDME-mediated pyroptosis is the important antiemetic mechanism of XBXD.

Topics: Animals; Antiemetics; Antineoplastic Agents; bcl-2-Associated X Protein; Caspase 3; Cisplatin; Inflammation; Kaolin; Nausea; Pica; Pyroptosis; Rats; Reactive Oxygen Species; Vomiting

Hydrocephalus is a neurological disease with an incidence of 0.3-0.7 per 1000 live births in the United States. Ventriculomegaly, periventricular white matter alterations, inflammation, and gliosis are among the neuropathologies associated with this disease. We hypothesized that hippocampus structure and subgranular zone neurogenesis are altered in untreated hydrocephalus and correlate with recognition memory deficits.. Hydrocephalus was induced by intracisternal kaolin injections in domestic juvenile pigs (43.6 ± 9.8 days). Age-matched sham controls received similar saline injections. MRI was performed to measure ventricular volume, and/or hippocampal and perirhinal sizes at 14 ± 4 days and 36 ± 8 days post-induction. Recognition memory was assessed one week before and after kaolin induction. Histology and immunohistochemistry in the hippocampus were performed at sacrifice.. The hippocampal width and the perirhinal cortex thickness were decreased (p < 0.05) in hydrocephalic pigs 14 ± 4 days post-induction. At sacrifice (36 ± 8 days post-induction), significant expansion of the cerebral ventricles was detected (p = 0.005) in hydrocephalic pigs compared with sham controls. The area of the dorsal hippocampus exhibited a reduction (p = 0.035) of 23.4% in the hydrocephalic pigs at sacrifice. Likewise, in hydrocephalic pigs, the percentages of neuronal precursor cells (doublecortin+ cells) and neurons decreased (p < 0.01) by 32.35%, and 19.74%, respectively, in the subgranular zone of the dorsal hippocampus. The percentage of reactive astrocytes (vimentin+) was increased (p = 0.041) by 48.7%. In contrast, microglial cells were found to decrease (p = 0.014) by 55.74% in the dorsal hippocampus in hydrocephalic pigs. There was no difference in the recognition index, a summative measure of learning and memory, one week before and after the induction of hydrocephalus.. In untreated juvenile pigs, acquired hydrocephalus caused morphological alterations, reduced neurogenesis, and increased reactive astrocytosis in the hippocampus and perirhinal cortex.

Topics: Animals; Gliosis; Hippocampus; Hydrocephalus; Inflammation; Kaolin; Neurogenesis; Swine

Popularly known as "escoba" (broom) or "escobilla china" (Chinese brush), Baccharis conferta Kunth (Asteraceae), is a plant widely used in Mexican folk medicine for alleviating muscular and rheumatic pain. A recent study described that dichloromethane extract as well as fractions and isolated compounds, possess anti-inflammatory activity in TPA-induced acute edema.. Based on the popular medicinal uses of B. conferta as well as previous studies on its anti-inflammatory activity, the aim of this research was to evaluate the anti-arthritic and anti-inflammatory effects of dichloromethane extract, fractions, and compounds from B. conferta in a monoarthritis model induced with kaolin/carrageenan (K/C).. Aerial parts of B. conferta were collected, dried, and macerated with dichloromethane. The dichloromethane extract (BcD) was separated by open column chromatography to obtain the BcD2 fraction where the diterpene kingidiol (KIN) was isolated and from the BcD3 fraction the flavonoid cirsimaritin (CIR), which are the most active compounds in the TPA model. In addition, the flavonoids acacetin, pectolinaringenin and 6-methoxykaempferide were identified and isolated from the BcD2 fraction. The content of the main compounds was estimated in BcD, BcD2 and BcD3. The anti-arthritic and anti-inflammatory effects of B. conferta were investigated by evaluating ankle joint inflammation, hyperalgesia using the hot plate test, and pro- and anti-inflammatory cytokine levels in the synovial capsule as well as histological changes in ankle joint tissue in a monoarthritis model induced with K/C in Balb/c mice.. Oral administration of BcD2 fraction (25 mg/kg) and KIN (10 mg/kg) reduced the ankle thickness induced by K/C and decreased the levels of TNF-α, IL-1β, IL-6 and IL-17, while BcD2 increased IL-10. In addition, BcD2 and KIN showed significant edema attenuation of the synovial membrane and decreased inflammatory infiltration and cartilage erosion compared to the VEH group. Finally, BcD (50 mg/kg), KIN (10 mg/kg) and CIR (5 mg/kg) decreased hyperalgesia.. B. conferta constitutes a therapeutic or preventive candidate for osteoarthritis, because of decreased articular inflammation and pain accompanied with the modulation of cytokine concentrations, which confirms the anti-arthritic and anti-inflammatory activities of B. conferta and support its popular use.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Baccharis; Carrageenan; Disease Models, Animal; Hyperalgesia; Inflammation; Kaolin; Male; Medicine, Traditional; Mice; Mice, Inbred BALB C; Plant Extracts

Necroptosis is widespread in neurodegenerative diseases. Here, we examined necroptosis in the hippocampus and cortex after hydrocephalus and found that a necroptosis pathway inhibitor alleviates necroptosis and provides neuroprotective effects.. Hydrocephalus was induced in C57BL/6 mice by kaolin. Haematoxylin and eosin (HE), Nissl, PI and Fluoro-Jade B (FJB) staining were used for general observations. Phosphorylated receptor-interacting protein kinase 3 (p-RIP3) and phosphorylated mixed lineage kinase domain-like (p-MLKL) were measured by Western blotting and immunohistochemistry. Scanning electron microscopy (SEM) was used to observe ependymal cilia. Magnetic resonance imaging (MRI) and the Morris water maze (MWM) test were used to assess neurobehavioral changes. Immunofluorescence was used to detect microglial and astrocyte activation. Inflammatory cytokines were measured by Western blotting and RT-PCR.. Obvious pathological changes appeared in the hippocampus and cortex after hydrocephalus, and expression of the necroptosis markers p-RIP3, p-MLKL and inflammatory cytokines increased. Necrostatin-1 (Nec-1) and GSK872 reduced necrotic cell death, attenuated p-RIP3 and p-MLKL levels, slightly improved neurobehaviours and inhibited microglial and astrocyte activation and inflammation.. RIP1/RIP3/MLKL mediates necroptosis in the cortex and hippocampus in a hydrocephalus mouse model, and Nec-1 and GSK872 have some neuroprotective effects.

Topics: Animals; Cytokines; Disease Models, Animal; GTPase-Activating Proteins; Hydrocephalus; Imidazoles; Indoles; Inflammation; Kaolin; Mice; Mice, Inbred C57BL; Necroptosis; Neuroprotective Agents; Phosphorylation; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction

Malva parviflora is used as food in the gastronomy of some regions of Mexico and, also, in Mexican traditional medicine for inflammation-related conditions like rheumatoid arthritis. The objective of this work was to evaluate its antiarthritic activity in a mice model. In ICR, female mice were tested the dichloromethane extract (MpD) and fractions MpF4 (extracted with a dichoromethane:methanol system) and MpFphy (a precipitate by acetone:methanol) by using the mono-arthritis with kaolin/carrageenan model. During the treatment, joint inflammation was measured daily, and hyperalgesia was measured using the hot plate test. The treatments diminished both joint inflammation and pain. At the end of the evaluation, the left joint and spleen were extracted for determination of pro- and anti-inflammatory cytokines. The results showed that the MpD, MpF4, and MpFphy treatments modulated the concentration of these proteins. Specifically, MpFphy at 1.0 mg/kg increased IL-4 and IL-10 and decreased IL-17, IL-1β, and TNF-α. GC-MS analysis showed that MpF4 contained a mixture of a total of nine compounds, three of them newly reported for the species. The studies confirmed the presence of five sterols in the MpFphy fraction, including stigmasterol and β-sitosterol. These results confirm the anti-rheumatoid and anti-inflammatory activities of a fraction rich in sterols from Malva parviflora. Graphical abstract.

Topics: Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Carrageenan; Cytokines; Female; Inflammation; Kaolin; Malva; Mice; Mice, Inbred ICR; Plant Extracts; Sterols

The benzylideneacetophenone derivative JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] (JC3) was synthesized by modifying yakuchinone B obtained from the seeds of Alpinia oxyphylla, a member of the ginger family (Zingiberaceae), which are widely used as a folk remedy and as an anti-inflammatory. The aim of this study was to investigate the anti-arthritic effects of JC3 in rat models of carrageenan-induced paw pain and carrageenan/kaolin-induced knee arthritis. The anti-nociceptive effect of JC3 was assessed by measuring paw withdrawal pressure thresholds using an analgesy-meter. Arthritic symptoms in our monoarthritic rat model were evaluated using weight distribution ratios (WDR), paw thicknesses, and serum prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and vascular endothelial growth factor (VEGF) levels (determined by ELISA). Histological analyses of knee joints were performed after injecting JC3 intraperitoneally into rats before carrageenan treatment at 5 or 10 mg/kg/day for 6 days. The anti-inflammatory effects of JC3 were investigated in vitro using interleukin-1beta (IL-1β)-stimulated fibroblast-like synoviocytes (FLS) derived from arthritis patients. PGE2, IL-6, and IL-8 levels were measured after treating FLS with JC3. In arthritis-induced rats, JC3 treatment significantly decreased nociceptive and arthritic symptoms at days 5 to 6 after carrageenan/kaolin injection. Histological staining of knee tissue showed that JC3 significantly reduced inflammatory areas in the knee joints. Furthermore, JC3 inhibited the expressions of IL-6 and IL-8 in FLS cells at concentrations of 5-10 μg/ml and decreased PGE

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Benzylidene Compounds; Carrageenan; Cytokines; Humans; Inflammation; Interleukin-1beta; Kaolin; Propiophenones; Rats; Synoviocytes

The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown.. To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus.. Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed.. Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement.. Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus.. NPH, normal pressure hydrocephalus.

Topics: Animals; Cognition; Disease Models, Animal; Female; Fibrosis; Gait; Hydrocephalus; Hydrocephalus, Normal Pressure; Inflammation; Kaolin; Locomotion; Magnetic Resonance Imaging; Radiography; Rats; Rats, Sprague-Dawley; Subarachnoid Space

The objective of the present study was to investigate the effect of the fucoxanthin (FUCO) alone and in combination with glucosamine hydrochloride (GAH) on carrageenan/kaolin-induced inflammatory arthritis model in rats and to explore its underlying mechanisms. Joint swelling, muscle weight ratio (%), histopathological examination and scoring, and proteoglycan degradation were examined. Pro-inflammatory interleukin (IL-1β) and tumor necrosis (TNF-α) levels, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase(iNOS) protein expression and nitric oxide (NO) level in knee synovial tissue extract were analyzed using enzyme-linked immunosorbent assay, western blotting analysis, and Griess reagent assay, respectively. FUCO and FUCO + GAH not only may significantly reduce degrees of knee joint swelling and prevent against muscle atrophy, but also may significantly attenuate inflammation in synovial tissue, cartilage erosion, and proteoglycan loss. The efficacies of FUCO + GAH were stronger than that of GAH or FUCO. FUCO alone and FUCO + GAH can significantly inhibit upregulation of COX-2 and iNOS protein expressions, decrease of IL-1β and TNF-α levels, and reduce NO production in knee synovial tissue extract. These results indicated that FUCO is an effective anti-arthritis agent through an antiinflammation mechanism. FUCO may enhance therapeutic effect of GAH on rat arthritis through mechanism of antiinflammation.

Topics: Animals; Arthritis, Experimental; Carrageenan; Cyclooxygenase 2; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Glucosamine; Inflammation; Inflammation Mediators; Interleukin-1beta; Kaolin; Knee Joint; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Proteoglycans; Rats; Rats, Sprague-Dawley; Synovial Membrane; Tumor Necrosis Factor-alpha; Xanthophylls

During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.. Acute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630.. URB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated.. These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.

Topics: Acute Disease; Amidohydrolases; Animals; Arthralgia; Benzamides; Carbamates; Carrageenan; Endocannabinoids; Hindlimb; Hyperalgesia; Indoles; Inflammation; Kaolin; Knee Joint; Male; Mice, Inbred C57BL; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Synovitis; Weight-Bearing

Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16-24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P < 0.001) and increasing BMI (P = 0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 ± 623 vs. 2184 ± 576 dyn/cm, P < 0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P = 0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Coagulation; C-Reactive Protein; Calcium Chloride; Coronary Artery Disease; Female; Fibrin; Fibrinogen; Humans; Inflammation; Kaolin; Male; Middle Aged; Risk Factors; Stents; Thrombelastography; Thrombophilia; Thrombosis

Severe hepatic injuries may be highly lethal, and perihepatic packing remains the mainstay of treatment. This is not always successful, particularly in the setting of hypothermia and coagulopathy. Kaolin-impregnated Combat Gauze (CG) is an effective hemostatic dressing used primarily to treat external wounds. The objective of this study was to determine the ability of CG to control severe hemorrhage in hypothermic, coagulopathic swine with a high-grade hepatic injury.. Anesthetized animals underwent splenectomy and were cooled to 32°C while undergoing a 60% exchange transfusion with Hextend. A grade V liver injury was created in the left middle hepatic lobe. Animals were allowed to freely bleed for 30 s and then randomized to treatment with CG or plain gauze laparotomy pads (PG) applied to the injury site. Animals were then resuscitated with warmed Hextend.. There was no difference between groups in preinjury hemodynamic or laboratory values. Animals packed with CG had less blood loss when compared with standard packing (CG = 25 mL/kg versus PG = 58 mL/kg, P = 0.05). There was a trend towards lower hetastarch resuscitation requirements in the CG group (CG = 7 mL/kg versus PG = 44 mL/kg, P = 0.06) but no statistically significant difference in mortality (CG = 13% versus PG = 50%, P = 0.11). Histology of the injury sites revealed more adherent clot in the CG group, but no inflammation, tissue necrosis, or residual material.. In pigs with severe hepatic injury, Combat Gauze reduced blood loss and resuscitation requirements when compared with plain laparotomy pads. Combat Gauze may be safe and effective for use on severe liver injuries.

Topics: Animals; Bandages; Blood Coagulation Disorders; Disease Models, Animal; Female; Hemorrhage; Hemostatic Techniques; Hemostatics; Hypothermia, Induced; Incidence; Inflammation; Kaolin; Liver; Male; Necrosis; Pilot Projects; Swine; Treatment Outcome

Olive leaf extract (OLE) has antioxidant and antiinflammatory actions. However, the role of OLE in mechanical inflammatory arthritis (osteoarthritis, OA) is unclear. This study investigated the effect of OLE on the development of kaolin and carrageenan-induced arthritis, a murine model of OA. Administration of OLE significantly ameliorated paw swelling, the paw Evans blue content and the histopathological scores. In the human monocyte cell line, THP-1, the OLE reduced the LPS-induced TNF-α production and was dose dependent. Croton oil-induced ear edema in mice also revealed that treatment with OLE suppressed ear edema, myeloperoxidase (MPO) production and was dose dependent. These results indicated that OLE is an effective antiarthritis agent through an antiinflammation mechanism. Also OLE may be beneficial for the treatment of OA in humans.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Carrageenan; Cell Line, Tumor; Croton Oil; Dose-Response Relationship, Drug; Edema; Evans Blue; Humans; Inflammation; Kaolin; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Olea; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

This study examined in an arthritis animal model whether elderly onset rheumatoid arthritis (EORA) is a more severe disease than younger onset rheumatoid arthritis. Arthritis was induced by injecting 5% kaolin/carrageenan into the left tibiotarsal ankles of 18-month-old and 4-week-old rats. Various parameters were measured to evaluate the arthritic progression of kaolin/carrageenan-induced arthritis in the rats. Immunohistochemical staining of arthritic joints was performed to determine the degree of inflammation in old and young rats. Measurements of ankle volume and thickness, arthritic index, number of squeaks, and the paw pressure test showed the 18-month-old rats had more severe disease than the young rats in a kaolin/carrageenan-induced arthritis model. The degree of inflammation and MMP-1 expression of arthritic joints in old rats was significantly higher than that of young rats based on histological evaluation with hematoxylin and eosin (H&E) staining and immunochemistry. More severe disease symptoms were found in old rats with EORA, but the molecular mechanisms still remain to be elucidated. Understanding the molecular mechanisms will be helpful to develop clinical protocols to efficiently treat patients with EORA, which is difficult to control with current protocols.

Topics: Acrylates; Age Factors; Animals; Arthritis, Experimental; Carrageenan; Inflammation; Joints; Kaolin; Matrix Metalloproteinase 1; Phenyl Ethers; Rats; Rats, Sprague-Dawley; Severity of Illness Index

When blood is exposed to negatively charged surface materials such as glass, an enzymatic cascade known as the contact system becomes activated. This cascade is initiated by autoactivation of Factor XII and leads to both coagulation (via Factor XI) and an inflammatory response (via the kallikrein-kinin system). However, while Factor XII is important for coagulation in vitro, it is not important for physiological hemostasis, so the physiological role of the contact system remains elusive. Using patient blood samples and isolated proteins, we identified a novel class of Factor XII activators. Factor XII was activated by misfolded protein aggregates that formed by denaturation or by surface adsorption, which specifically led to the activation of the kallikrein-kinin system without inducing coagulation. Consistent with this, we found that Factor XII, but not Factor XI, was activated and kallikrein was formed in blood from patients with systemic amyloidosis, a disease marked by the accumulation and deposition of misfolded plasma proteins. These results show that the kallikrein-kinin system can be activated by Factor XII, in a process separate from the coagulation cascade, and point to a protective role for Factor XII following activation by misfolded protein aggregates.

Topics: Adsorption; Blood Coagulation; Circular Dichroism; Factor XI; Factor XII; Humans; Inflammation; Kallikreins; Kaolin; Microscopy, Electron, Transmission; Models, Biological; Protein Denaturation; Protein Folding; Protein Structure, Secondary; Time Factors

The majority of rodent models used to evaluate analgesic drug effects rely on evoked measures of nociceptive thresholds as primary outcomes. These approaches are often time-consuming, requiring extensive habituation sessions and repeated presentations of eliciting stimuli, and are prone to false-positive outcomes due to sedation or tester subjectivity. Here, we describe the reduction of spontaneous activity by adjuvant (RSAA) model as an objective and quantifiable behavioral model of inflammatory pain that can predict the analgesic activity of a variety of agents following single-dose administration. In the RSAA model, activity was measured in nonhabituated rats using standard, photocell-based monitors. Bilateral inflammation of the knee joints by complete Freund's adjuvant (CFA) reduced the normal level of activity (horizontal locomotion and vertical rearing) by approximately 60% in a novel environment. This reduction in activity was dose-dependently reversed by ibuprofen, rofecoxib, celecoxib, piroxicam, and dexamethasone, whereas gabapentin and amitriptyline were inactive. Morphine significantly reversed the activity-suppressing effects of CFA, at 1 mg/kg s.c., but at higher doses locomotor activity progressively declined, coincident with the induction of sedation. In contrast to morphine and anti-inflammatory therapies, amphetamine did not affect vertical rearing, even though it increased horizontal locomotion. Thus, unlike standard measures of analgesia such as alteration in thermal or mechanical sensitivity, the RSAA model operationally defines analgesia as a drug-induced increase in spontaneous behavior (vertical rearing in a novel environment). We conclude that the RSAA model is valuable as an objective measure of analgesic efficacy that is not dependent on an evoked stimulus response.

Topics: Analgesia; Analgesics; Animals; Carrageenan; Celecoxib; Dexamethasone; Dose-Response Relationship, Drug; Freund's Adjuvant; Inflammation; Kaolin; Male; Models, Animal; Morphine; Motor Activity; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides

Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological method for pain management. Commercial TENS units differ in their waveform characteristics. However, effects of different waveforms on analgesia produced by TENS are unknown. Therefore, we compared effects of high-frequency TENS with different waveforms--asymmetric biphasic square and symmetric biphasic square--on inflammatory hyperalgesia. Paw withdrawal latency to heat (PWL) was assessed prior to inflaming the knee joint with 3% carrageenan/kaolin in rats. Four hours after induction of inflammation, PWL significantly decreased in all groups, indicating development of hyperalgesia. High-frequency TENS was then applied to the inflamed knee joint for 20 minutes while the rat was lightly anesthetized with halothane. TENS treatment with either the asymmetric or symmetric waveform significantly increased the PWL when compared with sham TENS. Thus, differences in waveform characteristics do not affect the anti-hyperalgesia produced by TENS.. This study shows that different waveforms of TENS do not affect analgesic efficacy. This suggests that clinicians can select different waveforms to provide comfort during treatment but that reduction in pain is not a factor for waveform selection.

Topics: Animals; Carrageenan; Dose-Response Relationship, Radiation; Hyperalgesia; Inflammation; Kaolin; Knee Joint; Male; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Reaction Time; Transcutaneous Electric Nerve Stimulation

We investigated effects of topical application of ketanserin, a 5-HT2A receptor antagonist, on hyperalgesia and edema in the arthritic rat, a chronic pain model with inflammation. Unilateral, but not bilateral, arthritis was induced with intra-articular injection of a mixture of kaolin and carrageenan in one side, as indicated by the shortened paw withdrawal latency and an increase in the circumference of the knee joint. Topical application of ketanserin onto skin over the arthritic joint delivered in a mixture of gelatin, glycerol and kaolin produced dose-dependent attenuation of nociceptive and inflammatory effects resulting from intra-articularly injected kaolin/carrageenan. One and 3% ketanserin produced significant or even complete anti-hyperalgesia, as well as a remarkable anti-inflammatory effect (50-70% reduction of edema) while 0.3% ketanserin and placebo failed to produce any effect. Moreover, the effects of ketanserin were maintained for 13 days without decline. In contrast, 3% ketanserin applied to skin of the knee joint on the non-inflamed side for 2 weeks did not alter nociceptive thresholds of the paw and the size of the knee joint in both the inflamed and non-inflamed limbs. These results indicate that 5-HT2A receptors in the periphery play a significant role in the maintenance and/or development of inflammatory pain. The present study suggests that topical ketanserin is a promising direction for potential clinical exploration to relieve established hyperalgesia and inflammation in arthritis without adverse effects and tolerance.

Topics: Administration, Topical; Analysis of Variance; Animals; Arthritis, Experimental; Behavior, Animal; Carrageenan; Hyperalgesia; Inflammation; Kaolin; Ketanserin; Lower Extremity; Male; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Serotonin Antagonists

This study focuses on evaluating accumulation of the low molecular peptides and proteins labelled with 99mTc in rat inflammatory/infection foci. Peptides (human leukocyte dialysate, HLD; thymosin fraction 5, TF5; aprotinin, APT), and proteins (human IgG, HIG) were labelled with 99mTc using redox polymer. The labelling efficiency was evaluated using paper, TLC and/or column chromatography. Biodistribution of labelled substances was evaluated in rats with Staphylococcus aureus infection or with sterile kaolin suspension inflammation 24 h after abscess induction. Accumulation of 99mTc activity was determinated both by external gamma camera imaging and by counting dissected tissues 4 h after administration. The evaluated peptides and proteins show high labelling efficiency (99mTc-HLD>98%, 99mTc-TF5>95%, 99mTc-APT>98%, 99mTc-HIG>95%). Usage of redox polymer for labelling increases the stability of 99mTc-labelled substances. The labelling efficiency stays nearly the same (95-98%) after 8 h at least. In experimentally induced inflammation the amount of 99mTc-peptides and 99mTc-HIG activity accumulated is 2.5-6.5 and 5.3-10.6 times higher than in a control tissue. When comparing two types of model inflammations (kaolin- and Staphylococcus-induced ones), the values measured with 99mTc-peptides are more than double than those of kaolin suspension inflammation. The studied low molecular peptides labelled with 99mTc allow rapid localisation of infection foci. 99mTc labelled HIG proved useful for detection of infections and inflammatory lesions.

Topics: Animals; Drug Stability; Humans; Inflammation; Kaolin; Molecular Weight; Peptides; Proteins; Radiopharmaceuticals; Rats; Rats, Wistar; Staphylococcal Infections; Technetium; Tissue Distribution; Whole-Body Counting

In laboratory animals many models of inflammation have been developed for preclinical evaluation of the pharmacological profiles of nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, in species of veterinary interest, including the cat, NSAIDs have been studied mainly using dose-titration or dose-confirmation studies in clinical subjects. This is due to the scarcity of appropriate animal models and to the associated lack of quantitative validated endpoints describing the magnitude and time course of drug response. Determination of pharmacokinetic/pharmacodynamic (PK/PD) relationships provides a powerful approach for the selection of effective and safe dosage regimens. In this study, a paw inflammation model in the cat was developed for the preclinical evaluation of NSAIDs using PK/PD modelling. Subcutaneous injection of 500 mg kaolin in the paw produced a well-defined and reproducible inflammatory response that lasted 4-5 days. Several endpoints were assessed for their clinical relevance and for their metrological performance (accuracy and reproducibility). Body temperature, lameness scoring, locomotion tests and possibly skin temperature were the most appropriate endpoints for testing the antipyretic, analgesic and anti-inflammatory effects of NSAIDs in the cat.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cat Diseases; Cats; Disease Models, Animal; Female; Inflammation; Injections, Subcutaneous; Kaolin; Lameness, Animal; Male; Pain Measurement; Reproducibility of Results

A simple, fast, precise and biologically relevant toxicity assay for screening cytotoxicity of minerals would have distinct advantages due to its cost benefits and relative savings in time. Furthermore, a bioassay to differentiate acute and chronic in vivo pulmonary reactions could have potential value as predictors of fibrogenicity and pathogenicity. In this study we examined the potential use of lucigenin as a probe to evaluate the correlation between chemiluminescence (CL) generated by alveolar macrophages with the known cytotoxicity and patho genicity by conventional bioassays. In this study, we used small doses of dust (20 microg) to minimize cellular overload and to maintain homeostasis. Crystalline silica a highly fibrogenic dust was used as positive control and results are compared with those for bentonite, kaolin and talc. Among the three minerals compared with silica, bentonite was more reactive (27%) in CL assay and declined sharply compared to other minerals. This sudden decline in bentonite CL is caused by cytotoxicity leading to cell death. CL-induced by talc was comparable to silica and declines slowly. Kaolin on the other hand produced relatively a weaker (25%) CL compared to silica. Our data using relatively low doses of dust suggest that the CL assay may have a better predictive value in cytotoxicity evaluations compared to conventional toxicity assays.

Topics: Acridines; Animals; Bentonite; Bronchoalveolar Lavage Fluid; Cell Survival; Cells, Cultured; Dust; Feasibility Studies; Inflammation; Kaolin; Kinetics; Luminescent Measurements; Macrophages, Alveolar; Male; Minerals; Models, Biological; Predictive Value of Tests; Quartz; Rats; Talc

Phosphorylation of a subunit of N-methyl-D-aspartate (NMDA) receptor by protein tyrosine kinase (PTK) Src or Trk is known to enhance its channel activity. We examined whether a spinally administered selective PTK inhibitor, lavendustin A, which has high affinity for Src and Trk tyrosine kinases, could influence the development and maintenance of inflammatory hyperalgesia or NMDA-induced hyperalgesia. Inflammation was induced by injection of a mixture of carrageenan and kaolin into the tail base of rats. In another group of rats, hyperalgesia was induced by intrathecal administration of NMDA. Intrathecal administration of lavendustin A (1.0 microg) or NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5,10-iminemaleate, MK-801 (3.0 microg) before injection of a mixture of carrageenan and kaolin or after the development of inflammation inhibited carrageenan-kaolin-induced mechanical hyperalgesia. Intrathecal injection of 1.0 microg NMDA produced thermal and mechanical hyperalgesia. Co-administration of 1.0 microg lavendustin A with NMDA significantly reduced the duration of spontaneous pain behaviour and inhibited NMDA-induced hyperalgesia. Lavendustin A itself did not cause any sedation, motor impairment or analgesia. Our results suggest that inhibition of PTK could be therapeutically effective as an analgesic in some NMDA receptor-mediated hyperalgesic states.

Topics: Animals; Carrageenan; Dizocilpine Maleate; Hot Temperature; Hyperalgesia; Inflammation; Injections, Spinal; Kaolin; Male; N-Methylaspartate; Pain; Pain Measurement; Phenols; Protein-Tyrosine Kinases; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord

Crohn disease is immunologically mediated and characterized by intestinal and systemic chronic inflammation. In a rat model, injection of peptidoglycan-polysaccharide complexes into the intestinal wall induced chronic inflammation in Lewis but neither Fischer nor Buffalo rats, indicating a differential genetic susceptibility. Proteolysis of plasma high molecular weight kininogen (HK) yielding bradykinin and cleaved HK (HKa) was faster in Lewis than in Fischer or Buffalo rat plasma. A single point mutation at nucleotide 1586 was found translating from Ser511 (Buffalo and Fisher) to Asn511 (Lewis). The latter defines an Asn-Xaa-Thr consensus sequence for N-glycosylation. We expressed these domains in Escherichia coli and found no differences in the rate of cleavage by purified kallikrein in the 3 strains in the absence of N-glycosylation. We then expressed these domains in Chinese hamster ovary (CHO) cells, which are capable of glycosylation, and found an increased rate of cleavage of Lewis HK. The Lewis mutation is associated with N-glycosylation as evidenced by a more rapid migration after treatment with N-glycosidase F. When CHO cells were cultured in the presence of tunicamycin, the kallikrein-induced cleavage rate of Lewis HK was not increased. This molecular alteration might be one contributing factor resulting in chronic inflammation in Lewis rats.

Topics: Animals; Bradykinin; CHO Cells; Cricetinae; Dextran Sulfate; DNA Restriction Enzymes; Escherichia coli; Glycosylation; Inflammation; Kaolin; Kininogens; Mutation; Peptidoglycan; Point Mutation; Polymerase Chain Reaction; Polysaccharides; Protein Structure, Tertiary; Rats; Rats, Inbred Lew; Species Specificity; Time Factors

Prostaglandins (PGs) are local mediators of several functions in the CNS. Both primary afferent neurons and intrinsic cells in the spinal cord produce PGs, with a marked upregulation during peripheral inflammation. Therefore, the significance of spinal PGs in the neuronal processing of mechanosensory information was herein investigated. In anesthetized rats, the discharges of spinal nociceptive neurons with input from the knee joint were extracellularly recorded. Topical administration of prostaglandin E(2) (PGE(2)) to the spinal cord facilitated the discharges and expanded the receptive field of dorsal horn neurons to innocuous and noxious pressure applied to the knee joint, the ankle, and the paw, thus mimicking inflammation-induced central sensitization. Conversely, topical administration of the PG synthesis inhibitor indomethacin to the spinal cord before and during development of knee joint inflammation attenuated the generation of inflammation-induced spinal neuronal hyperexcitability. However, after development of inflammation, the responses of spinal neurons to mechanical stimuli were only reduced by systemic indomethacin but not by indomethacin applied to the spinal cord. Thus, spinal PG synthesis is important for the induction and initial expression but not for the maintenance of spinal cord hyperexcitability. Spinal PGE(2) application facilitated dorsal horn neuronal firing elicited by ionophoretic delivery of NMDA, suggesting that an interaction of PGs and NMDA receptors may contribute to inflammation-induced central sensitization. However, after development of inflammation, spinal indomethacin failed to reduce responses to ionophoretic delivery of NMDA or AMPA, suggesting that such an interaction is not required for the maintenance of central sensitization.

Topics: Action Potentials; Administration, Topical; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Carrageenan; Dinoprostone; Excitatory Amino Acid Agonists; Hindlimb; Hyperesthesia; Indomethacin; Inflammation; Injections, Spinal; Iontophoresis; Joints; Kaolin; Male; N-Methylaspartate; Nociceptors; Physical Stimulation; Posterior Horn Cells; Prostaglandins; Rats; Rats, Wistar; Spinal Cord

Nocistatin is a biologically active peptide derived from prepronociceptin, and its intrathecal administration has been reported to reduce nociceptin- or prostaglandin E2-induced hyperalgesia and allodynia in mice. In this study, we investigated the effects of intracerebroventricular (i.c.v.) administration of nocistatin on the inflammatory hyperalgesia induced by hindlimb intraplantar injection of carrageenan/kaolin in the rat paw-pressure test. Intracerebroventricular administration of nocistatin (0.5-50 pmol/rat) dose-dependently reduced carrageenan/kaolin-induced hyperalgesia, which peaked at 15-30 m. However, i.c.v. administration of nocistatin (50 pmol/rat) had no effect on the nociceptive threshold of non-inflamed rats. These results indicate that nocistatin has anti-hyperalgesic effects on the inflammatory hyperalgesia induced by carrageenan/kaolin at the supraspinal level.

Topics: Animals; Carrageenan; Drug Evaluation, Preclinical; Hindlimb; Hyperalgesia; Inflammation; Injections, Intraventricular; Kaolin; Male; Opioid Peptides; Rats; Rats, Sprague-Dawley

We examined with electrophysiological techniques the effects of experimentally induced inflammation on the mechanosensitive afferent units in the rotator cuff of the shoulder joint of 21 rabbits. We identified 21 mechanosensitive units belonging to group III. 12 units had mechanical thresholds of > 7.0 g and 9 units had thresholds of < 7.0 g. After injection of inflammatory agents, kaolin and carrageenan, into the joint space, ongoing afferent discharge rates increased in all units. The average discharge rate increased significantly from 7 imp/s to 15 imp/s after injection. 5 units had a decreased mechanical threshold after the injection. Acute inflammation seems to have an excitatory and sensitizing effect on the high- and low-threshold units in the rotator cuff.

Topics: Acute Disease; Afferent Pathways; Animals; Carrageenan; Disease Models, Animal; Electrophysiology; Humans; Inflammation; Kaolin; Male; Mechanoreceptors; Rabbits; Rotator Cuff; Sensory Thresholds; Shoulder Joint; Tendinopathy

Intrathecal (i.t.) administration of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline enhances pain behaviors in the formalin test. This study examined whether bicuculline also increases the peripheral inflammation induced by formalin. Subcutaneous injection of 0.25 to 5.0% formalin in the plantar surface of one hindpaw of the rat produced a concentration-dependent increase in plasma extravasation as measured by the Evans Blue method. Pretreatment with 0.3 microg i.t. bicuculline neither enhanced nor suppressed formalin-induced plasma extravasation. This dose of bicuculline also did not affect plasma extravasation induced by injection of 3% kaolin/3% carrageenan in the knee of the rat. These data indicate that the enhancement of formalin-induced pain behaviors by i.t. bicuculline is not secondary to enhanced peripheral inflammation, but more likely reflects enhancement of nociceptive transmission in the spinal cord.

Topics: Animals; Arthritis; Bicuculline; Carrageenan; Coloring Agents; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; GABA Antagonists; Hindlimb; Inflammation; Injections, Spinal; Kaolin; Knee Joint; Male; Pain Measurement; Rats; Rats, Sprague-Dawley

1. The effects of a novel, potent and orally active nonpeptide bradykinin B2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2 ,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylamin ocarbonyl) cinnamylamide hydrochloride) were tested in three different in vivo models of inflammation. 2. Oral administration of FR167344 inhibited carrageenin-induced paw oedema in rats (carrageenin: 1%, 0.1 ml per animal, intraplantar), with an ID50 of 2.7 mg kg(-1) at 2 h after carrageenin injection (n=10 or 11). 3. Oral administration of the compound also inhibited kaolin-induced writhing (kaolin: 250 mg kg(-1), i.p.) in mice, with ID50 of 2.8 mg kg(-1) in 10 min writhing and 4.2 mg kg(-1) in 15 min writhing (n=19 or 20). 4. Additionally, oral administration of FR167344 inhibited caerulein-induced pancreatic oedema with an ID50 of 13.8 mg kg(-1) as well as increases in amylase and lipase of blood samples with ID50 of 10.3 and 7.4 mg kg(-1), respectively, in rats (n=10). 5. These results show that FR167344 is an orally active, anti-inflammatory and anti-nociceptive agent in carrageenin-induced paw oedema, kaolin-induced writhing and caerulein-induced pancreatitis. FR167344 may have therapeutic potential against inflammatory diseases by oral administration and it may be a useful tool for studying the involvement of B2 receptors in various in vivo models of inflammation.

Topics: Administration, Oral; Animals; Antidiarrheals; Bradykinin Receptor Antagonists; Carrageenan; Ceruletide; Disease Models, Animal; Excipients; Gastrointestinal Agents; Inflammation; Kaolin; Male; Mice; Mice, Inbred ICR; Pain; Pancreatitis; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin

1. Injection of kaolin and carrageenan into the knee joint of cats or monkeys resulted in an acute inflammation. Four hours after injection of the knee joint, efferent activity could be evoked in articular afferent fibers and in dorsal root filaments. We interpret this efferent activity to be dorsal root reflexes (DRRs). Under our experimental conditions, the DRRs were generally synchronized compound action potentials, although in some cases single-unit activity was also observed. 2. DRRs were not produced in animals with uninflamed knee joints and normal body temperatures. 3. Recordings from two different sites on cut dorsal root filaments ipsilateral to the inflamed knee joint allowed the determination of the conduction velocities of groups of afferent fibers carrying DRRs. The DRRs occurred in A beta-, A delta-, and C fibers. However, in these experiments the peripheral destination of the afferent fibers was unknown. 4. To prove that DRRs occurred in joint afferents, recordings were made from two different sites on the proximal stump of the medial articular nerve that innervated the inflamed knee. The DRRs were again found in all fiber types, i.e., group II, III, and IV (A beta, A delta, and C) articular afferent fibers. 5. Compound DRRs were recorded from the central end of a cut dorsal root filament after electrical stimulation at C fiber intensity of a dorsal root adjacent to the filament. This DRR activity was eliminated by extensive dorsal rhizotomies of the L2-S1 roots.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Afferent Pathways; Animals; Arthritis; Cats; Disease Models, Animal; Efferent Pathways; Ganglia, Spinal; Inflammation; Joints; Kaolin; Macaca mulatta; Nerve Fibers; Reflex

The distribution of NADPH-diaphorase was studied in retrogradely labelled dorsal root ganglion cells innervating the knee joint of the cat. A strong staining reaction was found in 7.5 +/- 1.9% (mean +/- S.D. of 9 normal joints and 6393 labelled perikarya) of the articular afferents. An acute inflammation (32 h) significantly increased this proportion to 10.9 +/- 2.2% (mean +/- S.D. of 5 inflamed joints and 3933 labelled perikarya). The diameter distribution of the somata with a positive NADPH-diaphorase reaction ranged from 18 to 46 microns with a maximum at 24-28 microns. These data indicate that a small proportion of knee joint primary afferents may be able to release nitric oxide playing a role in synaptic transmission and in regulatory functions within the peripheral tissue under normal and pathophysiological conditions.

Topics: Amidines; Animals; Carrageenan; Cats; Female; Fluorescent Antibody Technique; Ganglia, Spinal; Inflammation; Kaolin; Knee Joint; Male; NADPH Dehydrogenase; Neurons, Afferent; Nitric Oxide; Nociceptors

Maximal complexing of alpha 2-macroglobulin (alpha 2M) and kallikrein (KK) occurs at a temperature of 22-24 rather than at 37 degrees C. The protease expressivity of the complex is also maximal at 22-24 degrees C. alpha 2M-KK complex, sustained permeability changes in guinea pig skin. These findings suggest that the complex, rather than free KK, could play a role in the kinin release reported in some late-phase reactions, some instances of delayed-type hypersensitivity and some cold-induced reactions.

Topics: alpha-Macroglobulins; Animals; Capillary Permeability; Factor XII; Female; Guinea Pigs; Humans; Hypersensitivity, Delayed; Inflammation; Kallikreins; Kaolin; Macromolecular Substances; Temperature

In ten cats, single unit electrical activity was recorded in the lumbosacral spinal cord from neurones driven by stimulation of afferent fibres from the ipsilateral knee joint. Tonic descending inhibition (TDI) on the responses of these cells was measured as increases in resting and evoked activity of the neurones following reversible spinalization of the animals with a cold block at upper lumbar level. Acute inflammation of the knee joint was induced in five of the cats by the injection of kaolin and carrageenan into the joint. TDI was observed in 25 of 33 neurones recorded in normal animals (76%) and in 36 of 40 (90%) neurones recorded in animals with acute knee joint inflammation. In both kinds of preparation TDI was more pronounced in neurones recorded in the deep dorsal horn and in the ventral horn than in those recorded in the superficial dorsal horn. There was a tendency in the whole sample for TDI to be greater in neurones with input from inflamed knees. We conclude that the spinal processing of afferent information from joints is under tonic descending influences and that the amount of TDI can be altered during acute arthritis.

Topics: Afferent Pathways; Animals; Carrageenan; Cats; Cold Temperature; Female; Hindlimb; Inflammation; Joint Diseases; Joints; Kaolin; Male; Nerve Fibers; Neurons; Pain; Spinal Cord

In anaesthetized spinal cats, the release of immunoreactive substance P in the spinal cord during development of an acute inflammation in one knee joint was studied with antibody microprobes. The microprobes bore antibodies directed to the C- or N-terminus of substance P. With the normal knee joint, innocuous mechanical stimuli (flexion, pressure) did not result in spinal release of immunoreactive substance P. Following injection of kaolin and carrageenan into a knee, evidence for release of substance P following joint stimulation was found in 7 of 10 cats. Such release did not occur for several hours after joint injection and was detected predominantly in the superficial dorsal horn, the dorsal columns and at the dorsal surface of the spinal cord. In some experiments release was detected in the deep dorsal horn and upper ventral horn. Release of immunoreactive substance P required periods of mechanical stimulation such as flexion of, or pressure to, the inflamed joint. The failure to detect central release of substance P from stimulation of normal joints, and the release of substance P, after a delay, from inflamed joints, suggest that the fibres releasing this compound require sensitization by inflammatory mediators before they are excited by joint stimuli.

Topics: Animals; Arthritis, Experimental; Carrageenan; Cats; Immunoassay; Inflammation; Joints; Kaolin; Pressure; Reference Values; Spinal Cord; Substance P

The results of immunomorphologic and histochemical investigations of 12 rabbits with experimental syringomyelia are presented. Chronic pachymeningitis of the hind brain, resulting from the administration of kaolin leads to the disorders of liquor circulation on the level of outlet of the fourth ventricle this being a start mechanism for the cavity formation in the spinal cord. The reactive inflammatory, degenerative and immune reactions accompany the formation of cavity in the nervous tissue. The formation of cavity is followed by asymmetrical segment demyelination and reparative hyperplasia of the astroglial cells and gliosis of the cavity walls.

Topics: Animals; Inflammation; Kaolin; Nerve Degeneration; Nerve Regeneration; Nervous System; Rabbits; Syringomyelia

1. The hypothesis of a pro-inflammatory activity in lymphocytes related to the development of nonimmune acute inflammation was tested in leucopenic rats injected subcutaneously with various stimuli representing different pharmacological classes of paw edema-inducing agents into the subplantar area of one of the hind paws. 2. Amethopterin-induced leucopenia rendered animals hyporeactive to carrageenin and trypsin, but not to kaolin or dextran. 3. Administration of splenic lymphocytes to leucopenic rats to correct lymphopenia partially restored the inhibited responses to carrageenin and the early phase of responses to trypsin. 4. These results suggest that lymphocytes may play a pro-inflammatory role in nonimmune acute inflammation, which is more demonstrable in some pharmacological classes of paw edema than in others.

Topics: Animals; Carrageenan; Dextrans; Edema; Hindlimb; Inflammation; Kaolin; Leukocyte Count; Leukopenia; Lymphocyte Depletion; Lymphocytes; Male; Methotrexate; Rats; Rats, Inbred Strains

This study was done with the aid of experimental models of inflammation provoked in air pouch, which was made subcutaneously on the back of rats, by applying a carrageenin solution or a suspension of kaolin in a carboxymethylcellulose solution as an irritant. Bradykinin in the inflammatory sites, determined by an enzyme immunoassay method, were comparatively high in the earliest stage of inflammation in both the models and responsible for the exudative reactions. With the passage of time, i.e. within 20 min in the case of kaolin and 120 min in carrageenin, tissue kininase entered the inflammatory site and reduced bradykinin to a very low level, though bradykinin was still being generated very actively. In this later stage, bradykinin collaborates with prostaglandin to bring about a significant increase in the vascular permeability.

Topics: Animals; Bradykinin; Capillary Permeability; Carrageenan; Disease Models, Animal; Immunoenzyme Techniques; Inflammation; Kaolin; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Time Factors

Topics: 3-Mercaptopropionic Acid; Animals; Bradykinin; Capillary Permeability; Exudates and Transudates; Inflammation; Kallikreins; Kaolin; Lysine Carboxypeptidase; Male; Rats; Rats, Inbred Strains; Trypsin Inhibitor, Kunitz Soybean

Experimental inflammation was induced by injection of a suspension of kaolin in carboxymethylcellulose solution into a subcutaneous air pouch preformed on the back of rats. Endogenous bradykinin generated in the inflammatory pouch declined quickly unless kininase inhibitors were administered into the pouch. Bradykinin injected into the pouch brought about no significant increase in plasma exudation in the pouch unless kininase inhibitors were administered simultaneously. Although kininase I and II activities were present in normal rat serum, kininase II rather than kininase I was mainly responsible for the degradation of bradykinin in rat serum. In the pouch challenged with the kaolin suspension and vehicle, kininase II originating from the pouch wall tissue played a predominant role in the degradation of bradykinin while the role of kininases derived from the blood and inflammatory cells was minor.

Topics: Animals; Bradykinin; Captopril; Carboxypeptidases; Exudates and Transudates; Immunoenzyme Techniques; Inflammation; Kaolin; Lysine Carboxypeptidase; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains

The effects of stem bromelain on the plasma kallikrein system, bradykinin levels and plasma exudation at the inflammatory site were examined in rats with a kaolin-induced inflammation of an air pouch. Bromelain (5, 7.5 mg/kg) caused a dose-dependent decrease of bradykinin levels at the inflammatory site and a parallel decrease of the prekallikrein levels in sera. Plasma exudation was also reduced dose dependently. Bradykinin-degrading activity in sera was elevated after treatment with bromelain, although it was unchanged in the pouch fluid. These data indicate that bromelain inhibits plasma exudation through inhibiting the generation of bradykinin at the inflammatory site via depletion of the plasma kallikrein system.

Topics: Animals; Bradykinin; Bromelains; Exudates and Transudates; Immunoenzyme Techniques; Inflammation; Injections, Intravenous; Kaolin; Lysine Carboxypeptidase; Male; Prekallikrein; Rats; Rats, Inbred Strains

Experiments were performed to investigate whether acute knee joint inflammation, induced by intra-articular injection of carrageenan and kaolin, significantly influences the magnitude of the flexion withdrawal reflex of knee flexors in the decerebrate, low-spinal cat. It was observed that after injection of these inflammatory agents, reflex intensity increased with a time course that matched the development of the inflammatory process, as assessed by monitoring the intra-articular temperature. Control experiments involving intra-articular injection of saline showed neither a rise in intra-articular temperature, nor any change in reflex intensity. The normal pattern of modulation of reflex intensity with changing joint angle was abolished in the inflamed joint with the reflex being equally intense at all positions tested. Abolition of neural activity in the inflamed joint by intra-articular injection of lignocaine resulted in a marked decrease in the reflex back to control values, suggesting that there is no maintained increase in central excitability in the absence of joint afferent input. It was also observed that the spontaneous activity of knee flexor motor units was modulated during continuous passive rotation of the knee, with activity being greater in extension than in flexion. This pattern reversed when the knee was acutely inflamed, but could be returned to the control pattern by joint anaesthesia, although now the response was attenuated when compared to the control.

Topics: Animals; Carrageenan; Cats; Decerebrate State; Electromyography; Inflammation; Joints; Kaolin; Neural Conduction; Reflex; Sciatic Nerve; Spinal Cord

We investigated how bradykinin mediates inflammatory reactions in rats, via measurements of bradykinin by enzyme immunoassay method in inflammatory tissue fluids. Vascular permeability was increased markedly during the first 10 min and then declined quickly after the infusion of a kaolin suspension (10 mg/ml) in 0.8% carboxymethl-cellulose solution into an air pouch formed on the back of rats. Bradykinin in the exudate reached a maximum 5 min after the challenge and then decreased quickly. Local treatment with DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid, an inhibitor of kininase I, and captopril, an inhibitor of kininase II in the first 10-min period, each enhanced the vascular permeability increase accompanied by the elevation of the bradykinin level, whereas soybean trypsin inhibitor, a plasma kallikrein inhibitor, lowered both vascular permeability and bradykinin. When applied in the period of 3.5 to 4 hr after the challenge, only the kininase II inhibitor was effective in elevating both vascular permeability and the bradykinin level, whereas soybean trypsin inhibitor was ineffective on vascular permeability. A bradykinin-degrading activity appeared in the exudate as early as 10 min after the challenge. These results suggest that bradykinin plays an essential role for the sudden rise of the vascular permeability observed immediately after the infusion of kaolin suspension. In the later stage (3.5-4 hr), bradykinin level remained below the assay limit of 0.07 ng/ml in spite of its active generation, presumably because of its rapid degradation by the kininases, although it still played a definite role in the vascular permeability increase.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Capillary Permeability; Captopril; Cross Reactions; Histamine; Indomethacin; Inflammation; Kaolin; Lysine Carboxypeptidase; Male; Rats; Rats, Inbred Strains; Serotonin; Trypsin Inhibitors

The regulatory mechanisms that determine the course of an inflammation induced by an intraperitoneal injection of kaolin were investigated in Listeria-susceptible CBA and Listeria-resistant B10 mice. The magnitude of the granulocyte inflammatory response in the peritoneal cavity was high in B10 mice (area under the curve; AUC0-48 h: 210.9 x 10(6) granulocytes/mouse x h) and lower in CBA mice AUC0-48 h: 136.8 x 10(6) granulocytes/mouse x h), whereas the reverse was seen for the granulocyte response in the peripheral blood (AUC0-48 h: 30.5 and 80.7 x 10(6) granulocytes/mouse x h, respectively). With respect to the presence of humoral factors that affect the number of granulocytes in the circulation, sera of both mouse strains sampled 24 h after the kaolin injection had granulocytosis-inducing effect in CBA recipient mice and did not induce a response in the B10 recipient mice. This divergent sensitivity to serum factors inducing granulocytosis is consistent with the difference in the blood granulocyte response of B10 and CBA mice but does not explain the divergent inflammatory responses in the peritoneal cavity. Computer simulation showed that at least two factors must be taken into consideration to explain the differences in the inflammatory response, i.e., a factor regulating the release of granulocytes from the bone marrow and a factor governing the rate of granulocyte efflux from the site of inflammation.

Topics: Animals; Computer Simulation; Female; Granulocytes; Inflammation; Kaolin; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Peritoneal Cavity

Experimental pleurisy was induced by intrapleural injection of carrageenin or kaolin in three strains of rat: Brown Norway-Katholiek (B/N-Ka), Brown Norway-Kitasato (B/N-Ki) and Sprague-Dawley (SD). B/N-Ka rats (kininogen-deficient) showed significantly less pleural fluid accumulation and exudation rate than SD rats or than B/N-Ki rats (normal). The result indicates the involvement of the plasma kallikrein-kinin system in these pleurisies and a role of high-molecular-weight kininogen is suggested.

Topics: Acute Disease; Aging; Animals; Body Weight; Carrageenan; Inflammation; Kallikreins; Kaolin; Kininogens; Kinins; Organ Size; Pleurisy; Rats; Rats, Inbred Strains; Species Specificity; Tetradecanoylphorbol Acetate

Topics: Animals; Bentonite; Inflammation; Kaolin; Male; Rats; Rats, Inbred Strains

The author compared the efficiency of 3-amino-4-mercapto-6-methylpyridazine (1; pyridazine S1) and some standard pharmaca by means of acute and subacute inflammation models. As evidence by the acute assay, the kaolin and carragheenin-induced oedemata of the rat paw as well as the Evans's blue excretion the potency of 1 compared with that of acetylsalicylic acid. Phenylbutazone and indomethacin exhibited a higher degree of activity. In the cotton-induced granuloma test, 1 was ineffective, whereas indomethacin applications had a powerful effect against inflammatory reactions. The results obtained during this investigation suggest that the activity spectrum of 1 is similar to that of acetylsalicylic acid.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Carrageenan; Disease Models, Animal; Edema; Evans Blue; Exudates and Transudates; Granuloma; Indomethacin; Inflammation; Kaolin; Male; Phenylbutazone; Pyridazines; Rats; Rats, Inbred Strains

The bentonite and kaolin oedemas were simultaneously induced in the rat hind paws and their courses and morphological patterns were observed under the conditions of the same biological background. Gross examination has confirmed the former experience that the kaolin oedema has a more pronounced acute phase (maximum after five to seven hours) followed by subsequent spontaneous regression of the oedema, while the bentonite oedema has its acute phase less pronounced, attains its peak only on the second day, maintaining this same size over several weeks without substantial changes. The courses of the two oedemas were in correlation with the results of histological evaluation (oedematous exudation, polymorphonuclear and mononuclear infiltration and the phagocytic activity of the latter). Resorption of kaolin in the newly-developed non-specific granulation tissue was much faster than that of bentonite (after about three weeks, while bentonite was not resorbed even after six weeks). Further, pharmacological and histological examination was performed of the effects on the bentonite oedema of sodium salicylate and Prednisone during the first 24 hours. Both substances suppressed the oedema, sodium salicylate delayed both polymorphonuclear and mononuclear infiltration, Prednisone delayed only mononuclear infiltration. The presence of mononuclear population was confirmed also by means of the positive activity of non-specific esterase and the negative activity of alkaline phosphatase. The bentonite rat-paw oedema has thus been proved to be a suitable model of inflammatory reaction for testing anti-inflammatory drugs not only in short-term (acute) tests, but also in long-term ones, where it yields a uniform picture of non-specific foreign-body low-turnover granuloma.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Bentonite; Edema; Female; Follow-Up Studies; Foot Diseases; Hindlimb; Inflammation; Kaolin; Male; Neutrophils; Phagocytes; Rats; Rats, Inbred Strains

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Copper; Disease Models, Animal; Edema; Guinea Pigs; Inflammation; Kaolin; Male; Rats

Topics: Carboxypeptidases; Humans; Inflammation; Kaolin; Kinins; Lysine Carboxypeptidase; Lysosomes; Molecular Weight; Neutrophils; Peptide Hydrolases; Peptidyl-Dipeptidase A

Several gold salts were compared in kaolin-induced rat paw oedema, u.v. erythema in guinea pigs, delayed type hypersensitivity and humoral immunity in mice, and adjuvant-induced arthritis in the rat. In the latter the additional parameters of serum gold and copper levels and lysosomal enzyme activity were determined. In addition, the in vitro inhibition of several lysosomal enzymes derived from mouse macrophages was studied. The gold compounds examined were aurothiomalate, aurothioglucose, triethylphosphine gold chloride (SK & F 36914) and its glucopyranoside derivative (SK & F D-39162), triphenylphosphine gold chloride and sodium gold chloride dihydrate. SK & F 36914 and SK & F D-39162 has significant activity after oral dosage upon paw kaolin and u.v. erythema in rats and guinea pigs, respectively. Gastric swelling also occurred. In Wistar rats, adjuvant arthritis was little affected by the gold salts but in the Lewis rats there was suppression. In both strains there was less elevation in serum copper levels with treatment by SK & F 36914 and SK & F D-39162, but not by aurothiomalate. None of the compounds had any measurable effect on delayed hypersensitivity or humoral antibody levels in mice. The in vitro activities of cathepsin B1 and cathepsin D were inhibited by all the gold compounds. Reactivity of gold compounds with glutathione and cysteine in vitro was dependent on compound solubility and the nature of the gold ligand. Considerable differences exist between the profiles of activity for the different gold salts evaluated. These observations indicate that some gold salts do possess anti-inflammatory activity with a potency similar to that of indomethacin.

Topics: Animals; Antibody Formation; Arthritis, Experimental; Cysteine; Edema; Erythema; Glutathione; Gold; Guinea Pigs; Hypersensitivity, Delayed; Immunity; Inflammation; Kaolin; Lysosomes; Male; Mice; Rats; Ultraviolet Rays

Agents formerly shown to induce rapid macrophage spreading were examined for their ability to modify the migration of macrophages in the capillary tube assay. Products of the activation of the contact phase of blood coagulation as well as the purified component Bb, the large cleavage fragment of factor B of the alternative complement pathway produced a dose-dependent inhibition of migration. In addition, inflammatory macrophages elicited with either a lipopolysaccharide endotoxin or thioglycollate medium exhibited rapid spreading and inhibited migration, whereas resident cells did not. A close correlation existed, therefore, between enhanced spreading and inhibited migration under both in vitro induced and in vivo situations. Cleavage products of component C5 of the classical complement pathway enhanced macrophage migration and did not alter spreading. In mixtures of C5 cleavage products and Bb, the predominant peptide determined the outcome of the reaction. Factor B, a normal secretory product of macrophages, may represent a common substrate for several of the proteases that induce spreading, inhibit migration, and lead to the generation of the enzymatically active fragment Bb.

Topics: Ascitic Fluid; Cell Migration Inhibition; Cell Movement; Complement C5; Complement Factor B; Complement Pathway, Alternative; Complement System Proteins; Enzyme Precursors; Inflammation; Kaolin; Macrophages

Levamisole potentiated paw oedema induced by carrageenan in the rat whereas penicillamine was without effect. On the other hand, levamisole inhibited paw oedema induced by kaolin, penicillamine again having no effect. The copper complex of penicillamine was inhibitory in the carrageenan test but failed to show inhibition in the kaolin model of inflammation. These results show that levamisole and penicillamine are capable of exerting anti-inflammatory activity in the rat but only under certain conditions.

Topics: Animals; Carrageenan; Edema; Female; Inflammation; Kaolin; Levamisole; Male; Penicillamine; Rats

Effect of tolmetin sodium(Tol) on acute and subacute exudative inflammation was tested in experimental animals. Tol had a potent inhibitory activity (ED50 = 0.75 mg/kg, p.o.) on the increased vascular permeability induced by acetic acid in mice, and the potency was about 0.4 times that of indomethacin (Ind), and 6-93 times that of ibuprofen (Ibu), phenylbutazone(Phe) and aspirin(Asp). The inhibitory activity of Tol(ED50 = 18.2 mg/kg, p.o.) on UV-induced erythema in guinea pigs was about 0.3 times that of Ind. A recovery of the hind paw edema of rats, produced by a mixture of kaolin and carrageenin, was promoted by oral administration of Tol(2.5 approximately 20 mg/kg x 5/2 days). Tol(80 mg/kg/day, p.o.) showed a significant activity in inhibiting the exudation caused by croton oil in rats, and the activity was about 0.025 times that of Ind and greater than that of Ibu, Phe and Asp. Tol(100-800 microgram/ml) inhibited in a dose-dependent manner the phytohemagglutinin-induced blast transformation of cultured lymphocytes from rat thymus, as did salicylic acid. In vitro, Tol showed a potent activity similar to that of Ibu and Phe in preventing the denaturation of bovine serum albumin and the lysis of rat erythrocytes. From these results, it is suggested that Tol has a particularly potent inhibitory activity on acute exudative inflammation, and the mode of action may be attributed to a mechanism similar to that seen with other acidic non-steroidal anti-inflammatory drugs.

Topics: Animals; Anti-Inflammatory Agents; Capillary Permeability; Carrageenan; Cell Differentiation; Edema; Erythrocyte Membrane; Exudates and Transudates; Guinea Pigs; Hemolysis; Hot Temperature; In Vitro Techniques; Inflammation; Kaolin; Lymphocytes; Male; Mice; Protein Denaturation; Pyrroles; Rats; Sunburn; Tolmetin

During kaolin-induced granuloma pouch inflammation in the rat the concentration of malondialdehyde (MDA) in the exudate, measured by the 2-thiobarbiturate method, steadily increased and this increase was correlated with the increase in granuloma weight. There was a complete lack of correlation between the concentrations of MDA and prostaglandin (PG)-like material in the inflammatory exudate. Whereas the concentration of PGs reached a maximum 1 day after the induction of inflammation and returned to control levels on day 4, the MDA concentration continuously increased from the initiation of inflammation up to day 16. During granuloma development the concentration of MDA in the plasma reached a maximum on day 2 in parallel with the concentration in the liver, then both plasma and liver MDA decreased to levels observed in control rats. Between day 2 and 8 of the inflammatory process homogenates of livers from inflamed rats showed an increased formation of MDA on incubation, the amount formed being maximal on day 4. The results of the present study are discussed in view of a possible involvement of lipid peroxidation in inflammation.

Topics: Animals; Exudates and Transudates; Granuloma; Inflammation; Kaolin; Kinetics; Liver; Male; Malonates; Malondialdehyde; Prostaglandins; Rats

Inflammation was induced by application of kaolin into the hind paws of rats and its development under the influence of carboxypeptidase N and aprotinin (Antilysin) was followed and compared with the effect of the phenylbutazone type of drugs. Partly purified rat serum carboxypeptidase N, applied subaponeurally (20 mg/kg) together with a nociceptive agent (kaolin), inhibited the inflammation very effectively. Aprotinin, applied as above (10,000 U/kg), enhanced the inflammatory reaction; if applied intraperitoneally 1 h before kaolin, it displayed anti-inflammatory effects similar to that of phenylbutazone (100 mg/kg). Carboxypeptidase N, administered intraperitoneally before kaolin, had a similar anti-inflammatory effect. The effect of phenylbutazone, ketazon and trimetazon on the bradykinin-induced rat uterus contraction was followed. All these substances inhibit the response of isolated rat uterus to bradykinin. From the results it can be assumed that phenylbutazone, ketazon and trimetazon exercise their effect by blocking centres of the rat uterus which are important for the constrictor effect of bradykinin.

Topics: Animals; Anti-Inflammatory Agents; Aprotinin; Carboxypeptidases; Drug Evaluation, Preclinical; Inflammation; Kaolin; Lysine Carboxypeptidase; Peptidyl-Dipeptidase A; Pyrazoles; Rats

Topics: Acute Disease; Animals; Cell-Free System; Hematopoiesis; Immunity; Inflammation; Kaolin; Latex; Leukocyte Count; Mice; Microspheres; Monocytes; Silicon Dioxide; Sodium Chloride; Time Factors; Titanium

The Freund's adjuvant technic, using killed Mycobacterium butyricum suspended in mineral oil, is a refined tool for anti-inflammatory drug evaluation. Its use has long been reserved for testing and not for screening due to technical problems in the preparation of valid animal models. After reviewing the methodology, the authors demonstrated that the availability of arthritic rats from a modern breeding center (Charles River France, SA, Elbeuf, France) make the procedure applicable to drug screening. This has both practical and economic advantages. The animals can be used as test organisms for drug evaluation 14 da after treatment. Three criteria for measuring the effectiveness of anti-arthritic drugs have been established: an arithritic index determined by examination of the 4 paws; changes in the erythrocyte sedimentation rate; and changes in levels of plasma fibrinogen. The curative activity of test substances can be evaluated by a single series of measurements of these 3 criteria after 14 da of treatment. This test was compared with 2 others; edema of the paw induced by the subcutaneous injection of kaolin or carrageenan, and was found to be superior.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Blood Sedimentation; Breeding; Carrageenan; Drug Evaluation, Preclinical; Edema; Fibrinogen; Freund's Adjuvant; Inflammation; Kaolin; Male; Rats; Specific Pathogen-Free Organisms

Subplantar administration of either Phytohaemagglutinin-P (PHA), Concanavalin-A (Con A) or kaolin into the rat hind paw produced a dose related oedema which was still present at 48 h. Both of the lectins were more inflammagenic than kaolin on a weight per weight basis. As a result of studies using mediator inhibitors and depletors it appears that 5HT, but not histamine, may play a role in the early phases (0.5-1.5 h) of both PHA and Con A responses. Neither mediator appears to be involved in the kaolin oedema. Kinins are also likely mediators of the inflammatory response to all three irritants and could be detected in irritant injected air blebs in the rat. Prostaglandins are unlikely to play a significant role in PHA or Con A oedema since indomethacin-induced inhibition of their synthesis has only a slight inhibitory effect on the lectin induced paw oedemas and only small amounts of prostaglandin-like material could be detected in PHA or Con A blebs. However, kaolin oedema appears to have a significant prostaglandin component since large amounts of prostaglandin-like materials were detected in kaolin blebs and also indomethacin reduced the kaolin induced paw oedema. Other mediators of the inflammatory process such as complement are likely to be involved in all three irritant induced oedemas.

Topics: Animals; Anti-Inflammatory Agents; Concanavalin A; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Histamine; Inflammation; Kaolin; Kinins; Lectins; Male; Prostaglandins; Rats; Serotonin

Walker tumor cells and carcinogens were implanted into the brains of rats and L1210, P388 and Ehrlich ascites tumors, in addition to inflammatory agents and hydrocarbons, injected cortically into mice. Behavioral changes were followed in such animals by several psychological criteria, a discriminated lever-press task in rats and an exploratory task, the poke test, in rats and mice. An activity wheel was also employed for further amplification of mouse behavior. No definite changes could be discerned by these tests between rats bearing tumor or carcinogen and the respective controls as was also the case with levels of activity in the mouse. In marked contrast, mice administered tumors or kaolin cortically demonstrated significant reductions in the mean number of pokes, especially with the higher numbers of cells injected and where neurological symptoms were evident. Behavioral changes, if any, were minimal in mice with cortically implanted carcinogens.

Topics: Animals; Behavior, Animal; Brain Diseases; Brain Neoplasms; Carcinogens; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Cerebral Cortex; Haplorhini; Hydrocarbons; Inflammation; Kaolin; Leukemia L1210; Male; Mice; Neoplasm Transplantation; Pectins; Rats; Talc

Topics: Age Factors; Albumins; Animals; Bradykinin; Carrageenan; Consciousness; Dextrans; Disease Models, Animal; Edema; Foot; Guinea Pigs; Histamine; Inflammation; Kaolin; Methods; Mice; Povidone; Rats; Saccharomyces cerevisiae; Serotonin; Sex Factors; Species Specificity; Temperature; Time Factors

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Drug Synergism; Edema; Hindlimb; Histamine; Histamine H1 Antagonists; Inflammation; Kaolin; Male; Rats; Serotonin; Serotonin Antagonists; Time Factors

Topics: Adrenalectomy; Animals; Carrageenan; Complement System Proteins; Inflammation; Kaolin

Topics: Adrenal Glands; Adrenalectomy; Animals; Carrageenan; Formaldehyde; Granulation Tissue; Histamine; Inflammation; Kaolin; Male; Rats; Serotonin; Time Factors; Yeasts

Topics: Acid Phosphatase; Animals; Anti-Inflammatory Agents; Inflammation; Kaolin; Lysosomes; Membranes; Phenylbutazone; Pyrazines; Rats

Topics: Animals; Carrageenan; Complement Inactivator Proteins; Hindlimb; Inflammation; Kaolin; Rats; Tissue Extracts

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Dialysis; Esterases; Exudates and Transudates; Indomethacin; Inflammation; Kaolin; Male; Mice; Mice, Inbred Strains; Rats; Sodium Hydroxide; Species Specificity; Time Factors; Tissue Extracts; Ultraviolet Rays

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Blood Proteins; Carrageenan; Collagen; Female; Fibrinogen; Hexosamines; Hydrocortisone; Hydroxyproline; Inflammation; Kaolin; Male; Neuraminic Acids; Phenylbutazone; Prednisolone; Pyrazoles; Rats; Terpenes

Topics: Animals; Edema; Esterases; Hindlimb; Inflammation; Kaolin; Kidney; Liver; Peptide Hydrolases; Phenylbutazone; Rats

Topics: Animals; Blood Proteins; Blood Viscosity; Carrageenan; Female; Fibrinogen; Glucose-6-Phosphatase; Glycoproteins; Hexosamines; Hydroxyproline; Inflammation; Kaolin; Male; Mucoproteins; Neuraminic Acids; Rats

Topics: Adrenocorticotropic Hormone; Aminopyrine; Animals; Anti-Inflammatory Agents; Aspirin; Carrageenan; Dextrans; Dimethyl Sulfoxide; Disease Models, Animal; Edema; Flufenamic Acid; Formaldehyde; Granuloma; Indomethacin; Inflammation; Kaolin; Male; Mefenamic Acid; Ovalbumin; Oxyphenbutazone; Phenylbutazone; Prednisolone; Rats; Sodium Salicylate; Trypsin

Topics: Acetophenones; Analgesics; Animals; Anti-Inflammatory Agents; Benzene Derivatives; Carrageenan; Chelating Agents; Chemical Phenomena; Chemistry; Edema; Granuloma; Inflammation; Kaolin; Rats

Topics: Animals; Blood Sedimentation; Carrageenan; Cholesterol; Copper; Female; Fucose; Hexosamines; Inflammation; Iron; Kaolin; Lipids; Male; Neuraminic Acids; Phospholipids; Rats; Triglycerides

Topics: Aniline Compounds; Animals; Anti-Inflammatory Agents; Asbestos; Dextrans; Disease Models, Animal; Drug Combinations; Edema; Evaluation Studies as Topic; Female; Formaldehyde; Granuloma; Indomethacin; Inflammation; Kaolin; Phenylbutazone; Prednisolone; Rats; Rats, Inbred Strains; Salicylates; Serotonin; Sodium Salicylate

Topics: Animals; Anthracenes; Arthritis; Carrageenan; Chlorpromazine; Diazepam; Edema; Foot; Hindlimb; Inflammation; Kaolin; Male; Pleurisy; Rats; Rats, Inbred Strains; Tranquilizing Agents; Turpentine

Topics: Acute Disease; Animals; Carrageenan; Formaldehyde; Immunization; Inflammation; Kaolin; Mice; Propionates; Saponins; Staphylococcus; Toxins, Biological

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Exudates and Transudates; Hindlimb; Inflammation; Kaolin; Male; Phenylbutazone; Quinones; Rats

Topics: Animals; Anti-Inflammatory Agents; Chemical Phenomena; Chemistry; Hydantoins; Inflammation; Kaolin; Rats; Uracil

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Edema; Hexosamines; Inflammation; Injections; Kaolin; Neuraminic Acids; Phenylbutazone; Rats

Topics: Acetylcholine; Aerosols; Albumins; Anaphylaxis; Animals; Anti-Inflammatory Agents; Bradykinin; Bronchial Spasm; Edema; Erythema; Exudates and Transudates; Female; Gossypium; Granuloma; Guinea Pigs; Histamine; History of Medicine; In Vitro Techniques; Inflammation; Irritants; Kaolin; Lung; Male; Prednisolone; Rats; Serotonin; Ultraviolet Rays; Vitamin K; Vitamin K 1

Topics: Abscess; Animals; Anti-Inflammatory Agents; Carrageenan; Croton Oil; Edema; Female; Formaldehyde; Gossypium; Granuloma; Inflammation; Irritants; Kaolin; Male; Models, Theoretical; Mononuclear Phagocyte System; Parabiosis; Rats; Saccharomyces; Thorium Dioxide; Zymosan

Topics: Animals; Antimetabolites; Inflammation; Kaolin; Male; Nucleosides; Rats

Topics: Aminopyrine; Animals; Anti-Inflammatory Agents; Edema; Hindlimb; Indomethacin; Inflammation; Kaolin; Male; Phenylbutazone; Rats; Sodium Salicylate

Topics: Analgesics; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antipyretics; Edema; Inflammation; Kaolin; ortho-Aminobenzoates; Pharmacology; Rats; Research; Toxicology

Topics: Aminopyrine; Analgesics; Analgesics, Non-Narcotic; Animals; Antipyretics; Antipyrine; Azoles; Edema; Inflammation; Kaolin; Magnesium; Phenacetin; Phenylbutazone; Prednisolone; Rats; Salicylamides