Application Of Non-steroidal Anti-inflammatory Drugs Research Articles

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers of Celecoxib for Topical Application – Preparation, Characterization and Drug Penetration Through Rat Skin

Lipid nanoparticles have been paid growing interest for topical application of non-steroidal anti-inflammatory drugs to increase skin penetration and to reduce side effects. Solid lipid nanoparticles and nanostructured lipid carriers of celecoxib were prepared by high-pressure homogenization technique. Transmission electron microscopy, fourier transform infrared spectroscopy, differential scanning calorimetry, photon correlation spectroscopy and laser diffraction were used for characterization of nanoparticles. Their physical stability was investigated for 6 months of storage at the room temperature, 4oC and 40oC. Nanoemulsions were also prepared at the same conditions for comparison with the aim of pyhsico-chemical characterization of nanoparticles. Spherical nanoparticles with high drug payload were obtained below 250 nm when similar particle sizes were observed for 3 months of storage at all temperatures. Low microparticle content was detected in formulations after 6 months when d(0.5) values were below 270 nm at room temperature and 4oC. 40oC was not detected as a suitable storage condition for formulations. Nanoparticles were observed to provide controlled drug release. Their release profiles fitted Korsmeyer-Peppas model indicating Fickian diffusion release (case I diffusional) as the dominant mechanism. In ex-vivo skin penetration experiments through abdominal rat skins, solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsion significantly increased drug penetration rate 1.4-2.2 times higher compared to a traditional gel formulation containing celecoxib (p0.05). Nanoemulsion displayed the highest drug penetration rate among nano-formulations. Lipid nanoparticles and nanoemulsion were found as good canditates in order to transport celecoxib through deeper skin layers increasing drug penetration.

Consideration of application of non-steroidal anti-inflammatory drugs in the treatment of allergic conjunctivitis

Allergic conjunctivitis is a very common pathology and its incidence has increased in developing countries with the development of industrialization.At present,the therapy of allergic conjunctivitis is mainly the use of topical eyedrops to eliminate causative factors,relieve symptoms and prevent complications.The drugs used in allergic conjunctivitis have 6 groups,including antihistamine,mastocyte stabilizer,drugs with dual effects (antihistamine and mastocyte stabilizer),non-steroidal anti-inflammatory drugs (NSAIDs),glucocorticoids and immunosuppressors.The goals of topical use of antihistamine,mastocyte stabilizer and drugs of dual effects are to remove the itching and hyperaemia of eye or to treat the patients with acute allergic conjunctivitis; while NSAIDs,glucocorticoids and immunosuppressors are used for the patients with severe or chronic allergic conjunctivitis.The glucocorticoid drugs are more effective because of their arresting effects in several links of the allergic response.Nevertheless,the long-term use of glucocorticoids probably results in ocular hypertension or posterior subcapsular cataract,furthermore,glucocorticoid drugs should be more cautionary in the application of the patients with corneal ulcer.Immunosuppressors inhibit abnormal immune responses,but these drugs should not be used for a long term because of higher cost and adverse effects.NSAIDs have a good anti-inflammatory effect and less irritant,so the topical use of NSAIDs for allergic conjunctivitis appears to be a better choice nowadays. Key words: Conjunctivitis, allergic/drug therapy; Ophthalmic solution/therapeutic use; Anti-allergic agent/therapeutic use; Anti-inflammatory agent/therapeutic use; Non-steroidal/therapeutic use

Dermal Cell Damage Induced by Topical Application of Non-Steroidal Anti-Inflammatory Drugs is Suppressed by Trehalose Co-Lyophilization in <i>Ex Vivo</i> Analysis

ABSTRACT Topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) is generally considered safer than oral administration, although the former can occasionally induce cutaneous irritation. We hypothesized that the cutaneous irritation by topical NSAIDs might be suppressed by trehalose, which has protective effects on biological membranes. Using the three-dimensional cultured human skin model, Living Skin Equivalent-high, we found that cutaneous damage due to NSAIDs was reduced by concomitant use of trehalose and that this effect of trehalose was reinforced by co-lyophilization of NSAIDs with trehalose. The anti-inflammatory effect of co-lyophilized NSAIDs with trehalose was comparable to that seen with NSAIDs alone in a rat model. Our results suggest that co-lyophilization of NSAIDs with trehalose might be a novel procedure that can help prevent NSAIDs-induced skin irritation.

Endovascular Cooling and Endothelial Activation in Hemorrhagic Stroke Patients

Little is known about endothelial activation under the influence of endovascular temperature management. This analysis was designed to measure the endothelial markers Angiopoietin-1 (Ang-1) and -2 (Ang-2) in endovascularly based prophylactic normothermia versus conventional temperature management. In this randomized controlled trial patients with spontaneous subarachnoid or spontaneous intracerebral hemorrhage were prospectively enrolled and randomized in two treatment arms: (a) prophylactic normothermia group with target core temperature 36.5°C using endovascular cooling, (b) active control group with conventional stepwise predefined fever management using antipyretic medication and surface cooling. Blood samples were obtained on days 1, 4, and 7. In a substudy Ang-1 and -2 were measured in 63 patients for whom samples on consecutive days were available. The median total fever burden during the course of treatment was 0.0°C and 5.9°Ch in the endovascular and the conventional group, respectively (P<0.0001). Angiopoietin serum levels did not yield a statistical difference when comparing the two treatment arms. Ang-1 was significantly lowered, whereas Ang-2 levels were significantly elevated on day 4 compared to baseline levels irrespective of group allocation (P<0.0001). The application of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with significantly increased Ang-1 (P<0.05) and lower Ang-2 levels on day 7 (P<0.05). Endovascular long-term temperature management did not alter Ang-1 and -2 levels compared to the control group indicating that the endovascular cooling technique itself does not lead to additional endothelial impairment. However, application of NSAIDs led to lower Ang-2 serum concentrations in the endovascular group.

Nem-szteroid gyulladásgátlók alkalmazása az 5-fluorouracil hatékonyságának növelésére kísérletes rendszerekben

The elevated cyclooxygenase-2 (COX-2) expression has been shown to affect the carcinogenesis and tumor progression processes, including cell proliferation, motility and angiogenesis. COX-2 is overexpressed in approximately 80% of sporadic colorectal carcinomas and COX-2 enzyme is the best defined target of non-steroidal anti-inflammatory drugs (NSAIDs). In the chemotherapy of colorectal carcinomas 5-fluorouracil (5-FU) has been the most important of the basic drugs for more than 40 years. In order to improve the effectiveness of 5-FU therapy different biological modifiers i.e. inhibitors of its catabolism or activators of anabolism have been studied recently. The rate-limiting enzyme of 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD) since more than 80% of the administered 5-FU is catabolized by DPD. Tumoral DPD has become of clinical interest because elevated intratumoral DPD can decrease the tumor response to 5-FU therapy. The main purpose of our experiments was to investigate the effect of COX inhibitors on the efficacy of 5-FU on high and low COX-2 expressing HCA-7 and HT-29 human colon adenocarcinoma cell lines, respectively, and also on xenografts derived from HT-29 cells. The cytotoxic and antitumor effects of 5-FU in the presence of low doses of indomethacin (non-selective COX-2 inhibitor) and that of NS-398 (highly selective COX-2 inhibitor) on HT-29 and HCA-7 cells and also on the HT-29 xenograft were investigated. In addition, our intention was to understand the mechanism(s) by which NSAIDs could enhance the cytotoxic effect of 5-FU. Our data indicated that the elevated COX-2 expression of HCA-7, the collagen-induced HT-29-C cells and of the HT-29 xenograft were associated with reduced 5-FU sensitivity. Based on the fact that at the same time DPD activity was also increased it might be conceivable that a possible explanation for the decrease of 5-FU sensitivity is the co-existence of high COX-2 and DPD activity. Indomethacin or NS-398 enhanced in a simultaneous and significant manner the sensitivity and cytotoxic effect of 5-FU on high COX-2 expressing cells and xenografts through the modulation of DPD - decrease of its mRNA expression and/or enzyme activity. Based on our results it could be presumable that 5-FU efficacy is limited by the COX-2 associated high DPD expression and activity in patients with colorectal cancer as well, therefore further clinical studies are warranted to decide if NSAIDs in the therapeutic protocol might improve the antitumor potency of 5-FU. Réti A. Application of non-steroidal anti-inflammatory drugs to enhance 5-fluorouracil efficacy in experimental systems.

231 Application of non-steroidal anti-inflammatory drugs to enhance 5-fluorouracil efficacy on experimental systems

Background & Aims: Many reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic effects, but the precise molecular mechanism(s) responsible are unclear. We evaluated the effect of cyclooxygenase (COX) inhibitors (NSAIDs) on human colon carcinoma cells (HCA-7) and identified several genes that are regulated after treatment with NS-398, a selective COX-2 inhibitor. Methods: Differential display polymerase chain reaction cloning techniques were used to identify genes regulated by treatment with NSAIDs and selective COX-2 inhibitors. Results: A prostate apoptosis response 4 (Par-4) gene was up-regulated after NSAID treatment. Par-4 was first isolated from prostate carcinoma cells undergoing apoptosis, and expression of Par-4 sensitized cancer cells to apoptotic stimuli. Par-4 levels were increased in cells treated with COX inhibitors such as NS-398, nimesulide, SC-58125, and sulindac sulfide. Treatment of HCA-7 cells with these agents also induced apoptotic cell death. Conclusions: The results suggest that regulation of Par-4 contributes to the proapoptotic effects of high-dose COX inhibitors (NSAIDs) by serving as a downstream mediator leading to initiation of programmed cell death.GASTROENTEROLOGY 2000;118:1012-1017

Application of non-steroidal anti-inflammatory drugs for palladium determination

AbstractA highly sensitive spectrophotometric method for palladium determination using piroxicam and tenoxicam as new chromogenic reagents has been developed. In the presence of sodium lauryl sulfate (SLS), palladium reacts with piroxicam (PX) or tenoxicam (TX) to form stable yellow orange complexes in an acetate buffer solution of pH 5.0 at 424 nm and 426 nm with molar absorptivity of 7.16 × 104 L mol−1 cm−1 and 1.20 × 105 L mol−1 cm−1, respectively. Sandell sensitivity, detection, and quantitation limits were also calculated. Optimum conditions were evaluated considering pH, reagent concentration, time, temperature, and surfactant concentration. The complex system conforms to Beer’s law over the range of 0.07–1.28 μg mL−1 palladium. The stoichiometric ratio and stability constant were also evaluated. Tolerance limits of many cations and anions were determined. Finally, the proposed method was applied successfully in the determination of palladium in jewellery, anode mud, synthetic mixtures, catalysts, and alloy samples.

New Therapeutic Approaches for the Treatment of Rheumatoid Arthritis may Rise from the Cholinergic Anti-Inflammatory Pathway and Antinociceptive Pathway

Due to the complex etiology of rheumatoid arthritis (RA), it is difficult to be completely cured at the current stage although many approaches have been applied in clinics, especially the wide application of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). New drug discovery and development via the recently discovered cholinergic anti-inflammatory and antinociceptive pathways should be promising. Based on the above, the nicotinic acetylcholine receptor agonists maintain the potential for the treatment of RA. Therefore, new therapeutic approaches may rise from these two newly discovered pathways. More preclinical experiments and clinical trials are required to confirm our viewpoint.

Effects of Diclofenac Epolamine Patch on Postoperative Sore Throat in Parturients After Cesarean Delivery Under Endotracheal General Anesthesia

Postoperative sore throat is a common problem. The efficacy of topical application of non-steroidal anti-inflammatory drugs in alleviating postoperative sore throat has not been established. Our aim was to evaluate the analgesic effects of diclofenac epolamine patch on postoperative sore throat. The study was conducted in a prospective, randomized, double-blind, and placebo-controlled manner. Two hundred and twenty women undergoing elective cesarean section (because of previous cesarean section) were randomized into two equal groups: the diclofenac epolamine patch group and the placebo group. The surgery was performed under general anesthesia after rapid sequence induction. Data of the baseline characteristics, the incidence and severity of sore throat and the adverse effects of diclofenac patch were collected. The participants were similar in baseline characteristics. The incidence of sore throat, as assessed 12, 24 and 48 hours after using the patch was significantly lower in the diclofenac patch group than in the placebo patch group, with p values 0.04, < 0.001 and 0.015, respectively. None of the participants dropped out of the study because of complications. The diclofenac epolamine patch is effective and safe in prevention of sore throat following intubation general anesthesia in cesarean section.

Exercise and weight loss are key to treating osteoarthritis.

Osteoarthritis is the most common joint disease and a leading cause of pain and disability in older people. Joint replacement for osteoarthritis of the hip is the only intervention with a large effect, but is only appropriate for patients with advanced disease. There is evidence that topical application of non-steroidal anti-inflammatory drugs (NSAIDs) is helpful. Although less effective in pain relief, oral paracetamol should be tried before oral NSAIDs as it has a lower risk of side effects. Some long-used treatments, such as arthroscopic debridement and glucosamine, are now thought to be ineffective.

Advance in clinical application of non-steroidal anti-inflammatory drugs

非甾体抗炎药(non-steroidal anti-inflammatory drugs,NSAIDs)应用广泛,不仅可用于抗炎、镇痛,在防治肿瘤、阿尔茨海默病及脑保护等方面也发挥一定疗效.过去认为其药理作用与抑制环氧合酶-2(COX-2)有关,而其副作用与抑制COX-1有关.近期的研究则发现,COX-1和COX-2在炎症反应部位和胃肠道、肾脏等器官均有表达,NSAIDs的药理作用和不良反应均与两者密切相关;同时发现特异性COX-2抑制剂因打破体内COX-1与COX-2的平衡而具有潜在心血管危险性.因而传统所谓COX-2抑制作用越特异,副作用越小的观点可能是错误的。

Prenatal Constriction of the Fetal Ductus Arteriosus - Related to Maternal Pain Medication?

Physiological fetal circulation requires patency of the ductus arteriosus. As gestation proceeds, the sensitivity of the ductus to dilating prostaglandins diminishes. The sensitivity to constricting agents like PGE-synthetase inhibitors, present in many analgetics, however, increases. Fetuses affected by an antenatal constriction of the ductus arteriosus (DC) may present with different signs of cardiac failure including dilated right ventricle, tricuspid regurgitation and abnormal venous Doppler. We report on four cases with prenatal DC, presenting at 34, 35, 36 and 37 weeks of gestation. They were referred to fetal echocardiography because of abnormal routine echo scans with unexplained signs of right heart decompensation. Three patients were medicated during pregnancy with either aspirin (low dose), metamizole or ibuprofen. One patient did not take any drugs, especially no pain medication drug in pregnancy. Immediate delivery was performed in all cases. The neonates were in a good condition; echocardiography showed different degrees of right heart hypertrophy which disappeared in all infants by the age of 3 months except in case 2. Unexplained fetal right heart decompensation requires detailed echocardiographic evaluation of the ductus arteriosus and a sophisticated medical history with regard to analgesics. In contrast to ibuprofen and high-dose aspirin, metamizole and low-dose aspirin have not yet been reported as possible agents constricting the fetal arterial duct. In any suspected context, early delivery as in our cases may save babies life. Any application of non-steroidal anti-inflammatory drugs in pregnancy requires close fetal follow-up due to their potentially life-threatening effect.

Changes in Mechanical, Chemical, and Thermal Sensitivity of the Cornea after Topical Application of Nonsteroidal Anti-inflammatory Drugs

In addition to their well-known anti-inflammatory actions, some of the nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have an analgesic effect. In human subjects, the changes in threshold and intensity of sensations evoked by mechanical, chemical, and thermal stimulation of the cornea induced by topical administration of two commercial NSAIDs, diclofenac sodium (Voltaren; Novartis, Basel, Switzerland) and flurbiprofen (Ocuflur; Allergan, Irvine, CA), were studied. Corneal sensitivity was measured in 10 young, healthy subjects with a gas esthesiometer. Chemical (10%-70% CO2 in air), mechanical (0-264 mL/min), and thermal (corneal temperature changes between -4.5 degrees C and +3 degrees C around the normal value) stimuli were applied to the center of the cornea. The intensity and perceived magnitude of the psychophysical attributes of the evoked sensation were scored at the end of the pulse in a 10-cm, continuous visual analog scale (VAS). The threshold was expressed as the stimulus intensity that evoked a VAS score >0.5. Sensitivity was measured in both eyes of each subject on two separate days, one without treatment and the other 30 minutes after topical application of 0.03% flurbiprofen (seven subjects) or 0.1% diclofenac sodium (six subjects). Diclofenac attenuated significantly all the sensation parameters evoked by high-intensity mechanical, chemical, and thermal stimuli. Flurbiprofen produced a slight reduction of the sensations evoked by mechanical and chemical stimulation that became significant only for the irritation caused by chemical stimuli of maximum intensity (70% CO2). None of the drugs modified significantly the detection threshold of the different stimuli. Flurbiprofen had a very limited effect on sensations evoked by corneal stimulation, whereas diclofenac reduced the intensity of sensations evoked by stimuli of different modality, suggesting a mild local anesthetic effect of this drug on all types of corneal sensory fibers. Such anesthetic action could explain the analgesic effect that has been reported after topical application of diclofenac in inflamed human eyes.

Acid-Induced Pain and Its Modulation in Humans

Despite the discovery of ion channels that are activated by protons, we still know relatively little about the signaling of acid pain. We used a novel technique, iontophoresis of protons, to investigate acid-induced pain in human volunteers. We found that transdermal iontophoresis of protons consistently caused moderate pain that was dose-dependent. A marked desensitization occurred with persistent stimulation, with a time constant of approximately 3 min. Recovery from desensitization occurred slowly, over many hours. Acid-induced pain was significantly augmented in skin sensitized by acute topical application of capsaicin. However, skin desensitized by repeated capsaicin application showed no significant reduction in acid-induced pain, suggesting that both capsaicin-sensitive and insensitive sensory neurons contribute to acid pain. Furthermore, topical application of non-steroidal anti-inflammatory drugs (NSAIDs) significantly attenuated acid-evoked pain but did not affect the heat pain threshold, suggesting a specific interaction between NSAIDs and peripheral acid sensors. Subcutaneous injection of amiloride (1 mm) also significantly inhibited the pain induced by iontophoresis of acid, suggesting an involvement of acid-sensing ion channel (ASIC) receptors. Conversely, iontophoresis of acid over a wide range of skin temperatures from 4 to 40 degrees C produced only minor changes in the induced pain. Together these data suggest a prominent role for ASIC channels and only a minor role for transient receptor potential vanilloid receptor-1 as mediators of cutaneous acid-induced pain.

Eudragit RS100 ® nanosuspensions for the ophthalmic controlled delivery of ibuprofen

Topical application of non-steroidal anti-inflammatory drugs on the eye is a common treatment used to contrast the miosis induced by surgical traumas, such as cataract extraction. With the aim of improving the availability of sodium ibuprofen (IBU) at the intraocular level, IBU-loaded polymeric nanoparticle suspensions were made from inert polymer resins (Eudragit RS100 ®). The nanosuspensions were prepared by a modification of the quasi-emulsion solvent diffusion technique using variable formulation parameters (drug-to-polymer ratio, total drug and polymer amount, stirring speed). Nanosuspensions had mean sizes around 100 nm and a positive charge ( ζ-potential of +40/+60 mV), this makes them suitable for ophthalmic applications. Stability tests (up to 24 months storage at 4 °C or at room temperature) or freeze-drying were carried out to optimize a suitable pharmaceutical preparation. In vitro dissolution tests indicated a controlled release profile of IBU from nanoparticles. In vivo efficacy was assessed on the rabbit eye after induction of an ocular trauma (paracentesis). An inhibition of the miotic response to the surgical trauma was achieved, comparable to a control aqueous eye-drop formulation, even though a lower concentration of free drug in the conjunctival sac was reached from the nanoparticle system. Drug levels in the aqueous humour were also higher after application of the nanosuspensions; moreover, IBU-loaded nanosuspensions did not show toxicity on ocular tissues.

Nutritional and botanical modulation of the inflammatory cascade--eicosanoids, cyclooxygenases, and lipoxygenases--as an adjunct in cancer therapy.

Emerging on the horizon in cancer therapy is an expansion of the scope of treatment beyond cytotoxic approaches to include molecular management of cancer physiopathology. The goal in these integrative approaches, which extends beyond eradicating the affected cells, is to control the cancer phenotype. One key new approach appears to be modulation of the inflammatory cascade, as research is expanding that links cancer initiation, promotion, progression, angiogenesis, and metastasis to inflammatory events. This article presents a literature review of the emerging relationship between neoplasia and inflammatory eicosanoids (PGE2 and related prostaglandins), with a focus on how inhibition of their synthesizing oxidases, particularly cyclooxygenase (COX), offers anticancer actions in vitro and in vivo. Although a majority of this research emphasizes the pharmaceutical applications of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors, these agents fail to address alternate pathways available for the synthesis of proinflammatory eicosanoids. Evidence is presented that suggests the inhibition of lipoxygenase and its by-products-LTB4, 5-HETE, and 12-HETE-represents an overlooked but crucial component in complementary cancer therapies. Based on the hypothesis that natural agents capable of modulating both lipoxygenase and COX may advance the efficacy of cancer therapy, an overview and discussion is presented of dietary modifications and selected nutritional and botanical agents (notably, omega-3 fatty acids, antioxidants, boswellia, bromelain, curcumin, and quercetin) that favorably influence eicosanoid production.

Many actions of cyclooxygenase-2 in cellular dynamics and in cancer.

Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenase, the enzyme that catalyzes the rate-limiting step in prostaglandin synthesis from arachidonic acid. Various prostaglandins are produced in a cell type-specific manner, and they elicit cellular functions via signaling through G-protein coupled membrane receptors, and in some cases, through the nuclear receptor PPAR. COX-2 utilization of arachidonic acid also perturbs the level of intracellular free arachidonic acid and subsequently affects cellular functions. In a number of cell and animal models, induction of COX-2 has been shown to promote cell growth, inhibit apoptosis and enhance cell motility and adhesion. The mechanisms behind these multiple actions of COX-2 are largely unknown. Compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is a key step in carcinogenesis. Overexpression of COX-2 is sufficient to cause tumorigenesis in animal models and inhibition of the COX-2 pathway results in reduction in tumor incidence and progression. Therefore, the potential for application of non-steroidal anti-inflammatory drugs as well as the recently developed COX-2 specific inhibitors in cancer clinical practice has drawn tremendous attention in the past few years. Inhibition of COX-2 promises to be an effective approach in the prevention and treatment of cancer, especially colorectal cancer.

Acetaminophen protects hippocampal neurons and PC12 cultures from amyloid β-peptides induced oxidative stress and reduces NF-κB activation

The present findings show that an atypical non-steroidal anti-inflammatory drug, such as acetaminophen, retains the ability to recover amyloid β-peptides driven neuronal apoptosis through the impairment of oxidative stress. Moreover, this compound reduces the increased NF-κB binding activity, which occurs in these degenerative conditions. Therapeutic interventions aimed at reducing the inflammatory response in Alzheimer’s disease (AD) recently suggested the application of non-steroidal anti-inflammatory drugs. Although the anti-inflammatory properties of acetaminophen are controversial, it emerged that in an amyloid-driven astrocytoma cell degeneration model acetaminophen proved to be effective. On these bases, we analyzed the role of acetaminophen against the toxicity exerted by different Aβ-peptides on rat primary hippocampal neurons and on a rat pheochromocytoma cell line. We found a consistent protection from amyloid β-fragments 1-40 and 1-42-induced impairment of mitochondrial redox activity on both cell cultures, associated with a marked reduction of apoptotic nuclear fragmentation. An antioxidant component of the protective activity emerged from the analysis of the reduction of phospholipid peroxidation, and also from a significant reduction of cytoplasmic accumulation of peroxides in the pheochromocytoma cell line. Moreover, activation of NF-κB by amyloid-derived peptides was greatly impaired by acetaminophen pre-treatment in hippocampal cells. This evidence points out antioxidant and anti-transcriptional properties of acetaminophen besides the known capability to interfere with inflammation within the central nervous system, and suggests that it can be exploited as a possible therapeutic approach against AD.

Assessment of acrylic bone cement as a local delivery vehicle for the application of non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used to reduce the inflammation and pain in patients suffering from arthritis. There is a possible use for these drugs in the treatment of inflammation associated with periodontitis. However, the propensity of NSAIDs to cause serious side effects, including gastrointestinal bleeding, has reduced their usefulness. The local application of NSAIDs can avoid these side effects by delivering low doses of drug directly to the affected site. Three NSAIDs (indomethacin, tolmetin and mefenamic acid) were incorporated into polymethylmethacrylate bone cement (PMMA) strips in a range of concentrations and their cytotoxicity, pattern of drug release and ability to suppress elevated levels of prostaglandin E 2 (PGE 2) in cultured human peridontal ligament fibroblasts (HPLF) assessed. The strips released between 10 and 30% of the total incorporated drug over 7 days, with the highest levels released by strips containing 20% w/w of drug. Strips containing 20% indomethacin and mefenamic acid released in excess of toxic levels in the first 24 h. Strips containing 20, 10 and 5% w/w NSAID significantly ( P<0.05) reduced the level of PGE 2 expression by E. coli lipopolysaccharide (LPS) challenged cells, with only the 20% mefenamic acid strip performing significantly better than the other drugs. We conclude that local delivery of NSAIDs using PMMA as a sustained release vehicle is a possible additional tool in the treatment of periodontitis.

Dose-dependent competitive block by topical acetylsalicylic and salicylic acid of low pH-induced cutaneous pain

In a human acid pain model, which uses continuous intradermal pressure infusion of a phosphate-buffered solution (pH 5.2) to induce localized non-adapting pain, the flow was adjusted to result in constant pain ratings of about 20% or 50% on a visual analog scale (VAS). Six volunteers in each group participated in 4 different placebo-controlled double-blind cross-over studies to measure rapidly evolving cutaneous analgesia from topically applied new ointment formulations of acetylsalicylic acid (ASA) and salicylic acid (SA) as well as of commercial ibuprofen and benzocain creams. Similar, log-linear dose-response curves were found for both ASA and SA, significant in effect at 3 g/ kg and higher drug contents and reaching saturation level at 15 or 30 g/ kg, respectively, which, 20 min after application, caused a mean pain suppression of 95% using ASA and 80% using SA. Half-maximal effects were achieved using 3 g/kg ASA or 15 g/kg SA. The SA action was also clearly slower to develop. With an increased flow of the acidic buffer, producing lower effective tissue pH and more intense pain, the effect of ASA and SA decreased to 73% pain suppression. A competitive mechanism of both drug effects was suggested by the fact that, with 15 g/kg ASA and SA, pain reduction could be reversed by increasing the buffer flow by a factor of 1.75., on average. Commercial ibuprofen (50 g/kg) and benzocain creams (100 g/kg) were comparably as effective as ASA and SA, but the local anesthetic caused a loss of all cutaneous sensations while the touch threshold (von Frey) under the specific analgesics was the same as under the placebo ointment. Thus, topical applications of non-steroidal anti-inflammatory drugs (NSAIDs) dissolved in different ointment formulations have proven dose-dependently effective and specific in suppressing experimental acidotic pain by a local and competitive mechanism.