Nonsteroidal Anti-inflammatory Ketorolac Research Articles

Chemoproteomic analysis of the promising candidate molecule of the indole derivative with lab code SV-1010 and other non-steroidal anti-inflammatory drugs

Introduction: For effective and safe pharmacotherapy of pain, it is important to evaluate the mechanisms and spectrum of action of non-steroidal anti-inflammatory drugs (NSAIDs), including their effect on the proteom, central effect, as well as pain relieving and anti-inflammatory effects. The aim of the study was to evaluate the complex of differences between the promising candidate-molecule of indole derivative SV-1010 and the well-known NSAIDs. Materials and Methods: Chemoproteomic moduling of pharmacological effects of SV-1010 and NSAID diclofenac, nimesulide and ketorolac on the rat proteom by means of topological analysis of chemographs. Results: The significant differences in the effects of the studied molecules were found for 820 proteins of the rat proteom. SV-1010, to a lesser degree than the other molecules, can inhibit dopamine D1- and D2-type receptors and, at the same time, stimulate the release of dopamine in the neostriatum (EC50 = 27 nM). SV-1010, to a greater extent than the other molecules, can inhibit the GABA conveyor (EC50 = 65 nM) and the NMDA receptors Grin1/Grin2b (IC50 175 nM). SV-1010 can activate Cannabinoid CB2 receptors, inhibit enzymes of leukotriene biosynthesis, CC receptors of pro-inflammatory chemokines and leukotrienes. Conclusion: The chemoreactomic and chemoproteomic profiling of SV-1010 indicated its potential central effect through dopaminergic and GABA-neurotransmission and additional anti-inflammatory mechanisms, which can help increase pain-relieving effects.

Effect of Transdermal Microneedle Patch Plus Nonsteroidal Anti-Inflammatory Drug in Knee Osteoarthritis: A Randomized, Double-Blind Study

Purpose: No recent clinical study has shown the efficacy of transdermal microneedle patch (TDM) plus nonsteroidal antiinflammatory drug (NSAID) in early knee osteoarthritis (OA). This study aimed to determine the effect of TDM plus NSAID on synovial hypertrophy, knee pain, and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score in osteoarthritic knees. Methods: A randomized, controlled, double-blind trial was conducted. One hundred participants, aged 40–70 years, with painful knee OA and radiographic nonstructural changes were randomly assigned into two groups to undergo TDM plus NSAID (ketorolac 30 mg) or TDM (placebo) at the medial joint line of the knee twice (once weekly). The synovial thickness was measured using ultrasonography at pretreatment, weeks 1, 2, and 4. The visual analog scale (VAS) for pain, WOMAC score, and adverse events (AEs) were also recorded. Results: The TDM plus NSAID group demonstrated a significant reduction in synovial thickness and VAS at weeks 2 and 4 compared with the placebo group (P<0.05). At week 4, the mean synovial thickness reduction was 1.1 and 0.3 mm, and the mean VAS reduction was 3.2 and 1.7 for the TDM plus NSAID and placebo groups, respectively. The mean WOMAC scores at week 4 were significantly reduced (5.7 and 0.9 for the TDM plus NSAID and placebo groups, respectively). No complication and treatment-related AEs occurred. Conclusions: TDM plus NSAID significantly reduced synovitis and improved the pain score in knee OA after 2 weeks. The WOMAC score improved at week 4 without any AEs. Thai Clinical Trials Registry (TCTR), TCTR identification number is TCTR20200613001.

Retrospective evaluation of the incidence of gastrointestinal bleeding in dogs receiving ophthalmic nonsteroidal anti-inflammatory drugs.

To report the incidence of gastrointestinal (GI) bleeding and associated risk factors in a population of dogs receiving ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs). Medical records of dogs prescribed ophthalmic NSAIDs (cases), dogs receiving systemic NSAIDs alone and dogs receiving systemic prednisone alone (controls). Data were collected retrospectively from the medical records of 204 dogs prescribed ophthalmic NSAIDs (diclofenac, ketorolac, or flurbiprofen), which were subdivided based on if they received any concurrent systemic NSAIDs or glucocorticoids, 136 dogs receiving a systemic NSAID (carprofen or meloxicam) alone, and 151 dogs receiving a systemic glucocorticoid (prednisone) alone at a referral hospital from 2015 to 2019. Gastrointestinal bleeds developed in 8/79 (10.1%) of topical NSAID-only cases, 10/136 (7.4%) of systemic NSAID controls, and 14/151 (9.3%) of systemic glucocorticoid controls, with no significant difference between the three groups (p = .6103). There were no significant differences in GI bleed rates between cases treated with ketorolac, diclofenac, or flurbiprofen (p = .160), although severe GI bleeding was only seen in ketorolac-treated dogs. Presence of a known concurrent risk factor for GI bleeding was significantly associated with the development of GI bleed in dogs on ophthalmic NSAIDs (p = .032). Dogs treated with ophthalmic NSAIDs developed GI bleeding at a frequency comparable to dogs receiving systemic NSAIDs or systemic glucocorticoids alone, suggesting that dogs receiving ophthalmic NSAIDs may be at increased risk of GI bleeding.

Non-steroidal anti-inflammatory drugs ketorolac and etodolac can augment the treatment against pneumococcal meningitis by targeting penicillin-binding proteins.

Streptococcus pneumoniae is the principal etiological agent of acute bacterial meningitis (ABM) which has fatal outcome in children and elderly. Due to poor blood-brain barrier (BBB) permeation, conventional β-lactam antibiotics fail to establish the requisite bactericidal concentration in central nervous system leading to resistance in meningeal infections. The present study intended to identify potential therapeutic alternatives against Streptococcal meningitis. Virtual screening, pharmacokinetics/pharmacodynamics (PK/PD) and anti-bacterial evaluations were employed to screen potential drugs. Molecular docking and structural dynamics simulations were performed to analyze the binding affinity and interaction stability of the drugs against the conventional Penicillin binding protein (PBP) targets. Screened drugs were also checked for interactions with other possible Streptococcal targets and relevant host targets. Non-steroidal anti-inflammatory drugs (NSAIDs) ketorolac and etodolac exhibiting high BBB-permeation and anti-bacterial potency were identified. Ketorolac and etodolac possessed uniform binding affinities against PBP1A, PBP2X, PBP2B and PBP3 with low inhibition constants (<50μM). Against PBP2B and PBP3, higher binding affinities were observed for ketorolac (-6.45 and -6Kcal/mol respectively) and etodolac (-6.36 and -6.55Kcal/mol respectively) than penicillin (-5.95 and -5.85Kcal/mol respectively) and cefotaxime (-5.08 and -5.07Kcal/mol respectively). The binding affinities were contributed by conventional H-bonds and non-canonical interactions with active site residues of PBPs. Structural dynamics simulations further indicated the overall stability of the drug-bound complexes through minimal overall average root-mean square fluctuations (RMSFs) (<1.0Å). The average binding affinities of Ketorolac and Etodolac with PBPs were marginally higher than other Streptococcal targets and comparable to their conventional inflammatory targets. Pharmacological and structural profiles indicated that ketorolac and etodolac can potentially subdue the cause and effects of streptococcal meningitis and hence encourage experimental validations.

Пролонгована паравертебральна аналгезія для знеболювання у хворих після торакотомії

Актуальність. Торакотомія відноситься до одного з найбільш травматичних втручань в хірургії, що супроводжується вираженим гострим болем після операції та розвитком хронічного больового синдрому у віддаленому післяопераційному періоді. Мета дослідження. Порівняти ефективність та безпечність різних методів знеболювання хворих після торакотомії. Матеріали та методи. Після торакотомії 85 хворих було розподілено на три дослідні групи. Знеболювання проводили за допомогою пролонгованої паравертебральної аналгезії (ПВА) (19 хворих) і пролонгованої епідуральної аналгезії (ЕДА) (36 хворих) 0,2% розчином ропівакаїну зі швидкістю 6 мл/год (у паравертебральний або епідуральний простір). У контрольній групі (30 хворих) знеболювання проводилось внутрішньовенною, контрольованою пацієнтом аналгезією розчином морфіну. Як ад’ювантний анальгетик у всіх трьох дослідних групах використовували нестероїдний протизапальний препарат кеторолаку трометамін внутрішньом’язово. У ранньому післяопераційному періоді оцінювали рівень болю в стані спокою та під час фізичного навантаження дихальної мускулатури (виконання спірометрії), показники функції зовнішнього дихання (ФЗД), а також частоту та тип ускладнень застосованих методів знеболювання. У віддаленому післяопераційному періоді оцінювали частоту виникнення хронічного болю. Результати. У групах з пролонгованою ПВА і ЕДА інтенсивність больового синдрому протягом трьох діб післяопераційного періоду за візуальною аналоговою шкалою (ВАШ) у стані спокою була меншою порівняно з контрольною групою. У групі ПВА рівень болю був від 29,1 бала через чотири години після операції до 18,7 бала в кінці третьої доби; у групі ЕДА — від 24,2 до 20,3 бала відповідно; у контрольній групі — від 48,8 до 38,0 бала відповідно. Під час дослідження ФЗД інтенсивність болю в групах ПВА і ЕДА також була нижчою порівняно з контрольною групою і становила 33,8 бала в групі ПВА, 38,7 бала — в групі ЕДА, 61,2 — у контрольній групі. Частоту виникнення хронічного больового синдрому оцінювали через 6 місяців після операції. Було відібрано по 15 хворих із кожної групи. У контрольній групі хронічний больовий синдром розвинувся у 8 хворих (53 %), у групі ЕДА — у 5 хворих (33,3 %), у групі ПВА — у 3 хворих (20 %). Найменша кількість ускладнень і технічних невдач спостерігалась у групі ПВА. Висновки. У групі з пролонгованою ПВА порівняно з пролонгованою ЕДА рівень болю за ВАШ був нижчим, частота випадків хронічного болю меншою, а кількість побічних ефектів мінімальною. Пролонгована паравертебральна блокада у хворих після торакотомії дає змогу ефективно контролювати гострий післяопераційний біль та зменшує розвиток хронічного больового синдрому.

Perioperative systemic nonsteroidal anti-inflammatory drugs (NSAIDs) in women undergoing breast surgery.

Perioperative systemic nonsteroidal anti-inflammatory drugs (NSAIDs) in women undergoing breast surgery.

Intravenous ibuprofen for acute treatment of migraine: A double-blind, randomized, placebo-controlled pilot study.

To evaluate the efficacy and safety of intravenous (IV) Ibuprofen for acute treatment of migraine. IV nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. To date, only three IV NSAIDs (ketorolac, ibuprofen, and meloxicam) are available in the United States for use in moderate and severe pain, but no placebo-controlled trial is available for migraine. We performed a single-center, double-blind, randomized, placebo-controlled pilot study to evaluate the efficacy and safety of IV ibuprofen as an acute treatment of migraine (NCT01230411). Individuals with episodic migraine were screened at the Jefferson Headache Center. Qualified subjects were treated for migraine attacks within 2-72h following the headache onset with either 800mg of IV ibuprofen or placebo in 250ml saline bolus. Migraine pain intensity (4-point Likert scale) and associated symptoms were assessed at predetermined time points (0.25, 0.5, 1, 1.5, 2, 4, 8, 24h). The primary endpoint was pain relief at 2h after infusion. Important secondary endpoints included pain freedom at 2h, sustained relief over 24h, use of rescue therapy, and absence of associated symptoms. Adverse events (AEs) were also collected. Seventy-four participants were enrolled between 2011 and 2017. Forty-four subjects (female 33/44; 75.0%) with mean (SD) age 41.0 (11.2) 11.2 years came for the treatment. All treated subjects (n=44) were included in the analysis. Among them, 23 were randomized to receive IV ibuprofen. Both groups were demographically similar except for longer migraine duration (i.e., years lived with disease) in the active treatment than in the placebo group. At 2h posttreatment, pain relief was found in 74% (17/23) and 48% (10/21) after IV ibuprofen and placebo, respectively (odds ratio [OR] 3.12, 95% CI: 0.88-11.0; p=0.078). Other secondary endpoints at 2 and 24h were not significant. The longitudinal repeated-measures analysis within 2h on ibuprofen treatment showed significant pain relief (OR 2.47, 95% CI 1.08-5.7; p=0.033) and absence of associated symptoms: photophobia (OR 4.0, 95% CI 1.57-10.3; p=0.004), phonophobia (OR 3.12, 95% CI 1.16-8.4; p=0.025), and osmophobia (OR 3.45, 95% CI 1.01-11.8; p=0.048). AEs were observed in seven subjects in both groups, with arm pain being the most common. No serious AE was reported. This study did not meet the primary endpoint but showed pain relief and elimination of several associated symptoms within 2h on repeated-measures analysis. Although limited by small sample size and high placebo response, our results indicate that IV ibuprofen may be a safe and effective option for acute treatment of migraine, but more extensive studies are necessary.

مروری بر داروهای مورد استفاده در درمان درد رنال کولیک در مقالات چاپ شده به زبان فارسی؛ یک مطالعه مروری روایتی

Introduction: Renal colic is the most common clinical manifestation of urinary stones and one of the most common urological emergencies that is very agonizing for the patient due to excruciating pain. Different therapeutic interventions are performed for relieving the pain in patients with renal colic. This narrative review study was performed, aiming to evaluate the medications used for pain management in patients with renal colic. Methods: The present study is a narrative review. In this study, to find related articles, researchers conducted a computer search in SID, Magiran, and Google Scholar databases using Persian keywords meaning renal colic and kidney colic. Studies were searched in Persian language databases without any time limit. Results: In reviewing the articles, various studies were performed on different drugs for controlling pain in patients with renal colic. Most of the studied drugs were opioids (morphine, buprenorphine, tramadol, and pethidine) and non-steroidal anti-inflammatory drugs (NSAIDs) (paracetamol, diclofenac, and ketorolac). Additionally, drugs such as ketamine, desmopressin, aminophylline, and intradermal administration of distilled water were also evaluated. Conclusion: Although narcotics are most effect for relieving pain in patients with renal colic, but the development of side effects such as inhibition of the respiratory center in the medulla and activation of the vomiting center (chemoreceptor trigger zone; CTZ) has limited the use of narcotics. Due to having analgesic effects similar to opioids and fewer side effects, it is recommended to use NSAIDs (Ketorolac) as the first line of treatment for renal colic patients.

Single-dose intravenous ketorolac for acute postoperative pain in adults.

Single-dose intravenous ketorolac for acute postoperative pain in adults.

Comparison of the Efficacy of Intravenous Ketorolac to that of Intravenous Pethidine in Pain Suppression in Patients with Biliary Colic

Aim: The study aimed to compare the effect of intravenous administration of the NSAID (Non-steroidal anti-inflammatory drugs) ketorolac to that of intravenous administration of the opioid pethidine in the suppression of pain in patients with biliary colic.&#x0D; Methodology: The present study is a trial study. Among all the biliary colic patients in Mashhad Referral Hospital Emergency in Iran, 58 patients with inclusion criteria were selected using convenience sampling. They were randomly divided into two groups of 29 patients. In the first group, 1 mg/kg IV pethidine, and in the second group, 30 mg IV ketorolac was injected. The pain severity was assessed prior to the treatment and 15, 30, and 60 minutes after the onset of the treatment using the Visual Analogue Scale (VAS). The data were analyzed using SPSS 20 and Chi-square tests.&#x0D; Findings: The patients' mean age was 45±15 years old (age ranged from 30 to 60 years old). The results showed no significant relationship between pain suppression and medicine type after 15 minutes (P=0.5), 30 minutes (P=0.6), and 1 hour (P=0.7). It means that pethidine and ketorolac have an equal effect on pain suppression in patients with biliary colic. Also, the more time passes from the injection, the more the medicines suppress pain.&#x0D; Conclusion: the results of this study show that the efficacy of NSAIDs in the suppression of moderate to severe pain; therefore, a plan to use NSAIDs instead of narcotics for this purpose is essential.

Effects of repeated treatment with monoamine-transporter-inhibitor antidepressants on pain-related depression of intracranial self-stimulation in rats.

Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks. The present study compared antinociceptive effects produced by repeated treatment with monoamine transporter inhibitors in a preclinical assay of pain-related depression of positively reinforced operant responding. Adult Sprague-Dawley rats equipped with microelectrodes targeting a brain-reward area responded for pulses of electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus that repeatedly depressed ICSS and also produced weight loss during 7days of repeated acid administration. Acid-induced depression of both ICSS and body weight were completely blocked by repeated pretreatment with the nonsteroidal anti-inflammatory drug ketorolac. The DAT-selective inhibitor bupropion also fully blocked acid-induced ICSS depression and weight loss throughout all 7days of treatment. The NET-selective inhibitor nortriptyline and the SERT-selective inhibitor citalopram were generally less effective, but both drugs blocked acid-induced ICSS depression by the end of the 7-day treatment. Acid-induced depression of ICSS and body weight were not blocked by the kappa opioid receptor (KOR) agonist U69593 or the KOR antagonist norbinaltorphimine. These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce significant but less reliable effects.

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.

Sonochemical Formation of Copper/Iron-Modified Graphene Oxide Nanocomposites for Ketorolac Delivery.

A feasible sonochemical approach is described for the preparation of copper/iron-modified graphene oxide nanocomposites through ultrasonication (20 kHz, 18 W cm-2 ) of an aqueous solution containing copper and iron ion precursors. Unique copper-, copper/iron- and iron-modified graphene oxide nanocomposites have a submicron size that is smaller than that of pristine GO and a higher surface area enriched with Cu2 O, CuO, and Fe2 O3 of multiform phases (α-, β-, ϵ-, or γ), FeO(OH), and sulfur- or carbon-containing compounds. These nanocomposites are sonochemically intercalated with the nonsteroidal anti-inflammatory drug ketorolac, which results in the formation of nanoscale carriers. Ketorolac monotonically disintegrates from these nanoscale carriers in aqueous solution upon adjustment of the pH from 1 to 8. The disintegration of ketorolac proceeds at a slower rate from the copper/iron-modified graphene oxide at increased pH, but at a faster rate from the iron-modified graphene oxide under acidic conditions.

Single-dose intravenous ketorolac for acute postoperative pain in adults

Single-dose intravenous ketorolac for acute postoperative pain in adults

Prospective, double-blind, randomized clinical trial comparing an ERAS pathway with ketorolac and pregabalin versus standard of care plus placebo during live donor nephrectomy for kidney transplant.

Opioid exposure is a concern after live donation for kidney transplant. We theorized that an enhanced recovery after surgery pathway (ERAS) using pregabalin preoperatively to desensitize nerves followed by the nonsteroidal anti-inflammatory drug ketorolac, during and after surgery, can control pain, thus requiring less perioperative narcotics. The aim of this study was to determine if the use of a nonopioid analgesic ERAS protocol for donor nephrectomies could decrease the use of narcotics without an increase in complications compared with standard of care (SOC). This is a single-center, prospective, double-blind, randomized clinical trial involving a total of 62 patients undergoing nephrectomy for live donor kidney transplant. Length of hospital stay (LOS) was significantly reduced by 10% in the ERAS group versus the SOC-plus-placebo group. Morphine dose equivalents were significantly reduced by 40% in the study group versus the SOC-plus-placebo group. The use of this nonopioid analgesic ERAS pathway for donor nephrectomies decreased the use of narcotics without an increase in complications compared with SOC. There was significantly reduced LOS and less narcotic use in the study group versus the SOC-plus-placebo group. (ClinicalTrials.gov registration number: NCT03669081).

The properties of the sonochemically functionalized nonsteroidal anti-inflammatory drug ketorolac in an Fe3O4–graphene oxide nanocomposite

A feasible sonochemical method is developed for the complexation of nonsteroidal anti-inflammatory drug ketorolac with the Fe3O4–graphene oxide nanocomposite.

Impact of topical nonsteroidal anti-inflammatory drugs in prevention of macular edema following cataract surgery in diabetic patients.

To evaluate the efficacy of prophylactic administration of topical non-steroidal anti-inflammatory drugs (NSAIDs) on macular edema following cataract surgery in diabetic patients, and to compare between types of NSAIDs (ketorolac tromethamine 0.4% and nepafenac 0.1%). Group 1 (control) received artificial tears substitute as a placebo group, group 2 (nepafenac) received topical nepafenac 0.1%, and group 3 (ketorolac) received topical ketorolac tromethamine 0.4%. Patients were examined postoperatively after completing one week, one month, two months and three months' intervals for evaluating cystoid macular edema (CME) development. The main study outcomes were achieving the best corrected visual acuity (BCVA) and change in the central macular thickness (CMT) measured with optical coherence topography (OCT). Eighty eyes of 76 patients were included in this study. BCVA showed a statistically significant difference at the third month postoperative follow up between the control group and the NSAIDs groups (P=0.04). There was an increase in the CMT in all cases starting from postoperative first week until third month. CMT showed a statistically significant difference between control group and NSAIDs groups from postoperative first month until third month (P=0.008, 0.027, 0.004). There was no statistically significant difference between nepafenac and ketorolac groups in BCVA and OCT CMT. Prophylactic preoperative and postoperative NSAIDs may have a role in reducing the frequency and severity of CME in diabetic eyes following cataract surgery.

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

BackgroundIn the past decade several studies have reported that in some brain areas, particularly, in the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. Given this evidence, in this study we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam microinjected into the rostral part of anterior cingulate cortex (ACC) in rats.MethodsMale Wistar experimental and control (saline) rats were implanted with a guide cannula in the ACC and tested for antinociception following microinjection of NSAIDs into the ACC in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.ResultsTreatment with each NSAID significantly enhanced the TF and HP latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented the analgesic effects of the three NSAIDs in both behavioral assays.ConclusionsThese findings support the concept that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

Synthesis and Biological Evaluation of Mutual Prodrugs of Carboxylic Group Containing Some Non-Steroidal Anti-Inflammatory Drugs and Propyphenazone.

The use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is not up to its potential because of their gastrointestinal side effects. Significant attention has been focused on the growth of bio-reversible derivatives, such as mutual prodrugs, to momentarily mask the acidic group of NSAIDs as a promising means of decreasing or eliminating the GI side effects. The aims of this paper are to synthesize the mutual prodrugs of selected NSAIDs (Ketorolac, niflumic acid, tolfenamic acid) with propyphenazone, a study on their several physicochemical characters, hydrolysis kinetics, antiinflammatory, analgesic activity and ulcerogenicity. Mutual prodrugs were synthesized and their structures were confirmed and characterized using IR, 1H NMR, 13C NMR, mass spectroscopy and their purity was established by elemental analysis. Synthesized prodrugs were subjected for pharmacokinetic studies, analgesic, anti-inflammatory activities and ulcerogenic index. In vitro hydrolysis study of synthesized prodrugs in enzyme-free simulated intestinal fluid (SIF, pH 7.4) and 80% human plasma showed encouraging hydrolysis rate following first order kinetics while found stable in simulated gastric fluid (SGF, pH 1.2). Considerable decrease in ulcerogenic index and better anti-inflammatory activities were found in most of the cases as compared to their parent drugs. Among all prodrugs, viz. KE and NG showed excellent pharmacological response. A very less irritation to gastric mucosal was observed with the synthesized prodrugs than their parent drugs and can be considered for sustained drug release. Encouraging hydrolysis rate in SIF and 80% human plasma, improved analgesic and anti-inflammatory activities and reduced ulcerogenic liabilities of synthesized prodrugs revealed enhancement in the therapeutic index of the parent drugs. On the basis of above observation, it is concluded that mutual prodrugs approach can be applied to obtain synergistic effect for analgesic and anti inflammatory activities as well as to minimize gastrointestinal toxicity of the drug.

Non-steroidal anti-inflammatory drugs attenuate agonist-evoked activation of transient receptor potential channels

Transient receptor potential (TRP) cation channels are the largest group of sensory detector proteins expressed in the nerve terminals of many receptors including nociceptors, and are activated by temperature and chemicals that elicit hot or cold sensations. Antagonists of these channels are likely promising targets for new analgesic drugs at the peripheral and central levels. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we investigated whether three widely used NSAIDs (diclofenac, ketorolac, and xefocam) affect thermal and mechanical hyperalgesia following the activation of TRPA1 and TRPV1 channels. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally at various time points following intraplantar injection of the TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC) or the TRPV1 agonist capsaicin, or vehicle. When pretreated with vehicle, intraplantar injection of CA, AITC and capsaicin each resulted in significant decreases in thermal withdrawal latency and mechanical threshold in the ipsilateral hindpaw that did not return to baseline for more than 2h. To test effects of NSAIDS either diclofenac, ketorolac or xefocam was pre-injected in the same hindpaw 35min prior to CA, AITC or capsaicin. Pretreatment with each of the three NSAIDs produced strong antinociceptive and antihyperalgesic effects lasting approximately 60min. Thus, we show for the first time that local administration of NSAIDs reduces thermal and mechanical hyperalgesia following TRPA1 or TRPV1 activation.