Effects of topical ketorolac tromethamine on tear parameters, meibography, goblet cell density, and conjunctival oxidative stress in healthy dogs.

OBJECTIVES: The objective of the study was to evaluate whether a twice-daily instillation of 0.45% preservative-free ketorolac tromethamine (FKT) or 0.4% benzalkonium chloride-preserved ketorolac tromethamine (BACKT), every 12 h for 30 days may affect tear film parameters and the meibography in healthy dogs. Additionally, we assessed whether the same treatments irritated the ocular surface, affected goblet cell density (GCD), and the levels of oxidative stress biomarkers (OSB) in the conjunctiva of the same dogs. PROCEDURES: Experimental and masked comparison study. In 11 healthy dogs baseline values of the lipid layer thickness, tear meniscus height, non-invasive tear breakup time (NI-TFBT), and the meibomian gland (MG) loss were assessed by OSAvet®. For each dog, one eye received 40 µL of BACKT, while the other received 40 µL FKT, every 12 h for 30 consecutive days. Tear parameters and meibography were repeated 15, 30, and 60 days post-treatments. Conjunctival hyperemia and blepharospasm were monitored at the same time points. At baseline and Day 30, a conjunctival biopsy was collected for GCD and OSB determination. RESULTS: Conjunctival hyperemia and blepharospasm were not observed. At Day 15, the MG loss increased only in FKT-treated eyes (p < .001). On Day 30, both treatment groups showed increased MG loss, shortened NI-TFBT, and reduced GCD and catalase (p < .05). At Day 30, BACKT-treated eyes showed lower levels of superoxide dismutase (SOD) (p = .006) and higher levels of malondialdehyde (MDA) (p = .02). Differences between treatments were not observed for any parameter at any time point (p > .05). 60 days after treatment, OSAvet® parameters tended to return to values assessed at baseline; however, significant differences remained for MG loss (p < .05). CONCLUSIONS: Twice-daily instillation of KT, containing or not BAC, for 30 consecutive days shortened NI-TFBT, decreased GCD, and increased the MG loss in healthy dogs. KT should be used with caution when prescribed for long periods, particularly in patients with tear film abnormalities. However, future controlled studies using KT, BAC, and other topical NSAIDs are indicated to further support this finding.

Ketorolac tromethamine represses senescence in aging articular chondrocytes.

The present study aims to explore the potential function of ketorolac tromethamine in treating osteoarthritis by examining its effects on interleukin-1ß (IL-1ß)-triggered cellular senescence in chondrocytes. More ß-galactosidase (SA-ß-Gal) positively stained cells, promoted cell fraction in the G0/G1 phase, increased release of matrix metalloproteinase (MMP)-3 and MMP-13, and upregulated cellular senescence-related genes (p21 and p53) were observed in IL-1ß-challenged HC-A cells, all of which were significantly reversed by 25 and 50 mg/mL ketorolac tromethamine. Furthermore, the upregulated cyclooxygenase-2 (COX-2) and elevated release of prostaglandin E2 in IL-1ß- challenged HC-A cells were dramatically repressed by ketorolac tromethamine. Lastly, the inhibitory effects of ketorolac tromethamine on the activation of SA-ß-Gal and the upregulation of p21 and p53 were greatly abolished by the overexpression of COX-2. Collectively, ketorolac tromethamine repressed cellular senescence in aging articular chondrocytes by inhibiting COX-2.

HPV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain.

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient's well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae's structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.

Pre-Emptive Topical Ketorolac Tromethamine 0.5% for Panretinal Photocoagulation.

Purpose: To evaluate the efficacy of topical ketorolac tromethamine 0.5% given pre-emptively a day before, for alleviating pain in patients undergoing panretinal photocoagulation (PRP) treatment. Methods: A controlled single-blinded study was conducted on 33 patients with diabetic retinopathy (DR; severe nonproliferative DR, proliferative DR, or advanced diabetic eye disease) who required PRP treatment in both eyes simultaneously. Each eye of the patients was randomly assigned for ketorolac tromethamine 0.5% eyedrop or placebo. Both eyedrop bottles were randomly labeled. Eyedrops were self-administered by the patients, 4 times a day before the procedure (at 6 am, 12 noon, 6 pm, and 12 midnight) and every 15 min for 1 h (4 times) before the laser. Each patient was subjected to PRP using a Visulas 532s Zeiss device set to spot size 200 µm, time 0.10 s, and ∼600 burns in each eye. The pain score was evaluated immediately after treatment in each eye independently with Scott's visual analog scale (VAS) and the McGill Pain Questionnaire (MPQ). Results: VAS pain score in ketorolac-treated eyes (median 3.0, interquatile range [IQR] ±2.5) was lower than in placebo-treated eyes (median 5.0, IQR ±3.0). Total Pain Rate Index score from MPQ was lower in ketorolac-treated eyes (median 3.0, IQR ±3.0) than in placebo-treated eyes (median 3.0, IQR ±2.5). Both pain score differences are statistically significant with P ˂ 0.05. Conclusion: Topical ketorolac tromethamine 0.5% given pre-emptively a day before is effective in alleviating pain in patients undergoing PRP treatment.

Acetaminophen, bupivacaine, Duramorph, and Toradol: A comparison of chondrocyte viability and gene expression changes in osteoarthritic human chondrocytes.

BACKGROUND: A multitude of chemical agents are currently used intra-articularly to decrease pain after orthopaedic procedures including total knee arthroplasty. However, the possible deleterious effects of these injectable chemicals on chondrocyte viability have not been weighed against their potential benefits. Using a human osteoarthritic chondrocyte model, the purpose of this study was to assess the potential for cartilage damage caused by bupivacaine, Toradol, Duramorph, and acetaminophen from surgical local anesthesia. METHODS: Human distal femur and proximal tibia cross sections were obtained during total knee arthroplasty and divided into control group and experimental groups treated by bupivacaine, Toradol, Duramorph, and acetaminophen respectively. Chondrocytes obtained from enzymatically digested cartilage were cultured using a 3D alginate bead culture method to ensure lower rates of dedifferentiation. Chondrocyte bead cultures were exposed to the study chemicals. The gene expression and chondrocyte viability were measured by RT-PCR and flow cytometry, respectively. RESULTS: Compared with untreated group bupivacaine treatment led to the greatest cellular apoptosis with 30.5 ± 11% dead cells (P = 0.000). Duramorph and acetaminophen did not result in a significant increase in cell death. Bupivacaine treatment led to an increase in Caspase 3 gene expression (P = 0.000) as well as the acetaminophen treatment (P = 0.001) when compared to control. CONCLUSION: Our data demonstrated that Duramorph and Toradol were not cytotoxic to human chondrocytes and may be better alternatives to the frequently used and more cytotoxic bupivacaine. Acetaminophen did not result in increased cell death; however, it did show increased caspase 3 gene expression and caution should be considered.

DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG.

Platinum based drugs alone or in combination with 5FU and docetaxel are common regimen chemotherapeutics for the treatment of advanced OSCC. Chemoresistance is one of the major factors of treatment failure in OSCC. Human RNA helicase DDX3 plays an important role in cell proliferation, invasion, and metastasis in several neoplasms. The potential role of DDX3 in chemoresistance is yet to be explored. Enhanced cancer stem cells (CSCs) population significantly contributes to chemoresistance and recurrence. A recent study showed that m6A RNA regulates self-renewal and tumorigenesis property in cancer. In this study we found genetic (shRNA) or pharmacological (ketorolac salt) inhibition of DDX3 reduced CSC population by suppressing the expression of FOXM1 and NANOG. We also found that m6A demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased m6A methylation in FOXM1 and NANOG nascent transcript that contribute to chemoresistance. Here, we found DDX3 expression was upregulated in both cisplatin-resistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. In a patient-derived cell xenograft model of chemoresistant OSCC, ketorolac salt restores cisplatin-mediated cell death and facilitates a significant reduction of tumor burdens. Our work uncovers a critical function of DDX3 and provides a new role in m6 demethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC.

Natamycin niosomes as a promising ocular nanosized delivery system with ketorolac tromethamine for dual effects for treatment of candida rabbit keratitis; in vitro/in vivo and histopathological studies.

OBJECTIVES: This study was aimed to develop dual-purpose natamycin (NAT)-loaded niosomes in ketorolac tromethamine (KT) gels topical ocular drug delivery system to improve the clinical efficacy of natamycin through enhancing its penetration through corneal tissue and reducing inflammation associated with Fungal keratitis (FK). SIGNIFICANCE: Nanosized carrier systems, as niosomes would provide great potential for improving NAT ocular bioavailability.NAT niosomal dispersion formulae were prepared and then incorporated in 0.5%KT gels using different mucoadhesive viscosifying polymers. METHODS: Niosomes were prepared using the reverse-phase evaporation technique. In vitro experimental, and in vivo clinical evaluations for these formulations were done for assessment of their safety and efficacy for treatment of Candida Keratitis in Rabbits. In vitro release study was carried out by the dialysis method. In vivo and histopathological studies were performed on albino rabbits. RESULTS: NAT niosomes exhibited high entrapment efficiency percentage (E.E%) up to96.43% and particle size diameter ranging from 181.75 ± 0.64 to 498.95 ± 0.64 nm, with negatively charged zeta potential (ZP). NAT niosomal dispersion exhibited prolonged in vitro drug release (40.96-77.49% over 24h). NAT-loaded niosomes/0.5%KT gel formulae revealed retardation in vitro release, compared to marketed-product (NATACYN®) and NAT-loaded niosomes up to57.32% (F8). In vivo experimental studies showed the superiority for F8 in treatment of candida keratitis and better results on corneal infiltration and hypopyon level. These results were consistent with histopathological examination in comparison with F5 and combined marketed products (NATACYN® and Ketoroline®). CONCLUSIONS: This study showed that F8 has the best results from all pharmaceutical in vitro evaluations and a better cure percent in experimental application and enhancing the prolonged delivery of NAT and penetrating the cornea tissues.

The R-Enantiomer of Ketorolac Delays Mammary Tumor Development in Mouse Mammary Tumor Virus-Polyoma Middle T Antigen (MMTV-PyMT) Mice.

Epidemiologic studies report improved breast cancer survival in women who receive ketorolac (Toradol) for postoperative pain relief compared with other analgesic agents. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. The goal of this study was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor virus-polyoma middle T-antigen model. Mice were administered ketorolac orally at 1 mg/kg twice daily to approximate the typical human dose. Mammary glands were analyzed for tumor number and immunohistochemical markers of proliferation and differentiation. R-ketorolac treatment significantly reduced mammary epithelial proliferation, based on Ki67 staining, and suppressed tumor development. Proliferative mammary epithelium from R-ketorolac-treated mice displayed greater differentiation, based on significantly higher total E-cadherin and decreased keratin 5 staining than epithelium of placebo-treated mice. No differences were detected in estrogen receptor, progesterone receptor, ß-catenin, or vimentin expression between placebo and R-ketorolac treatment groups. These findings indicate that R-ketorolac treatment slows tumor progression in an aggressive model of breast cancer. R-ketorolac may thus represent a novel therapeutic approach for breast cancer prevention or treatment based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor.

In vitro anti-LPS dose determination of ketorolac tromethamine and in vivo safety of repeated dosing in healthy horses.

Flunixin meglumine (FM) is a commonly used Nonsteroidal anti-inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti-inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)-induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5 mg/kg and 1.1 mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS-induced Thromboxane B2 (TXB2 ) and Prostaglandin E2 (PGE2 ) production in vitro for up to 12 hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5 mg/kg IV inhibited LPS-induced eicosanoids in vitro, and repeated dosing for up to 3 days appears safe in healthy horses. Investigation of in vivo anti-inflammatory and analgesic effects of KT is warranted.

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels.

PURPOSE: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed. METHODS: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. RESULTS: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. CONCLUSIONS: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

Development and Evaluation of Sustained Oral Ketorolac Tromethamine Particulate Matrix via Bioadhesive Chitosan Based Freeze-Dried Solid Dispersions.

OBJECTIVES: This study aimed to develop and evaluate chitosan (CTS) solid dispersion particulate matrix (SDPM) for sustained oral delivery of ketorolac tromethamine (KT). METHODS: SDPM formulations were prepared by freeze drying method and characterized for their effectiveness and biological activities via in vitro and in vivo assessment. KEY FINDINGS: Powder's flowability and bioadhesion of SDPM increased compared to KT-CTS physical mixtures and the raw materials. DSC analysis proved that the extent of drug crystallinity in matrix particles reduced as the amount of CTS content increased. FT-IR spectroscopy suggested drug-polymer interaction that was prominent in SDPM (1:7). In vitro drug release and simulated plasma profiles showed the superiority of SDPM (1:7) in sustaining drug release up to 12h. The optimized formula was stable during the storage time whereas the similarity factor (f2) for in vitro release data before and at the end of the study was 92%. Furthermore, in vivo bioactivity studies confirmed that the ulcerogenic property of SDPM (1:7) remarkably decreased compared to the standard drug while the analgesic and anti-inflammatory properties were maintained. CONCLUSION: Results suggested freeze-dried chitosan based SDPM (1:7) as a potential candidate for sustained oral administration of KT.

pH-sensitive interpenetrating polymer network microspheres of poly(vinyl alcohol) and carboxymethyl cellulose for controlled release of the nonsteroidal anti-inflammatory drug ketorolac tromethamine.

In this study, we aimed to produce pH-sensitive microspheres for the controlled release of the nonsteroidal anti-inflammatory drug, ketorolac tromethamine (KT). For this purpose, an interpenetrating polymer network (IPN) of microspheres of poly(vinyl alcohol) (PVA)/sodium carboxymethyl cellulose (NaCMC) were prepared, based on different formulations using glutaraldehyde (GA) (0.66 M) and hydrochloric acid (HCl) (3%, v/v). The preparation conditions of the microspheres were optimized by considering the percentage of entrapment efficiency and swelling capacity of the microspheres, and their release data. The effects of PVA and NaCMC ratio on the release of KT for over a period of 6 h, at three pH values (1.2, 6.8, and 7.4), have been discussed.

Ketorolac eye drops reduce inflammation and delay re-epithelization in response to corneal alkali burn in rabbits, without affecting iNOS or MMP-9.

PURPOSES: To assess the effects of 0.5% ketorolac tromethamine without preservatives on the expression of iNOS and MMP-9 in alkali burn ulcers. METHODS: Twelve eyes of 120-day-old male rabbits were treated (TG) every 6 h with 0.5% ketorolac tromethamine and 12 other eyes were treated with saline solution (CG), immediately after the occurrence of ulcers by 1 M sodium hydroxide (NaOH). Re-epithelialization was monitored using fluorescein every 6 h. After 24 h, six corneas (n=6) of each group were collected (M1). The others (n=6) were collected after reepithelialization (M2). At both moments, the inflammatory infiltrate and the conditions of the newly formed epithelium were histologically analyzed. iNOS and MMP-9 were evaluated by immunohistochemistry. RESULTS: Mean epithelialization time in TG was 55 ± 0.84 h. In CG, it was 44 ± 1.06 h (p=0.001). At M1, corneas of TG had lower inflammatory exudation compared with (p <0.001). At M2, TG revealed discrete inflammatory exudation (p>0.05) and lower numbers of epithelial layers compared with CG. The mean iNOS in stromal cells did not differ in TG over both moments compared with CG (p>0.05) At M2, the central corneal region expressed more iNOS in both groups compared with the peripheral region. No significant differences were observed in iNOS scores of epithelial immunostaining between the groups and across M1 and M2 (p=0.69). Epithelial immunostaining scores for MMP-9 did not differ in TG compared with CG (p=0.69). The average immunostaining score of MMP-9 in stromal cells showed no differences between groups or moments. There was no correlation between immunostaining of iNOS and MMP-9 or between the amount of inflammatory cells and immunostaining of iNOS. CONCLUSIONS: Use of 0.5% keratolac tromethamine reduced inflammation and delayed reepithelialization in a cornea alkali burn model without impacting the expression of iNOS or MMP-9.

Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations.

The effect of weight average molecular weight (Mw) of methyl cellulose (MC) on the gelation behavior of Poloxamer 407 (PM) and in vitro release of Ketorolac Tromethamine (KT) from different ophthalmic formulations based on PM is examined. A drop of gelation temperature of PM is observed using MC of various M(w) by test tube tilting method, UV-vis spectroscopy, viscometry and rheometry. It is also observed that the viscosity and gel strength of all the formulations are increased with the increase in Mw of MC. PM with highest Mw of MC provides best drug release property among all the formulations. It is evident from this investigation that there is a distinct effect of M(w) of MC on the gelation behavior of PM as well as on the drug release profile of KT from PM-MC based ophthalmic formulations.

[Pharmacological correction of the ulcerogenic action of NSAIDs in rats].

Experimental preclinical investigations on a group of 90 white outbred male rats showed that preliminary preventive introduction of procaine (novocaine, 1.07 mg/kg) or taurine (7.14 mg/kg) during 7 days before the administration of ketorolak trometamine significantly reduced the number of erosive-ulcerous lesions (by more than 87%, p < 0.001) and decreased the extent of pathological changes in the morphological structure of stomach mucus membrane.

The effect of ketorolac tromethamine, methylprednisolone, and platelet-rich plasma on human chondrocyte and tenocyte viability.

PURPOSE: The purpose of this study was to evaluate the effect on cell viability of the isolated and combined use of allogeneic platelet-rich plasma (PRP) and ketorolac tromethamine on human chondrocytes and tenocytes in a highly controlled in vitro environment. METHODS: PRP was produced from 8 subjects. Human chondrocytes (Lonza, Hopkinton, MA) and tenocytes isolated from samples of the long head of the biceps tendons were treated in culture with PRP, ketorolac tromethamine, and methylprednisolone, both alone and in combination. Control samples were treated in media containing 2% or 10% fetal bovine serum (FBS). Cells were exposed for 1 hour. Luminescence assays were obtained to examine cell viability after 24 hours and long-term effects on cell viability after 120 hours. Radioactive thymidine assay was used to measure proliferation after 120 hours. RESULTS: For chondrocytes, cell viability (120 hours) increased significantly with the treatment of PRP alone (43,949 ± 28,104 cells; P < .001) and with the combination of ketorolac tromethamine and PRP (43,276 ± 31,208; P < .001), compared with the 2% FBS group (7,397 ± 470). Cell viability decreased significantly after exposure to methylprednisolone (1,323 ± 776; P < .001) and its combination with PRP (4,381 ± 5,116; p < .001). For tenocytes, cell viability (120 hours) was significantly higher with the treatment of PRP (61,287 ± 23,273; P < .001) and the combined treatment of ketorolac tromethamine and PRP (52,025 ± 17,307; P < .001), compared with the 2% FBS group (23,042 ± 2,973). Cell viability decreased significantly after exposure to methylprednisolone (3,934 ± 1,791; P = .001) and its combination with PRP (5,201 ± 2,834; P = .003), compared with 2% FBS. CONCLUSIONS: Tendon and cartilage cells showed increased cell viability after an exposure to allogeneic PRP and ketorolac tromethamine. Exposure to methylprednisolone alone decreased cell viability, and addition of PRP could partially reverse this negative effect. CLINICAL RELEVANCE: Intra-articular injections of pain-modifying or anti-inflammatory drugs are routinely given in orthopaedic practice. Among the many agents available for intra-articular injection, corticosteroids and local anesthetics are the most common in clinical practice. Potential detrimental side effects of intra-articular injections of corticosteroids and local anesthetics have prompted investigation into alternative treatment options such as combinations of PRP and ketorolac tromethamine. In vitro evaluation of their effect on cell viability might build a basis for further translational research and clinical application.

Persistent hyperalgesia in the cisplatin-treated mouse as defined by threshold measures, the conditioned place preference paradigm, and changes in dorsal root ganglia activated transcription factor 3: the effects of gabapentin, ketorolac, and etanercept.

BACKGROUND: Painful neuropathy is a dose-limiting side effect in cancer chemotherapy. To characterize this phenomenon, we examined pain behavior and analgesic actions in a mouse model of cisplatin polyneuropathy. METHODS: Male C57BL/6 mice received intraperitoneal cisplatin or saline (2.3 mg/kg/d) every other day 6 times over 2 weeks for a total dose of 13.8 mg/kg. Thermal escape latencies, mechanical allodynia using von Frey hairs, and observation of behavior/morbidity and body weights were assessed. After onset of allodynia, we examined the actions of intraperitoneal gabapentin (100 mg/kg), etanercept (20 and 40 mg/kg), ketorolac (15 mg/kg), and morphine (1, 3, and 10 mg/kg). Additionally, using the conditioned place preference (CPP) paradigm, we examined the effects of gabapentin and ketorolac on the presumed pain state initiated by cisplatin. Additionally, we examined the spinal cord and dorsal root ganglia (DRG) of cisplatin-treated mice. RESULTS: Cisplatin, but not saline treatment, produced persistent hindpaw tactile allodynia, which persisted 46 days with no effect on thermal escape. Gabapentin and morphine, but neither etanercept nor ketorolac, produced a complete but transient (2-hour) reversal of the allodynia. Etanercept (40 mg/kg) pretreatment resulted in a delay in onset of mechanical allodynia. Using CPP, gabapentin, but not ketorolac, in cisplatin animals resulted in a significant preference for the drug-associated treatment compartment. There was no place preference in non-cisplatin-treated (nonallodynic) mice after gabapentin injection. Immunohistochemistry in cisplatin-treated mice showed no change in glial fibrillary acidic protein (astrocyte) or Iba1 (ionized calcium binding adaptor molecule 1) (microglia) activation states, but a significant increase in activated transcription factor 3 was observed in the DRG. CONCLUSIONS: Cisplatintreated mice display allodynia and an activation of DRG activated transcription factor 3, which is paralleled by its effects on behavior in the CPP system, wherein gabapentin, but not ketorolac, in the presence of the cisplatin polyneuropathy, is positively rewarding, confirming that this neuropathy is an aversive (painful) state that is ameliorated by gabapentin.

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins.

ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [N(G)-monomethyl-L-arginine (L-NMMA)] and cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P = 0.22-0.99). In protocol 2 (n = 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 ± 24%; high = 706 ± 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (ΔFVC = -31 ± 11%)- and high-dose ATP (ΔFVC -25 ± 11%; P = 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans.

Effects of antithrombogenic agents on microvenous anastomoses in a rat model.

OBJECTIVE: To compare venous thrombosis rates among animals treated with aspirin, clopidogrel bisulfate, and ketorolac tromethamine using an anastomotic "tuck" model. DESIGN: Single-blind randomized animal study. SETTING: An animal laboratory at a tertiary care academic referral center. SUBJECTS: Forty-two retired Lewis breeder rats divided into 3 equal groups. INTERVENTIONS: Before surgical intervention, 1 group received aspirin (10 mg/kg) through gavage; 1 group, clopidogrel bisulfate (5 mg/kg) through gavage; and the final group, ketorolac tromethamine (3 mg/kg) through intramuscular injection. Each rat was then anesthetized, and the femoral veins were prepared bilaterally. A 180° venotomy was made, and the vessels were anastomosed with the tuck model set-up for anastomotic failure. The vessels were checked for patency every 15 minutes for 2 hours after clamp removal. MAIN OUTCOME MEASURES: The rate of venous thrombosis and the time to thrombosis. RESULTS: In both the aspirin and clopidogrel groups, 2 of 28 vessels (7%) were thrombosed. Thrombosis occurred in 3 of 28 vessels (11%) in the ketorolac group (P = .86). All thromboses in the aspirin and clopidogrel groups took place at 7.5 minutes after clamp removal. In the ketorolac group, the mean time to thrombosis was 7.5 minutes (range, 0-22.5 minutes). There was no difference in time to thrombosis among the 3 groups (P = .86). CONCLUSION: Using a microvenous tuck model set-up for anastomotic failure, we found no difference in the rate of thrombosis or the time to thrombosis in rats pretreated with aspirin, clopidogrel, or ketorolac.

[Intravitreal injection of ketorolac tromethamine in patients with diabetic macular edema refractory to retinal photocoagulation]. / Injeção intravítrea de cetorolaco de trometamina em pacientes com edema macular diabético refratário à fotocoagulacão retiniana.

PURPOSE: To evaluate the effect of a single dose of intravitreous injection of ketorolac tromethamine (500 µg/0.1 ml) in patients with diabetic macular edema refractory to retinal photocoagulation. METHODS: Prospective study. Twenty patients with bilateral diabetic macular edema and ETDRS best-corrected visual acuity between 20/50 and 20/200 were selected. Patients who had other ocular diseases or previous eye surgery were excluded. Preservative-free ketorolac tromethamine was injected intravitreally (500 µg in 0.1 ml) in 20 eyes; fellow eyes served as controls. Ophthalmic examinations included ETDRS best-corrected visual acuity, measurement of intraocular pressure and optical coherence tomography. The examinations were performed preoperatively, 1 week and 1 month postoperatively. RESULTS: A statistically significant increase in visual acuity over time in the treated eye compared with the fellow eye was noted (p=0.039). There were no statistically significant differences in the assessment of intraocular pressure (p=0.99), foveal thickness (p=0.86) and macular volume (p=0.23) during the period. CONCLUSION: Patients with diabetic macular edema refractory to photocoagulation showed improvement in visual acuity over a one month period with a statistically significant difference when compared with the control eye. There were no statistically significant differences in intraocular pressure, foveolar thickness and macular volume between the treated and control eyes.