Oxicam NSAIDs Research Articles

Ultrasensitive and simultaneous detection of 6 nonsteroidal anti-inflammatory drugs by colloidal gold strip sensor

In this work, an oxicam group-selective monoclonal antibody against 6 nonsteroidal anti-inflammatory drugs (NSAID; meloxicam, lornoxicam, piroxicam, sudoxicam, droxicam, and tenoxicam) was prepared. Also, a spacer arm with carboxyl group was derived at the hydroxyl of meloxicam to generate the meloxicam hapten. The half-maximal inhibitory concentrations (IC50) were, respectively, 0.31 ng/mL for meloxicam, 0.49 ng/mL for lornoxicam, 2.90 ng/mL for piroxicam, 1.95 ng/mL for sudoxicam, 3.08 ng/mL for droxicam, and 5.36 ng/mL for tenoxicam. A colloidal gold immunochromatographic strip based on the monoclonal antibody was developed for the detection of these 6 NSAID in milk. The results could be obtained by the naked eye in 10 min, and the cut-off values and the visual limits of detection in real samples were 5, 5, 10, 10, 25, and 25 ng/mL, and 0.25, 1, 0.5, 0.5, 1, and 1 ng/mL, respectively. This immunochromatopgraphic strip is a suitable tool for on-site detection and screening of oxicam NSAID in milk samples.

Abstract 4304: Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort

Abstract SJS and TEN are extremely rare (approximately 2-7 cases per million per year) hypersensitivity reactions most commonly attributed to medications. The life-threatening nature of SJS/TEN necessitates early diagnosis and immediate identification and withdrawal of causative agents. Some of the most commonly associated culprits include sulfonamide antibiotics, aromatic anticonvulsants (phenytoin, carbamazepine, lamotrigine), -oxicam NSAIDs (e.g., meloxicam), allopurinol, and nevirapine. Individual case reports of SJS/TEN have been associated with anti-cancer agents, but a comprehensive assessment has not been performed. A large-scale retrospective analysis of the prevalence of SJS/TEN in cancer patients treated at Moffitt Cancer Center (MCC) between Jan 1, 2002 - Dec 31, 2014 was conducted. A total of 104,917 cancer patients were screened for SJS/TEN-related ICD-9 codes in the MCC health research informatics database. SJS/TEN diagnoses were identified in 121 patients. Manual chart review of physician, dermatology, and pathology notes confirmed SJS/TEN in 47 patients (in-patient + historical) and possible SJS/TEN in an additional 17 patients, corresponding to an overall prevalence of 0.06%. Confirmed in-patient cases of SJS/TEN were more common in hematologic malignancies compared to solid tumors (n = 12 vs. n = 7, respectively). Notably, 5 of the 19 (26.3%) confirmed cases were observed in patients with acute myeloid leukemia. Physician-reported culprits for SJS/TEN diagnoses included antibiotics, immunomodulators, anticonvulsants, and anti-cancer agents. The observed prevalence of SJS/TEN was higher in cancer patients than previous reports from the general USA population. There were 19 confirmed in-patient diagnoses of SJS/TEN and an additional 45 historical and possible cases of SJS/TEN in 104,917 cancer patients, corresponding to an overall prevalence of 0.018% to 0.06%, an approximately 90-fold increase when compared to the general population. Possible explanations for increased risk in cancer patients include increased exposure to culprit medications, cancer disease process, immunocompromised state, or synergy between risk factors. A thorough understanding of the factors that increase risk to SJS/TEN in cancer patients is critical to facilitate culprit withdrawal and maximize patient outcomes and survival. Citation Format: Nancy K. Gillis, Gillian C. Bell, Howard L. McLeod, Amy J. Brandt. Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4304.

Antecedent Drug Exposure Aetiology and Management Protocols in Steven-Johnson Syndrome and Toxic Epidermal Necrolysis, A Hospital Based Prospective Study.

The study sought to identify the magnitude and characteristic of severe cutaneous adverse reactions (SCAR's) like Steven-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). A prospective study was conducted by the Department of Pharmacology in association with Department of Dermatology in SMHS hospital. The study was carried out from June 2013-June 2015 on hospitalized cases of cutaneous adverse drug reaction reporting in hospital. The SCAR's were reported in a structured questionnaire based on adverse drug reaction (ADR) reporting form provided by the Central Drug Standard Control Organization (CDSCO) Ministry of Health and Family welfare, Government of India. The SCAR's were analysed for their characteristics, causality, severity and prognosis. Causality assessment was done by using a validated ADR probability scale of Naranjo as well as WHO Uppsala Monitoring Center (WHO-UMC) system for standardized case causality assessment. The management protocol were analysed for their clinical outcome through a proper follow up period. A total of 52 hospitalized cases of cutaneous adverse drug reactions were reported during the study period. We identified a total of 15 cases (28%) of SCAR's involving 9(17%) of SJS and 6 (12%) of TEN. SJS was seen in 2(22%) males and 7(78%) females. TEN was seen in all females (100%) and in no male. Drugs implicated in causing these life threatening reactions were identified as anticonvulsant agents like carbamazepine (CBZ), phenytoin (PHT) and Lamotrigine (LTG), oxicam NSAID, Sulfasalazine and levofloxacin. Despite higher reported mortality rates in SJS and TEN all patients survived with 2 patients surviving TEN suffered from long term opthalmological sequelae of the disease. Present study suggest that drug induced cutaneous eruptions are common ranging from common nuisance rashes to rare life threatening diseases like SJS and TEN, SJS/TEN typically occur 1-3 weeks after initiation of therapy. Aromatic AED's, LTG, oxicam NSAID's, sulfasalazine and levofloxacin have a tremendous potential to trigger SCARS's. To ensure safe use of pharmaceutical agents and better treatment outcomes post marketing voluntary reporting of severe rare and unusual reactions remains inevitable.

Tooth pain management of chronic pulpitis in a patient with toxic epidermal necrolysis- A Case Report -

Toxic epidermal necrolysis (TEN) is acute life threatening mucocutaneous reactions due to various drugs. Oxicam NSAIDs, Acetic acid NSAIDs (e.g.: diclofenac), aminopenicillins and Cephalosporins are lower risk group of drugs that cause epidermal necrolysis. Protocol for medication is early recognition and withdrawal of the offending drugs and supportive care. Healing of extracted socket and mucosa is compromised due to various factors of toxic epidermal necrolysis. Impaired alimentation, photophobia and painful micturition and malabsorption cause impaired wound healing. This case study discuss about interventions to manage odontogenic pain in a patient with TEN.

Spectroscopic studies of the binding of Cu(II) complexes of oxicam NSAIDs to alternating G-C and homopolymeric G-C sequences

Drugs belonging to the Non-steroidal anti-inflammatory (NSAID) group are not only used as anti-inflammatory, analgesic and anti-pyretic agents, but also show anti-cancer effects. Complexing them with a bioactive metal like copper, show an enhancement in their anti-cancer effects compared to the bare drugs, whose exact mechanism of action is not yet fully understood. For the first time, it was shown by our group that Cu(II)-NSAIDs can directly bind to the DNA backbone. The ability of the copper complexes of NSAIDs namely meloxicam and piroxicam to bind to the DNA backbone could be a possible molecular mechanism behind their enhanced anticancer effects. Elucidating base sequence specific interaction of Cu(II)-NSAIDs to the DNA will provide information on their possible binding sites in the genome sequence. In this work, we present how these complexes respond to differences in structure and hydration pattern of GC rich sequences. For this, binding studies of Cu(II) complexes of piroxicam [Cu(II)-(Px)2 (L)2] and meloxicam [Cu(II)-(Mx)2 (L)] with alternating GC (polydG–dC) and homopolymeric GC (polydG–polydC) sequences were carried out using a combination of spectroscopic techniques that include UV–Vis absorption, fluorescence and circular dichroism (CD) spectroscopy. The Cu(II)-NSAIDs show strong binding affinity to both polydG–dC and polydG–polydC. The role reversal of Cu(II)-meloxicam from a strong binder of polydG–dC (Kb=11.5×103M−1) to a weak binder of polydG–polydC (Kb=5.02×103M−1), while Cu(II)-piroxicam changes from a strong binder of polydG–polydC (Kb=8.18×103M−1) to a weak one of polydG–dC (Kb=2.18×103M−1), point to the sensitivity of these complexes to changes in the backbone structures/hydration. Changes in the profiles of UV absorption band and CD difference spectra, upon complex binding to polynucleotides and the results of competitive binding assay using ethidium bromide (EtBr) fluorescence indicate different binding modes in each case.

Enzymatic Probing of Model Lipid Membranes: Phospholipase A2 Activity toward Monolayers Modified by Oxicam NSAIDs

Three nonsteroidal anti-inflammatory oxicam drugs, namely meloxicam, piroxicam, and tenoxicam, were used to modify the properties of monomolecular films formed with 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine, or 1,2-dilauroyl-sn-glycero-3-phospho-(1-rac-glycerol). These systems were examined via surface pressure and surface electrical potential measurements, polarization modulation infrared reflection absorption spectroscopy, and Brewster angle microscopy. Moreover, phospholipase A2 activity was used to differentiate between the three drugs. Our results reveal that the oxicams studied modify membrane properties, namely hydration of the lipid polar heads, orientation of the molecules, and morphology of the domains. Phospholipase A2 was shown to be sensitive to the presence of the drugs in the systems studied; the activity of the enzyme correlates with the effect of meloxicam, piroxicam, and tenoxicam on the monolayer properties. The latter indicates that the anti-inflammatory action of oxicams may be related to interference with phospholipase activity in addition to cyclooxygenase inhibition.

Interaction of Oxicam NSAIDs with lipid monolayer: Anomalous dependence on drug concentration

Surface pressure ( π) versus specific molecular area ( A) isotherms of Langmuir monolayers of dimyristoylphosphatidylcholine (DMPC) lipid on pure water were studied in pristine form and in presence of three non-steroidal anti-inflammatory drugs, meloxicam (MX), piroxicam (PX) and tenoxicam (TX) in the subphase. Data were taken at three drug/lipid (D/L) ratios of 0.026, 0.05, and 0.1. Integration of drug to the lipid monolayer was measured by the increase in A (Δ A) of DMPC monolayer due to the presence of drugs. All three drugs could be integrated in the monolayer resulting in a positive value of Δ A for D/L ratio of 0.026. Above this D/L value, there is an anomalous, monotonic decrease in Δ A for MX and TX resulting, finally, in negative Δ A values. For PX, however, decrease in Δ A values at D/L of 0.05 is partially compensated at D/L of 0.1. We have tentatively explained these observations by invoking two competing forces in the overall drug–lipid interaction. One of these is an ‘in-plane’ force that tends to integrate the drug molecule to the plane formed by the lipid monolayer and the other is an ‘out-of-plane’ force that perturbs the drug and the lipid molecules such that the monolayer plane is no longer well defined.

Efficacy of Levobupivacaine Wound??Infiltration With and Without??Intravenous Lornoxicam for??Post-Varicocoele Analgesia

The oxicam NSAID lornoxicam is a potent analgesic with excellent anti-inflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain. Levobupivacaine, the S-(-)-isomer of bupivacaine, is a long-acting local anaesthetic that can be infiltrated into wounds for management of postoperative pain. We assessed the analgesic efficacy of lornoxicam when administered as an adjuvant to levobupivacaine wound infiltration after varicocoele operation. Sixty patients who underwent varicocoele surgery were randomly assigned to three different treatment groups. Before skin closure, patients received the following treatments: group I (n=20) patients received normal saline 20 mL wound infiltration and intravenous lornoxicam (Xefo, Nycomed Pharma AS, Roskilde, Denmark) 2 mL (8 mg); group II (n=20) patients received 0.25% levobupivacaine (Chirocaine, Abbott Scandinavia AB, Solna, Sweden) 10mL with normal saline 10 mL wound infiltration and intravenous normal saline 2 mL; group III (n=20) patients received 0.25% levobupivacaine 10 mL with normal saline 10 mL wound infiltration and intravenous lornoxicam 2 mL (8 mg). Pain scores and total pethidine (meperidine) consumption were measured at 1, 2, 4, 6, 12 and 24 hours postoperatively. Time to first analgesic requirement and patient satisfaction were also compared post-surgery. Pain scores during the first 6 hours postoperatively were significantly lower in group III than in group I and group II (p<0.01). Total pethidine consumption was significantly lower in group III (34.0+/-28.0 mg) than in group I (74.0+/-25 mg) and group II (76.0+/-29 mg) [p<0.01]. Time to first analgesic was also significantly longer in group III (14.8+/-8.4 hours) than in group I (6.2+/-5.2 hours) and group II (5.8+/-7.1 hours) [p<0.01]. The incidence of postoperative nausea and vomiting was significantly lower in group III than in group I and group II (p<0.05). More patients in group III described their analgesia as good or excellent than in group I or group II (p<0.01). In this study, levobupivacaine wound infiltration with adjuvant intravenous lornoxicam administration was associated with better postoperative analgesia during the early postoperative hours after varicocoele surgery than that induced by lornoxicam alone or levobupivacaine wound infiltration alone.

Direct binding of Cu(II)-complexes of oxicam NSAIDs with DNA backbone

Drugs belonging to the non-steroidal anti-inflammatory drug group (NSAID) are not only used as anti-inflammatory and analgesic agents, but also exhibit chemopreventive and chemosuppressive effects on various cancer cell lines. They exert their anticancer effects by inhibiting both at the protein level and/or at the transcription level. Cu(II) complexes of these NSAIDs show better anti-cancer effects than the bare drugs. Considering the above aspects, it is of interest to see if Cu(II) complexes of these drugs can exert their effects directly at the DNA level. In this study, we have used UV–Vis spectroscopy to characterize the complexation between Cu(II) and two NSAIDs belonging to the oxicam group viz. piroxicam and meloxicam, both of which exhibit anticancer properties. For the first time, this study shows that, Cu(II)–NSAID complexes can directly bind with the DNA backbone, and the binding constants and the stoichiometry or the binding site sizes have been determined. Thermodynamic parameters from van’t Hoff plots showed that the interaction of these Cu(II)–NSAID complexes with ctDNA is an entropically driven phenomenon. Circular dichroism (CD) spectroscopy showed that the binding of these Cu(II)–NSAIDs with ctDNA result in DNA backbone distortions which is similar for both Cu(II)–piroxicam and Cu(II)–meloxicam complexes. Competitive binding with a standard intercalator like ethidium bromide (EtBr) followed by CD as well as fluorescence measurements indicate that the Cu(II)–NSAID complexes could intercalate in the DNA.

Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam in Brazilians

Background Piroxicam (P), a widely prescribed NSAID, is eliminated by hydroxylation catalyzed by CYP2C9 enzyme, which is encoded by the polymorphic CYP2C9 gene. Methods Single oral doses (20 mg) of P were given to healthy, adult Brazilian volunteers with distinct CYP2C9 genotypes. The plasma P concentration and the P-induced changes in the activity of cyclooxygenase 1 (COX-1; ex-vivo formation of tromboxane B2 in blood) were measured from zero to 240h. Results P′s oral CL/F was significantly reduced, and both AUC and t1/2 were increased in carriers of variant alleles *2 and *3 in heterozygosis or homozygosis. There was no difference in these pharmacokinetic parameters between genotypes *1/*2 and *1/*3. Cmax was not affected by CYP2C9 genotype. (see Table) The AUC for the inhibitory effect of P on the activity of COX-1, expressed relative to the pre-dosing value (units.h) increased with the number of variant CYP2C9 alleles, from 110± 23 (*1/*1, n= 5) to 172± 44 (combined *1/*2 and *1/*3, n =12) and to 208 - 223 (combined *2/*2 and *3/*3, n =2). Conclusion We confirmed our previous observation with tenoxicam that both the variant alleles CYP2C9*2 and *3 significantly influence the pharmacokinetics of oxicam NSAIDs. We also show that both alleles *2 and *3 are associated with the intensity of the inhibitory effect of P on COX-1. Clinical Pharmacology & Therapeutics (2005) 77, P62–P62; doi: 10.1016/j.clpt.2004.12.127 Table 1. Pharmacokinetics of piroxicam in healthy Brazilians Parameter *1/*1 (n = 14) *1/*2 (n = 9) *1/*3 (n = 10) *2/*2 (n = 1) *2/*3 (n = 1) *3/*3 (n = 1) Cmax(mgL−1) 2.4 ± 0.7 2.2 ± 0.4 2.5 ± 0.4 1.6 1.9 2.6 AUC0-240h(mg.L−1) 136 ± 34 220 ± 77 221 ± 67 197 186 501 CL/F (L.h−1) 0.14 ± 0.03 0.09 ± 0.03 0.08 ± 0.02 0.09 0.07 0.01 t1/2 (h) 40.3 ± 9.8 72.8 ± 19.9 80.1 ± 24.7 94.6 118.5 674.1

Comparison of Reporting of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Association with Selective COX-2 Inhibitors

Stevens-Johnson syndrome and toxic epidermal necrolysis are closely related severe acute life-threatening, drug-induced skin disorders. The US FDA Adverse Events Reporting System (AERS) has received reports of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of the recently introduced selective cyclo-oxygenase (COX)-2 inhibitor NSAIDs, two of which are also sulfonamides. The objective of this study is to review cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA associated with the use of the selective COX-2 inhibitor NSAIDs celecoxib, rofecoxib and valdecoxib, and to compare reporting rates of the two conditions associated with these drugs to each other, meloxicam (an oxicam NSAID that came on the US market at a similar time) and the background incidence rate. We reviewed all US cases of Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the FDA AERS database associated with the use of celecoxib, rofecoxib, valdecoxib and meloxicam since these agents were first marketed. We utilised AERS and drug use data to calculate reporting rates for each drug after the first 2 years of marketing. We obtained the background rate from the medical literature. Up to the end of March 2004, there were 63 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis reported with valdecoxib use, 43 with celecoxib, 17 with rofecoxib (the non-sulfonamide coxib) and none for meloxicam. In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib. The reporting rates for the sulfonamide coxibs were substantially higher than the background rate of 1.9 cases per million population per year, with the valdecoxib rate being 8-9 times that of celecoxib and approximately 25 times that of the background rate. There is a strong association between Stevens-Johnson syndrome/toxic epidermal necrolysis and the use of the sulfonamide COX-2 inhibitors, particularly valdecoxib. Physicians should be aware of the possibility of this serious life-threatening event when prescribing these drugs and advise patients to discontinue use at the earliest possible sign or symptom.

Metabolism of modafinil in mice, rats, guinea-pigs and rabbits

The nature of the enzyme(s) catalyzing the major metabolic pathway (5′-hydroxylation) of oxicam NSAIDs was investigated in subcellular preparations of human liver tissue. Microsomal, but not cytosolic, fractions catalyzed the 5′-hydroxylation of tenoxicam. This reaction required NADPH and was inhibited by various nonselective P450 inhibitors (CO, SKF-525A, ketoconazole), but not by the peroxidase inhibitor NaN3. Tenoxicam 5′-hydroxylation exhibited simple Michaelis-Menten kinetics compatible with catalysis by a single enzyme, but it strongly inhibited its own oxidation at concentrations higher than 100–150 μM. Piroxicam competitively inhibited tenoxicam 5′-hydroxylation and, conversely, tenoxicam competitively inhibited piroxicam 5′-hydroxylation. Tenoxicam 5′-hydroxylation kinetics were similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6). Dextromethorphan (CYP2D6 prototype substrate) and midazolam (CYP3A prototype substrate) had no influence on tenoxicam 5′-hydroxylation, whereas mephenytoin, tolbutamide and sulfaphenazole (Ki ≈ 0.1 μM) inhibited it. This indicates that the 5′-hydroxylation of both piroxicam and tenoxicam is predominantly catalyzed by at least one cytochrome P450 isozyme of the CYP2C subfamily.

In vitro oxidation of oxicam NSAIDs by a human liver cytochrome P450

The nature of the enzyme(s) catalyzing the major metabolic pathway (5′-hydroxylation) of oxicam NSAIDs was investigated in subcellular preparations of human liver tissue. Microsomal, but not cytosolic, fractions catalyzed the 5′-hydroxylation of tenoxicam. This reaction required NADPH and was inhibited by various nonselective P450 inhibitors (CO, SKF-525A, ketoconazole), but not by the peroxidase inhibitor NaN 3. Tenoxicam 5′-hydroxylation exhibited simple Michaelis-Menten kinetics compatible with catalysis by a single enzyme, but it strongly inhibited its own oxidation at concentrations higher than 100–150 μM. Piroxicam competitively inhibited tenoxicam 5′-hydroxylation and, conversely, tenoxicam competitively inhibited piroxicam 5′-hydroxylation. Tenoxicam 5′-hydroxylation kinetics were similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6). Dextromethorphan (CYP2D6 prototype substrate) and midazolam (CYP3A prototype substrate) had no influence on tenoxicam 5′-hydroxylation, whereas mephenytoin, tolbutamide and sulfaphenazole (K i ≈ 0.1 μM) inhibited it. This indicates that the 5′-hydroxylation of both piroxicam and tenoxicam is predominantly catalyzed by at least one cytochrome P450 isozyme of the CYP2C subfamily.

Droxicam, a new oxicam NSAID, has analgesic, antiinflammatory and antipyretic properties similar to other NSAIDs. In addition, its adverse effect profile, particularly in terms of adverse GI events, appears to be better than some other NSAIDs.

Droxicam, a new oxicam NSAID, has analgesic, antiinflammatory and antipyretic properties similar to other NSAIDs. In addition, its adverse effect profile, particularly in terms of adverse GI events, appears to be better than some other NSAIDs.