Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity.

Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. Methods: Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the 177Lu-labeled PSMA ligands were tested in vitro using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. Results: The PSMA ligands were obtained in moderate yields at high purity (>99%). 177Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. In vitro assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. 177Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. Conclusion: The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. 177Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation.

Ester coupling of ibuprofen in hydrogel matrix: A facile one-step strategy for controlled anti-inflammatory drug release.

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID) commonly used in the treatment of pain, fever and inflammation. However, the administration of IBU in its free carboxylic acid form is strongly dependent on its limited solubility in aqueous solution. This mandates for an increased drug concentration to reach the therapeutic window, and promotes the alternative use of IBU sodium salt, even if this latter form poses significant constraints in terms of tunable release due to its uncontrolled and rapid diffusion. A potential solution is represented by oral administration through physical encapsulation of ibuprofen in designed carriers, despite this route limits the application of this therapeutic agent. In this work, we propose the covalent tethering of ibuprofen to a hydrogel matrix via esterification reaction. Exploiting the cleavability of the ester bond under physiological conditions, we propose a controlled drug delivery system where the whole drug payload can be released, thus overcoming the questioned aspects of over-dosage and solubility-dependent administration. In particular, we tested the biological activity of cleaved ibuprofen in terms of cyclooxygenase inhibition, reporting that chemical tethering did not alter the efficiency of the NSAID. Moreover, due to the sol-gel transition of the hydrogel matrix, these ibuprofen-functionalized hydrogels could be used as injectable tools in several clinical scenarios, performing a localized drug release and opening advanced avenues for in situ treatments.

Radiosynthesis and Preclinical Evaluation of 11C-VA426, a Cyclooxygenase-2 Selective Ligand.

Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37-148 GBq/µmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.

New approaches to tumor therapy with siRNA-decorated and chitosan-modified PLGA nanoparticles.

Objective: In this study, we aimed to develop a candidate modifited polymeric nanoparticle (NP) system that will kill cancer cells by facilitated to apoptosis and also reduce pain. Significance: The primary goal of treatment, especially for metastatic cancers, is to control the growth of the cancer and to alleviate the symptoms. Pain is one of the commonest symptoms of cancer. In cancer treatment, directing cancer cells to death while simultaneously relieving pain will be a new approach. Methods: Chitosan-modified PLGA NPs were prepared using an nanoprecipitation technique. The NPs were loaded with flurbiprofen and decorated with folic acid. STAT3-siRNA was adsorbed to these polymeric NPs using antisense technology. Results: The NPs were small in size (176.9-220.3 nm) with positive zeta potential (+14.1 mV to +27.2 mV). They had high loading capacity and prolonged release properties over 144 hours. Cytotoxicity studies performed with siRNA showed effective electrostatic interaction due to the positively charged NPs. Folic acid facilitated entry into cancer cells and helped to kill them. Conclusion: The formulation we developed is a potential carrier system for both treatment of cancer and prevention of pain, especially for metastatic cancers.

[Aspirin and preeclampsia]. / Aspirine et prééclampsie.

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.

Resveratrol: An overview of its anti-cancer mechanisms.

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.

Designing Natural Product Hybrids Bearing Triple Antiplatelet Profile and Evaluating Their Human Plasma Stability.

Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustible source of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities that take advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.

Pharmacokinetics and efficacy of intraocular flurbiprofen.

PURPOSE: Intravitreal delivery of non-steroidal anti-inflammatory drugs could be an effective way to treat macular edema caused by posterior segment inflammation. In this study, we evaluated the intravitreal bioavailability and anti-inflammatory efficacy of flurbiprofen in rabbit eyes. METHODS: For pharmacokinetics, 0.1 ml of 7.66 mg/ml flurbiprofen solution was injected intravitreally and vitreous drug levels were analyzed at specific time points using LC-MS technique. For efficacy, 100 ng lipopolysaccharide of E.coli was injected intravitreally in rabbits to induce inflammation. The animals were separated in three groups and received intraocular flurbiprofen, dexamethasone and PBS to serve as control. Complete ocular examination and total cell count in aqueous fluid were determined to evaluate the extent of inflammation. Eyes were then enucleated for histopathology analysis. The efficacy in the uveitis model was determined by clinical signs of inflammation, total leukocyte count and histology findings. RESULTS: No adverse events were observed during pharmacokinetic assessment. No signs of inflammation, hemorrhage or retina detachment were detected. The recovery of flurbiprofen from vitreous samples was 92.6%. The half-life of flurbiprofen was estimated to be 1.92 h with an elimination constant rate (K) of 0.36. Treatment with intraocular injections of flurbiprofen and dexamethasone significantly reduced total leukocyte count in a manner comparable to dexamethasone [reduction of 96.84% (p < 0.05) and 97.44% (p < 0.05), respectively]. Histologic studies demonstrated significantly less signs of ocular inflammation after flurbiprofen injection compared to control eyes. CONCLUSIONS: Flurbiprofen is effective in suppressing inflammation in this experimental uveitis model. In our experimental setting, intravitreal flurbiprofen seem to have a therapeutic result comparable to dexamethasone. However, the half-life of the drug remains short, necessitating further research to prolong its presence in the vitreous cavity.

Low-Dose Aspirin Acetylates Cyclooxygenase-1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer.

The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.

Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%-100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%-25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

Selective COX-1 inhibition as a target of theranostic novel diarylisoxazoles.

Cyclooxygenase(COX)-1 role in some diseases is increasingly studied. 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a highly selective cyclooxygenase-1 inhibitor, was used as a "lead" to design new isoxazoles (2a-m), differently selective towards COX-1. Those isoxazoles might be useful as novel theranostic agents and also to better clarify COX-1 role in the human physiology and diseases. 2a-m were prepared in fair to good yields developing suitable synthetic strategies. They were evaluated in vitro for their COX-inhibitory activity and selectivity. Structure-activity relationship studies of the novel set of diarylisoxazoles allowed to identify new key determinants for COX-1 selectivity, and to uncover compounds appropriate for a deep pharmacokinetic and pharmacodynamic investigation. 3-(5-Chlorofuran-2yl)-4-phenylisoxazol-5-amine (2f) was the most active compound of the series, its inhibitory activity was assessed in purified enzyme (COX-1 IC50 = 1.1 µM; COX-2 IC50 > 50 µM) and in the ovarian cancer cell line (OVCAR-3) expressing only COX-1 (IC50 = 0.58 µM). Furthermore, the high inhibitory potency of 2f was rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-1 binding site. We found critical interactions between the inhibitor and constriction residues R120 and Y355 at the base of the active site, as well as with S530 at the top of the side pocket.

Aspirin Half Maximal Inhibitory Concentration Value on Platelet Cyclooxygenase1 in Severe Type-2 Diabetes Mellitus is not Significantly Different from that of Healthy Individuals.

It is implicated that diabetic patients are more resistant to aspirin therapy than patients with other diseases or healthy individuals. We evaluated the inhibitory effects of aspirin on aggregation and the cyclooxygenase activity of platelets of 10 patients with severe type-2 diabetes mellitis (DM) and compared the results with those of healthy individuals. Although platelet aggregation had a tendency to be more resistant to aspirin with the DM group, there was no significant difference in half maximal inhibitory concentration 50 values of aspirin on the cyclooxygenase activity between the patients with DM and healthy individuals. Thus, the residual platelet aggregability uninhibited by aspirin appears to be independent of the cyclooxygenase activity. Since adenosine diphosphate (ADP) receptor blocking almost completely inhibited the residual platelet aggregability, it is suggested that hyperreactivity to ADP is more prevalent in patients with DM.

Reduction of vitreous prostaglandin E2 levels after topical administration of ketorolac 0.45%.

IMPORTANCE: Inhibition of proinflammatory prostaglandins in the retina may have therapeutic effects for retinal disease. OBJECTIVE: To determine vitreous levels of ketorolac and prostaglandin E2 (PGE2) in eyes treated with topical ketorolac tromethamine 0.45% (Acuvail). DESIGN, SETTING, AND PARTICIPANTS: A prospective comparative interventional study, performed in a university academic hospital, included 24 eyes in 22 consecutive patients undergoing pars plana vitrectomy. INTERVENTION: Application of topical ketorolac 0.45%, 4 times daily, for 3 days before pars plana vitrectomy in the first 12 consecutive eyes. The next 12 eyes were untreated and served as controls. Undiluted vitreous samples were obtained at the time of surgery and immediately frozen at -80 °C. MAIN OUTCOMES AND MEASURES: Vitreous ketorolac and PGE2 levels. RESULTS: Seven of the 12 eyes (58%) had ketorolac levels above the lower limit of quantitation. All 7 were in pseudophakic eyes, and 4 of the 5 below this limit were phakic (P = .01). The mean ketorolac level in the 7 eyes was 7.55 ng/mL (range, 5.0-14.9 ng/mL). The mean (SD) PGE2 levels were 13.8 (3.8) pg/mL in control eyes and 11.7 (4.4) pg/mL in ketorolac-treated eyes (P = .04). Treatment with ketorolac resulted in a 15% reduction in PGE2 levels. When only pseudophakic eyes were analyzed, mean (SD) PGE2 levels were 14.1 (4.1) pg/mL in control eyes and 11.6 (4.5) pg/mL in ketorolac-treated eyes (P < .05). CONCLUSIONS AND RELEVANCE: Topical ketorolac 0.45% can obtain a vitreous level that exceeds its median inhibitory concentration and can significantly decrease vitreous PGE2 levels. Vitreous levels of ketorolac were significantly higher in pseudophakic eyes than in phakic eyes. The results of this study suggest that topically administered ketorolac 0.45% may allow meaningful inhibition of prostaglandins in the retina. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01609881.

Influence of CYP2C8 polymorphisms on the hydroxylation metabolism of paclitaxel, repaglinide and ibuprofen enantiomers in vitro.

CYP2C8 plays an important role in the metabolism of various drugs, such as paclitaxel, repaglinide and ibuprofen. Polymorphisms in the CYP2C8 gene were shown to influence interindividual differences in the pharmacokinetics of paclitaxel, repaglinide and ibuprofen enantiomers. In this study, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3 and CYP2C8.4) and wild-type CYP2C8 (CYP2C8.1) were co-expressed for the first time with human cytochrome P450 oxidoreductase (POR) and cytochrome b5 by using a baculovirus-assisted insect cell expression system. Further, the effects of genotype-phenotype correlations of CYP2C8 alleles on the metabolism of paclitaxel, repaglinide and ibuprofen enantiomers were evaluated. The CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 for paclitaxel were 47.7%, 64.3% and 30.2% of that of CYP2C8.1 (p<0.01). The CLint values of CYP2C8.2 and CYP2C8.4 for repaglinide were 77.9% and 80.2% of that of CYP2C8.1 (p<0.05), respectively, while the CLint value of CYP2C8.3 was 1.31-fold higher than that of CYP2C8.1 (p<0.05). The relative CLint values of CYP2C8.2, CYP2C8.3 and CYP2C8.4 were 110.5%, 72.3% and 49.7% of that of CYP2C8.1 and were 124.6%, 83.4% and 47.4% of that of CYP2C8.1 for R-ibuprofen and S-ibuprofen, respectively. Comparing hydroxylation by CYP2C8.1 and CYP2C8.3 resulted in higher and lower intrinsic clearance of repaglinide and ibuprofen enantiomers, respectively. These in vitro findings were consistent with the pharmacokinetics in volunteers who were heterozygous or homozygous carriers of CYP2C8*3. The results of this study provide useful information for predicting CYP2C8 phenotypes and may contribute to individualized drug therapy in the future.

Pharmacokinetics and safety of single and multiple oral doses of meloxicam in adult horses.

BACKGROUND: Safety of meloxicam, a potent NSAID with selective COX-2 inhibition, has not been evaluated in horses. OBJECTIVES: To evaluate pharmacokinetics and safety of single and repeated oral doses of meloxicam in adult horses. ANIMALS: Forty-nine healthy, university-owned adult lightbreed horses. METHODS: Study conducted in 2 parts. Part I addressed pharmacokinetics of single oral dose meloxicam (0.6 mg/kg) in 16 horses. Part II, 33 horses were randomly assigned to 5 treatment groups to assess prolonged administration (0.6 mg/kg PO q24h for 6 weeks, n = 7) or higher doses (1.8 mg/kg, n = 7, or 3.0 mg/kg PO q24h, n = 7) of meloxicam for 2 weeks, compared with control horses (placebo, n = 7, or phenylbutazone, 4.4 mg/kg q12h on day 1, 2.2 mg/kg q12h for 4 days, then 2.2 mg/kg q24h for 9 days, n = 5). RESULTS: Maximum plasma concentration following a single oral dose of meloxicam was 915.1 ± 116.9 ng/mL and elimination half-life 10.2 ± 3.0 hours. Meloxicam (0.6 mg/kg, q24h, PO for 6 weeks) yielded plasma concentrations between 100 and 1000 ng/mL and was well tolerated by healthy adult horses. Administration of 3-5 times the recommended dose of meloxicam was associated with decreased total serum protein and albumin concentrations, gastrointestinal damage, renal damage, or bone marrow dyscrasia. PBZ administration was associated with the development right dorsal colitis, gastric ulceration, and protein losing enteropathy in 2 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Administration meloxicam at 0.6 mg/kg q24h was well tolerated for 6 weeks, without drug accumulation in plasma. Higher doses were associated with dose-dependent adverse effects typical of class of drugs.

Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in industrialized countries. Chemoprevention is a promising approach, but studies demonstrating their usefulness in large populations are still needed. Among several compounds with chemopreventive ability, cyclooxygenase inhibitors have received particular attention. However, these agents are not without side effects, which must be weighed against their beneficial actions. Early diagnosis is critical in the management of CRC patients, because, in early stages, surgery is curative in >90% of cases. If diagnosis occurs at stages II and III, which is often the case, neoadjuvant chemotherapy and radiotherapy before surgery are, in a few cases, recommended. Because of the high risk of recurrence in advanced cancers, chemotherapy is maintained after tumor resection. Chemotherapy is also indicated when the patient has metastases and in advanced cancer located in the rectum. In the last decade, the use of anticancer drugs in monotherapy or in combined regimens has markedly increased the survival of patients with CRC at stages III and IV. Although the rate of success is higher than in other gastrointestinal tumors, adverse effects and development of chemoresistance are important limitations to pharmacological therapy. Genetic profiling regarding mechanisms of chemoresistance are needed to carry out individualized prediction of the lack of effectiveness of pharmacological regimens. This would minimize side effects and prevent the selection of aggressive, cross-resistant clones, as well as avoiding undesirable delays in the use of the most efficient therapeutic approaches to treat these patients.

High on treatment platelet reactivity.

The addition of clopidogrel to aspirin for patients undergoing percutaneous coronary intervention (PCI) had significantly reduced cardiovascular events. However, despite dual antiplatelet therapy ischaemic events still occur, especially stent thrombosis, which is associated with a high mortality rate. Inter-individual response to clopidogrel is highly variable. It was shown that 4-46% could be considered as high on treatment platelet reactivity (HTPR). Recent studies had demonstrated a relationship between HTPR and ischaemic events in the setting of PCI. Actually the assessment of platelet reactivity in routine practice and its interpretation to make a decision is a debatable issue.

Aspirin intake suppresses MMC-induced genotoxicity in mice.

The genotoxicity induced by mitomycin C (MMC) was found to be decreased by aspirin on alkaline single cell gel electrophoresis (SCG) assay in multiple organs of mice. Aspirin at doses of 0.5, 5 and 50 mg/kg and MMC at 2 mg/kg were administered and then liver, lung, kidney, spleen, colon and bone marrow were sampled after 3 h. Significant protective effects of aspirin against MMC-induced genotoxicity was observed in all but the bone marrow, where no change was evident. The results suggest that the radical scavenging ability of aspirin prevents danage by MMC-induced reactive oxygen species (ROS) in multiple organs.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with allopurinol, celecoxib and cimetidine in healthy subjects.

OBJECTIVE: Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters). RESEARCH DESIGN AND METHODS: Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS. RESULTS: Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]). CONCLUSIONS: In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.

Binary polymeric blends to microencapsulate nitroflurbiprofen: physicochemical and in silico studies.

Nitroflurbiprofen, NFP, a practically insoluble liquid drug, was microencapsulated in hydrophilic micromatrices made of poly(N-vinylpyrrolidone) (PVP), or polyaminomethacrylate (PAMA), or binary blends of polymers thereof. The PAMA/PVP miscibility was assessed both in the solid state (DSC and ATF-FTIR spectroscopy) and in solution by viscometric measurements. The in vitro NFP release test was carried out in over saturation condition to discriminate the increase of NFP apparent solubility (supersaturation degree, SD). Drug/polymer/polymer/water interactions were studied in silico by molecular dynamic (MD) simulations. PAMA and PVP resulted miscible only in aqueous solution. The release of NFP from microparticles occurred according to a non-monotonic pattern due to the formation of instable supersaturated systems and the drug separation in the dissolution medium. After 5 min, the SD was at least 3. The use of PVP/PAMA micromatrices reduced the instability of the supersaturated solutions. MD simulations evidenced that water molecules play a key role in the PAMA/PVP compatibilization process and in stabilization of NFP supersaturated systems by means of H-bond. The docking analyses here find a novel and successful application to predict the different ability of a drug to interact with polymeric blends in solution.