mobic and Colorectal-Neoplasms

A hundred years after the introduction of aspirin as the first effective anti-inflammatory drug, problems of tolerability still beset this class of drugs, in particular, gastrointestinal toxicity. Despite this, NSAIDs are among the most widely used and prescribed drugs world-wide. Many agents have been used to counteract these side-effects with varying degrees of success and acceptance. Although the central mechanism of NSAID action, reduced prostaglandin production by cyclooxygenase (COX) inhibition, was first described 25 years ago, the recent discovery of a second, inducible form of cyclooxygenase, COX-2, has stimulated research and interest in producing NSAIDs that are inherently safer whilst maintaining efficacy. Specific COX-2 inhibitors, the first of which has recently been marketed in the UK, offer real hope as safer NSAIDs and this may be realised when drugs with even greater specificity become available. However, long-term safety and efficacy need to be demonstrated in clinical practice, and questions remain unanswered about possible physiological roles for COX-2. Other approaches to improving the safety of NSAIDs, including profound acid suppression and nitric oxide donation, may prove to be as successful in this rapidly changing field.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Eicosanoids; Humans; Isoenzymes; Meloxicam; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Thiazines; Thiazoles

The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10

Topics: Calcium Chloride; Chemistry, Pharmaceutical; Colorectal Neoplasms; Drug Carriers; Gels; Meloxicam; Polysaccharides, Bacterial; Thiazines; Thiazoles

Chemoprevention is a strategy which uses drugs which are traditionally not used as anti-cancer drugs; however, they prevent the carcinogenesis. Meloxicam (MLX) is traditionally used as a non-steroidal anti-inflammatory drug (NSAID), but it has been proven to have activity against colorectal cancer. Subsequently MLX seems to be a likely candidate to be utilized in the chemopreventive therapy of colorectal cancer. However, MLX poses shortcomings with respect to its dose required to elicit cytotoxicity. To improve the formulation, we used Quality by design (QbD) for optimization. QbD is a method that employs quality-improving scientific methods that build quality into the formulation by isolating the factors which affect the critical quality attributes of the formulation. The aim of the present study was to utilize the principles of QbD to formulate MLX into a formulation so as to exploit its potential to the fullest.. Conventional (CLM) and PEGylated liposomes (MPL) of MLX was prepared using hydrogenated soya phosphatidylcholine (HSPC), distearyl phosphatidyl glycerol (DSPG), cholesterol and 1, 2-distearoyl- phosphatidylethanolamine-methyl-polyethyleneglycol conjugate-2000 sodium salt (MPEG 2000 DSPE). The liposomes were prepared using thin film hydration method. The optimization of the formulation was done by employing the QbD approach. The formulation was optimized on the basis of the factors which were affecting the critical quality attributes (CQAs) such as particle size and entrapment efficiency. The final optimized formulation was characterized by assessing the particle size, percent entrapment efficiency, zeta potential, long-term stability, morphology, in vitro release and in vitro cytotoxic activity.. PEGylated liposomes having high percent entrapment efficiency (87.25 %±0.72%) could be obtained. The entrapment of drug in the liposomes was confirmed using Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FT-IR) and Powder X-Ray diffraction (PXRD) studies. The mean particle size of the liposomes was 113 nm±67nm and they were found to exhibit sustained release profile (56.59 %±0. 43% drug in 24h). The Small Angle Neutron Scattering (SANS) analysis revealed that the liposomes were uniform sized LUVs (nm) and were spherical in shape. The shape of the liposomes was further confirmed by transmission electron microscopy (TEM). Long term stability study indicated that the formulation was stable for three months. Sulphorhodamine B (SRB) cytotoxicity assay was carried out in HT-29 cell to prove that the PEGylated liposomal formulations had higher cytotoxicity than the conventional liposomes after 48 hours of incubation.. The study affirmed that MLX loaded PEGylated liposomes had superior in vitro cytotoxicity as compared to the free drug as well as conventional liposomes. QbD resulted in the fabrication of a stable liposomal formulation with all the desirable characteristics. Hence, MLX loaded PEGylated liposomes can be considered to be a promising system for the delivery of MLX.

Topics: Antineoplastic Agents; Cell Survival; Colorectal Neoplasms; Drug Carriers; Drug Compounding; Drug Liberation; HT29 Cells; Humans; Liposomes; Meloxicam; Particle Size; Phosphatidylcholines; Phosphatidylethanolamines; Polyethylene Glycols

The objective of the present study was to develop a colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer. Efficacy of selective cyclooxygenase-2 inhibitors has been proven in colorectal cancer. Meloxicam is a selective cyclooxygenase-2 inhibitor with pH-dependent solubility. To achieve pH-independent drug release of meloxicam, pH modifying agents (buffering agents) were used. Meloxicam tablets containing polyethylene oxide were dually coated with ethyl cellulose containing hydrophilic material, polyethylene glycol as an inner coating layer and methyl acrylate, methyl methacrylate, and methacrylic acid copolymer (Eudragit® FS 30D) as outer coating layer for colon targeting. Optimized tablet formulations demonstrated good potential to deliver the drug to the colon by successfully exhibiting a lag time of 5 h during in vitro drug release study. An in vivo evaluation study conducted to ascertain pharmacokinetic parameters in rabbits revealed that the onset of drug absorption from the coated tablets (T(lag time) = 4.67 ± 0.58 h) was significantly delayed compared to that from the uncoated tablets. The AUC(0→)(t) and AUC(0→∞) for coated tablets were lower than of uncoated tablets, although the difference was not significant (p > 0.01). The roentgenography study revealed that the tablet remained intact, until it reached the colon (5 h), which demonstrates that the system can efficiently deliver the drug to the colon. This study demonstrated that a meloxicam-loaded colon targeted system exhibited promising targeting and hence may be used for prophylaxis of colorectal cancer.

Topics: Animals; Cellulose; Chemistry, Pharmaceutical; Colon; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Delayed-Action Preparations; Drug Delivery Systems; Drug Stability; Hydrogen-Ion Concentration; Meloxicam; Polyethylene Glycols; Polymethacrylic Acids; Rabbits; Solubility; Tablets; Thiazines; Thiazoles

Nonsteroidal anti-inflammatory drugs are known to reduce the risk and mortality from colorectal carcinoma by inhibiting cyclo-oxygenases (COX). COX-2 expression was investigated immunohistologically in 57 patients with colorectal carcinomas and in the corresponding liver metastases using tissue microarray analysis. Ex vivo COX-2 inhibition with assessment of apoptosis was performed using precision-cut tissue slices of three human liver metastases. Following stimulation with different concentrations of the selective COX-2 inhibitor meloxicam, apoptosis was assessed immunohistochemically after 6 h and 12 h. All primary carcinomas and 56 out of the 57 liver metastases showed various degrees of cytoplasmatic COX-2 expression being with a reduction and in the liver metastases. There was a time- and concentration-dependent change in the number of apoptotic cells in tissue slices, however, this was without statistical significance. COX-2 is constantly involved in the carcinogenesis and metastatic process of colorectal cancer. The antineoplastic effect of COX-2 inhibition may be based on different pathways, including changes in sensitivity to apoptosis.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Male; Meloxicam; Middle Aged; Thiazines; Thiazoles; Tissue Array Analysis

COX-2 is involved in tumor angiogenesis and modulation of the production of angiogenetic factors by colorectal carcinoma cells. It has been shown that COX-2 inhibitors have inhibitory activities against various types of tumor, including colorectal carcinoma. In this study, we investigated the tumor vessels of small metastatic liver tumors in rats and the effect of meloxicam, a selective COX-2 inhibitor, on their growth and microvasculature.. The metastatic liver tumors were produced by intraportal inoculation of RCN-H4 cells in male F344/DuCrj rats (n = 40). The microvasculature was examined by scanning electron microscopy and stereomicroscopy. Microvascular casts were produced by perfusion via the abdominal aorta 14 days after tumor inoculation. Four groups (control, groups 1-3) of rats were treated with meloxicam 0, 0.6, 1.0 and 3.0 mg/kg/day, respectively, by oral gavage 5 days/week for two weeks from the day of inoculation of RCN-H4 cells.. The mean number of tumors was significantly decreased in groups 1-3 (5.6+/-0.8 standard deviation, SD; 3.6+/-1.1; and 5.5+/-1.1, respectively) compared with control (11.2+/-2.7; P = 0.0002, each). Meloxicam also significantly reduced the mean diameter of the tumor: 730+/-254, 685+/-212 and 644+/-139 in groups 1-3, respectively, in comparison with 870+/-276 in control (P = 0.0025, 0.0011 and <0.0001, respectively).. Meloxicam's anti-angiogenic activity interferes with the growth of metastatic liver tumors. Meloxicam might have therapeutic potential for liver metastasis of colorectal carcinoma.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Liver Neoplasms; Male; Meloxicam; Microcirculation; Microscopy, Electron, Scanning; Rats; Rats, Inbred F344; Thiazines; Thiazoles

Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Division; Collagen; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Drug Combinations; Humans; Isoenzymes; Laminin; Meloxicam; Membrane Proteins; Mice; Mice, Nude; Neoplasm Transplantation; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Thiazines; Thiazoles; Transplantation, Heterologous; Tumor Cells, Cultured