The Antiinflammatory Action and Pharmacokinetics of a Novel Glucosamine-based Di-Peptide Aminosugar

Purpose. We have previously shown favorable in vitro gut permeability for three novel dipeptide esters of glucosamine (GlcN) likely facilitated by the peptide transporter 1 (PepT1). Herein, we report the development of a novel assay for the determination of bioavailability of the peptide ester of interest, the anti-inflammatory properties of a glycine-valine ester derivative of GlcN (GVG) as well as its pharmacokinetics under healthy and inflammatory conditions. Methods. A pre-column derivatization (with 9-fluorenylmethoxycarbonyl) HPLC assay was developed to study bioavailability of GVG, GlcN or cleaved GlcN in the rats that were cannulated in their right jugular vein for blood collection. The compounds of interest were orally administered to both healthy and arthritic rats. Serial blood samples and urine were collected and assayed for the compounds. The stability of the GVG was also tested after incubation with the rat feces. Efficacy of GVG was tested in inflamed rats (injection of 0.2 mL of Mycobacterium butyricum in squalene) following GVG (20 and 30 mg/kg/day GlcN equivalent) or GlcN (20 and 90 mg/kg/day) administration. Arthritis index was calculated at the end of the experiment. Results. The assay was linear (ranged between 0.05-20 mu g/mL) and reproducible (intra- and inter-day\u3c10%). Among the tested compounds, only GVG showed a significantly higher plasma concentrations and urinary excretion than GlcN (approximate to 3-fold increase). GVG showed a favorable stability in the rat feces. Adjuvant arthritis was completely prevented with doses greater than 20 mg/kg/day with GVG being 3-fold more potent than GlcN. Conclusion. The examined glycine-valine-GlcN di-peptide aminosugar is a potent anti-inflammatory compound due to its favorable properties to deliver GlcN into the systemic circulation

The recrystallization and dissolution of acetylsalicylic acid

Observations that some samples of commercial acetylsalicylic acid had different dissolution rates were followed by reports that acetylsalicylic acid exists in more than one polymorphic form. The evidence for polymorphism has been questioned by a number of authors and the effects of such factors as crystal habit, particle size, crystal imperfection, the presence of salicylic acid and spherulites of acetylsalicylic acid have been discussed in an attempt to explain the anomalous behaviour. This work attempts to resolve the conflicting points of view. Acetylsalicylic acid was recrystallized from ethanol in a crystallizer which permitted control of the degree of supersaturation and, therefore, growth rate. In addition, a number of other recrystallization techniques and solvents were used to produce acetylsalicylic acid crystals with a wide variety of habits and varying amounts of salicylic acid. The crystals were compressed into discs both with and without prior size reduction and sieving. Intrinsic dissolution rates, measured using a rotating disc technique showed that the rates were independent of crystal growth rate, crystal size and habit, the content of salicylic acid (up to 3.8% w/w) and the presence of spherulites of acetylsalicylic acid. X-ray diffraction patterns revealed no differences between the various crystals and the original commercial material. Melting points, however, were dependent on the method of measurement and the crystal size and habit. Using the hot-stage method and heating at a rate of 0.2°per minute from a starting temperature of 2° below the approximate melting point (previously determined), acetylsalicylic acid melted, with decomposition, in the range of 128.3 to 132.7°, (excluding spherulites). When heating was started at 100° the melting range became very broad with small unaggregated particles starting to melt at temperatures between 103° and 112°. Analysis of the melt showed that the proportion of salicylic acid increased with decrease in particle size of the original acetylsalicylic acid crystals. Hence, the depression of the melting point of individual crystals is related to the increased susceptibility of small particles to thermal decomposition with the formation of salicylic acid. Evidence for the existence of metastable polymorphs of acetylsalicylic acid rests on the reported properties of needle-like crystals recrystallized from n-hexane and spherulites grown in thin films from saturated alcoholic solution. The needle-like crystals melted over the range 123.9° to 130.1° using a heating rate of 0.2° per minute from a starting temperature 2° below the approximate melting point. The wide melting range is probably due to decomposition of the fine needles and the formation of salicylic acid as discussed above. Spherulites of acetylsalicylic acid underwent a thermal transformation over the range 104° to 128° to form elongated prisms and a solution phase transformation into well defined prisms when in contact with a saturated solution of acetylsalicylic acid in various alcohols. The intrinsic dissolution rates of compressed discs prepared from the needle-like crystals and spherulites were the same as the other acetylsalicylic acid crystals. Moreover, X-ray diffraction patterns of the needle-like crystals, the spherulites and the crystals formed from the spherulites after thermal and solution phase transformation were identical with each other and the original aspirin. Hence, the needle-like crystals and spherulites are not metastable polymorphic forms of acetylsalicylic acid. It is suggested that both the thermal and solution phase transformation are growth processes.Pharmaceutical Sciences, Faculty ofGraduat

Renal Adverse Effects of Nonsteroidal Anti-Inflammatory Drugs

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored

Effect of Inflammation on Kidney Function and Pharmacokinetics of COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs Rofecoxib and Meloxicam

Chronic arthritis adversely affects glomerular function and nonsteroidal anti-inflammatory drugs (NSAIDs) reduce electrolyte urinary excretion. In addition, both acute and chronic inflammations may alter clearance of drugs. We studied (a) the effects of inflammation on the renal function and pharmacokinetics of rofecoxib and meloxicam; (b) whether inflammation could exacerbate reduced electrolytes excretion changes observed with NSAIDs; and (c) the influence of inflammation on distribution of these drugs into the kidney. Single oral doses of rofecoxib (10 mg kg-1), meloxicam (3 mg kg -1) or placebo were administered to normal or pre-adjuvant arthritic rats. Blood and urine samples were collected for the measurement of plasma nitrite, BUN and creatinine. The urinary excretion of sodium and potassium was also determined. Nitrite, BUN and plasma creatinine were increased starting on day 9 in the groups with inflammation. Sodium and potassium excretion rates were not affected by inflammation. Meloxicam did not alter the electrolyte excretion in any of the groups. Rofecoxib significantly decreased sodium and potassium excretion in normal rats and potassium excretion in inflamed rats. Inflammation significantly increased plasma concentrations of rofecoxib, but not meloxicam. The ratios of the kidney:plasma concentrations were not significantly altered by inflammation following either drug. Inflammation altered kidney function, demonstrated by increases in BUN and plasma creatinine. However, it did not influence the urinary electrolytes excretion. Since we have observed similar patterns of the effect of NSAIDs on kidney under healthy and inflammatory conditions, one may conclude that inflammation does not exacerbate the adverse effect

Drug Disease Interactions: Role of Inflammatory Mediators in Pain and Variability in Analgesic Drug Response

Pain has both physical and emotional components. Physical noxious stimuli activate peripheral sensory neurons that, in turn, relay signals to the spinal and supraspinal nuclei. Subsequently, these signals activate areas within the brain associated with pain. Despite considerable knowledge in this area, analgesics may provide pain complete relief in only one out of five patients. Failure to manage pain may be due to a lack of understanding of the neurobiological processing of pain. Factors such as anticipation, anxiety and pain history play roles in the perception of pain. Non-neuronal cells such as those of the immune system influence perception and modulation of pain by the nervous system. In post-dental surgery patients, the severity of the pain and the relief following administration of anti-inflammatory analgesics has been linked to the time course of inflammatory mediators. Similarly, the relief of post-operative pain after abdominal surgery is also associated with a reduction in expression of pro-inflammatory mediators. Administration of anti-cytokines to sciatica patients and subsequent pain relief further emphasizes the role of pro-inflammatory mediators in modulation of pain. Increased expression of inflammatory mediators may also alter response to analgesia. For example, rheumatoid patients with temporal mandibular joint disease with increased expression of interleukins prior to treatment demonstrate inadequate pain relief after administration of anti-TNF-?. In addition, pain or its trauma impairs absorption of oral analgesics causing therapeutic failure. Improved analgesic pharmacotherapy may require a better understanding of the involvement of the inflammatory pathways

Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor\u27s files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail

Synthesis and Characterization of a New Peptide Prodrug of Glucosamine with Enhanced Gut Permeability

The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a quick cleavage to GlcN after exposure to the liver homogenate. In conclusion, a novel prodrug of glucosamine with superior gut permeability compared to GlcN was developed and successfully tested in vitro