The purpose of this work was to assess the colloidal stability of novel milk-based formulations.Milk-based formulations were prepared in situ by adding into milk alkaline- or ethanolic-drug solutions containing an array of drugs namely; ketoprofen, tolfenamic acid, meloxicam, tenoxicam and nimesulide, mefenamic acid, cyclosporine A, danazol and clopidogrel besylate. The produced formulations were characterized by means of dynamic lightscattering, ζ-potential studies, atomic force microscopy, fluorescence spectroscopy, Raman spectroscopy complemented with ab initio calculations and stability studies.The presence of the drugs did not induce significant changes in most cases to the particle size and ζ-potential values of the emulsions pointing to the colloidal stability of these formulations. Raman spectroscopy studies revealed interactions of the drugs and the milk at the intermolecular level. Complementary analysis with ab initio calculations confirmed the experimental observations obtained by Raman spectroscopy. Finally the produced drug containing alkaline/ethanolic solutions exhibited stability over a period of up to 12 months.The current data demonstrate that milk is a promising drug carrier.

Surgical correction of left displaced abomasum (LDA) is common in lactating dairy cattle. Despite the growing acceptance that abdominal surgery is painful, few cows are administered analgesia following LDA surgery. The objective of this research was to examine the effect of administering a label dose of ketoprofen on physiological and behavioral indicators of pain in dairy cattle. Holstein cows were enrolled in a field study following LDA surgery. Surgery was performed using the standing right flank (RF) approach or the paramedian (PARA) approach. Using a triple-blind randomized trial, each animal was assigned to receive either 3mg of ketoprofen/kg of body weight or saline (the equivalent volume) by intramuscular injection immediately following surgery and 24h postoperatively. Physiological parameters (heart rate, respiration rate, and rumen motility), blood β-hydroxybutyrate (BHBA) levels, and an assessment of cow attitude were measured on the day of surgery, and at 2 follow-up visits (visit 1=3 ± 0.9 d and visit 2=9 ± 1.2 d postsurgery; n=175). Milk production and culling were recorded for all cows enrolled in the study. Producers assessed their cows' attitudes and appetites daily for the first 3 d following surgery. A subset of cows (n=37) were fitted on the day of surgery with a 3-axis accelerometer on the hind leg to assess lying behavior. Continuous and binary outcome data were analyzed using multivariable mixed linear and mixed logistic models, respectively, with cow modeled as a random effect. Ketoprofen did not alter the physiological measures, BHBA levels, or behavioral outcomes measured. Cows subjected to RF surgery had longer lying times [model coefficient β=228.9 min; 95% confidence interval (CI): 122.2 to 335.6] in the first 3 d following surgery, and lower heart rates (β=-9.4 beats/min; 95% CI: -12 to -6.9 beats/min) at the follow-up visits, compared with animals that underwent PARA surgery. Regardless of surgical procedure, BHBA decreased from surgery day to visit 1 (β=-1.9 mmol/L; 95% CI: -2.1 to -1.7) and visit 2 (β=-2.0 mmol/L; 95% CI: -0.2.2 to -1.8). Producer reports indicated that animals that received ketoprofen were more likely to begin eating when provided fresh feed during the first 3 d following surgery compared with those that received saline (odds ratio=4.8; 95% CI: 0.97 to 23.8). These results indicate that PARA surgery may be more painful relative to lying down than the RF approach. The apparent differences in appetite or attitude in cows that received ketoprofen reported by producers warrant further investigation.

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, "downstream" inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.

Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain.The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY).In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses.ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.

Visceral pain is an important and prevalent clinical condition whose treatment is challenging. Sigma-1 (σ1) receptors modulate somatic pain, but their involvement in pure visceral pain is unexplored.The authors evaluated the role of σ1 receptors in intracolonic capsaicin-induced visceral pain (pain-related behaviors and referred mechanical hyperalgesia to the abdominal wall) using wild-type (WT) (n = 12 per group) and σ1 receptor knockout (σ1-KO) (n = 10 per group) mice, selective σ1 receptor antagonists (BD-1063, S1RA, and NE-100), and control drugs (morphine and ketoprofen).The intracolonic administration of capsaicin (0.01-1%) induced concentration-dependent visceral pain-related behaviors and referred hyperalgesia in both WT and σ1-KO mice. However, the maximum number of pain-related behaviors induced by 1% capsaicin in σ1-KO mice (mean ± SEM, 22 ± 2.9) was 48% of that observed in WT animals (46 ± 4.2). Subcutaneous administration of the σ1 receptor antagonists BD-1063 (16-64 mg/kg), S1RA (32-128 mg/kg), and NE-100 (8-64 mg/kg) dose-dependently reduced the number of behavioral responses (by 53, 62, and 58%, respectively) and reversed the referred hyperalgesia to mechanical control threshold (0.53 ± 0.05 g) in WT mice. In contrast, these drugs produced no change in σ1-KO mice. Thus, the effects of these drugs are specifically mediated by σ1 receptors. Morphine produced an inhibition of capsaicin-induced visceral pain in WT and σ1-KO mice, whereas ketoprofen had no effect in either mouse type.These results suggest that σ1 receptors play a role in the mechanisms underlying capsaicin-induced visceral pain and raise novel perspectives for their potential therapeutic value.

ABSTRACT:

INTRODUCTION:

Although the safety of celecoxib has been investigated, limited data are available on complications affecting the entire (upper and lower) gastrointestinal (GI) tract, with no patient-level pooled analyses of upper and lower GI outcomes available. We therefore evaluated the upper and lower GI safety of celecoxib by using patient-level data from randomized controlled trials (RCTs).

METHODS:

This patient-level pooled analysis included 52 prospective, randomized, double-blind parallel-group studies from the Celecoxib Clinical Database. Each study had a planned duration of continuous treatment with celecoxib or a nonselective nonsteroidal antiinflammatory drug (nsNSAID), rofecoxib, or the placebo comparator arm for at least 4 weeks. All studies with final reports completed by 1 October 2007 were included. The primary end point was the combined incidence of clinically significant upper and lower GI events (CSULGIEs). An independent blinded committee reviewed and adjudicated all end points by using predefined criteria and all available reported adverse events, laboratory data, and case narratives. All doses of celecoxib and all doses of all nsNSAIDs were pooled for analysis.

RESULTS:

The pooled analysis involved 51,048 patients; 28,614 were randomized to celecoxib; 15,278 to nsNSAIDs (including 3,248 patients taking naproxen, 2,640 taking ibuprofen, 8,066 taking diclofenac, 1,234 taking loxoprofen, and 90 taking ketoprofen); 5,827 to placebo and 1,329 to rofecoxib. The mean age was 60 years, and 65% were women. Data on 1,042 patients with potential GI events were reviewed for end-points adjudication; the adjudication committee confirmed 89 patients with CSULGIEs. The majority were in the celecoxib and nsNSAID groups (with raw incidence proportions of 37 (0.1%) and 40 (0.3%), respectively). The incidence rates were 0.3, 0.9 and 0.3 per 100 patient-years in the celecoxib, nsNSAID, and placebo groups, respectively. The time to incidence of CSULGIEs was significantly longer with celecoxib than with nsNSAIDs (P = 0.0004).

CONCLUSIONS:

When compared with nsNSAIDs, celecoxib is associated with a significantly lower risk of all clinically significant GI events throughout the entire GI tract. This pooled analysis of 52 RCTs significantly advances the understanding of the upper and lower GI safety profile of celecoxib and its potential benefits to patients.

Perioperative treatment of several rats in our facility with ketoprofen (5 mg/kg SC) resulted in blood loss, peritonitis, and death within a day to a little more than a week after surgery that was not related to the gastrointestinal tract. Published reports have established the 5-mg/kg dose as safe and effective for rats. Because ketoprofen is a nonselective nonsteroidal antiinflammatory drug that can damage the gastrointestinal tract, the putative diagnosis for these morbidities and mortalities was gastrointestinal toxicity caused by ketoprofen (5 mg/kg). We conducted a prospective study evaluating the effect of this therapeutic dose of ketoprofen on the rat gastrointestinal tract within 24 h. Ketoprofen (5 mg/kg SC) was administered to one group of rats that then received gas anesthesia for 30 min and to another group without subsequent anesthesia. A third group was injected with saline followed by 30 min of gas anesthesia. Our primary hypothesis was that noteworthy gastrointestinal bleeding and lesions would occur in both groups treated with ketoprofen but not in rats that received saline and anesthesia. Our results showed marked gastrointestinal bleeding, erosions, and small intestinal ulcers in the ketoprofen-treated rats and minimal damages in the saline-treated group. The combination of ketoprofen and anesthesia resulted in worse clinical signs than did ketoprofen alone. We conclude that a single 5-mg/kg dose of ketoprofen causes acute mucosal damage to the rat small intestine.

Orally administrated nonsteroidal anti-inflammatory drugs are effective in the treatment of a variety of acute and chronic pain conditions but their use may be associated with serious systemic adverse effects which are correlated with the therapeutic plasma levels of the drug. In order to minimize the incidence of drug related systemic events, topical formulations of the nonsteroidal anti-inflammatory drugs have been developed. A recently performed review of the evidence from randomized, double-blind, placebo controlled trials with topically applied NSAIDs in the treatment of acute pain confirmed the previously described pain relief effectiveness. For all topical nonsteroidal anti-inflammatory drugs combined, in comparison to placebo, the number needed to treat (NNT) to achieve a clinically meaningful pain relief of 50 % was 4.5 (3.9 to 5.3) for treatment periods of 6 to 14 days. Local skin reactions were generally mild and transient, and did not differ from placebo.The present is an observational, multicenter, open-label, non-interventional, post-authorization safety study as it is defined by Article 21 of the European Clinical Trials Directive 2001/20/EC. The main objective of this study was to evaluate the local tolerability and the therapeutic efficacy of static and pain on movement intensity reduction of Ketospray® 10% cutaneous spray solution administered in accordance with the terms of the marketing authorization and last version of summary of product characteristics approved by National Medicines Agency of Romania.In compliance with the Post-marketing study type, the assignment of the patient to a particular therapeutic strategy fell within current practice. The prescription of the medicine was not subject to compliance with predefined patients' characteristics. No specific, out of the daily practice routine diagnostic, monitoring, instrumental or laboratory assessments were foreseen by the study protocol. Patients' data were collected into respective case report forms. Study medication, Ketoprofen 10% Cutaneous Spray Solution was administered to the affected area at the dose of 3-6 spray puffs, 2-3 times a day, for 7 days. According to the study type, descriptive statistical methods were applied. Since almost half of the patients were treated with combination of the pain relieving medications, sizing of the pain relieving effects, as NNT, between the two groups was made.There were 2020 study subjects in safety and ITT analysis population and 1802 (89%) in PP efficacy analysis population. There were 4 types of injuries: non-complicated strain-sprain (555), soft tissue contusion (323), low back pain (461) and osteoarthritis (681 patients). Ten patients reported 13 side effects of which 10 were recognized by investigators as adverse drug reactions. All side effects were non-serious, listed, application site skin changes. Remarkable reductions of static and pain on movement intensity were experienced by patients irrespective of the type of the injury and the type of the treatment. However, a clinically meaningful benefit of the concomitantly prescribed pain relieving medications was not observed for any type of pain. The lowest NNT (14) was obtained for the reduction of pain at rest in patients with strain-sprain or soft tissue contusions. The highest NNT (283) was for pain at rest in patients treated for the exacerbation of the chronic pain.The results of the current post-authorization study confirm beneficial pain intensity reducing efficacy of Ketospray 10% associated with good local tolerability of 7 days treatment course. Concomitant administration of systemic pain relieving medication did not substantially contribute neither to the relief of pain at rest nor of pain on movement among the subjects of respective study populations.

Using rabbit corneal epithelial cells (RCECs), the transport of a nonsteroidal anti-inflammatory drug (NSAID) [(3)H]ketoprofen across the cornea was investigated with the aim of revealing the mechanism of uptake.[(3)H]Ketoprofen transport was evaluated by measuring the permeability across the RCECs layers.[(3)H]Ketoprofen uptake was time, temperature and pH dependent. Maximal uptake occurred from a solution with a pH of 5.25. Uptake was also reduced by metabolic inhibitors (sodium azide and dinitrophenol (DNP)) and proton-linked monocarboxylate transporter (MCT) inhibitors (carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and α-cyano-4-hydroxycinnamic acid (CHC)). [(3)H]Ketoprofen uptake was significantly inhibited by various monocarboxylates and other NSAIDs and by MCT and/or organic anion transporter (OAT) inhibitors probenecid and p-aminohippurate, but was unaffected by organic anion-transporting polypeptide (OATP) inhibitors bromosulfophthalein and taurocholate. The specific uptake of [(3)H]ketoprofen was saturable. Eadie-Hofstee plots indicated the involvement of high- and low-affinity components. The K(m) and V(max) values for the high- and low-affinity components of [(3)H]ketoprofen uptake were 0.56 and 24 mm, and 0.37 and 61 nmol/min/mg of protein, respectively. Benzoic acid, a substrate and inhibitor of MCTs, selectively inhibited low-affinity [(3)H]ketoprofen uptake. Conversely, indometacin inhibited high-affinity [(3)H]ketoprofen uptake.The results of this study suggest that the monocarboxylate transport system partly accounts for the low-affinity component of [(3)H]ketoprofen uptake, and that the carrier-mediated transport systems such as the OAT family, shared by NSAIDs account for the high-affinity component.

Microchannels based microfluidic systems are able to obtain monodispersed microparticles but are limited by cost, time and channel clogging. We succeeded in on the fly encapsulation of high ketoprofen contents in acrylate-based copolymer microbeads by environment friendly UV induced free radical polymerization in off-the-shelf co-axial microfluidic device. FTIR shows complete polymerization of acrylate monomers and interaction between carboxylic group of ketoprofen and ester group of monomers. DSC and XRD confirm amorphous nature of drug in microbeads. Different comonomer content formulations show limited drug release at low pH, a helpful properties to avoid gastric irritating effect of ketoprofen associated with conventional dosage forms. At pH 6.8 microbeads release higher content of drug by a non-Fickian diffusion mechanism. Their drug release rate depends upon the weight content of ethyl acrylate in the formulation as well as their size, increasing by increasing the former and decreasing the later.