Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology.

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.

New insights into the use of currently available non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs), which act via inhibition of the cyclooxygenase (COX) isozymes, were discovered more than 100 years ago. They remain a key component of the pharmacological management of acute and chronic pain. The COX-1 and COX-2 isozymes have different biological functions; analgesic activity is primarily (although not exclusively) associated with inhibition of COX-2, while different side effects result from the inhibition of COX-1 and COX-2. All available NSAIDs, including acetaminophen and aspirin, are associated with potential side effects, particularly gastrointestinal and cardiovascular effects, related to their relative selectivity for COX-1 and COX-2. Since all NSAIDs exert their therapeutic activity through inhibition of the COX isozymes, strategies are needed to reduce the risks associated with NSAIDs while achieving sufficient pain relief. A better understanding of the inhibitory activity and COX-1/COX-2 selectivity of an NSAID at therapeutic doses, based on pharmacokinetic and pharmacodynamic properties (eg, inhibitory dose, absorption, plasma versus tissue distribution, and elimination), and the impact on drug tolerability and safety can guide the selection of appropriate NSAIDs for pain management. For example, many NSAIDs with moderate to high selectivity for COX-2 versus COX-1 can be administered at doses that maximize efficacy (~80% inhibition of COX-2) while minimizing COX-1 inhibition and associated side effects, such as gastrointestinal toxicity. Acidic NSAIDs with favorable tissue distribution and short plasma half-lives can additionally be dosed to provide near-constant analgesia while minimizing plasma concentrations to permit recovery of COX-mediated prostaglandin production in the vascular wall and other organs. Each patient's clinical background, including gastrointestinal and cardiovascular risk factors, should be taken into account when selecting appropriate NSAIDs. New methods are emerging to assist clinicians in the selection of appropriate NSAIDs and their doses/schedules, such as biomarkers that may predict the response to NSAID treatment in individual patients.

New problems arising from old drugs: second-generation effects of acetaminophen.

Acetaminophen (APAP)/paracetamol is one of the most commonly used over-the-counter drugs taken worldwide for treatment of pain and fever. Although considered as safe when taken in recommended doses not higher than 4 g/day, APAP overdose is currently the most important cause of acute liver failure (ALF). ALF may require liver transplantation and can be fatal. The reasons for APAP-related ALF are mostly intentional (suicidal) or unintentional overdose. However, results from large scale epidemiological studies provide increasing evidence for second generation effects of APAP, even when taken in pharmacological doses. Most strikingly, APAP medication during pregnancy has been associated with health problems including neurodevelopmental and behavioral disorders such as attention deficit hyperactivity disorder and increase in the risk of wheezing and incidence of asthma among offspring. This article reviews the epidemiological findings and aims to shed light into the molecular and cellular mechanisms responsible for APAP-mediated prenatal risk for asthma.

Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study.

OBJECTIVES: To prevent pain inhibiting their performance, many athletes ingest over-the-counter (OTC) analgesics before competing. We aimed at defining the use of analgesics and the relation between OTC analgesic use/dose and adverse events (AEs) during and after the race, a relation that has not been investigated to date. DESIGN: Prospective (non-interventional) cohort study, using an online questionnaire. SETTING: The Bonn marathon 2010. PARTICIPANTS: 3913 of 7048 participants in the Bonn marathon 2010 returned their questionnaires. PRIMARY AND SECONDARY OUTCOMES: Intensity of analgesic consumption before sports; incidence of AEs in the cohort of analgesic users as compared to non-users. RESULTS: There was no significant difference between the premature race withdrawal rate in the analgesics cohort and the cohort who did not take analgesics ('controls'). However, race withdrawal because of gastrointestinal AEs was significantly more frequent in the analgesics cohort than in the control. Conversely, withdrawal because of muscle cramps was rare, but it was significantly more frequent in controls. The analgesics cohort had an almost 5 times higher incidence of AEs (overall risk difference of 13%). This incidence increased significantly with increasing analgesic dose. Nine respondents reported temporary hospital admittance: three for temporary kidney failure (post-ibuprofen ingestion), four with bleeds (post-aspirin ingestion) and two cardiac infarctions (post-aspirin ingestion). None of the control reported hospital admittance. CONCLUSIONS: The use of analgesics before participating in endurance sports may cause many potentially serious, unwanted AEs that increase with increasing analgesic dose. Analgesic use before endurance sports appears to pose an unrecognised medical problem as yet. If verifiable in other endurance sports, it requires the attention of physicians and regulatory authorities.

E-pharmacovigilance: development and implementation of a computable knowledge base to identify adverse drug reactions.

AIMS: Computer-assisted signal generation is an important issue for the prevention of adverse drug reactions (ADRs). However, due to poor standardization of patients' medical data and a lack of computable medical drug knowledge the specificity of computerized decision support systems for early ADR detection is too low and thus those systems are not yet implemented in daily clinical practice. We report on a method to formalize knowledge about ADRs based on the Summary of Product Characteristics (SmPCs) and linking them with structured patient data to generate safety signals automatically and with high sensitivity and specificity. METHODS: A computable ADR knowledge base (ADR-KB) that inherently contains standardized concepts for ADRs (WHO-ART), drugs (ATC) and laboratory test results (LOINC) was built. The system was evaluated in study populations of paediatric and internal medicine inpatients. RESULTS: A total of 262 different ADR concepts related to laboratory findings were linked to 212 LOINC terms. The ADR knowledge base was retrospectively applied to a study population of 970 admissions (474 internal and 496 paediatric patients), who underwent intensive ADR surveillance. The specificity increased from 7% without ADR-KB up to 73% in internal patients and from 19.6% up to 91% in paediatric inpatients, respectively. CONCLUSIONS: This study shows that contextual linkage of patients' medication data with laboratory test results is a useful and reasonable instrument for computer-assisted ADR detection and a valuable step towards a systematic drug safety process. The system enables automated detection of ADRs during clinical practice with a quality close to intensive chart review.

Lateralization of responses to vibrissal stimulation: connectivity and information integration in the rat sensory-motor cortex assessed with fMRI.

Rats move their whiskers or vibrissae to gain sensory information about the world surrounding them. A single whisker can work as an independent detector but normal whisking involves the use of several vibrissae in a bilateral fashion. Here we used blood oxygen level dependent (BOLD) contrast to acquire functional magnetic resonance images (fMRI) of the rat brain activity during uni- and bilateral whisker stimulations with different timing schemes under Isoflurane anesthesia. Experiments were performed to assess the integration of bilateral information produced by normal whisking behavior. First, we showed that it was possible to obtain BOLD whisker activations using Isoflurane harmless for the animals and thus allowing for future repetitive/longitudinal studies. Second, we obtained different BOLD activation patterns depending on the number of stimulated whiskers and timing of the stimulation scheme. Third, we found lateralization of BOLD activations in the somatosensory-motor cortex. It manifested itself in considerably larger activations in the right hemisphere during equal bilateral whisker stimulation. Fourth, we found Granger Causality Analysis (GCA) to be a useful tool in information integration analysis, as it reproduced the stimulus specific Cross-correlation Analysis results. Both analyses showed that the amount of whiskers stimulated and the timing of stimulation lead to specific dynamic connectivity patterns. Finally, by adding directionality information GCA revealed meaningful lateralization of information processing in the rat whisker system consistent with the observed BOLD activation patterns.

Paracetamol and cyclooxygenase inhibition: is there a cause for concern?

Paracetamol is recommended as first-line therapy for pain associated with osteoarthrosis and is one of the most widely used over-the-counter analgesic drugs worldwide. Despite its extensive use, its mode of action is still unclear. Although it is commonly stated that paracetamol acts centrally, recent data imply an inhibitory effect on the activity of peripheral prostaglandin-synthesising cyclooxygenase enzymes. In this context paracetamol has been suggested to inhibit both isoforms in tissues with low levels of peroxide by reducing the higher oxidation state of cyclooxygenase enzymes. Two recent studies have also demonstrated a preferential cyclooxygenase 2 (COX-2) inhibition by paracetamol under different clinically relevant conditions. This review attempts to relate data on paracetamol's inhibitory action on peripheral cyclooxygenase enzymes to the published literature on its anti-inflammatory action and its hitherto underestimated side-effects elicited by cyclooxygenase inhibition. As a result, a pronounced COX-2 inhibition by paracetamol is expected to occur in the endothelium, possibly explaining its cardiovascular risk in epidemiological studies. A careful analysis of paracetamol's cardiovascular side-effects in randomised studies is therefore strongly advised. On the basis of epidemiological data showing an increased gastrointestinal risk of paracetamol at high doses or when co-administered with classic cyclooxygenase inhibitors, paracetamol's long-term gastrointestinal impact should be investigated in randomised trials. Finally, paracetamol's fast elimination and consequently short-lived COX-2 inhibition, which requires repetitive dosing, should be definitely considered to avoid overdosage leading to hepatotoxicity.

Evaluation of NT-proBNP and high sensitivity C-reactive protein for predicting cardiovascular risk in patients with arthritis taking longterm nonsteroidal antiinflammatory drugs.

OBJECTIVE: Patients with arthritis frequently are at increased risk for future cardiovascular (CV) events. We investigated the performance of the cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) for predicting CV events in patients with arthritis taking chronic nonsteroidal antiinflammatory drugs (NSAID). METHODS: We evaluated 2-year CV outcomes in a prospective, nested biomarker study among patients (N = 6273) with rheumatoid arthritis and osteoarthritis treated with NSAID in the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long-term) trial. Patients were stratified by quartiles of baseline NT-proBNP and established cutpoints of NT-proBNP and hsCRP. RESULTS: NT-proBNP demonstrated a strong graded relationship with CV outcomes, including CV death (p for trend < 0.0001), myocardial infarction (MI) (p for trend = 0.02), heart failure (HF) (p for trend < 0.0001), and a composite of thrombotic events (CV death, MI, stroke) or HF (p for trend < 0.0001). Baseline levels of hsCRP were not associated with CV events (CV death/MI/stroke/HF; p for trend = 0.65). NT-proBNP remained strongly predictive of CV events after adjustment for age, sex, diabetes, hypertension, hyperlipidemia, smoking, type of arthritis, body mass index, creatinine clearance, history of CV disease, and hsCRP (CV death/MI/stroke/HF: Q4 vs Q1 hazard ratio 3.53, 95% CI 1.89-6.58). Patients with a NT-proBNP level below 100 pg/ml had a 0.94% rate of thrombotic events or heart failure at 2 years. CONCLUSION: NT-proBNP is a simple and robust noninvasive indicator of CV risk in patients with arthritis. Risk stratification based on NT-proBNP may facilitate identification of patients with arthritis who are at low CV risk during chronic NSAID treatment.

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system.

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene.

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the α2δ family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (α2δ3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, α2δ3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in α2δ3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in α2δ3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

Using pharmacokinetic principles to optimize pain therapy.

Cyclo-oxygenase (COX) inhibitors are widely used to relieve musculoskeletal pain. These agents block the production of prostaglandins (PGs) at sites of inflammation by inhibiting the activity of two COX enzymes necessary for PG production and normal organ homeostasis. Inhibition of PG production at sites unrelated to pain is associated with adverse drug reactions (ADRs). The degree of analgesic efficacy, as well as the incidence and the localization of ADRs, are critically influenced by the pharmacokinetics (absorption, distribution and elimination) of these drugs. Ideally, sufficient and permanent inhibition of COX enzymes should be achieved in target tissues, with minimal ADRs. To minimize underdosing or overdosing, which result in therapeutic failure or ADRs, the COX inhibitor with the most appropriate pharmacokinetic properties should be selected on the basis of a thorough pharmacokinetic-pharmacodynamic analysis. In this Review, the pharmacokinetics of the prevailing COX inhibitors will be discussed and enigmatic aspects of these intensively used drugs will be considered.

Effect of maximum OTC doses of naproxen sodium or acetaminophen on low-dose aspirin inhibition of serum thromboxane B2.

OBJECTIVES: This study evaluated the platelet inhibitory effects of low-dose enteric-coated aspirin (EC-ASA) when used concomitantly with maximum over-the-counter (OTC) doses of naproxen sodium (NAPSO) or acetaminophen to determine whether NAPSO and acetaminophen interfere with the anti-platelet effect of aspirin. RESEARCH DESIGN AND METHODS: Phase I, randomized, open-label, multi-dose, three-period, parallel group, pharmacodynamic trial conducted in healthy male and female volunteers (n = 47 randomized subjects and n = 37 evaluable subjects), mean age 40.2 years. All subjects received 5 days of EC-ASA 81 mg once daily followed by 5 days of EC-ASA 81 mg once daily alone or co-administered with either NAPSO 220 mg three times daily or acetaminophen 1 g four times daily. PRIMARY OUTCOME MEASURE: Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured on Day 11. RESULTS: Mean inhibition of TXB(2) on Day 11 was >99% for subjects taking EC-ASA alone as well as for those who received EC-ASA co-administered with NAPSO or acetaminophen. For subjects taking EC-ASA monotherapy, mean serum TXB(2) inhibition was 99.7% (range 99.0-100%), for those taking EC-ASA with acetaminophen it was 99.6% (range 98.3-99.9%), and for those taking EC-ASA with NAPSO, mean serum TXB(2) inhibition was 99.7% (range 99.2-100%). STUDY LIMITATION: Small sample size and open-label trial design. CONCLUSIONS: The anti-platelet effect of EC-ASA 81 mg once daily was maintained following its co-administration with maximum OTC doses of NAPSO or acetaminophen.

Absorption and distribution of etoricoxib in plasma, CSF, and wound tissue in patients following hip surgery--a pilot study.

The perioperative administration of selective cyclooxygenase-2 (COX-2)-inhibitors to avoid postoperative pain is an attractive option: they show favorable gastro-intestinal tolerability, lack inhibition of blood coagulation, and carry a low risk of asthmatic attacks. The purpose of this study was to determine the cerebrospinal fluid (CSF), plasma, and tissue pharmacokinetics of orally administered etoricoxib and to compare it with effect data, i.e., COX-2-inhibition in patients after hip surgery. The study was performed in a blinded, randomized, parallel group design. A total of 12 adult patients were included who received 120 mg etoricoxib (n = 8) or placebo (n = 4) on day 1 post-surgery. Samples from plasma, CSF, and tissue exudates were collected over a period of 24 h post-dosing and analyzed for etoricoxib and prostaglandin E(2) (PGE(2)) using liquid chromatography-tandem mass spectrometry and immuno-assay techniques. CSF area under the curve (AUC) [AUCs((O-24h))] for etoricoxib amounted to about 5% of the total AUC in plasma (range: 2-7%). Individual CSF lag times with respect to (50%) peak plasma concentration were

Combining functional magnetic resonance imaging with mouse genomics: new options in pain research.

This functional magnetic imaging study investigated the functional implications of genetic modification and pharmacological intervention on cerebral processing of heat-induced nociception in mice. Comparing dynorphin-overexpressing dream(-/-) with wild-type mice, smaller activated cortical and limbic brain structure sizes could be observed. Moreover, significantly reduced blood oxygenation level-dependent signal amplitudes were found in pain-related brain structures: sensory input, thalamic regions, sensory cortex, limbic system, basal ganglia, hypothalamus and periaqueductal grey. Administration of the specific kappa-opioid-receptor antagonist nor-binaltorphimine to dream(-/-) mice reversed this reduction to wild-type level in the same brain structures. These results show that blood oxygenation level-dependent functional magnetic imaging in the pain system of (transgenic) mice is feasible. Genetic modifications and pharmacological interventions modify brain responses in a structure-specific manner.

Drug utilisation on a preterm and neonatal intensive care unit in Germany: a prospective, cohort-based analysis.

PURPOSE: This study aims to describe the drug use on a Neonatal Intensive Care Unit (NICU) at a University Children's Hospital in Germany, to investigate the licensing status of the drugs used and to conclude critical areas in neonatal intensive care to support prioritisation of future research. METHODS: An 11-month, prospective cohort study was conducted on the NICU at the University Children's Hospital Erlangen, Germany. All products prescribed during the study period were analysed whether or not the SPC contains information on term and preterm neonates. RESULTS: A total of 183 patients (102 male) with a mean gestational age of 33.6 weeks (minimum = 24, maximum = 42) were included. The mean length of hospitalisation was 19.4 days (minimum = 2, maximum = 167). On average, patients received 11.1 drugs (minimum = 0, maximum = 46). The majority of prescriptions were accounted for by antibiotics (n = 515), which were received by 90% of all patients, followed by CNS drugs (n = 448) and respiratory drugs (n = 306). Of all the different drugs prescribed (n = 102) only 38% had information regarding their use in patients aged less than 1 month in their SPC. Analgesics and cardiovascular drugs were prescribed frequently, but without having information for use in neonates. Seventy percent of all patients and 100% of very preterm infants received at least one of these drugs. CONCLUSIONS: Treatment strategies on a preterm intensive care unit are complex and little information is available for the drugs used. Analgesics and cardiovascular drugs are of major concern. Efforts will have to be made to conduct well-designed and powered studies in this vulnerable population.

Influence of cyclooxygenase inhibitors on the function of the prostaglandin transporter organic anion-transporting polypeptide 2A1 expressed in human gastroduodenal mucosa.

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E(2) with IC(50) values of 6.2 +/- 1.2 and 3.1 +/- 1.2 microM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE(2) transport by 162.7 +/- 13.9, 77.2 +/- 3.6, and 32.3 +/- 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.