Experiments on inflammatory edema modeling by sub-plantar injection of carrageenan lambda (1 %) and formalin (2 %) showed substantial differences betwe- en the two models during long-term observation, including irreversible damage caused by formalin (at reversible carrageenan action) and high intensity of for- malin edema (in contrast to carrageenan edema) in mice. We propose a new approach to evaluation of the so-called total inflammatory burden (experimental analog of disease outcome) by calculating the area under the inflammation intensity versus time curve. With the use of this approach, we showed the absence of any effect of conventional NSAIDs (naproxen, diclofenac. indomethacin) on the total inflammatory burden induced by carrageenan or formalin injections in mice and rat paw edema models. These results show the need for using new approaches in the search for potential anti-inflammatory agents.

PGE2 is found to attenuate the bactericidal effects of kanamycin or ampicillin in Staphylococcus aureus, as well as the methicillin-resistant S. aureus (MRSA). Co-treatment with cyclooxygenase (COX) inhibitors (celecoxib, aspirin or naproxen) synergistically enhances kanamycin or ampicillin-induced cell death of S. aureus and MRSA. COX inhibitors repressed bacterial multidrug resistance through down-regulating efflux pump activity in antibiotics-treated S. aureus and MRSA. However, this synergistic bactericidal effects are reduced by the treatment with PGE2. PGE2 restores the efflux pump activity as well as increases biofilm formation in S. aureus and MRSA. Collectively, the enhancement of efflux pump activity and biofilm formation with PGE2 might partially explain the resistance to synergistic bactericidal effects between COX inhibitors and antibiotics in PGE2-treated S. aureus.

Epidemiological studies show that there is limited evidence that tobacco smoking causes breast cancer in humans. In rodents, many tobacco smoke chemicals cause mammary gland tumors. This study evaluated the mammary gland differentiation in mice exposed to environmental cigarette smoke (ECS), using 3R4F Kentucky reference cigarettes, starting after birth and continuing daily for 10 weeks (total particulate exposure 95 mg/m3; CO 610 ppm). We also analyzed the effects of oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (1600mg/kg) or naproxen (320mg/kg), on mammary gland differentiation, either in unexposed or ECS-exposed mice. The ECS exposure caused delay of mammary glands development. We speculate that this delay may result from aryl hydrocarbon receptor (AHR) signaling activation, which has an antiestrogenic effect and crosstalk to the estrogen metabolism pathway. Similarly, naproxen impaired gland differentiation in unexposed and ECS-exposed mice, while aspirin hindered its development only in unexposed mice. The lack of differentiation induced by the NSAIDs could be explained by their antiestrogenic effect through inhibition of aldo-keto reductases. In ECS-exposed animals, aspirin induced intense lobular formation, which could indicate that aspirin is counteracting the AHR signaling induced by ECS. Based on the differentiation induced by aspirin in ECS-exposed animals, we postulate that these mice would be less susceptible to mammary carcinogenesis. Our results suggest that exposure to smoke at an early age impairs the development of the mammary gland, thus resulting in a longer period of susceptibility and increased risk of breast cancer. However, addition of aspirin can abrogate this effect.

The effect of PF-06372865, a subtype selective positive allosteric modulator (PAM) of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo and active-controlled Phase 2 clinical trial. The parallel treatment group trial consisted of a 1 week single-blind placebo run in phase, followed by 4 weeks double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen or placebo BID for 4 weeks. The primary endpoint was the numerical rating score (NRS) of low back pain intensity (LBPI) after 4 weeks of active treatment. Secondary endpoints included the Roland Morris Disability Questionnaire (RMDQ) and the Hopkins Verbal Learning Test-Revised™ (HVLT-R). The trial had predefined decision rules based on the probability that PF-06372865 was better than placebo. The study was stopped at the interim analysis for futility. At this time a total of 222 patients were randomised and the mean PF-06372865 4-week response on the LBPI was 0.16 units higher (worse) than placebo (90% C.I. -0.28, 0.60). There were small, statistically significant reductions in the delayed recall test score with PF-06372865, as measured by HVLT-R. The effects of naproxen were in line with expectations. PF-06372865 was well tolerated. The most common treatment related adverse events in the PF-06372865 arm were somnolence (5 mild, 4 moderate), dizziness (2 mild, 3 moderate), and nausea (2 mild). Whilst the reason for the lack of analgesic effect is not completely clear, it may be a result of not achieving sufficient receptor occupancy to drive efficacy.

Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the most widely used drugs. Results of recent large meta-analyses have shown that the cardiovascular risk of NSAIDs is more serious than originally believed and is not associated exclusively with coxibs; it is also increased when using so called traditional NSAIDs. Data obtained to date show the safest drugs of this class in terms of cardiovascular risk are naproxen and ibuprofen at low doses. The position of naproxen as the safest NSAID has been challenged by some more recent findings. The authors examine some results of meta-analyses and conclusions of regulatory agencies.Key words: cardiovascular risk - coxibs - diclofenac - ibuprofen - naproxen - non-steroidal anti-inflammatory drugs.

Patients with spondylocostal dysostosis (SCD) have congenital spine and rib deformities associated with frequently severe thoracic insufficiency and respiratory compromise. The literature is largely composed of case reports and small cohorts, and there is little information regarding adults with this condition. In this report, we describe the natural history of a conservatively treated patient and include quality-of-life issues such as childbearing, athletic participation, and occupational selection.

Based on systematic surveillance of more than 110 medical journals, 247 studies met criteria as POEMs (patient-oriented evidence that matters) in 2017. Members of the Canadian Medical Association identified 20 of these POEMs as most relevant to practice. This article reviews the clinical questions and bottom-line answers from these studies. Blood pressure should be measured after a period of rest, using a bare arm, and orthostatic blood pressure is more predictive when measured after one minute of standing rather than three minutes. Intensive blood pressure lowering results in cardiovascular benefits but also renal harms in high-risk patients with an average age of 68 years. The initiation of a statin for primary prevention does not reduce cardiovascular events in adults 65 years or older. Sterile gloves do not reduce the risk of infection for common outpatient skin procedures, and the preferred approach to managing onychomycosis is empiric oral terbinafine. Routine home glucose monitoring is not needed in patients with type 2 diabetes mellitus, and trying to achieve an A1C target level of 6.0% rather than 7.0% to 7.9% does not improve outcomes and may be harmful. Fasting blood glucose and A1C levels have limited accuracy for identifying glucose intolerance, and patients 65 years and older with thyroid-stimulating hormone levels between 4.6 and 10.0 mIU per mL should be rechecked before considering treatment. Gabapentin and pregabalin are not effective for acute or chronic low back pain, even in patients with sciatica. Physical therapy does not provide any additional benefit over usual care in patients with acute ankle sprain, and corticosteroid injections for knee osteoarthritis are ineffective and may damage cartilage. A two-question screening test can rule out depression in older adults; a large U.S. trial continued to find no benefit to prostate cancer screening; and clinicians need to be thoughtful about how they discuss recommendations to stop screening for cancer in older patients. Finally, ibuprofen, naproxen, and celecoxib have similar risks of adverse events, and continuous positive airway pressure in patients with obstructive sleep apnea does not reduce the risk of cardiovascular events.

A novel concept for automation of nanostructured hollow-fiber supported microextraction, combining the principles of liquid-phase microextraction (LPME) and sorbent microextraction synergically, using mesofluidic platforms is proposed herein for the first time, and demonstrated with the determination of acidic drugs (namely, ketoprofen, ibuprofen, diclofenac and naproxen) in urine as a proof-of-concept applicability. Dispersed carbon nanofibers (CNF) are immobilized in the pores of a single-stranded polypropylene hollow fiber (CNF@HF) membrane, which is thereafter accommodated in a stereolithographic 3D-printed extraction chamber without glued components for ease of assembly. The analytical method involves continuous-flow extraction of the acidic drugs from a flowing stream donor (pH 1.7) into an alkaline stagnant acceptor (20 mmol L-1 NaOH) containing 10% MeOH (v/v) across a dihexyl ether impregnated CNF@HF membrane. The flow setup features entire automation of the microextraction process including regeneration of the organic film and on-line injection of the analyte-laden acceptor phase after downstream neutralization into a liquid chromatograph (LC) for reversed-phase core-shell column-based separation. Using a 12-cm long CNF@HF and a sample volume of 6.4 mL, linear dynamic ranges of ketoprofen, naproxen, diclofenac and ibuprofen, taken as models of non-steroidal anti-inflammatory drugs, spanned from ca. 5-15 µg L-1 to 500 µg L-1 with enhancement factors of 43-97 (against a direct injection of 10 µL standards into LC), and limits of detection from 1.6 to 4.3 µg L-1. Relative recoveries in real urine samples ranged from 97% to 105%, thus demonstrating the reliability of the automatic CNF@HF-LPME method for in-line matrix clean-up and determination of drugs in urine at therapeutically relevant concentrations.