Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma.

BACKGROUND: Exposure to traffic-derived air pollutants, particularly diesel emissions, has been associated with adverse health effects, predominantly in individuals with pre-existing respiratory disease. Here the hypothesis that this heightened sensitivity reflects an augmentation of the transient inflammatory response previously reported in healthy adults exposed to diesel exhaust is examined. METHODS: 32 subjects with asthma (mild to moderate severity) and 23 healthy controls were exposed in a double-blinded crossover control fashion to both filtered air and diesel exhaust (100 µg/m(3) PM(10)) for 2 h. Airway inflammation was assessed by bronchoscopy 18 h postexposure. In addition, lung function, fraction of exhaled nitric oxide and bronchial reactivity to metacholine were examined in the subjects with asthma. RESULTS: In healthy control subjects a significant increase in submucosal neutrophils (p=0.004) was observed following the diesel challenge. Significant increases in neutrophil numbers (p=0.01), and in the concentrations of interleukin 6 (p=0.03) and myeloperoxidase (p=0.04), were also seen in bronchial wash after diesel, relative to the control air challenge. No evidence of enhanced airway inflammation was observed in the subjects with asthma following the diesel exposure. CONCLUSIONS: Exposure to diesel exhaust at concentrations consistent with roadside levels elicited an acute and active neutrophilic inflammation in the airways of healthy subjects. This response was absent in subjects with asthma, as was evidence supporting a worsening of allergic airway inflammation.

Intravenous paracetamol (acetaminophen).

Intravenous paracetamol (rINN)/intravenous acetaminophen (USAN) is an analgesic and antipyretic agent, recommended worldwide as a first-line agent for the treatment of pain and fever in adults and children. In double-blind clinical trials, single or multiple doses of intravenous paracetamol 1 g generally provided significantly better analgesic efficacy than placebo treatment (as determined by primary efficacy endpoints) in adult patients who had undergone dental, orthopaedic or gynaecological surgery. Furthermore, where evaluated, intravenous paracetamol 1 g generally showed similar analgesic efficacy to a bioequivalent dose of propacetamol, and a reduced need for opioid rescue medication. In paediatric surgical patients, recommended doses of intravenous paracetamol 15 mg/kg were not significantly different from propacetamol 30 mg/kg for the treatment of pain, and showed equivocal analgesic efficacy compared with intramuscular pethidine 1 mg/kg in several randomized, active comparator-controlled studies. In a randomized, noninferiority study in paediatric patients with an infection-induced fever, intravenous paracetamol 15 mg/kg treatment was shown to be no less effective than propacetamol 30 mg/kg in terms of antipyretic efficacy. Intravenous paracetamol was well tolerated in clinical trials, having a tolerability profile similar to placebo. Additionally, adverse reactions emerging from the use of the intravenous formulation of paracetamol are extremely rare (<1/10 000). [table: see text].

Japanese encephalitis vaccine (inactivated, adsorbed) [IXIARO].

The Japanese encephalitis vaccine IC-51 (IXIARO) is an inactivated virus (strain SA(14)-14-2) that is manufactured in cultured Vero cells and is currently being developed for preventive vaccination against the Japanese encephalitis virus. black triangle Administration of IXIARO as a two-dose treatment in healthy adults provided high levels of seroprotection against Japanese encephalitis virus. Immune responses at 56 days post-vaccination, including seroconversion rates and geometric mean titres, were noninferior to those seen with a currently available licensed vaccine. Seroprotection was achieved 1 week after second vaccination. black triangle Long-term seroprotection was also observed with the vaccine, with seroconversion rates and geometric mean titres maintained at both 6 and 12 months post-vaccination. black triangle Coadministration with a hepatitis A vaccine had no effect on the immunogenicity of IXIARO. Additionally, the vaccine immunogenicity was not compromised in subjects with pre-existing vaccine-induced antibodies for tick-borne encephalitis, a related flavivirus. black triangle Vaccine immunogenicity was also observed in paediatric volunteers, with seroconversion rates not significantly different to an active comparator at 56 days post-vaccination. black triangle The safety and tolerability profile of IXIARO was generally similar to that of placebo with respect to systemic adverse events, and was associated with a numerically lower frequency of local injection site adverse events than the active comparator vaccine. [fig: see text]

Antioxidant responses to acute ozone challenge in the healthy human airway.

The aim of the study was to characterize ozone-induced antioxidant responses in the human airway, including the resident leukocyte population, bronchial mucosa, and respiratory-tract lining fluids. Fifteen healthy subjects were exposed to 0.2 ppm ozone for 2 h, with bronchial wash, bronchoalveolar lavage, and biopsy sampling performed 6 h postexposure. Nasal lavage was also performed at multiple time points pre- and postexposure to evaluate responses during the actual exposure period. During the ozone challenge significant losses of nasal lining fluid urate and vitamin C were observed, which resolved 6 h postexposure. At this time point, increased numbers of neutrophils and enhanced concentrations of total glutathione, vitamin C, and urate were seen in bronchial airway lavages. In bronchoalveolar lavage, increased concentrations of total glutathione, vitamin C, urate, alpha-tocopherol, and extracellular superoxide dismutase occurred 6 h post ozone. In alveolar leukocytes significant losses of glutathione were observed, whereas ascorbate concentrations in endobronchial mucosal biopsies were elevated after ozone at this time. These data demonstrate that ozone elicits a broad spectrum of airway antioxidant responses, with initial losses of vitamin C and urate followed by a phase of augmentation of low-molecular-weight antioxidant concentrations at the air-lung interface. The temporal association between the increased RTLF glutathione following ozone and the loss of this thiol from macrophages implies a mobilization to the lung surface, despite the absence of a quantitative association. We propose this constitutes an acute protective adaptation to ozone.

Correction to: Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

An Online First version of this article was made available online at https://rd.springer.com/article/10.1007/s40265-019-01083-3 on the 8th of March 2019. One error was identified in the article; please note the following.

Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

Triamcinolone acetonide extended-release (ER) 32 mg (Zilretta®) is approved in the USA for the management of osteoarthritis (OA) pain of the knee and is administered as a single, 5 mL intra-articular (IA) injection. Although the therapeutic effects from IA corticosteroids are typically short-lived, triamcinolone acetonide ER is formulated in poly (lactic-co-glycolic acid) (PLGA) microspheres that slowly release triamcinolone acetonide in the synovium, enabling their prolonged presence in the joint. This reduces systemic exposure and lessens corticosteroid-related systemic adverse reactions, such as blood glucose elevations. In a 24-week, randomized, phase III clinical trial, triamcinolone acetonide ER 32 mg significantly improved mean average daily pain intensity in patients with knee OA relative to placebo, and pain, stiffness and physical function (according to WOMAC criteria) relative to placebo and triamcinolone acetonide crystalline suspension (CS). Triamcinolone acetonide ER was generally well tolerated, with a tolerability profile similar to that of triamcinolone acetonide CS and placebo. Findings from a single-arm phase IIIb study indicated that a repeat administration of triamcinolone acetonide ER may be similarly efficacious to an initial injection without having deleterious effects on cartilage or other aspects of joint structure. Thus, triamcinolone acetonide ER expands the treatment options available for the management of OA pain of the knee.

Correction to: Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

The original article has been corrected.

Correction to: Triamcinolone Aceonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

An Online First version of this article was made available online at.

Niraparib: A Review in Ovarian Cancer.

Niraparib (Zejula®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Approval was based on the results of the randomized, double-blind, placebo-controlled phase III NOVA trial. In NOVA, niraparib significantly prolonged progression-free survival (primary endpoint), chemotherapy-free interval and time to first subsequent therapy compared with placebo in patients with recurrent, platinum-sensitive, high grade serous ovarian, fallopian tube or primary peritoneal cancer. The beneficial effects of niraparib were consistent regardless of BRCA mutation or homologous recombination deficiency (HRD) status. Niraparib had a manageable tolerability profile, with the majority of grade 3 or 4 adverse events being haematologic abnormalities (e.g. thrombocytopenia, anaemia, neutropenia). Adverse events were generally well managed with dose interruption or modification of niraparib. Current evidence suggests that niraparib is an effective new option with a manageable tolerability profile for the maintenance treatment of recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults, with or without BRCA1/2 mutation or HRD.

Belimumab: A Review in Systemic Lupus Erythematosus.

Belimumab (Benlysta®) is a human immunoglobulin G1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells. It is the only biological agent currently approved for the treatment of non-renal systemic lupus erythematosus (SLE). Belimumab is approved in the EU, the USA and other countries as add-on therapy in adult patients with active, autoantibody-positive SLE despite standard therapy. In phase III trials, treatment with IV or SC belimumab plus standard therapy was effective in terms of reducing overall disease activity and reducing the incidence and severity of flares, without worsening of patients' overall condition or the development of significant disease activity in new organ systems. Sustained disease control was maintained during longer-term (up to 10 years) treatment with IV belimumab. Belimumab also demonstrated steroid-sparing effects and was associated with clinically meaningful improvements in health-related quality of life and fatigue. Belimumab was generally well tolerated in clinical trials, with low rates of immunogenicity. In view of the flexibility regarding the route of administration and the convenience of the once-weekly, self-administered, SC regimen, add-on therapy with belimumab is a useful treatment option for patients with active, autoantibody-positive SLE despite standard therapy.

Ulipristal Acetate: A Review in Symptomatic Uterine Fibroids.

Oral ulipristal acetate (Esmya®; Fibristal®), a synthetic selective progesterone receptor modulator, is the first selective progesterone modulator to be approved for the treatment of uterine fibroids. It was initially approved for the preoperative treatment of moderate to severe uterine fibroid symptoms in women of reproductive age. Recently, the indication was extended in the EU to include the intermittent treatment of moderate to severe uterine fibroid symptoms. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the preoperative and intermittent use of ulipristal acetate in patients with symptomatic uterine fibroids. Ulipristal acetate is an effective and generally well tolerated treatment for patients with symptomatic uterine fibroids, both as preoperative, single-course treatment and as intermittent, longer-term treatment. It is noninferior in efficacy to intramuscular leuprolide acetate, as a preoperative treatment, and is associated with a lower rate of hot flashes, a common adverse event with gonadotropin-releasing hormone analogues. Thus, ulipristal acetate is an effective option for both preoperative and intermittent treatment of moderate to severe, symptomatic uterine fibroids in women of reproductive age.

Lisdexamfetamine: A Review in Binge Eating Disorder.

Oral lisdexamfetamine dimesylate (Vyvanse®; lisdexamfetamine), a prodrug of dextroamfetamine, is currently the only drug to be approved in the USA for the treatment of moderate to severe binge eating disorder (BED) in adult patients. Its approval was based on the results of two pivotal short-term (12 weeks) phase III studies, which showed a significantly greater reduction in binge eating days/week at the end of the study with lisdexamfetamine 50-70 mg/day than with placebo. The findings of these studies have been supported and extended by the results of longer-term (≤ 52 weeks) phase III studies, including one with a randomized 26-week withdrawal phase, which showed that lisdexamfetamine markedly reduced the risk of BED relapse relative to placebo. Lisdexamfetamine was generally well tolerated in clinical trials in patients with moderate to severe BED, with a tolerability profile similar to that observed in ADHD patients; most treatment-emergent adverse events (TEAEs) were of mild or moderate intensity. The most common TEAEs in phase III trials included dry mouth, headache and insomnia; TEAEs infrequently led to study drug discontinuation. In conclusion, lisdexamfetamine 50-70 mg/day is an effective and generally well tolerated option for treating moderate to severe BED in adults.

Ustekinumab: A Review in Moderate to Severe Crohn's Disease.

Ustekinumab (Stelara®) has been recently approved in the EU and the USA as intravenous induction and subcutaneous maintenance therapy for adult patients with moderately to severely active Crohn's disease who have failed or were intolerant to treatment with immunomodulators, corticosteroids or at least one tumour necrosis factor (TNF) antagonist. Ustekinumab, a monoclonal antibody to the shared p40 subunit of the proinflammatory interleukin (IL)-12 and IL-23 cytokines, has a unique mechanism of action distinct from that of TNF antagonists. In pivotal phase III trials, compared with placebo, ustekinumab induction therapy improved clinical response and remission rates in patients who had previously failed or were intolerant to conventional therapies or at least one TNF antagonist. When administered as subcutaneous maintenance therapy, ustekinumab continued to offer benefits over placebo for clinical response and remission in patients who had clinically responded to the induction therapy. Ustekinumab was generally well tolerated as both induction and maintenance therapy; serious infections and malignancies were rare. Thus, ustekinumab presents a promising alternative treatment option in patients with moderately to severely active Crohn's disease who have failed or are intolerant to treatment with conventional therapies or TNF antagonists.

Selexipag: A Review in Pulmonary Arterial Hypertension.

Selexipag (Uptravi®) is an orally active, first-in-class, selective prostacyclin IP receptor agonist. Selexipag was approved recently in the EU for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II or III as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor or as monotherapy in patients who are not candidates for these therapies, and in the USA for the treatment of PAH (WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Selexipag (200-1600 µg twice daily, as tolerated) significantly reduced the risk of the primary composite endpoint of all-cause death or a complication related to PAH (whichever happened first) versus placebo in patients with PAH (mainly WHO FC II or III) in the large, randomized, placebo-controlled GRIPHON study. The treatment effect was largely driven by significant reductions in disease progression and hospitalization for PAH. However, selexipag did not significantly reduce all-cause mortality. Additionally, the observed treatment effect was consistent in a broad range of prespecified subgroups, including treatment-naïve patients and those patients who were already receiving PAH-specific treatment at baseline. Exercise capacity was also improved with selexipag versus placebo. Selexipag was generally well tolerated, with an adverse event profile consistent with other therapies targeting the prostacyclin pathway. Thus, selexipag extends the treatment options available in patients with PAH.

Etanercept (SB4): A Review in Autoimmune Inflammatory Diseases.

Etanercept (SB4) [Benepali(®)], a tumour necrosis factor inhibitor that is a biosimilar of reference etanercept (Enbrel(®)), is approved in the EU for use in all adult indications for which reference etanercept is approved, namely rheumatoid arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), psoriatic arthritis, and plaque psoriasis. The approval of etanercept (SB4) was based on the results of stringent comparability exercises designed to demonstrate similarity to reference etanercept in terms of quality, biological activity, efficacy, safety, and immunogenicity. In two well-designed clinical trials, etanercept (SB4) was equivalent to reference etanercept with regard to pharmacokinetic properties in healthy volunteers and in terms of efficacy in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Longer-term efficacy (up to 52 weeks) was also similar in both treatment groups. Etanercept (SB4) was generally well tolerated, with a similar safety profile to that of reference etanercept. Preliminary results of the open-label extension period (100 weeks) suggest that transitioning from reference etanercept to etanercept (SB4) was associated with sustained efficacy and no change in the adverse event profile or immunogenicity. In conclusion, etanercept (SB4) provides therapeutically equivalent alternative in adult patients with autoimmune inflammatory diseases requiring treatment with etanercept.

Trifluridine/Tipiracil: A Review in Metastatic Colorectal Cancer.

Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.

Combustion of dried animal dung as biofuel results in the generation of highly redox active fine particulates.

BACKGROUND: The burning of biomass in the developing world for heating and cooking results in high indoor particle concentrations. Long-term exposure to airborne particulate matter (PM) has been associated with increased rates of acute respiratory infections, chronic obstructive lung disease and cancer. In this study we determined the oxidative activity of combustion particles derived from the biomass fuel dung cake by examining their capacity to deplete antioxidants from a model human respiratory tract lining fluid (RTLF). For comparison, the observed oxidative activity was compared with that of particles derived from industrial and vehicular sources. RESULTS: Incubation of the dung cake particle suspensions in the RTLF for 4 h resulted in a mean loss of ascorbate of 72.1 +/- 0.7 and 89.7 +/- 2.5% at 50 and 100 microg/ml, respectively. Reduced glutathione was depleted by 49.6 +/- 4.3 and 63.5 +/- 22.4% under the same conditions. The capacity of these samples to deplete ascorbate was in excess of that observed with diesel or gasoline particles, but comparable to that seen with residual oil fly ash and considerably in excess of all three control particles in terms of glutathione depletion. Co-incubation with the metal chelator diethylenetriaminepentaacetate inhibited these losses, whilst minimal inhibition was seen with superoxide dismutase and catalase treatment. The majority of the activity observed appeared to be contained within aqueous particle extracts. CONCLUSION: These data demonstrate that biomass derived particles have considerable oxidative activity, largely attributable to their transition metal content.

Pegylated liposomal doxorubicin: a guide to its use in various malignancies.

Pegylated liposomal doxorubicin (Caelyx(®) [EU], Doxil(®) [USA]) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. As shown by evidence from clinical trials, intravenous pegylated liposomal doxorubicin is a useful option in the treatment of various malignancies, including metastatic breast cancer, ovarian cancer, multiple myeloma, and AIDS-related Kaposi sarcoma. It has a favourable safety profile relative to conventional doxorubicin and other available chemotherapy agents.

Pitavastatin: a review of its use in the management of hypercholesterolaemia or mixed dyslipidaemia.

Pitavastatin (Livazo®, Livalo®), an inhibitor of HMG-CoA reductase (statin), is indicated for the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, in adult patients with primary hypercholesterolaemia and mixed dyslipidaemia, when response to diet and other non-pharmacological measures is inadequate. Pitavastatin has a favourable pharmacological profile following oral administration, including its long half-life (up to 12 hours), selective uptake into hepatocytes and minimal metabolism by cytochrome P450 (CYP) enzymes. This latter property decreases the likelihood of drug-drug interactions with agents that are metabolized by, inhibit or induce CYP enzymes. Pitavastatin improved the lipid profile (including LDL-C, TC and high-density lipoprotein cholesterol levels) in patients with hypercholesterolaemia and mixed dyslipidaemia, according to large, pivotal phase III studies of up to 60 weeks' duration. In these trials, pitavastatin for 12 weeks was noninferior to simvastatin and atorvastatin in terms of the improvement from baseline in LDL-C levels. In similarly designed trials, pitavastatin improved lipid profiles and was noninferior to simvastatin in patients with high cardiovascular risk and demonstrated significantly greater LDL-C reduction than pravastatin in elderly patients. Furthermore, in patients with type 2 diabetes mellitus, although noninferiority criteria for the comparison with atorvastatin were not met in terms of the improvement from baseline in LDL-C levels, pitavastatin was associated with some improvements in the lipid profile. Pitavastatin also demonstrated substantial lipid-modifying effects in exclusively Asian populations in well designed clinical trials. Pitavastatin was generally well tolerated in clinical trials of up to 60 weeks' duration, with a tolerability profile generally similar to that of atorvastatin and simvastatin. Therefore, pitavastatin appears to be an attractive alternative for the treatment of patients with primary hyperlipidaemia or mixed dyslipidaemia who have not responded adequately to diet and other non-pharmacological measures, and may present a useful treatment option in patients requiring polypharmacy, such as those at high risk of cardiovascular disease. Further studies evaluating the effects of pitavastatin on clinical endpoints, such as cardiovascular morbidity and mortality, are required to confirm the longer-term benefits of pitavastatin.

Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery.

Rivaroxaban (Xarelto®), an oral oxazolidinone-based anticoagulant, is a potent, selective, direct inhibitor of factor Xa that is used in the prevention of venous thromboembolism (VTE) in adult patients after total hip replacement (THR) or total knee replacement (TKR) surgery. In large, clinical trials, oral rivaroxaban 10 mg once daily was more effective than subcutaneous enoxaparin 40 mg once daily in preventing postoperative VTE in patients undergoing THR or TKR surgery. Rivaroxaban was associated with significantly lower incidences of the primary endpoint, total VTE (composite of deep vein thrombosis, non-fatal pulmonary embolism, or death from any cause) compared with enoxaparin regimens across all studies. For example, in the largest trial in patients undergoing THR, total VTE occurred in 1.1% of rivaroxaban recipients and 3.7% of enoxaparin recipients (absolute risk reduction 2.6% [95% CI 1.5, 3.7]) in the modified intent-to-treat population. Notably, the greater efficacy of rivaroxaban was achieved without a significant increase in the incidence of major bleeding episodes compared with enoxaparin; bleeding events were the most frequently reported adverse events across clinical trials. Pyrexia, vomiting, nausea, and constipation were the most frequently reported of the non-bleeding treatment-emergent adverse events in rivaroxaban recipients and occurred at a similar rate to that with enoxaparin treatment. In addition, preliminary pharmacoeconomic analyses in Canada and the US indicate that rivaroxaban is a cost-saving treatment strategy versus enoxaparin. Although the position of rivaroxaban relative to other therapies remains to be fully determined, it is an effective option for the prophylaxis of VTE following THR and TKR.