[Topical application of hypotensive drugs for the prevention of intraocular pressure elevation after intravitreal injections of anti-VEGF drugs]. / Mestnoe primenenie gipotenzivnykh preparatov s tsel'yu profilaktiki povysheniya urovnya vnutriglaznogo davleniya posle intravitreal'nykh in"ektsii anti-VEGF-preparatov.

The management protocol for patients with neovascular age-related macular degeneration (nAMD) involves multiple intravitreal injections (IVI) of anti-VEGF drugs. The ability to reduce the peak intraocular pressure (IOP) rise is greatly important in clinical practice. PURPOSE: This study evaluates the effect of topical hypotensive drugs on the short-term IOP rise after IVI of anti-VEGF drugs in patients with nAMD. MATERIAL AND METHODS: The prospective study included 80 patients with newly diagnosed nAMD. Before the start of treatment, the patients were divided into 4 groups of 20 people each: 1st - controls, who received no prophylactic drugs, in the 2nd, 3rd and 4th groups local instillations of one drop of hypotensive drugs brinzolamide 1%, brinzolamide-timolol, brimonidine-timolol were performed in the conjunctival sac twice: 1 day before the injection (at 20:00) and on the day of the injection 2 hours before the manipulation (at 08:00), respectively. IOP was measured in each patient using ICare Pro non-contact tonometer before injection, as well as 1 min, 30 and 60 min after injection. RESULTS: Prophylactic use of hypotensive drugs was associated with a significant decrease in IOP immediately after IVI compared to the same parameter in the 1st group (p<0.001), the maximum decrease in IOP values was observed when using a fixed combination of brimonidine-timolol by 12.1 mm Hg compared to the controls (p<0.001), the combination of brinzolamide-timolol reduced IOP by 8.5 mm Hg (p<0.001), brinzolamide 1% led to the smallest decrease in IOP - by 5.1 mm Hg (p<0.001). CONCLUSION: Study patients that received instillations of brimonidine-timolol combination of one drop into the conjunctival sac 1 day before the injection and on the day of the injection showed the maximum decrease in IOP compared to patients of the other groups.

Consumption of Non-Nutritive Sweetener, Acesulfame Potassium Exacerbates Atherosclerosis through Dysregulation of Lipid Metabolism in ApoE-/- Mice.

Obesity is associated with the risk of cardiovascular disease, and non-nutritive sweetener, such as acesulfame potassium (AceK) has been used to combat obesity. However, the effects of AceK on cardiovascular disease are still unclear. In this study, high cholesterol diet (HCD)-fed ApoE-/- mice had dysregulated plasma lipid profile, and developed atherosclerosis, determined by atherosclerotic plaque in the aorta. Supplement of AceK in HCD worsened the dyslipidemia and increased atherosclerotic plaque, as compared with HCD-fed ApoE-/- mice. Since treatment of AceK in RAW264.7 macrophages showed no significant effects on inflammatory cytokine expressions, we then investigated the impacts of AceK on lipid metabolism. We found that AceK consumption enhanced hepatic lipogenesis and decreased ß-oxidation in ApoE-/- mice. In addition, AceK directly increased lipogenesis and decreased ß-oxidation in HepG2 cells. Taken together, a concurrent consumption of AceK exacerbated HCD-induced dyslipidemia and atherosclerotic lesion in ApoE-/- mice, and AceK might increase the risk of atherosclerosis under HCD.

Transcriptomics analysis of hepatotoxicity induced by the pesticides imazalil, thiacloprid and clothianidin alone or in binary mixtures in a 28-day study in female Wistar rats.

Co-occurrence of pesticide residues in food commodities raises a potential safety issue as their mixture effects on human health are largely unknown. In a previous study, we reported the toxicological effects (pathology and histopathology) of imazalil (IMZ), thiacloprid (THI), and clothianidin (CTD) alone and in binary mixtures in a 28-day oral gavage study in female Wistar rats. Five dose levels (up to 350 mg/kg body weight/day) ranging from a typical toxicological reference value to a clear effect dose were applied. In the present study, we undertook a transcriptomics analysis of rat livers by means of total RNA sequencing (RNA-Seq). Bioinformatic data analysis involving Ingenuity Pathway Analysis (IPA) was used to gain mechanistic information on hepatotoxicity-related pathways affected after treatment with the pesticides, alone and in mixtures. Our data show that 2986 genes were differentially regulated by CTD while IMZ and THI had effects on 194 and 225 genes, respectively. All three individual compounds shared a common subset of genes whose network is associated with xenobiotic metabolism and nuclear receptor activation. Similar networks were retrieved for the mixtures. Alterations in the expression of individual genes were in line with the assumption of dose addition. Our results bring new insight into the hepatotoxicity mechanisms of IMZ, THI, and CTD and their mixtures.

In vitro and in vivo antimicrobial activities of a novel piperazine-containing benzothiazinones candidate TZY-5-84 against Mycobacterium tuberculosis.

A piperazine-containing benzothiazinones lead compound PBTZ169, served as DprE1 inhibitor, displays nanomolar bactericidal activity against Mycobacteria tuberculosis. Here, we systematically evaluate anti-tuberculosis activity of one of PBTZ169 analogues, TZY-5-84, in vitro and in vivo. The MIC value of TZY-5-84 against M. tuberculosis H37Rv ranged from 0.014 to 0.015 mg/L, lower than those of INH, RFP and BDQ. Five susceptible and thirteen drug-resistant clinical isolates were also susceptive to TZY-5-84. It had anti-tuberculosis activity against intracellular bacilli in infected macrophage model. It exhibited its activity in time-dependent manner and against intracellular bacilli in infected macrophage cells. However, the MIC of TZY-5-84 against three laboratory PBTZ169-induced resistant isolates increased four-fold increment compared to that of H37Rv. No antagonism was observed in any combination between TZY-5-84 and seven commonly used anti-tuberculosis drugs in an in vitro checkerboard assay. In murine infection model, TZY-5-84 at lower dosage (12.5 mg/kg) was found to be comparatively efficacious as PBTZ169 at 25 mg/kg. Our research suggests TZY-5-84 can be a promising preclinical candidate for further study on TB treatment.

Regression of macular edema with topical brinzolamide and nepafenac alone and identification of a novel gyrate atrophy mutation / Regressão de edema macular com o uso tópico de brinzolamida e nepafenac e identificação de uma nova mutação na atrofia girata

ABSTRACT Gyrate atrophy is a rare metabolic autosomal recessive disorder caused by ornithine aminotransferase enzyme deficiency that leads to characteristic progressive, degenerative chorioretinal findings. Patients complain mostly of low vision, night blindness, and peripheral vision loss. Posterior subcapsular cataract, myopia, choroid neovascularization, and intraretinal cysts may be accompanying factors related to vision loss. We encountered a patient with vision loss secondary to posterior subcapsular cataract and intraretinal cysts. After treatment with topical brinzolamide and nepafenac (and without any diet mo dification and/or supplementation), we observed 143- and 117-mm macular thickness resolutions with 2 and 1 Snellen lines of visual gain in his right and left eyes, respectively. Also, we detected a novel homozygous mutation in the ornithine aminotransferase gene: c.1253T>C (p.Leu418Pro). Carbonic anhydrase inhibitors and/or non-steroid anti-inflammatory drugs can control macular edema in patients with gyrate atrophy-associated intraretinal cysts. The genetic variants may also be a determinant in the responsiveness to the therapy type.

RESUMO A atrofia girata é um distúrbio autossômico recessivo metabólico raro causado pela deficiência da enzima ornitina ami notransferase, que leva a achados degenerativos coriorretinianos progressivos característicos. Os pacientes queixam-se principalmente de baixa visão, cegueira noturna e perda de vi são periférica. A catarata subcapsular posterior, a miopia, a neovascularização da coróide e os cistos intrarretinianos podem ser fatores associados à perda da visão. Encontramos um paciente com perda de visão secundária à catarata subcapsular posterior e cistos intrarretinianos. Após o tratamento com brinzolamida tópica e nepafenaco (e sem modificação e/ou suplementação da dieta), observamos resoluções de espessura macular de 143 e 117 mm e com 2 e 1 linhas de Snellen de ganho visual nos olhos direito e esquerdo, respectivamente. Além disso, detectamos uma nova mutação homozigótica no gene da ornitina aminotransfera se: c.1253T>C (p.Leu418Pro). Inibidores da anidrase carbônica e/ou drogas anti-inflamatórias não esteróides podem controlar o edema macular em pacientes com cistos intrarretinianos associados à atrofia girata. As variantes genéticas também podem ser determinantes na responsividade ao tipo de terapia.

Co-delivery of brinzolamide and miRNA-124 by biodegradable nanoparticles as a strategy for glaucoma therapy.

Co-delivery nanoparticles with characteristics of intracellular precision release drug have been generally accepted as an effective therapeutic strategy for eye diseases. In this study, we designed a new co-delivery system (miRNA/NP-BRZ) as a lasting therapeutic approach to prevent the neuro-destructive after the long-term treatment of glaucoma. Neuroprotective and intraocular pressure (IOP) response were assessed in in vivo and in vitro models of glaucoma. At the meaning time, we describe the preparation of miRNA/NP-BRZ, drug release characteristics, intraocular tracing, pharmacokinetic and pharmacodynamics study and toxicity test. We found that miRNA/NP-BRZ could remarkably decrease IOP and significantly prevent retinal ganglion cell (RGC) damages. The new formula of miRNA-124 encapsulated in PEG-PSA-BRZ nanoparticles exhibits high encapsulation efficiency (EE), drug-loading capacity (DC), and stable controlled-release efficacy (EC). Moreover, we also verified that the miRNA/NP-BRZ system is significantly neuroprotective and nontoxic as well as lowering IOP. This study shows our co-delivery drug system would have a wide potential on social and economic benefits for glaucoma.

Regression of macular edema with topical brinzolamide and nepafenac alone and identification of a novel gyrate atrophy mutation.

Gyrate atrophy is a rare metabolic autosomal recessive disorder caused by ornithine aminotransferase enzyme deficiency that leads to characteristic progressive, degenerative chorioretinal findings. Patients complain mostly of low vision, night blindness, and peripheral vision loss. Posterior subcapsular cataract, myopia, choroid neovascularization, and intraretinal cysts may be accompanying factors related to vision loss. We encountered a patient with vision loss secondary to posterior subcapsular cataract and intraretinal cysts. After treatment with topical brinzolamide and nepafenac (and without any diet mo dification and/or supplementation), we observed 143- and 117-mm macular thickness resolutions with 2 and 1 Snellen lines of visual gain in his right and left eyes, respectively. Also, we detected a novel homozygous mutation in the ornithine aminotransferase gene: c.1253T>C (p.Leu418Pro). Carbonic anhydrase inhibitors and/or non-steroid anti-inflammatory drugs can control macular edema in patients with gyrate atrophy-associated intraretinal cysts. The genetic variants may also be a determinant in the responsiveness to the therapy type.

Efficacy of Topical Brinzolamide Treatment in Posterior Microphthalmos-Related Macular Cystoid Lesions: A Case Series

The aim of this study was to report the outcome of topical brinzolamide 1% treatment on macular cystoid lesions resembling retinoschisis in 4 patients diagnosed with posterior microphthalmia. The medical records of 4 patients with a clinical diagnosis of posterior microphthalmia who had started topical brinzolamide 1% treatment were reviewed. Visual acuity, central foveal thickness, and cystoid lesion area percentage were used to evaluate treatment response. In the follow-up, there was a decrease in central foveal thicknesses and cystoid lesion area percentages in both eyes of 3 of the patients. However, 1 patient showed increases in both parameters. Visual acuity remained stable in 5 eyes and increased in 3 eyes. Topical brinzolamide treatment may have some positive effects on macular cystoid lesions in selected cases.

Effect of Topical Hypotensive Medications for Preventing Intraocular Pressure Increase after Cataract Surgery in Eyes with Glaucoma.

PURPOSE: To compare the effects of a topical intraocular pressure (IOP)-lowering medication for preventing an IOP increase after cataract surgery in eyes with glaucoma. DESIGN: Randomized clinical study. METHODS: A total of 165 eyes of 165 patients with primary open-angle glaucoma or pseudoexfoliation glaucoma scheduled for phacoemulsification were randomly assigned to 1 of 3 groups to receive each medication immediately postoperatively: 1) prostaglandin F2α analog (travoprost), 2) ß-blocker (timolol maleate), or 3) carbonic anhydrase inhibitor (brinzolamide). Intraocular pressure (IOP) was measured using a rebound tonometer at 1 hour preoperatively, at the end of surgery, and at 2, 4, 6, 8, and 24 hours postoperatively. The incidence of eyes exhibiting a marked IOP increase to greater than 25 mm Hg was compared among the groups. RESULTS: At 1 hour preoperatively and at the end of surgery, mean IOP did not differ significantly among the groups. Mean IOP increased significantly between 4 and 8 hours postoperatively and then decreased at 24 hours postoperatively in all groups (P < .0001). Mean IOP was significantly lower in the brinzolamide group than in the travoprost or timolol group at 4, 6, and 8 hours postoperatively (P ≤ .0374) and did not differ significantly among groups at 2 and 24 hours postoperatively. The incidence of an IOP spike was significantly lower in the brinzolamide group than in the travoprost and timolol groups (P = .0029). CONCLUSIONS: Brinzolamide reduces the short-term IOP increase after cataract surgery more effectively than travoprost or timolol in eyes with glaucoma, suggesting that brinzolamide is preferable for preventing an IOP spike.

Immunostimulating and cancer-reductive experimental therapy with the oxazaphosphorine cytostatic SUM-IAP.

SUM-IAP is an aldo-ifosfamide-perhydrothiazine derivative that, under physiological conditions, spontaneously hydrolyzes to SUM-aldo-ifosfamide. In SUM-IAP, one 2-chloroethyl group of the alkylating function of aldo-ifosfamide-perhydrothiazine is substituted by a mesyl-ethyl group. The compound was synthesized to investigate the influence of the alkylating function of aldo-ifosfamide on the antitumor activity of oxazaphosphorine cytostatics. In chemotherapy experiments in CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells, the primary tumor was reduced below the detection level with two highly dosed injections on days 7 and 8, but after 14 days, the primary tumor was measurable again. The primary tumor and detectable metastases killed the animals 29-30 days after SUM-IAP application. When, however, the animals were treated again with two highly dosed injections on day 14 and 15, a 4-5 times increase in the number of leukocytes was measured and all animals survived the observation period of 100 days. In the high, cancer-reductive dose range, SUM-IAP is not only a cytotoxic but also an immunostimulating oxazaphosphorine cytostatic.

Increased survival of honeybees in the laboratory after simultaneous exposure to low doses of pesticides and bacteria.

Recent studies of honeybees and bumblebees have examined combinatory effects of different stressors, as insect pollinators are naturally exposed to multiple stressors. At the same time the potential influences of simultaneously occurring agricultural agents on insect pollinator health remain largely unknown. Due to different farming methods, and the drift of applied agents and manure, pollinators are most probably exposed to insecticides but also bacteria from organic fertilizers at the same time. We orally exposed honeybee workers to sub-lethal doses of the insecticide thiacloprid and two strains of the bacterium Enterococcus faecalis, which can occur in manure from farming animals. Our results show that under laboratory conditions the bees simultaneously exposed to the a bacterium and the pesticide thiacloprid thiacloprid had significant higher survival rates 11 days post exposure than the controls, which surprisingly showed the lowest survival. Bees that were exposed to diet containing thiacloprid showed decreased food intake. General antibacterial activity is increased by the insecticide and the bacteria, resulting in a higher immune response observed in treated individuals compared to control individuals. We thus propose that caloric restriction through behavioural and physiological adaptations may have mediated an improved survival and stress resistance in our tests. However, the decreased food consumption could in long-term also result in possible negative effects at colony level. Our study does not show an additive negative impact of sub-lethal insecticide and bacteria doses, when tested under laboratory conditions. In contrast, we report seemingly beneficial effects of simultaneous exposure of bees to agricultural agents, which might demonstrate a surprising biological capacity for coping with stressors, possibly through hormetic regulation.

A randomized multicenter clinical trial of 99 Tc-methylene diphosphonate in treatment of rheumatoid arthritis.

AIM: To investigate the efficacy and safety of technetium-99 conjugated with methylene diphosphonate (99 Tc-MDP, Yunke Pharmaceutical industry) in the treatment of rheumatoid arthritis (RA). METHODS: A total of 120 patients with active RA were randomly divided into three groups: Group A (receiving oral meloxicam tablets); Group B (receiving intravenous drip of 99 TC-MDP); Group C (receiving combination treatment of intravenous drip of 99 Tc-MDP and oral meloxicam tablets). The main clinical and laboratory parameters were evaluated at baseline and after 14 days of therapy. RESULTS: After 14 days of treatment, American College of Rheumatology 20 response was 15.62%, 34.04% and 48.78% in the three groups, respectively. The incidence of adverse events in three groups were 3.13%, 8.51% and 9.76% respectly, and has no significant difference. In addition, biochemical markers of bone metabolism including bone alkaline phosphatase (BAP), tartrate resistant acid phosphatase (TRAP) and dickkopf-1 (DKK-1), all improved in the three groups, although more significant in Group B than Group A, and more significant in the combination group than monotherapy groups. CONCLUSION: 99 Tc-MDP has good efficacy and safety in the treatment of active RA patients; the benefit was more remarkable when 99 Tc-MDP was combined with NSAIDs. 99 Tc-MDP may also have potential to improve bone metabolism.

Analgesics promote welfare and sustain tumour growth in orthotopic 4T1 and B16 mouse cancer models.

Murine orthotopic cancer models often require surgery, potentially causing pain or distress. However, analgesics are often withheld because they may alter tumour development. Two orthotopically implanted cancers were investigated in mice pre-treated with meloxicam (10 mg/kg), buprenorphine (0.2 mg/kg) or saline (1 ml/kg). Tumours were imaged and welfare was assessed using body weight, behaviour and nociceptive responses. In study 1, BALB/c mice were inoculated with 4T1 mammary carcinoma or saline during surgery or anaesthesia. As pre-treatment with a single buprenorphine dose appeared beneficial to cancer growth consistency, a second cohort of mice additionally received saline or buprenorphine at 12 and 24 h. Surgery resulted in increased mammary tumour growth and lung metastases. These unwanted effects were lessened by buprenorphine pre-treatment, especially when given repeatedly. Mammary tumour-bearing mice became less active and nociceptive thresholds declined over time, indicating some discomfort as tumours grew. In study 2, C57BL/6 mice received B16 melanoma. This non-surgical model was used to determine whether meloxicam or buprenorphine affected cancer seeding of the lungs. While meloxicam reduced B16 lung seeding, buprenorphine did not. Mechanical thresholds decreased as cancer developed in mice bearing melanoma, but the magnitude of this was insufficient to conclude that there were any significant welfare concerns. This study highlights the scientific value in utilising non-surgical models, where possible. When surgery must be performed at the time of tumour inoculation, the effects of this should be controlled with appropriate analgesics to enhance the value and possibly translation of the research.

Evaluation of WO2017098421: GSK's benzothiazine compounds as CD73 inhibitor filings.

INTRODUCTION: There are considerable interests in the development of novel small-molecule CD73 inhibitors for the treatment of cancers, autoimmune diseases, precancerous syndromes, and other diseases associated with CD73 activity. Areas covered: The application claims novel substituted benzothiadiazine derivatives as CD73 inhibitors for the treatment of cancer, precancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Many of the exemplified compounds have pIC50 values between 5 to 8.4 against CD73. Expert Opinion: These benzothiadiazine derivatives provide good leads for the discovery of potent CD73 inhibitors for the treatment of cancer and other diseases mediated by adenosine and its action on adenosine receptors.

Cyclodextrin-based oral dissolving films formulation of taste-masked meloxicam.

This work deals with fast-dissolving drug delivery systems of meloxicam (MX) derived from electrospun polyvinylpyrrolidone (PVP)/2-hydroxypropyl-ß-cyclodextrin (HPßCD) nanofiber mats. Electrospinning of solutions with different solvent systems [dimethylformamide (DMF) and ethyl alcohol (EtOH)] was performed. Prepared films were evaluated for morphology, physical, and mechanical properties. MX content, dissolving time, MX release, and cytotoxicity of films were investigated. In vivo studies were also performed in healthy human volunteers. The results showed that MX/HPßCD complexes improved the solubility of MX. PVP also increased MX solubility and the stability of MX/HPßCD complexes. Films were successfully prepared by two solvent systems with fiber in the nanometer range. MX was well incorporated into the films (100% efficiency). The X-ray patterns and DSC experiment indicated an amorphous form of MX. A fast disintegration time and burst release of MX was obtained from EtOH system. Cytotoxicity testing of the films produced by EtOH system proved safer than the DMF system. In vivo studies revealed that films rapidly dissolved in the mouth and had a less bitter taste than MX. These results suggest that electospun films from EtOH system may be a good candidate for fast-dissolving drug delivery systems to increase palatability of dosage forms.

Use of an intraoperative navigation system and piezoelectric surgery for styloidectomy in a patient with Eagle's syndrome: a case report.

BACKGROUND: Elongated styloid process syndrome (Eagle's syndrome) is the term given to the symptomatic elongation of the styloid process or the mineralization of the stylohyoid or stylomandibular ligament. The two commonly used approaches for the surgical treatment of this syndrome are the transcervical and transoral approaches. Both have their limitations and specific intraoperative risks. Here, we report the treatment of a patient with Eagle's syndrome using the transoral approach in conjunction with piezoelectric surgery, surgical planning, and intraoperative navigation to reduce the risk of complications. CASE PRESENTATION: The elongated styloid process was resected in a 45-year-old Japanese man using a minimally invasive approach with an intraoperative navigation system. Preoperative preparation involved the use of a custom interocclusal splint to produce the mouth opening conditions required during surgery. Using the three-dimensional position of the navigation probe, the location of the elongated styloid process was identified. After confirmation of the resection spot via the transoral approach, the styloid process was dissected by piezoelectric surgery. Follow-up examination showed an uneventful recovery with no associated complications. CONCLUSION: The resection of the styloid process using an intraoperative navigation system and a custom interocclusal splint during a transoral approach, together with a piezoelectric cutting device, is safe and effective for the treatment of Eagle's syndrome.

Mitigation of electroencephalographic and cardiovascular responses to castration in Bos indicus bulls following the administration of either lidocaine or meloxicam.

OBJECTIVE: To investigate the mitigating effects of administration of local anaesthetic or systemic meloxicam on the electroencephalographic (EEG) and cardiovascular responses during surgical castration of Bos indicus bull calves. STUDY DESIGN: Prospective, randomized, experimental study. ANIMALS: Thirty-six 6-8 month-old Bos indicus bull calves, with a mean ± standard deviation weight of 237 ± 19 kg. METHODS: Animals were allocated randomly to three groups of 12 (group L, 260 mg of 2% lidocaine subcutaneously and intratesticularly 5 minutes prior to castration; group M, 0.5 mg kg-1 of meloxicam subcutaneously 30 minutes prior to castration; group C, no preoperative analgesia administered). Anaesthesia was induced and maintained with halothane (0.9-1.1%) in oxygen. Electroencephalogram, heart rate (HR) and mean blood pressure (MAP) were recorded for 300 seconds prior to (baseline, B) and from the start of surgery (first testicle removal, T1). HR and MAP were compared at 10 second intervals for 90 seconds from the start of T1. Median frequency (F50), spectral edge frequency (F95) and total power of the EEG (Ptot) were analysed using area under the curve comparing T1 to B. RESULTS: All EEG variables were significantly different between B and T1 (p ≤ 0.0001). No differences in F50 were found between groups during T1 (p = 0.6491). F95 and Ptot were significantly different between group L and groups C and M during T1 (p = 0.0005 and 0.0163, respectively). There were transient significant changes in HR and MAP in groups L and M compared to group C during the 20-50 second periods. CONCLUSIONS: The EEG changes indicate nociceptive responses in all three groups during surgical castration, greater in group L compared to groups C and M. Both analgesics attenuated the peracute cardiovascular response. Lidocaine and meloxicam administered prior to castration attenuated these responses in Bos indicus bull calves. CLINICAL RELEVANCE: These findings provide support for the preoperative administration of lidocaine and potentially meloxicam for castration in Bos indicus bull calves.

Electroencephalographic assessment of oral meloxicam, topical anaesthetic cream and cautery iron for mitigating acute pain in pigs (Sus scrofa) undergoing tail docking.

OBJECTIVE: To evaluate the efficacy of oral meloxicam, topical anaesthetic cream and cautery iron in mitigating acute nociceptive responses of pigs to tail docking. STUDY DESIGN: A prospective, randomized, controlled experimental study. ANIMALS: A total of 40 healthy Large WhitexLandrace pigs aged 21±1 days, weighing 6.1±0.9 kg. METHODS: Pigs were randomly assigned to one of four treatments (n=10 per treatment): CONTROL: docked using clippers without analgesia; MEL: docked using clippers after administration of oral meloxicam; EMLA: docked using clippers after application of topical anaesthetic cream; and CAUT: docked using a cautery iron without analgesia. Anaesthesia was induced and maintained with halothane in oxygen. Following induction, end-tidal halothane was stabilized at 0.95-1.05% and electroencephalograph (EEG) recording commenced. After 5 minutes of baseline data collection, tail docking was performed and recording continued for a further 10 minutes. The EEG summary variables median frequency (F50), 95% spectral edge frequency (F95) and total power (PTOT) were calculated for the baseline period and for consecutive 30-second intervals following docking. RESULTS: Following docking, F50 increased and PTOT decreased significantly in CONTROL and MEL pigs. EMLA pigs exhibited no change in any variable, whilst CAUT pigs exhibited a reduction in PTOT but no change in F50. F50 was higher in control pigs than in EMLA pigs 30-60 seconds after docking (p≤0.01). PTOT was lower in CONTROL than in EMLA pigs 30-90 seconds after docking (p<0.03) and in CAUT pigs 60 seconds after docking (p=0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Prior application of EMLA cream abolished EEG indicators of nociception in pigs docked using clippers. Docking using a cautery iron without analgesia ameliorated EEG indicators of nociception, relative to using clippers without analgesia. Prior administration of EMLA cream or the use of cautery instead of clippers may reduce the acute pain experienced by pigs undergoing tail docking.

[Cognitive-cytokine effect of nonsteroidal antiinflammatory drugs in the therapy of elderly patients with osteoarthritis].

The purpose of the study was to evaluate the influence of long-term non-steroidal anti-inflammatory drugs (NSAID) therapy on the dynamics of the severity of cognitive deficits and its association with changes in the level of cytokines in elderly patients with osteoarthritis (OA). The authors performed a prospective observational study during 540±5,5 days, presented in two stages: phase I - the stage of active NSAID therapy; phase II - the stage of non-pharmacological correction of OA. The first stage included 128 patients with OA from 65 to 75 years (average age 70±4,6 years, 10,2% of males and 89,8% female). Patients from the main group were divided into four subgroups: patients of the 1st group (n=30) received the drug etoricoxib at a dose of 60 mg per day; patients of the 2nd group (n=32) - celecoxib at a dose of 200 mg daily, patients of the 3rd group (n=32) - nimesulide in dose of 100 mg per day; patients of the 4th group (n=34) - meloxicam at a dose of 7,5 mg per day. The comparison group consisted of 40 patients with similar clinical and demographic characteristics of OA, not taking NSAIDs in the previous 6 months or during the study. It was determined the pain and stiffness indexes by the WOMAC initially and evaluated the patient status at the MoCA scale and carried out laboratory diagnosis of contents in serum TGF-ß1, IL-1ß and IL-6 at all visits. Statistically significant decrease in the level of cytokines was detected during the period of 1st-3rd visits for all patients in the groups receiving NSAID, also there was an increase in cognitive function on a scale of MoCA with a high degree of correlation in relation to the performance of cytokines to the end of the study. The results of our research allow us to speak about possible influence on cognitive functions of NSAID therapy in elderly patients with OA in real clinical practice.

Evaluation of High Dosages of Oral Meloxicam in American Kestrels ( Falco sparverius ).

To evaluate the toxicity of short-term high doses of meloxicam in American kestrels ( Falco sparverius ), 32 male captive-born, 1- to 4-year-old American kestrels were randomly assigned to 4 groups: 3 groups treated with meloxicam (n = 9 per group) and a control group (n = 5). Meloxicam was administered orally via feeding tube in the proventriculus at 2, 10, and 20 mg/kg every 12 hours for 7 days for the treatment groups, while the control group received saline solution. The birds were evaluated for the presence of clinical signs, abnormalities in the complete blood cell count and in the plasma biochemical panel for the 20-mg/kg group, and gross and histopathologic lesions. No clinical signs or mortality were observed in any group. No significant differences of clinical relevance were found in results of the packed cell volume, total solids, and biochemical panel, and no evidence of renal toxicity was found in the treatment or control groups. A significant correlation was found between hepatic lipidosis and meloxicam dose (P = .02). Two of 9 birds in the 20-mg/kg group developed gastric ulcers, although this result was not significant. None of the birds in the 2- and 10-mg/kg groups had similar lesions. Finally, meloxicam dosages up to 20 mg/kg did not result in nephrotoxicity in American kestrels. Further toxicologic studies to evaluate hepatotoxicity and gastrotoxicity of meloxicam in avian species are needed.