Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg.

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 d for intravenous treated and for 40 d from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Noncompartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 d for intravenous and 14.3 d for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 d and 81 d, respectively, with maximum residue limits (1.3 µg/g) at 13 d and 171 d, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA.

Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.

Pharmacokinetics of intravenously and trans-dermally administered fluralaner in healthy laying shaver hens: fluralaner in chickens.

Ectoparasite infestations negatively affect both backyard and commercial chicken flocks in the United States. Fluralaner is an isoxazoline shown to be efficacious in treating mite and bed bug infestations in poultry. Fluralaner is approved to treat fleas and ticks in dogs and cats in the United States and to treat mite infestations of chickens in Europe and Australia; however, the use of fluralaner in poultry is not yet approved in the United States. This study aimed to investigate the plasma fluralaner pharmacokinetic profile of intravenous and transdermal routes and apparent bioavailability of fluralaner administered trans-dermally in healthy shaver hens. A total of 12 individually housed healthy shaver hens received a single dose of either intravenous technical grade fluralaner at 0.5 mg/kg, or transdermal fluralaner (Bravecto (fluralaner transdermal solution) for dogs, 280 mg/mL, Merck Animal Health) at mean 58.7 mg/kg. Plasma from each hen was collected from the jugular, ulnar, or medial metatarsal vein at multiple intervals. Fluralaner concentrations in plasma were determined using Ultra Performance Liquid Chromatography with Mass Spectrometry (UPLC/MS). Noncompartmental analysis revealed that the geometric mean elimination half-life for intravenous and transdermal routes were 80.5 and 179.6 h, respectively. The geometric mean apparent bioavailability of transdermal routes was estimated as 3.4%. Prolonged fluralaner concentration in plasma above minimum inhibitory concentration of bed bugs following the single dose was observed in healthy shaver hens for both routes. It is important to understand the pharmacokinetic profile could be useful in determining the appropriate treatment strategy.

Pharmacokinetics of fluralaner as a systemic drug to control infestations of the common bed bug, Cimex lectularius, in poultry facilities.

BACKGROUND: Bed bug infestations are re-emerging in the poultry industry throughout the USA. Although the impacts of bed bugs on birds' health and welfare are poorly understood, adverse outcomes are expected, including stress, anemia, infections and lower production rates. Worker welfare is also an important consideration in commercial poultry farms. A limited number of insecticides are available for use in the complex spatial environment of commercial farms. Systemic drugs have the potential to overcome the limitations of existing pest management tactics. A recent study showed that fluralaner administered to chickens caused high levels of mortality in bed bugs. METHODS: To further understand the efficacy of this approach, we evaluated the pharmacokinetics of an oral solid formulation of fluralaner in 11 chickens and quantified its plasma concentration in chickens using UPLC/MS. We administered fluralaner to chickens with two doses of Bravecto® (each 0.5 mg/kg body mass) via gavage 1 week apart and evaluated its efficacy on bed bugs that fed on medicated chickens for up to 28 days post-treatment. RESULTS: Bed bugs that fed on fluralaner-treated chickens experienced > 50% mortality within 30 min of the administration of Bravecto and 100% mortality 2 days post-treatment. Mortality slowly declined to 66.6% by day 28. Fluralaner was quantifiable in the hens' plasma for at least 28 days post-treatment. The treatment resulted in maximal plasma concentrations (Cmax) of 106.4 ng/ml around day 9.0 (Tmax), substantially higher than the LC90, the concentration needed to kill 90% of the bed bugs. CONCLUSIONS: Fluralaner appears to be a promising candidate for bed bug control in poultry farms, with a treatment effect lasting at least 28 days.

Pharmacokinetics and Safety of Sulfamethoxazole-Trimethoprim After Oral Administration of Single and Multiple Doses to Rhode Island Red Chickens (Gallus gallus domesticus).

Sulfamethoxazole-trimethoprim (SMZ-TMP), a commonly prescribed antibiotic for backyard hens, is neither Food and Drug Administration approved nor prohibited in laying hens in the United States. The aim of this study was to determine whether plasma concentrations above targeted minimum inhibitory concentration breakpoint values for Enterobacteriaceae could be achieved with oral dosing. Five Rhode Island red hens (Gallus gallus domesticus) were administered a single dose of 96 mg/kg SMZ-TMP (80 mg/kg SMZ and 16 mg/kg TMP) IV followed by the same dose orally after a washout period. Following oral dosing, mean SMZ concentrations exceeded the target breakpoint for approximately 12 hours; however, TMP only briefly exceeded the target breakpoint. Bioavailability was 60.5% for SMZ and 82.0% for TMP. Ten naïve birds were allocated into control (n = 4) and treatment (n = 6) groups for a 7-day multi-dose study. Treatment birds received an oral suspension dosed at 16 mg/kg TMP and 80 mg/kg SMZ every 48 hours (on days 1, 3, 5, and 7); TMP tablets were additionally dosed at 25 mg/bird on days 1, 3, 5, and 7, and 50 mg/bird on days 2, 4, and 6. Plasma SMZ-TMP concentrations were measured on a multiple time interval by ultraperformance liquid chromatography-mass spectrometry, and pharmacokinetic analyses were performed using a noncompartmental model. No accumulation for either drug was noted following repeated dosing, and no statistical differences in biochemical values, packed cell volumes, or weight were found between pre- and posttreatment in either the treatment or control groups. Sulfamethoxazole (80 mg/kg q48h PO) and TMP (24.1-28.0 mg/kg q24h PO) maintained therapeutic plasma concentrations at or exceeding the minimum inhibitory concentration breakpoint of Enterobacteriaceae for 72 and 24 hours for TMP and SMZ, respectively, without evidence of adverse effects or drug accumulation. Further studies are needed to refine this dosage regimen and evaluate adverse effects in ill birds.

Progress of Diabetic Macular Edema after Loading Injection of Anti-Vascular Endothelial Growth Factor Agents in Real-World Cases.

Background and Objectives: To evaluate the recurrence of diabetic macular edema (DME) after loading an injection of anti-VEGF agents by a pro re nata (PRN) protocol using central retinal thickness (CRT) as a re-injection criterion. Materials and Methods: This is a retrospective, observational single-center study. DME patients with a central retinal thickness (CRT) over 350 µm received a PRN injection of anti-VEGF agents following one to three consecutive monthly loading injections (bevacizumab, ranibizumab, and aflibercept) for 6 months from January 2012 to June 2019. Results: We enrolled a total of 72 eyes for loading injections and the mean CRT improved from 434.04 ± 139.4 µm (before treatment) to 362.9 ± 125.0 µm after the loading injection. One week after injection, 36 eyes (50%) obtained a CRT of ≤350 µm. Fourteen eyes (19.4%) remained with a CRT of ≤350 µm for 6 months without additional injections. A total of 22 eyes (30.6%) had a CRT of >350 µm at 6 months. Fifteen eyes did not receive additional injections because of visual improvement. Conclusions: About 20% of DME patients can be maintained at a CRT of ≤350 µm for 6 months with only a loading injection. However, there is a tendency to delay additional injections for patients with recurrences using PRN protocol.

Preliminary evaluation of the effects of grapiprant compared with carprofen on acute pain and inflammation following ovariohysterectomy in dogs.

OBJECTIVE: To compare the analgesic efficacy of grapiprant to carprofen for the treatment of postoperative pain and inflammation in dogs following ovariohysterectomy. ANIMALS: 12 purpose-bred adult sexually intact female Beagles. PROCEDURES: Dogs were randomly assigned to 1 of 2 treatment groups: grapiprant (2 mg/kg, PO; n = 6) or carprofen (4.4 mg/kg, PO; n = 6), 1.5 hours prior to ovariohysterectomy (OVH) and every 24 hours afterward for 3 total doses. An ultrafiltration probe was placed within the OVH incision to collect interstitial fluid (ISF). Pain and inflammation were assessed by masked investigators via mechanical nociceptive threshold testing and the short form of the Glasgow Composite Pain Scale before drug administration and at multiple time points for 72 hours following dosing and surgery. ISF samples were collected at the same time points to assess prostaglandin E2 concentrations at the site of inflammation. RESULTS: In both groups, pain scale scores were highest in the immediate postoperative period and decreased over time. In both treatment groups, there were significant (P = 0.003) differences in mechanical nociceptive threshold results over time when compared with baseline, but there was no difference between groups. Prostaglandin E2 concentrations in ISF were higher in dogs receiving grapiprant compared with carprofen (P < 0.001). One dog in the carprofen group required rescue analgesia. CLINICAL RELEVANCE: Results of this preliminary study suggested both carprofen and grapiprant may be effective for postoperative pain following OVH in dogs; however, additional studies are warranted to determine grapiprant's effectiveness in a larger and more diverse population of dogs.

Control of ticks on horses using abamectin-impregnated ear tags. A pharmacokinetic and pharmacodynamic study.

Several different tick species are known to infest horses. Aside from causing serious health and welfare issues, including anaemia, ill thrift, and immunosuppression, ticks can transmit a variety of important, sometimes zoonotic, pathogens. The successful prevention and treatment of tick infestations have been described, but the information is scarce and, in many instances, anecdotal. Here we describe a practical and affordable prevention of tick infestation by using abamectin-impregnated cattle ear tags affixed to a safety collar. We have assessed the radial distribution of abamectin by analyzing hair samples, as well as its efficacy against tick infestations. The study results show that abamectin distributes across horse skin from the site of application and its associated effectiveness in reducing the tick burden.

Ceftazidime pharmacokinetics in dogs after intravenous injection and delivered with the RxActuator Mini-Infuser infusion pump.

OBJECTIVE: To test the feasibility of an SC mini-infusion pump to deliver ceftazidime in dogs and produce plasma concentrations sufficient to reach a therapeutic target for 48 hours. SETTING: University research laboratory. ANIMALS: Six healthy Beagle dogs. INTERVENTIONS: Ceftazidime was administered by 2 routes to 6 healthy Beagle dogs. The first route was an IV bolus injection into a cephalic vein at a dose of 25 mg/kg. Blood samples were collected for 8 hours following injection. The second route was a SC infusion for 48 hours using the RxActuator Mini-Infuser wearable SC constant rate infusion pump. Blood samples were collected for 58 hours following application of the pump. All plasma samples were analyzed by high-pressure liquid chromatography and subject to pharmacokinetic analysis. MAIN RESULTS: After the IV bolus injection, there was rapid distribution and elimination. The elimination half-life was 0.95 hours, and the clearance was rapid at 0.176 ml/h/kg. After the 48-hour SC infusion, the half-life was slightly shorter, and the clearance was higher. The percent bioavailability from the SC infusion was approximately 72%. The SC infusion maintained plasma concentration near our target of 8 µg/ml for most of the dose interval but slightly lower after 24 hours. The concentrations below the target were attributed to slight drug loss, less than 100% bioavailability, and faster clearance from SC administration. CONCLUSIONS: This study demonstrated the successful application of the RxActuator Mini-Infuser wearable SC constant rate infusion pump for delivering an antimicrobial needed for serious, and sometimes resistant, infections in dogs.

Pharmacokinetics of intravenous, oral transmucosal, and intranasal buprenorphine in healthy male dogs.

Effective management of pain in animals is of critical importance but options are limited for treating acute pain in dogs on an outpatient basis. The objective of this study was to compare the plasma concentrations and pharmacokinetics of a concentrated solution of buprenorphine, 1.8 mg/ml (Simbadol™) administered intravenously, intranasally, and via the oral transmucosal (OTM) route in healthy male dogs. Five healthy castrated adult male Beagle-cross dogs were included in this randomized blocked crossover study. The dogs received 0.03 mg/kg body weight buprenorphine intravenously, intranasally, or via the OTM route, with a minimum 72-h washout period between treatments. Blood samples were collected at multiple intervals up to 24 h post administration and buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. Non-compartmental pharmacokinetic analysis revealed that the area under the curve of intravenous, intranasal, and OTM routes were 28.0 (15.1-41.3) h × ng/ml, 16.1 (3.4-28.7) h × ng/ml and 10.8 (8.8-11.8) h × ng/ml, respectively. The bioavailability of intranasal and OTM routes were 57.5 (22.7-93.7)% and 41.1 (25.5-69.4)%, respectively. Intranasal and OTM routes of administration of concentrated buprenorphine in dogs may allow for the provision of analgesic care at home.

Effects of suspension of anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration in clinical setting.

PURPOSE: To investigate the outcomes of a suspension of anti-vascular endothelial growth factor (anti-VEGF) treatments in the eyes with neovascular age-related macular degeneration (nAMD). METHODS: This was a retrospective study that examined eyes having no exudation for 48 weeks while undergoing intravitreal anti-VEGF injections every 12 to 16 weeks. The rate and time of recurrences, best-corrected visual acuity (BCVA), central subfield thickness (CST), number of visits, and reactivity to anti-VEGF were determined after the suspension of the anti-VEGF treatments. RESULTS: In 34 eyes of 34 patients, 17 eyes (50.0%) had a recurrence during the 24-month follow-up period. The median time of a recurrence was 10 months. The BCVA was maintained for 24 months after the suspension regardless of the development of any recurrences. In 41.7% of the eyes that resumed treatment, the duration of exudation suppression by the anti-VEGF therapy was shorter than 12 weeks during the 12 months after restarting the anti-VEGF treatments. There was a significant increase in the number of visits during the first year after beginning the suspension versus during the 1 year before the suspension (non-recurrence group; P = 0.007, recurrence group; P = 0.001). CONCLUSION: Although one-half of the eyes had a recurrence within 24 months after a suspension of anti-VEGF treatment, the BCVA was maintained after a resumption of the anti-VEGF treatments. However, the number of hospital visits increases regardless of the recurrences and the lesion stability is altered by the anti-VEGF suspension. Clinicians should explain both the advantages and disadvantages of anti-VEGF suspension to nAMD patients.

Development and evaluation of a bovine lung-on-chip (bLOC) to study bovine respiratory diseases.

Purpose: Current air-liquid interface (ALI) models of bovine proximal airways have their limitations. They do not simulate blood flow necessary to mimic systemic drug administration, and repeated sampling requires multiple, independent cultures. A bovine lung-on-chip (bLOC) would overcome these limitations, providing a convenient and cost-effective model for pharmacokinetic or pathogenicity studies. Methods: Bovine pulmonary arterial endothelial cells seeded into the endothelial channel of an Emulate Lung-Chip were interfaced with bovine bronchial epithelial cells in the epithelial channel. Cells were cultured at ALI for up to 21 days. Differentiation was assessed by mucin quantification, phase-contrast light microscopy and immunofluorescence of cell-specific markers in fixed cultures. Barrier integrity was determined by FITC-labelled dextran 3-5 kDa permeability. To evaluate the model, endothelial-epithelial transport of the antibiotic drug, danofloxacin, was followed using liquid chromatography-mass spectrometry, with the aim of replicating data previously determined in vivo. Results: bLOC cultures secreted quantifiable mucins, whilst cilia formation was evident in the epithelial channel. Barrier integrity of the model was demonstrated by resistance to FITC-Dextran 3-5 kDa permeation. Bronchial epithelial and endothelial cell-specific markers were observed. Close to plasma, representative PK data for danofloxacin was observed in the endothelial channel; however, danofloxacin in the epithelial channel was mostly below the limit of quantification. Conclusion: A co-culture model of the bovine proximal airway was successfully generated, with potential to replace in vivo experimentation. With further optimisation and characterisation, the bLOC may be suitable to perform drug pharmacokinetic studies for bovine respiratory disease (BRD), and other applications.

Effects of housing environment on oral absorption of acetaminophen in healthy Beagles.

OBJECTIVE: To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs. ANIMALS: 6 healthy Beagles. PROCEDURES: Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography. RESULTS: A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments. CLINICAL RELEVANCE: Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Egg residue and depletion in Rhode Island Red hens (Gallus gallus domesticus) following multiple oral doses of trimethoprim-sulfamethoxazole.

Sulfamethoxazole-Trimethoprim residues in eggs can cause risks to human health. The most common cause of residues in eggs results from failure to meet an appropriate withdrawal interval. The aim of this study was to determine the quantity and duration of sulfamethoxazole-trimethoprim residues in eggs and evaluate the drug elimination parameters in egg components and whole egg to better estimate the withdrawal interval of sulfamethoxazole and trimethoprim following oral administration for 7 days at a purposed dosage regimen (time average 46 mg kg-1 day-1 for sulfamethoxazole, time average 25 mg kg-1 day-1 for trimethoprim). Residues of sulfamethoxazole and trimethoprim in albumen and yolk were analyzed by ultra-performance liquid chromatography mass spectrometry. A greater percentage of sulfamethoxazole was distributed into the albumen (91.53-96.74%) and a greater percentage of trimethoprim was distributed into yolk (63.92-77.36%) during treatment. The residues levels in whole egg declined below or reached the limit of quantification until 13 days for SMZ and TMP respectively. The withdrawal interval for SMZ and TMP were 43 days and 17 days respectively using the FDA tolerance method.

In vivo assessment of a delayed release formulation of larazotide acetate indicated for celiac disease using a porcine model.

There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32-1.76 µM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02-0.47 µM) in the distal duodenum and in proximal jejunum (0.00-0.43 µM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.

Case with metastatic cutaneous malignant melanoma that developed Vogt-Koyanagi-Harada-like uveitis following pembrolizumab treatment.

PURPOSE: The study reports a case with metastatic cutaneous malignant melanoma that developed Vogt-Koyanagi-Harada-like uveitis during pembrolizumab treatment. The uveitis improved by discontinuation of pembrolizumab and use of oral and topical steroids. Full-field flicker ERGs were used to monitor the retinal function before and after the steroid treatments. CASE REPORT: A 68-year-old women presented with blurred vision in both eyes 3 months after beginning pembrolizumab adjuvant therapy for a malignant melanoma on the lower thigh. Optical coherence tomography showed a serous retinal detachment (SRD) in the right eye and marked choroidal thickening in both eyes. Fluorescein angiography showed spotted hyperfluorescence in the right eye and leakage of fluorescein from both optic disks. Indocyanine green angiography showed dark hypofluorescent spots in both eyes. She was diagnosed with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab and discontinued the pembrolizumab. She was then treated with oral prednisolone and topical betamethasone. One week later, the symptoms were improved, and 1 month later the choroidal thickening in both eyes and the SRD of the right eye were not present. The implicit time of the full-field flicker ERGs recorded by RETeval system was significantly delayed at the initial examination but improved within a few weeks after the steroid replacement treatment. CONCLUSION: Our case with Vogt-Koyanagi-Harada-like uveitis induced by pembrolizumab had a reduction in the degree of uveitis after discontinuation of the pembrolizumab and use of oral prednisolone and topical betamethasone. Flicker ERGs were helpful in monitoring the retinal function before and after the steroid treatment.

The effect of combined carprofen and omeprazole administration on gastrointestinal permeability and inflammation in dogs.

BACKGROUND: Proton pump inhibitors (eg, omeprazole) commonly are administered concurrently with nonsteroidal anti-inflammatory drugs (NSAIDs; eg, carprofen) as prophylaxis to decrease the risk of gastrointestinal (GI) injury. However, evidence to support this practice is weak, and it might exacerbate dysbiosis and inflammation. HYPOTHESIS/OBJECTIVES: To evaluate the effect of carprofen alone or combined with omeprazole in dogs. We hypothesized that coadministration of omeprazole and carprofen would significantly increase GI permeability and dysbiosis index (DI) compared to no treatment or carprofen alone. ANIMALS: Six healthy adult colony beagle dogs. METHODS: Gastrointestinal permeability and inflammation were assessed by serum lipopolysaccharide (LPS) concentration, plasma iohexol concentration, fecal DI, and fecal calprotectin concentration in a prospective, 3-period design. In the first 7-day period, dogs received no intervention (baseline). During the 2nd period, dogs received 4 mg/kg of carprofen q24h PO for 7 days. In the 3rd period, dogs received 4 mg/kg of carprofen q24h and 1 mg/kg of omeprazole q12h PO for 7 days. Gastrointestinal permeability testing was performed at the end of each period. Data were analyzed using repeated measures mixed model analysis of variance with Tukey-Kramer post hoc tests (P < .05). RESULTS: Serum LPS and plasma iohexol concentrations did not differ between treatments. Fecal calprotectin concentrations differed between treatments (P = .03). The DI varied over time based on the treatment received (P = .03). Coadministration of omeprazole and carprofen significantly increased fecal calprotectin concentration and DI compared to baseline and carprofen alone. CONCLUSIONS AND CLINICAL IMPORTANCE: Omeprazole prophylaxis induces fecal dysbiosis and increases intestinal inflammatory markers when coadministered with carprofen to otherwise healthy dogs with no other risk factors for GI bleeding.

Optic Neuritis Possibly Induced by Anti-PD-L1 Antibody Treatment in a Patient with Non-Small Cell Lung Carcinoma.

BACKGROUND: Recent immune therapy with checkpoint inhibitors (CPIs) has demonstrated remarkable antitumor effects on specific tumors, such as malignant lymphoma and non-small cell lung carcinoma. By contrast, CPIs cause an imbalance in the immune system, triggering a wide range of immunological side effects termed immune-related adverse effects (irAEs). Here, we report a rare case of optic neuritis and hypopituitarism during anti-programmed death-ligand 1 (PD-L1) antibody treatment. CASE PRESENTATION: A patient with non-small cell lung carcinoma received anti-PD-L1 antibody treatment every 3 weeks; however, the patient started experiencing headaches, general fatigue, anorexia, and diarrhea approximately 1 year after the initiation of the treatment. Moreover, sudden visual loss of the right eye occurred 1 week after the interruption of the anti-PD-L1 antibody treatment. MRI findings showed gadolinium enhancement in the left optic nerve, but no enlargement of the pituitary gland and stalk. Laboratory data showed decreased serum adrenocorticotropic hormone (ACTH), cortisol, and free T4 levels, and a hormone tolerance test indicated hypopituitarism, hypothyroidism, and hypoadrenocorticism. The central scotoma caused by optic neuritis completely disappeared immediately after a course of steroid pulse therapy, and no recurrence occurred up to 2 years after initiation of the steroid pulse therapy while replacement therapy for hypothyroidism and hypoadrenocorticism was continued. CONCLUSIONS: The patient presented with optic neuritis and hypopituitarism, possibly due to irAEs of the anti-PD-L1 antibody treatment. Steroid pulse therapy was effective for optic neuritis, suggesting underlying immunological mechanisms. Neurological complications including optic neuritis should be considered when examining patients with cancer undergoing CPI treatment.

Evaluation of Oxygen Supplementation Status as a Risk Factor Associated with the Development of Severe Retinopathy of Prematurity.

PURPOSE: The effects of oxygen supplementation status and other clinical risk factors on the development of severe retinopathy of prematurity (ROP) were evaluated. METHODS: Clinical records of 143 newborn infants with a gestational age of 32 weeks or less were reviewed. Severe ROP was diagnosed when photocoagulation due to progression to stage 3 was identified or when 'plus disease' developed. The factors were evaluated with univariate and multivariate logistic regression analyses between the groups with severe (n = 24) and non-severe (n = 119) ROP. RESULTS: Gestational age, birth weight, duration of oxygen supplementation, duration of directional positive air pressure and maximum fraction of inspiratory oxygen (FiO2) were significantly associated with severe ROP in the univariate analyses. In the multivariate analysis, a longer duration of oxygen supplementation and a higher maximum FiO2 were revealed as significant risk factors associated with severe ROP. CONCLUSIONS: Duration of oxygen supplementation and maximum FiO2 required were important factors associated with severe ROP.

[Granulocyte-colony stimulating factor-producing urothelial carcinoma of right renal pelvis : a case report].

A 78-year-old female patient with fever and general malaise was referred to our hospital. Laboratory examination showed the marked elevation of leukocyte and serum granulocyte-colony stimulating factor (GCSF) concentration without any infectious sign. A computed tomography scan demonstrated irregular enhanced mass of the right kidney with liver metastasis. The pathological findings of the needle biopsy was high-grade urothelial cancer with positive staining for G-CSF antibody. Systemic chemotherapy with gemcitabine and cisplatin was administered. The patient showed a partial response and the serum G-CSF level was normalized after 1 course of chemotherapy. After four courses of chemotherapy, the extent of liver metastasis increased and the G-CSF concentration became elevated. Although combined chemotherapy with paclitaxel and gemcitabine was administered, the patient died 7 months after her first visit.