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CORD-19:d3b4cd3d7aa46f8795e95ed4734b69ae69870504 JSONTXT 7 Projects

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Id Subject Object Predicate Lexical cue
T1 0-190 Sentence denotes Pain management for laboratory rodents often requires repeated restraint of the animals and injection of analgesic drugs at intervals of 6-8 h, which can cause stress 1 and potential injury.
T2 191-371 Sentence denotes Analgesics that have longer durations of activity 2 can allow investigators to manage pain in laboratory animals with a single dose of drug, minimizing potential stress and injury.
T3 372-417 Sentence denotes This is a goal of long-acting opiate therapy.
T4 418-522 Sentence denotes Previous research has established the efficacy of opiates such as buprenorphine in animals [3] [4] [5] .
T5 523-629 Sentence denotes Buprenorphine has a high therapeutic index and a 35-year history of safe use in veterinary medicine 6, 7 .
T6 630-848 Sentence denotes Moreover, because opiates are a front-line therapy for pain management in humans, their use in laboratory animals comports with the objective of harmonizing pharmacology between laboratory models and human diseases 8 .
T7 849-1004 Sentence denotes Despite these advantages, opiate analgesia is rarely used with laboratory animals for various reasons 9 , including its potential to cause adverse effects.
T8 1005-1186 Sentence denotes Reported adverse effects of opiate therapy include weight loss [10] [11] [12] , nausea [13] [14] [15] [16] and dermal lesions at drug injection sites [17] [18] [19] [20] [21] [22] .
T9 1187-1335 Sentence denotes Extended-release buprenorphine has a defined safety profile in mice 23 , but a comprehensive understanding of its safety profile in rats is lacking.
T10 1336-1452 Sentence denotes We aimed to determine whether an extended-release cholesterol-buprenorphine suspension could be used safely in rats.
T11 1453-1647 Sentence denotes When designing safety studies for veterinary pharmaceutical products, the US Food and Drug Administration advises investigators to follow guidance for target animal safety (TAS) studies 24, 25 .
T12 1648-1854 Sentence denotes This guidance Lack of adverse effects during a target animal safety trial of extended-release buprenorphine in Fischer 344 rats Alan Cowan, PhD 1 , Rachel Sarabia-Estrada, DVM, PhD 2 , Gina Wilkerson, DVM 3
T13 1856-1996 Sentence denotes Extended-release buprenorphine is an effective analgesic in laboratory animals, and its safety has been established in mice but not in rats.
T14 1997-2108 Sentence denotes The authors used a target animal safety trial to evaluate the safety of extended-release buprenorphine in rats.
T15 2109-2416 Sentence denotes Fischer 344 rats received post-surgical subcutaneous injections of 1.3 mg, 3.9 mg or 6.5 mg buprenorphine per kg body weight (two times, six times or ten times the intended dose, respectively), and their body weight, clinical signs and symptoms, clinical pathology and histopathology were monitored for 4 d.
T16 2417-2524 Sentence denotes Body weight was not significantly different in rats that received buprenorphine compared with control rats.
T17 2525-2617 Sentence denotes Signs of nausearelated behavior were observed in 25% of the rats treated with buprenorphine.
T18 2618-2821 Sentence denotes Clinical pathology results for all rats were normal, and gross and microscopic histopathology examinations identified no substantial abnormalities, suggesting that this behavior was of minor consequence.
T19 2822-2991 Sentence denotes Other adverse events previously reported to occur with opiate therapy, including weight loss and dermal lesions at drug injection sites, were not observed in this study.
T20 2992-3270 Sentence denotes The results of this study show that post-surgical administration of an extended-release buprenorphine product is safe in Fischer 344 rats and does not necessarily cause substantial adverse effects, confirming that opiate therapy is a viable choice in laboratory animal medicine.
T21 3271-3436 Sentence denotes indicates that TAS studies should include clinical observations for pain and distress as well as complete clinical pathology and histopathology examinations 24, 25 .
T22 3437-3578 Sentence denotes European regulatory authorities use similar guidelines to determine the effects of drugs on major organ systems in target animal species 26 .
T23 3579-3858 Sentence denotes In TAS studies, animals are often challenged by administration of two-to ten-fold overdoses of the drug of interest in order to expose weak drug detoxification systems, potential risks in animal models of disease, and potential outcomes of accidental overdoses in the real world.
T24 3859-4001 Sentence denotes We designed and carried out a TAS study for postsurgical administration of extended-release buprenorphine in male and female Fischer 344 rats.
T25 4002-4144 Sentence denotes The intended dose of extended-release buprenorphine for rodents is 0.65 mg per kg body weight, as indicated on the FDA-approved product label.
T26 4145-4211 Sentence denotes We evaluated the safety of three different doses of buprenorphine:
T27 4212-4354 Sentence denotes 1.3 mg per kg body weight (two-fold overdose), 3.9 mg per kg body weight (six-fold overdose) or 6.5 mg per kg body weight (ten-fold overdose).
T28 4355-4546 Sentence denotes We administered buprenorphine or a control suspension to rats immediately after surgery and measured body weight, made clinical observations and analyzed clinical pathology over the next 4 d.
T29 4547-4622 Sentence denotes We also analyzed gross and microscopic histopathology at 4 d after surgery.
T30 4623-4776 Sentence denotes Here we report some of these results with a particular focus on adverse events associated with these overdoses of extended-release buprenorphine in rats.
T31 4777-4842 Sentence denotes This study was approved by the IACUC of Johns Hopkins University.
T32 4843-4966 Sentence denotes We obtained 32 Fischer 344 rats (16 male, 16 female) aged 6-8 weeks and weighing 180-220 g from Taconic Farms (Hudson, NY).
T33 4967-5156 Sentence denotes Rats were housed in an environmentally controlled room with temperature of 20-26 °C and relative humidity of 30-70% on a 12-h:12-h light:dark cycle (with the lights coming on at 6:00 a.m.).
T34 5157-5572 Sentence denotes Health surveillance was carried out using a soiled-bedding sentinel system, which indicated that rats were negative for pneumonia virus of mice, reovirus, Sendai virus, lymphocytic choriomeningitis virus, rat coronavirus, sialodacryoadenitis virus, rat parvovirus, Kilham rat virus, Toolan H1 parvovirus, rat theilovirus, cilia-associated respiratory bacillus, Pneumocysti carinii, Mycoplasma pulmonis and pinworms.
T35 5573-5720 Sentence denotes Upon their arrival at our facility, rats were quarantined and acclimated to the facility for 6 d, during which no disease-related signs were noted.
T36 5721-5800 Sentence denotes Rats were then evaluated and approved for study use by a clinical veterinarian.
T37 5801-6082 Sentence denotes After the acclimation period we weighed the rats on a balance (Explorer Pro EP4102C, Ohaus, Parsippany, NJ) and randomized them by body weight using random numbers generated by Excel (Microsoft Corporation, Redmond, WA) into four groups of eight rats each (four male, four female).
T38 6083-6153 Sentence denotes The weight of each rat was within 10% of the mean weight of its group.
T39 6154-6239 Sentence denotes At the start of the test the mean body weight of all females was approximately 130 g.
T40 6240-6394 Sentence denotes The mean body weight of all males was approximately 180 g, with the exception of one heavier group that weighed a mean body weight of approximately 195 g.
T41 6395-6609 Sentence denotes Rats were tagged with unique ear tags (Kent Scientific, Torrington, CT) for identification and were housed in groups of two or three with cagemates of the same sex that were assigned to the same experimental group.
T42 6610-6793 Sentence denotes Rats were housed in individually ventilated cages (Innovive, San Diego, CA) during the quarantine period and were housed individually in the same type of cage during the study period.
T43 6794-7102 Sentence denotes Rats were provided with soft fiber bedding (Carefresh Natural, Ferndale, WA), ad libitum access to drinking water (from municipal sources) in disposable water bottles (Aquavive Rat 850 mL, Innovive, San Diego, CA) and ad libitum access to Certified Global Rodent Diet 2016C (Harlan TEKLAD, Indianapolis, IN).
T44 7103-7211 Sentence denotes Rats were also provided polycarbonate red tubes (Bio Services, Uden, The Netherlands) as enrichment devices.
T45 7212-7382 Sentence denotes We carried out sham surgeries for all the rats on day 0 and administered a single subcutaneous injection of buprenorphine or control suspension immediately after surgery.
T46 7383-7644 Sentence denotes Rats in each of the four experimental groups (n = 8 per group, 4 male, 4 female) received a different injection: the control suspension, 1.3 mg buprenorphine per kg body weight, 3.9 mg buprenorphine per kg body weight or 6.5 mg buprenorphine per kg body weight.
T47 7645-7750 Sentence denotes The heavier group of males was included in the group that received the dose of 3.9 mg per kg body weight.
T48 7751-7811 Sentence denotes The study period lasted 4 d after the surgery and injection.
T49 7812-7972 Sentence denotes We made clinical observations twice per day on days 1-3 and once on day 4, and we measured body weight and collected blood and urine samples on day 2 and day 4.
T50 7973-8031 Sentence denotes On day 4, at the end of the study, we euthanized the rats.
T51 8032-8178 Sentence denotes We began surgery at approximately 7:00 a.m. and used a surgical procedure that mimics the subcutaneous implantation of a pump or recording device.
T52 8179-8349 Sentence denotes We anesthetized each rat using an anesthesia machine (E-Z Anesthesia, Palmer, PA) with isoflurane gas at approximately 3% and oxygen at 1% (exact flow rate not recorded).
T53 8350-8484 Sentence denotes We then shaved the scapular region (between the shoulder blades), washed it with ethanol and painted it with povidone-iodine solution.
T54 8485-8592 Sentence denotes We transferred the rat to a clean procedural area and assessed the depth of anesthesia by pinching the toe.
T55 8593-8695 Sentence denotes Failure to respond to the toe pinch indicated that the rat had reached a surgical plane of anesthesia.
T56 8696-8836 Sentence denotes Once this had occurred, we visually npg assessed and documented the rat's respiratory rate and capillary fill rate after pinching a toenail.
T57 8837-9036 Sentence denotes We used clean, sterilized forceps to gently grasp the skin, and clean, sterilized scissors to make a 4-to 5-mm incision at the scapular region through the skin without penetrating the muscle or bone.
T58 9037-9153 Sentence denotes We then used the scissors to separate the skin and create a subcutaneous pocket measuring approximately 2 cm × 4 cm.
T59 9154-9271 Sentence denotes We apposed the edges of the incision and stapled them closed using a 9-mm Autoclip (Kent Scientific, Torrington, CT).
T60 9272-9367 Sentence denotes We documented the rat's respiratory rate and capillary refill time at the end of the procedure.
T61 9368-9538 Sentence denotes Immediately after surgery and before the rat recovered from anesthesia, we administered the designated dose of control suspension or buprenorphine suspension to each rat.
T62 9539-9718 Sentence denotes The control suspension consisted of cholesterol and glycerol tristearate (96:4) suspended in a mediumchain triglyceride oil (8 mg per 100 ml; Animalgesics Labs, Millersville, MD).
T63 9719-9919 Sentence denotes The buprenorphine suspension consisted of buprenorphine, cholesterol and glycerol tristearate suspended in a medium-chain triglyceride oil (Animalgesics for Mice; Animalgesics Labs, Millersville, MD).
T64 9920-10114 Sentence denotes We administered the dose by subcutaneous injection in the mid-dorsal area about 1 cm rostral to the surgical incision using a 25-gauge needle attached to a 1-ml syringe (BD, Franklin Lakes, NJ).
T65 10115-10204 Sentence denotes We then transferred the rat to a recovery cage and placed it on a heating pad to recover.
T66 10205-10330 Sentence denotes Once the rat regained consciousness, began moving normally and showed no signs of distress, it was returned to its home cage.
T67 10331-10569 Sentence denotes Clinical observations were carried out by two male observers certified by the American Association for Laboratory Animal Science, one as a Lab Animal Technologist and one as a Lab Animal Technician, who were blinded to experimental group.
T68 10570-10830 Sentence denotes During each observation period one of these two observers would observe the rats and, afterward, complete the appropriate report form for either morning or afternoon observations, noting the presence of clinical signs or symptoms and adding comments as needed.
T69 10831-10955 Sentence denotes Morning observations took place before 9:00 a.m. on days 1-4, and rats were observed without being removed from their cages.
T70 10956-11279 Sentence denotes Observers noted morbidity; mortality; signs of pain or stress including abnormal respiration, tremors, ocular discharge, facial expression (squinting, eyes closed), posture and movement; overall appearance including condition of the hair coat; and condition of the incision site (bleeding, swelling and signs of infection).
T71 11280-11425 Sentence denotes Afternoon observations took place after 2:00 p.m. on days 1-3, and rats were removed from their cages and observed individually for 3-5 min each.
T72 11426-11696 Sentence denotes Observers noted abnormal clinical signs (ocular discharge, motor activity and signs of pain or distress); the condition of the incision site (bleeding, edema, inflammation and signs of infection); and condition of the entire skin surface including hair loss and lesions.
T73 11697-11917 Sentence denotes Observers noted in comments on the report form any hair loss and the presence of lesions as evidence of excessive grooming or self-gnawing behavior, but they did not grade the amount of hair loss or the degree of biting.
T74 11918-12149 Sentence denotes We considered any reports of hair loss or lesions on the paws to be signs of nausea-related behavior, and we recorded the number of rats of each sex in each experimental group that showed these signs during each observation period.
T75 12150-12275 Sentence denotes An observer who was blinded to experimental group weighed each rat on a balance on days 0, 2 and 4 at approximately 6:30 a.m.
T76 12276-12312 Sentence denotes Weights are expressed as mean ± s.d.
T77 12313-12428 Sentence denotes We collected samples of about 0.5 ml blood from each rat on the mornings of days 2 and 4 via jugular vein puncture.
T78 12429-12513 Sentence denotes We then refrigerated blood samples at 3-8 °C until they were delivered for analysis.
T79 12514-12771 Sentence denotes We measured buprenorphine concentrations in blood samples from three rats of each sex that received 1.3 mg buprenorphine per kg body weight, which satisfied the minimum sample size required by the US Food and Drug Administration for a pharmacokinetic study.
T80 12772-12960 Sentence denotes We used a Shimadzu LC-20AD (Columbia, MD) and Applied Biosystems 4000 QTrap (Carlsbad, CA) to carry out a liquid chromatography-mass spectroscopy assay that requires 0.25 ml of plasma 23 .
T81 12961-13245 Sentence denotes We also carried out hematology tests on blood samples from all rats using a Hemavet 950 Hematology System (Drew Scientific, Waterbury, CT) and we carried out chemistry panels on blood samples from all rats using a VetACE Clinical Chemistry system (Alfa Wassermann, West Caldwell, NJ).
T82 13246-13445 Sentence denotes We collected urine samples from each rat on the afternoons of day 2 and day 4 by placing the rat on a clean surface, expressing urine and transferring it to a sterile centrifuge tube using a pipette.
T83 13446-13608 Sentence denotes We then analyzed the urine using urine dip sticks (Bayer Multistix 10 SG Reagent Strips, Romeoville, IL) and visually assessed the assays for abnormal parameters.
T84 13609-13720 Sentence denotes On the afternoon of day 4, we euthanized the rats by carbon dioxide inhalation in custom-made plastic chambers.
T85 13721-13802 Sentence denotes We then carried out a thoracotomy and confirmed death by cessation of heart beat.
T86 13803-14046 Sentence denotes We carried out a comprehensive necropsy for each rat as described previously 23, 25 , collecting 33 tissues and organs for histopathological examination, including the dorsal skin surrounding the injection site, for the complete npg TAS study.
T87 14047-14232 Sentence denotes We weighed organs; incised the stomachs and examined the contents; and examined the entire gastrointestinal tract for any signs of blockage, distension, inflammation, edema or necrosis.
T88 14233-14378 Sentence denotes We carried out separate one-way analysis of variance tests (ANOVAs) to compare body weights between groups for rats within each sex for each day.
T89 14379-14487 Sentence denotes We made pairwise comparisons between groups within sexes and within each day using Dunnett's post hoc tests.
T90 14488-14635 Sentence denotes We used a zero-inflated Poisson regression model 27 to estimate how sex and experimental group influenced the incidence of nausea-related behavior.
T91 14636-14722 Sentence denotes We used zero-inflation to account for control rats that did not receive buprenorphine.
T92 14723-14947 Sentence denotes We also used one-way ANOVAs and Dunnett's post hoc tests to compare organ weights and clinical pathology parameters between groups for rats of each sex as part of the TAS study, whose complete results are not described here.
T93 14948-15015 Sentence denotes For all analyses P < 0.05 was considered statistically significant.
T94 15016-15150 Sentence denotes We carried out calculations and modeling using the R language version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria).
T95 15151-15276 Sentence denotes Body weight was not significantly different between groups of either sex during the study (F 3,12 < 3.4, P > 0.05, Table 1 ).
T96 15277-15440 Sentence denotes Male rats that received 1.3 mg buprenorphine per kg body weight generally lost weight between day 0 and day 2, but generally gained weight between day 2 and day 4.
T97 15441-15599 Sentence denotes Female rats that received 1.3 mg buprenorphine per kg body weight generally lost weight between day 0 and day 2, and also lost weight between day 2 and day 4.
T98 15600-15704 Sentence denotes All male rats that received 3.9 mg buprenorphine per kg body weight lost weight between day 0 and day 2.
T99 15705-15891 Sentence denotes Two of these males continued to lose weight between day 2 and day 4, whereas the other two males gained weight between day 2 and day 4 and had an overall weight gain from day 0 to day 4.
T100 15892-16111 Sentence denotes Among female rats that received 3.9 mg buprenorphine per kg body weight, one lost weight from day 0 to day 2 and all four lost weight between day 2 and day 4, but only two had an overall weight loss from day 0 to day 4.
T101 16112-16258 Sentence denotes All male rats that received 6.5 mg buprenorphine per kg body weight lost weight between day 0 and day 2 but gained weight between day 2 and day 4.
T102 16259-16432 Sentence denotes On the other hand, all of the female rats treated with 6.5 mg buprenorphine per kg body weight gained weight between day 0 and day 2 but lost weight between day 2 and day 4.
T103 16433-16525 Sentence denotes Observers noted no signs of pain or distress in any of the animals as part of the TAS study.
T104 16526-16730 Sentence denotes Signs of nausea-related behavior were never observed during the morning observation periods but were observed during the afternoon periods when each rat was removed from its cage for physical examination.
T105 16731-16778 Sentence denotes These signs were observed only on the forepaws.
T106 16779-16845 Sentence denotes No signs of nausea-related behavior were observed in control rats.
T107 16846-16998 Sentence denotes Signs of nausea-related behavior were first noted in a male rat 1 d after receiving an injection of 3.9 mg buprenorphine per kg body weight ( Table 2) .
T108 16999-17166 Sentence denotes Among rats that received the lowest dose of 1.3 mg buprenorphine per kg body weight, only one female rat showed signs of nausea-related behavior on day 2 and on day 3.
T109 17167-17431 Sentence denotes Among rats that received 3.9 mg buprenorphine per kg body weight, the incidence of signs of nausea-related behavior increased during the study from one male on day 1 to two rats (one male and one female) on day 2 and three rats (one male and two females) on day 3.
T110 17432-17520 Sentence denotes The incidence of signs of nausearelated behavior was highest in this experimental group.
T111 17521-17775 Sentence denotes Among rats that received the highest dose of 6.5 mg buprenorphine per kg body weight, the onset of signs of nausea-related behavior was delayed and the incidence was lower: two rats (one male, one female) showed signs of nausea-related behavior on day 3.
T112 17776-17905 Sentence denotes Across the three groups of rats that received buprenorphine, 6 of 24 rats (25%) showed signs of nausea-related behavior on day 3.
T113 17906-18082 Sentence denotes Treatment group was a statistically significant predictor of the number of rats that showed signs of nausearelated behaviors (β = 1.01, standard error (s.e.) = 0.41, P = 0.01).
T114 18083-18248 Sentence denotes The incidence of signs of nausearelated behavior was similar in male and female rats taBLe 1 | Mean ± s.d. body weight (g) of male and female rats at day 0, 2 and 4.
T115 18249-18368 Sentence denotes Single-sex groups of rats (n = 4) received either a control injection or one of three different doses of buprenorphine.
T116 18369-18478 Sentence denotes Body weight did not differ significantly between groups of male or female rats at any point during the study.
T117 18480-18719 Sentence denotes Blood concentrations of buprenorphine in rats that received 1.3 mg buprenorphine per kg body weight averaged 5, 7, 5 and 4 ng/ml on days 1-4, respectively, for males and averaged 10, 7, 7 and 2 ng/ml on days 1-4, respectively, for females.
T118 18720-18822 Sentence denotes Clinical pathology data showed no significant differences between the control and drug treated groups.
T119 18823-18974 Sentence denotes Most animals in all groups, including the negative controls, had moderate levels of protein in the urine that did not discernibly differ between doses.
T120 18975-19090 Sentence denotes Hematology and clinical chemistry analyses identified no abnormal blood chemistry that could indicate renal damage.
T121 19091-19203 Sentence denotes Necropsy examinations identified no gross abnormalities, including macroscopic skin lesions, in any of the rats.
T122 19204-19365 Sentence denotes Among all organs, only spleen weight differed significantly among groups (F 3,12 = 3.96, P = 0.036), but this was not considered indicative of an adverse effect.
T123 19366-19515 Sentence denotes Microscopic examination identified no abnormalities in dorsal skin tissue, spleen or any other tissues or organs from rats in any experimental group.
T124 19516-19697 Sentence denotes Post-mortem examination of the stomach contents and gastrointestinal tracts showed no anomalies or signs of blockage, distension, inflammation, edema or necrosis in any of the rats.
T125 19698-19878 Sentence denotes The efficacy of long-acting opiate analgesics in laboratory animals has been established 2 , but less information is available about the safety of these veterinary pharmaceuticals.
T126 19879-20029 Sentence denotes In this study, we examined whether an extended-release buprenorphine suspension with a defined safety profile in mice 23 could be used safely in rats.
T127 20030-20549 Sentence denotes We administered three different doses of buprenorphine to rats (1.3 mg per kg body weight, 3.9 mg per kg body weight or 6.5 mg per kg body weight) immediately after surgery and measured body weight, made clinical observations and analyzed clinical pathology and histopathology over the next 4 d to identify adverse events including weight loss 10-12 , nausea [13] [14] [15] [16] and dermal lesions at drug injection sites [17] [18] [19] [20] [21] [22] , which have previously been reported to occur with opiate therapy.
T128 20550-20770 Sentence denotes Blood concentrations of buprenorphine in rats that received the lowest dose of 1.3 mg buprenorphine per kg body weight exceeded the threshold of 1 ng/ml that has been consistently associated with analgesic efficacy 2,7 .
T129 20771-20909 Sentence denotes Body weight was not significantly different in rats that received buprenorphine compared with control rats of either sex during the study.
T130 20910-21003 Sentence denotes Signs of nausea-related behavior were observed in 25% of the rats treated with buprenorphine.
T131 21004-21151 Sentence denotes Clinical pathology results for all rats were normal, and gross and microscopic histopathology examinations identified no substantial abnormalities.
T132 21152-21245 Sentence denotes We did not observe significant weight loss in rats that received buprenorphine in this study.
T133 21246-21392 Sentence denotes A similar absence of weight loss was also reported in rats that received 1.2 mg buprenorphine per kg body weight in a polymer formulation 19, 28 .
T134 21393-21555 Sentence denotes These results contrast with previous reports of significant weight loss after post-surgical oral and subcutaneous administration of buprenorphine [10] [11] [12] .
T135 21556-21678 Sentence denotes Weight loss in some cases was associated with gastric distress and pica (consumption of non-nutritive substances) 10, 11 .
T136 21679-21843 Sentence denotes Pica occurs in response to nausea induced by opiate therapy 3,10 and has been reported in Sprague-Dawley 13,16 , Long-Evans 15 , Wistar 14 and Dark Agouti rats 12 .
T137 21844-21920 Sentence denotes Pica is a complex phenomenon that might be beneficial in some circumstances.
T138 21921-22101 Sentence denotes Consumption of kaolin (a behavior indicative of pica) after treatment with a nausea-inducing compound was correlated with less weight loss and greater food consumption in rats 29 .
T139 22102-22153 Sentence denotes Pica can also have dangerous consequences, however.
T140 22154-22338 Sentence denotes Previously in our laboratory, 1 of 15 male Fischer 344 rats was found dead on day 3 of a pilot study after it was treated with a single dose of 1.3 mg buprenorphine per kg body weight.
T141 22339-22440 Sentence denotes Upon necropsy, the stomach and esophagus of the rat were noted to be compacted with hardwood bedding.
T142 22441-22608 Sentence denotes This is consistent with a previous report that Sprague-Dawley rats consumed hardwood bedding and experienced gastric distention after treatment with buprenorphine 16 .
T143 22609-22886 Sentence denotes In another study in which rats were housed on corncob bedding, pica-related mortality was reported in 5 of 25 animals treated post-surgically with buprenorphine or fentanyl, but no deaths occurred among 30 control rats npg or 20 rats treated with acetaminophen or flunixin 30 .
T144 22887-23007 Sentence denotes Another study reported no deaths in rats treated with buprenorphine and housed for 1-2 d on grid floors or on paper 12 .
T145 23008-23142 Sentence denotes In this study, we observed no deaths and no signs of pica among 32 rats treated with buprenorphine and housed with soft fiber bedding.
T146 23143-23404 Sentence denotes These results suggest that, although opiate-induced pica can have severe and even lethal consequences for rats housed with hardwood and corncob bedding 13, 14 , these can be minimized if researchers instead use alternative bedding materials, such as soft fiber.
T147 23405-23557 Sentence denotes Although we did not note weight loss or signs of pica in this study, we did observe signs of nausea-related behavior in rats treated with buprenorphine.
T148 23558-23670 Sentence denotes Nausea is a common adverse effect of opiate therapy in humans and animals and can confound experimental results.
T149 23671-23762 Sentence denotes We observed signs of nausea-related behavior in 25% of the rats treated with buprenorphine.
T150 23763-23880 Sentence denotes This incidence is similar to the incidence of nausea reported among human patients treated with opiate therapies 31 .
T151 23881-24067 Sentence denotes The male rat that first showed signs of nausea-related behavior on day 1 was one of two male rats receiving 3.9 mg buprenorphine per kg body weight that lost weight throughout the study.
T152 24068-24187 Sentence denotes Clinical pathology results for all rats were normal, however, suggesting that consequences of this behavior were minor.
T153 24188-24348 Sentence denotes The presence of moderate levels of protein in expressed urine could generally indicate renal damage, but this was not supported by the blood chemistry findings.
T154 24349-24634 Sentence denotes Signs of nausea-related behavior were not observed in a similar TAS study of the safety of buprenorphine in mice 23 , and we are unaware of previous reports describing excessive grooming and self-gnawing behavior associated with long-acting buprenorphine therapy in laboratory animals.
T155 24635-24780 Sentence denotes Whether the signs we observed (hair loss and lesions on the forepaws) in this study are entirely related to nausea requires further verification.
T156 24781-25059 Sentence denotes Future studies of nausea-related behavior in rats treated with buprenorphine are also needed to address whether its incidence can be reduced by lower doses of drug; to assess its incidence, duration and intensity; and to determine whether it occurs in other rat strains 32, 33 .
T157 25060-25202 Sentence denotes The use of light and dark surveillance 9 and automated tracking 34 techniques in such studies might help to better characterize this behavior.
T158 25203-25497 Sentence denotes Dermal lesions have been reported at the sites of subcutaneous injections of buprenorphine-loaded polymers in mice 17, 18 , rats 19 , dogs 20 , minipigs 21 and nonhuman primates 22 but were not observed at the site of subcutaneous injection of a cholesterolbuprenorphine suspension in mice 23 .
T159 25498-25604 Sentence denotes Lipid encapsulation is a well-known mechanism used to decrease toxicity and prolong delivery of drugs 35 .
T160 25605-25794 Sentence denotes In this study we observed no skin lesions upon gross examination and histopathologic analysis of the site of subcutaneous injection of the same cholesterol-buprenorphine suspension in rats.
T161 25795-25988 Sentence denotes To our knowledge, the previous report on the safety of an extended-release buprenorphine suspension describes the first use of a TAS study to evaluate a drug specifically designed for mice 23 .
T162 25989-26066 Sentence denotes This study used a similar protocol to examine the safety of the drug in rats.
T163 26067-26301 Sentence denotes The results indicate that post-surgical administration of extended-release buprenorphine is safe and does not cause substantial adverse effects in relatively young Fischer 344 rats of both sexes under appropriate husbandry conditions.
T164 26302-26432 Sentence denotes The safety of the drug in older rats, in rats of different strains and in the context of different surgical procedures is unknown.
T165 26433-26665 Sentence denotes Yet we conclude that long-acting opiate therapy is a viable analgesic strategy in laboratory animal medicine and, with appropriate husbandry, could markedly expand options for providing post-surgical pain therapy to laboratory rats.