Lisa Krugner-higby
University of Wisconsin-Madison, Dept. of Surgical Sciences, Faculty Member
... Stephen H. Caldwell1, Abdullah Al-Osaimi1, Charissa Chang1, Christie Davis1, Elizabeth E. Hespenheide1, Lisa Krugner-Higby2, Anita Impaglizzo Hylton1, Julia C. Iezzoni1, Tri H. Le3, Robert K. Nakamoto1, Jan Redick1, and Theresa... more
... Stephen H. Caldwell1, Abdullah Al-Osaimi1, Charissa Chang1, Christie Davis1, Elizabeth E. Hespenheide1, Lisa Krugner-Higby2, Anita Impaglizzo Hylton1, Julia C. Iezzoni1, Tri H. Le3, Robert K. Nakamoto1, Jan Redick1, and Theresa Peterson4 1 ...
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To compare serum concentrations of liposome-encapsulated butorphanol tartrate (LEBT) and standard butorphanol tartrate (STDBT) following SC and IM administration, respectively, and to evaluate analgesic effects of LEBT and STDBT after... more
To compare serum concentrations of liposome-encapsulated butorphanol tartrate (LEBT) and standard butorphanol tartrate (STDBT) following SC and IM administration, respectively, and to evaluate analgesic effects of LEBT and STDBT after parenteral administration to Hispaniolan parrots. 11 adult Hispaniolan parrots. The ability of LEBT to prolong the duration of analgesia in an avian species was tested. Blood samples were collected at serial time points after SC administration of LEBT (10 mg/kg or 15 mg/kg) or IM administration of STDBT (5 mg/kg). Serum concentrations of butorphanol tartrate were determined by use of a commercial immunoassay that measured parent drug and metabolites. Analgesic efficacy was evaluated in parrots exposed to electrical and thermal stimuli. Foot withdrawal thresholds were recorded at baseline and at serial time points after LEBT (15 mg/kg), liposome vehicle, STDBT (2 mg/kg), or physiologic saline (0.9% NaCl) solution administration. LEBT had a prolonged in vivo release for up to 5 days. Negligible serum butorphanol and butorphanol metabolite concentrations were obtained at 24 hours after IM administration of STDBT. Analgesic efficacy of LEBT as measured by foot withdrawal threshold to noxious thermal and electrical stimuli persisted for 3 to 5 days following SC administration of LEBT. SC administration of LEBT provided analgesia and detectable serum butorphanol concentrations in Hispaniolan parrots for up to 5 days. The use of LEBT may allow for substantial improvement in long-term pain relief without subjecting birds to the stress of handling and multiple daily injections.
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Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating... more
Myeloid neoplasia has been studied extensively in human beings but has not been reported in macaques. A 2-year-old female rhesus macaque that was experimentally exposed to lead as a neonate, was noted to have immature circulating myelocytic cells, including 1% blasts, and normocytic normochromic anemia on a blood sample obtained for monthly health monitoring. The animal was treated with hydroxyurea, blood transfusion, and recombinant human erythropoietin to reduce the leukocytosis and correct the anemia. The disease had a relatively indolent course for 3 months, when it progressed to blast crisis. After the onset of blast crisis, the animal was euthanized because of bleeding problems, anemia, and a progressive decline in her health. The animal was negative by serology, polymerase chain reaction (PCR) assays, and/or culture for simian retrovirus (SRV), simian T-lymphotropic virus type I (STLV-I), and simian immunodeficiency virus (SIV). PCR assay for the bcr-ABL chromosomal transloca...
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We characterized abnormalities of carbohydrate and lipid metabolism and determined whether those metabolic abnormalities are associated with extremity lesions in California mice (Peromyscus californicus). Blood samples were evaluated for... more
We characterized abnormalities of carbohydrate and lipid metabolism and determined whether those metabolic abnormalities are associated with extremity lesions in California mice (Peromyscus californicus). Blood samples were evaluated for glucose, cholesterol, triglyceride, and insulin concentrations. Necropsy and histologic evaluation were done on selected mice, including staining pancreatic sections for insulin. Physical examinations also were performed. California mice were found to have Type 2 diabetes mellitus (T2DM). Sections of pancreas from diabetic and prediabetic mice had pathologic changes consistent with T2DM. After six months of feeding a low-fat diet, mice were normoglycemic, normotriglyceridemic, and normocholesterolemic. Some mice remained hyperinsulinemic. Traumatic lesions were not associated with T2DM. California mice develop diet-related T2DM when fed a diet containing 25.8% kcal from fat. California mice may be a useful animal model of human T2DM, and traumatic l...
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OBJECTIVE-To evaluate the analgesic efficacy of meloxicam in parrots with experimentally induced arthritis, with extent of weight bearing and rotational perch walking used as outcome measures. ANIMALS-15 adult Hispaniolan parrots (Amazona... more
OBJECTIVE-To evaluate the analgesic efficacy of meloxicam in parrots with experimentally induced arthritis, with extent of weight bearing and rotational perch walking used as outcome measures. ANIMALS-15 adult Hispaniolan parrots (Amazona ventralis). PROCEDURES-Arthritis was experimentally induced via intra-articular injection of microcrystalline sodium urate suspension (MSU) into 1 intertarsal joint. Parrots were treated in a crossover design. Five treatments were compared as follows: meloxicam (4 dosages) at 0.05, 0.1, 0.5, and 1.0 mg/kg (IM, q 12 h, 3 times) and 0.03 mL of saline (0.9% NaCl) solution (IM, q 12 h, 3 times). The first treatment was given 6 hours following MSU administration. Lameness was assessed by use of a biomechanical perch to record weight-bearing load and a rotational perch to determine dexterity. Feces were collected to assay for occult blood. RESULTS-Parrots treated with meloxicam at 1.0 mg/kg had significantly better return to normal (baseline) weight bearing on the arthritic pelvic limb, compared with control parrots or parrots treated with meloxicam at 0.05, 0.1, and 0.5 mg/kg. All fecal samples collected from parrots following induction of arthritis and treatment with meloxicam had negative results for occult blood. CONCLUSIONS AND CLINICAL RELEVANCE-Meloxicam administered at 1.0 mg/kg, IM, every 12 hours effectively relieved arthritic pain in parrots.
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The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations... more
The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations would be advantageous for this species. A single subcutaneous injection of a liposome-encapsulated (LE) preparation of oxymorphone was compared with multiple injections of buprenorphine or saline in outbred mice undergoing splenectomy. Control groups were given isoflurane alone or isoflurane and an injection of LE oxymorphone but did not undergo surgery. The following parameters were evaluated for 5 days after surgery and were compared with presurgical baseline data for each group: food and water consumption, body weight, ethographic score, and voluntary exercise on a running wheel. Ethographic scores indicated less postsurgical pain in both groups of mice that received either analgesic preparation compared with mice that received only saline. Howeve...
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Ulcerative dermatitis (UD) is a common cause of morbidity and euthanasia in mice with a C57BL/6 (B6) background. The purposes of the current study were to determine whether UD lesions could be reliably produced in B6 mice lacking... more
Ulcerative dermatitis (UD) is a common cause of morbidity and euthanasia in mice with a C57BL/6 (B6) background. The purposes of the current study were to determine whether UD lesions could be reliably produced in B6 mice lacking stearoyl-CoA desaturase 1 (SCD1(-/-) mice), to ascertain whether the UD lesions in SCD1(-/-) mice were similar to those found in other B6 mice, and to characterize the cell invasion phenotype of Staphlococcus xylosus cultured from the lesions. S. xylosus isolates from the environment and human skin were used as controls. SCD1(-/-) (n = 8 per group) and nontransgenic B6 control mice (n = 22 mice pooled from 3 groups that received different concentrations of conjugated linoleic acid) were fed standard rodent chow or a semipurified diet (NIH AIN76A) for 4 wk. Samples from other B6 mice with UD (field cases; n = 7) also were submitted for histology and culture. All of the SCD1(-/-) mice developed UD lesions by 4 wk on NIH AIN76A. None of SCD1(-/-) fed standard ...
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An extended-release formulation of oxymorphone was produced by encapsulation into liposomes, using a novel technique. Liposome-encapsulated morphine was produced, using a standard technique These preparations were tested in an animal... more
An extended-release formulation of oxymorphone was produced by encapsulation into liposomes, using a novel technique. Liposome-encapsulated morphine was produced, using a standard technique These preparations were tested in an animal model of neuropathic pain. Male Sprague-Dawley rats (approx. 300 g) were allotted to control (non-loaded liposomes) and treatment (liposome-encapsulated oxymorphone or morphine) groups. Drugs were administered subcutaneously to all rats immediately prior to sciatic nerve ligation. Thermal withdrawal latencies were measured at baseline and daily for seven days after sciatic nerve ligation. A second experiment involved subcutaneous administration of non-loaded liposomes, morphine, or oxymorphone to rats that did not undergo sciatic nerve ligation. Thermal withdrawal latencies in sciatic nerve-ligated rats given non-loaded liposomes decreased significantly by day four, with maximal decrease at day seven after surgery, indicating development of full hyperal...
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Reports of severe enteric disease of unknown etiology affecting lactating mice have appeared in the literature. Clostridial disease similar to that seen in cattle and sheep on high-carbohydrate rations and caused by Clostridium... more
Reports of severe enteric disease of unknown etiology affecting lactating mice have appeared in the literature. Clostridial disease similar to that seen in cattle and sheep on high-carbohydrate rations and caused by Clostridium perfringens has been suspected in these mouse outbreaks but has not been isolated from affected mice. The present report describes a severe, necrotizing enterocolitis associated with overgrowth of C. perfringens type A in lactating Swiss-derived (ND4) mice. Mice nursing large litters of pups in the second week of life were the most severely affected. The organism isolated from dead or moribund mice was positive by polymerase chain reaction assay for the gene for the C. perfringens a toxin, but actual toxin production was not determined. The disease in this mouse colony was ameliorated by increasing the fat and calorie content of the diet of lactating dams, which each received 1 g peanut butter every 48 h.
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Biology, Lactation, Medicine, Neonatal Necrotizing Enterocolitis, Biological Sciences, and 14 moreBacterial Toxins, Mice, Female, Animals, Polymerase Chain Reaction, Kidney Disease, Gastrointestinal Tract, Calcium Binding Proteins, Clinical Signs, Clostridium perfringens, Germ-free, Necrotic Enteritis, High Carbohydrate Diet, and Medical and Health Sciences
We present approaches for using thin film polymeric electrode arrays for use in applications of minimally invasive neurological monitoring. The flexibility and unique surface properties of the thin-film polyimide substrate in combination... more
We present approaches for using thin film polymeric electrode arrays for use in applications of minimally invasive neurological monitoring. The flexibility and unique surface properties of the thin-film polyimide substrate in combination with a compact device platform make them amenable to a variety of surgical implantation procedures. Using a rapid-prototyping and fabrication technique, arrays of various geometries can be fabricated within a week. In this paper we test two different approaches for deploying electrode arrays through small cranial openings.
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Electroencephalography, Medicine, Rapid Prototyping, Brain, Animals, and 12 moreThin Film, Cadaver, Surface Properties, Reproducibility of Results, Macaca Mulatta, Elastic Modulus, Sensitivity and Specificity, Action Potentials, Minimally Invasive, Equipment Design, Equipment Failure Analysis, and Electric Conductivity
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The studies described in this paper for the first time characterize the acute and chronic performance of optically transparent thin-film μECoG grids implanted on a thinned skull as both an electrophysiological complement to existing... more
The studies described in this paper for the first time characterize the acute and chronic performance of optically transparent thin-film μECoG grids implanted on a thinned skull as both an electrophysiological complement to existing thinned skull preparation for optical recordings/manipulations, and a less invasive alternative to epidural or subdurally placed μECoG arrays. In a longitudinal chronic study, μECoG grids placed on top of a thinned skull maintain impedances comparable to epidurally placed μECoG grids that are stable for periods of at least one month. Optogenetic activation of cortex is also reliably demonstrated through the optically transparent ECoG grids acutely placed on the thinned skull. Finally, spatially distinct electrophysiological recordings were evident on μECoG electrodes placed on a thinned skull separated by 500-750 micrometers, as assessed by stimulation evoked responses using optogenetic activation of cortex as well as invasive and epidermal stimulation o...
Clinical outcomes after nerve injury and repair remain suboptimal. Patients may be plagued by poor functional recovery and painful neuroma at the repair site, characterized by disorganized collagen and sprouting axons. Collagen deposition... more
Clinical outcomes after nerve injury and repair remain suboptimal. Patients may be plagued by poor functional recovery and painful neuroma at the repair site, characterized by disorganized collagen and sprouting axons. Collagen deposition during wound healing can be intrinsically imaged using second harmonic generation (SHG) microscopy. The purpose of this study was to develop a protocol for SHG imaging of nerves and to assess whether collagen alignment can be quantified after nerve repair. Sciatic nerve transection and epineural repair was performed in male rats. The contralateral nerves were used as intra-animal controls. Ten-millimeter nerve segments were harvested and fixed onto slides. SHG images were collected using a 20× objective on a multiphoton microscope. Collagen fiber alignment was calculated using CurveAlign software. Alignment was calculated on a scale from 0 to 1, where 1 represents perfect alignment. Statistical analysis was performed using a linear mixed-effects mo...
The health of laboratory animals is an ethical responsibility of researchers and a critical determinant of experimental outcome. Therefore, all husbandry procedures should be evaluated for their effects on mortality, behavior, and... more
The health of laboratory animals is an ethical responsibility of researchers and a critical determinant of experimental outcome. Therefore, all husbandry procedures should be evaluated for their effects on mortality, behavior, and physiology to maximize animal welfare and minimize experimental variability. For adult zebrafish, the excision of a small portion of the caudal fin (that is, 'fin clipping') under MS222 anesthesia is a common procedure to obtain tissue for genotyping. The potential effect of this procedure on behavioral and physiologic assays of feeding, anxiety, and stress has not previously been assessed. Here, we evaluated feeding behavior, anxiety-associated behaviors, and physiologic indicators of stress at multiple time points within 24 h after performing a standard fin-clip procedure under MS222 anesthesia. Within 1 h of the procedure, fin-clipped fish showed a mild increase in anxiety and exhibited reduced feeding; however, these effects were short-lived, a...
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Transparent graphene-based neural electrode arrays provide unique opportunities for simultaneous investigation of electrophysiology, various neural imaging modalities, and optogenetics. Graphene electrodes have previously demonstrated... more
Transparent graphene-based neural electrode arrays provide unique opportunities for simultaneous investigation of electrophysiology, various neural imaging modalities, and optogenetics. Graphene electrodes have previously demonstrated greater broad-wavelength transmittance (∼90%) than other transparent materials such as indium tin oxide (∼80%) and ultrathin metals (∼60%). This protocol describes how to fabricate and implant a graphene-based microelectrocorticography (μECoG) electrode array and subsequently use this alongside electrophysiology, fluorescence microscopy, optical coherence tomography (OCT), and optogenetics. Further applications, such as transparent penetrating electrode arrays, multi-electrode electroretinography, and electromyography, are also viable with this technology. The procedures described herein, from the material characterization methods to the optogenetic experiments, can be completed within 3-4 weeks by an experienced graduate student. These protocols shoul...
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Cognitive Science, Deep Brain Stimulation, Epilepsy, Electroencephalography, Brain Computer Interface, and 11 moreEvoked Potentials, Animals, Thin Film, Motor Cortex, Microelectrodes, Clinical Sciences, Computer User Interface Design, Macaca fascicularis, Equipment Design, Neurosciences, and Craniotomy
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Although Cu complexes have been investigated as anticancer agents, there has been no description of Cu itself as a cancer killing agent. A stealth liposomal Cu formulation (LpCu) was studied in vitro and in vivo. LpCu was evaluated in... more
Although Cu complexes have been investigated as anticancer agents, there has been no description of Cu itself as a cancer killing agent. A stealth liposomal Cu formulation (LpCu) was studied in vitro and in vivo. LpCu was evaluated in prostate cancer origin PC-3 cells by a metabolic cytotoxicity assay, by monitoring ROS, and by flow cytometry. LpCu efficacy was evaluated in vivo using intratumoral and intravenous injections into mice bearing PC-3 xenograft tumors. Toxicology was assessed by performing hematological and blood biochemistry assays, and tissue histology and Cu distribution was investigated by elemental analysis. LpCu and free Cu salts displayed similar levels of cell metabolic toxicity and ROS. Flow cytometry indicated that the mechanisms of cell death were both apoptosis and necrosis. Animals injected i.t. with 3.5 mg/kg or i.v. with 3.5 and 7.0 mg/kg LpCu exhibited significant tumor growth inhibition. Kidney and eye were the main organs affected by Cu-mediated toxicities, but spleen and liver were the major organs of Cu deposition. LpCu was effective at reducing tumor burden in the xenograft prostate cancer model. There was histological evidence of Cu toxicity in kidneys and eyes of animals treated at the maximum tolerated dose of LpCu 7.0 mg/kg.
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The analgesic efficacy of liposomal hydromorphone (LE-hydro) was tested in dogs undergoing limb amputation. The positive controls (n = 10) received subcutaneous (SQ) hydromorphone (0.2 mg/kg) and 1.5 mL of blank liposomes before surgery;... more
The analgesic efficacy of liposomal hydromorphone (LE-hydro) was tested in dogs undergoing limb amputation. The positive controls (n = 10) received subcutaneous (SQ) hydromorphone (0.2 mg/kg) and 1.5 mL of blank liposomes before surgery; fentanyl continuous rate infusion (CRI), 5-10 μg/kg/hr IV, during and for 24 hr after surgery; and a fentanyl patch at extubation. The negative controls (n = 7) received SQ hydromorphone (0.2 mg/kg) and 1.5 mLs of blank liposomes SQ before surgery, fentanyl CRI (5-10 μg/kg/hr IV) during surgery but stopped at extubation, and a fentanyl patch at extubation. The test group (n = 11) received 3 mg/kg of LE-hydro and 1.5 mL of saline SQ before surgery, 1.5 mL of saline SQ, and a saline CRI during surgery. All groups received a bupivacaine block in the limb prior to amputation and carprofen prior to surgery. Treatment failures, pain scores, opioid side effects, heart rate, respiratory rate, temperature, and client-reported pain and side effects were evalu...
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Dogs, Female, Animals, Male, Sarcoma, and 4 moreLiposomes, Amputation, Postoperative pain, and Hydromorphone
Colonies of nonhuman primates at the Bowman Gray School of Medicine (BGSM) were tested for antibodies to two retroviruses associated with immunodeficiency by indirect immunofluorescence (IFA) and western blot. A total of 471 cynomolgus... more
Colonies of nonhuman primates at the Bowman Gray School of Medicine (BGSM) were tested for antibodies to two retroviruses associated with immunodeficiency by indirect immunofluorescence (IFA) and western blot. A total of 471 cynomolgus macaques (Macaca fascicularis), 144 rhesus monkeys (M. mulatta) and 67 stumptail monkey M. arctoides) were tested for SRV-1, and 152 African green monkeys (Cercopithecus aethiops) were tested for SIV. Of the macaques tested, 170 (36%) cynomolgus, 5 (3%) rhesus and 8 (12%) stumptails were positive for SRV-1 antibodies by IFA. Of the African green monkeys, 54 (36%) were IFA positive for SIV antibodies. A total of 143 African green monkeys tested by IFA also were tested by western blot. In the African green monkeys, the IFA had a positive predictive value of 98% and a negative predictive value of 96%. Of 176 IFA positive macaque sera tested by western blot, 49 (28%) were positive, 55 (31%) were considered equivocal (only one band, usually to p27 core pro...
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Gastric trichobezoars (hair balls) are frequently found in rabbits but are rarely reported in rats. Several Wistar-Kyoto rats fed a semi-purified diet developed anorexia and abdominal tenderness. Proteolysis therapy with fresh papaya and... more
Gastric trichobezoars (hair balls) are frequently found in rabbits but are rarely reported in rats. Several Wistar-Kyoto rats fed a semi-purified diet developed anorexia and abdominal tenderness. Proteolysis therapy with fresh papaya and commercially prepared enzyme was attempted in these rats but was not successful. The prevalence of trichobezoars at necropsy was 100%. We conclude that semi-purified diets contribute to trichobezoar formation in rats, but proteolysis therapy is not effective in dissolving the trichobezoars.
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An extended-release formulation of oxymorphone was produced by encapsulation into liposomes, using a novel technique. Liposome-encapsulated morphine was produced, using a standard technique These preparations were tested in an animal... more
An extended-release formulation of oxymorphone was produced by encapsulation into liposomes, using a novel technique. Liposome-encapsulated morphine was produced, using a standard technique These preparations were tested in an animal model of neuropathic pain. Male Sprague-Dawley rats (approx. 300 g) were allotted to control (non-loaded liposomes) and treatment (liposome-encapsulated oxymorphone or morphine) groups. Drugs were administered subcutaneously to all rats immediately prior to sciatic nerve ligation. Thermal withdrawal latencies were measured at baseline and daily for seven days after sciatic nerve ligation. A second experiment involved subcutaneous administration of non-loaded liposomes, morphine, or oxymorphone to rats that did not undergo sciatic nerve ligation. Thermal withdrawal latencies in sciatic nerve-ligated rats given non-loaded liposomes decreased significantly by day four, with maximal decrease at day seven after surgery, indicating development of full hyperal...
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Liposome encapsulation of opioids by using an ammonium-sulfate-gradient loading technique significantly slows the release time of the drug. This study evaluated the duration of analgesia in a rodent model of monoarthritis after epidural... more
Liposome encapsulation of opioids by using an ammonium-sulfate-gradient loading technique significantly slows the release time of the drug. This study evaluated the duration of analgesia in a rodent model of monoarthritis after epidural administration of liposome-encapsulated hydromorphone (LE-hydromorphone; prepared by ammonium-sulfate-gradient loading) compared with standard hydromorphone and a negative control of blank liposomes. Analgesia was assessed by changes in thermal withdrawal latency, relative weight-bearing, and subjective behavioral scoring. Analgesia in arthritic rats was short-lived after epidural hydromorphone; increases in pain threshold were observed only at 2 h after administration. In contrast, thermal pain thresholds after epidural LE-hydromorphone were increased for as long as 72 h, and subjective lameness scores were lower for as long as 96 h after epidural administration. Injection of LE-hydromorphone epidurally was associated with various mild changes in CN...
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The objective of this research was to determine body composition, total fat content, fat distribution, and serum leptin concentration in hyperlipidemic (high responder, HR) and normolipidemic (low responder, LR) California mice... more
The objective of this research was to determine body composition, total fat content, fat distribution, and serum leptin concentration in hyperlipidemic (high responder, HR) and normolipidemic (low responder, LR) California mice (Peromyscus californicus). In our initial experiments, we sought to determine whether differences in regional fat storage were associated with hyperlipidemia in this species. To further characterize the hepatic steatosis in the mice, we performed 2 additional experiments by using a diet containing 45% of energy as fat. The body fat content of mice fed a low fat-diet (12.3% energy as fat) was higher than that of mice fed a moderate-fat diet (25.8% energy as fat). Total body fat did not differ between HR and LR mice. There was no significant difference between intraabdominal, gonadal, or inguinal fat pad weights. Liver weights of HR mice fed the moderate-fat diet were higher than those of LR mice fed the same diet, and the moderate-fat diet was associated with ...
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California mice (Peromyscus californicus) develop type II diabetes mellitus when fed a high-fat diet. We undertook the current studies to determine whether hyperlipidemia precedes the development of insulin resistance and to establish... more
California mice (Peromyscus californicus) develop type II diabetes mellitus when fed a high-fat diet. We undertook the current studies to determine whether hyperlipidemia precedes the development of insulin resistance and to establish breeding colonies of hyperlipidemic and normolipidemic mice. For 6 wk, mice (n = 24) received a diet containing 25.8% of energy from fat. Mice representing the upper and lower quartiles of serum triacylglycerol (TAG) response (mean, >1000 mg/dl versus <300 mg/dl, respectively; 6 mice per group) were designated as high (HR) and low (LR) responders, respectively, and were used for further study. After 12 wk of consuming the high-fat diet, HR mice remained hypertriglyceridemic and developed hyperinsulinemia (5.1 +/- 1.3 ng/ml), hypercholesterolemia (309.3 +/- 31.0 mg/dl), and hyperglycemia (205.9 +/- 30.3 mg/dl) compared with LR mice. HR mice were not hyperphagic or obese. Offspring of HR x HR mice had elevated serum TAG concentrations (mean, 1752.2...
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The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations... more
The use of mice in biomedical research is increasing, largely due to the production and use of genetically engineered animals. Providing postoperative pain control in mice presents many challenges, and long-acting analgesic preparations would be advantageous for this species. A single subcutaneous injection of a liposome-encapsulated (LE) preparation of oxymorphone was compared with multiple injections of buprenorphine or saline in outbred mice undergoing splenectomy. Control groups were given isoflurane alone or isoflurane and an injection of LE oxymorphone but did not undergo surgery. The following parameters were evaluated for 5 days after surgery and were compared with presurgical baseline data for each group: food and water consumption, body weight, ethographic score, and voluntary exercise on a running wheel. Ethographic scores indicated less postsurgical pain in both groups of mice that received either analgesic preparation compared with mice that received only saline. Howeve...
Research Interests:
While developing a rat model for human short bowel syndrome, we noted that untreated rats as well as rats administered buprenorphine after intestinal resection exhibited behavior and appearance consistent with visceral pain and distress.... more
While developing a rat model for human short bowel syndrome, we noted that untreated rats as well as rats administered buprenorphine after intestinal resection exhibited behavior and appearance consistent with visceral pain and distress. To provide appropriate analgesics, we developed criteria to assess pain-related behavioral changes and conducted an experiment to evaluate the effectiveness of buprenorphine versus oxymorphone to alleviate the pain induced by intestinal resection. Rats underwent either small-bowel resection or transection surgery; in addition, animals received jugular catheterization for the delivery of total parenteral nutrition (TPN). Rats treated with buprenorphine received 0.5 mg/kg every 6 h subcutaneously, and rats treated with oxymorphone received 0.03 mg/kg hourly for 32 h via continuous intravenous (i.v.) infusion with TPN solution. Rats treated with buprenorphine exhibited behavior and appearance consistent with pain and distress for as long as 32 h postop...
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Opioids have been shown to relieve thermal hyperalgesia associated with neuropathic pain. We used a novel technique to produce liposome-encapsulated hydromorphone (LEH), which we then tested in a chronic constriction injury (CCI) thermal... more
Opioids have been shown to relieve thermal hyperalgesia associated with neuropathic pain. We used a novel technique to produce liposome-encapsulated hydromorphone (LEH), which we then tested in a chronic constriction injury (CCI) thermal hyperalgesia model of neuropathic pain. Rats were divided into sham-operated and CCI groups. Treatments consisted of LEH or standard hydromorphone, administered at surgery or 3 d after surgery, when thermal hyperalgesia had developed in the CCI rats. We measured thermal withdrawal latencies on days 0, 3, and 5. CCI rats given liposome-encapsulated vehicle or standard hydromorphone at surgery developed full thermal hyperalgesia. CCI rats given LEH at surgery exhibited no significant change compared with baseline values in thermal withdrawal latency, indicating that this preparation prevented hyperalgesia after a single injection. CCI rats given LEH on day 3 (that is, after they had developed hyperalgesia) showed reversal of hyperalgesia that persiste...
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Chronic imaging of the peripheral nervous system with contemporary techniques requires repetitive surgical procedures to reopen an area of interest in order to see underlying biological processes over time. The recurrence of surgical... more
Chronic imaging of the peripheral nervous system with contemporary techniques requires repetitive surgical procedures to reopen an area of interest in order to see underlying biological processes over time. The recurrence of surgical openings on an animal increases trauma, stress, and risk of infection. Such effects can greatly lessen the physiological relevance of any data recorded in this manner. In order to bypass repetitive surgery, a Peripheral Nerve Window (PNW) device has been created for chronic in vivo imaging purposes. Intravital imaging window devices have been used previously to image parts of the rodent model such as the brain, spinal cord, and mammary tissue, but currently have not been used in the peripheral nervous system because of lack of bone anchoring and access to deep nerve tissue. We demonstrate a novel surgical technique in a rat which transposes the sciatic nerve above the surrounding muscle tissue allowing the PNW access to an 8mm section of the nerve. Subs...
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The purpose of this study was to determine the experimental side effects of liposome-encapsulated hydromorphone (LE-Hydro) in beagles and to evaluate LE-Hydro analgesia in dogs undergoing ovariohysterectomies (OVH). Beagles were injected... more
The purpose of this study was to determine the experimental side effects of liposome-encapsulated hydromorphone (LE-Hydro) in beagles and to evaluate LE-Hydro analgesia in dogs undergoing ovariohysterectomies (OVH). Beagles were injected subcutaneously with 1-3 mg/kg LE-Hydro or 0.1 mg/kg hydromorphone. Dogs were evaluated for sedation, temperature, respiratory rate, and heart rate. OVH dogs were injected with 2 mg/kg LE-Hydro subcutaneously or 0.2 mg/kg morphine and 0.05 mg/kg acepromazine intramuscularly. Side effects of LE-Hydro were within clinically acceptable limits. The analgesic efficacy was superior in dogs administered LE-Hydro at 12 hr postsurgically. LE-Hydro provided adequate, durable analgesia in dogs undergoing OVH.
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Membrane-interactive phospholipids (PLs), previously evaluated for activity against HIV-1 in vitro, are known to affect late steps in viral replication. Studies were done to determine the effects of PL analogs on post-translational... more
Membrane-interactive phospholipids (PLs), previously evaluated for activity against HIV-1 in vitro, are known to affect late steps in viral replication. Studies were done to determine the effects of PL analogs on post-translational processing of HIV-1 proteins, binding of viral surface gp160/gp120 to CD4 receptor, and HIV-1-induced cell fusion. Results of this investigation indicated that PL alone (1-octadecanamido-2-ethoxypropyl-rac-3-phosphocholine, CP-51) and PL-AZT conjugate (1-octadecanamido-2-ethoxypropyl-rac-3-phospho-3&amp;amp;#39;- azido-3&amp;amp;#39;-deoxythymidine, CP-92) have no effect on HIV-1-induced syntheses or processing of gp160/gp120, pr51, p24, or p17 (including myristoylation) in infected cells. Progeny HIV-1 particles made in CP-92-treated H9IIIB cells contained gp120, pr51, and p24; however, these virus particles had reduced capacity to bind to CD4+ cells. Both CP-51 and CP-92 inhibited syncytium (cell fusion) formation between treated HIV-1-infected cells and uninfected CD4+ cells, and, they reduced HIV-1 gp160/gp120 binding to CD4+ cells and monoclonal antibody. These results suggest that anti-HIV-1 activity of PL compounds involves alteration of cell surface membranes and viral envelopes. Phospholipid compounds are a novel class of membrane interactive compounds with potential use in blocking the spread of HIV-1 infection and pathogenesis in AIDS.
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Reports of severe enteric disease of unknown etiology affecting lactating mice have appeared in the literature. Clostridial disease similar to that seen in cattle and sheep on high-carbohydrate rations and caused by Clostridium... more
Reports of severe enteric disease of unknown etiology affecting lactating mice have appeared in the literature. Clostridial disease similar to that seen in cattle and sheep on high-carbohydrate rations and caused by Clostridium perfringens has been suspected in these mouse outbreaks but has not been isolated from affected mice. The present report describes a severe, necrotizing enterocolitis associated with overgrowth of C. perfringens type A in lactating Swiss-derived (ND4) mice. Mice nursing large litters of pups in the second week of life were the most severely affected. The organism isolated from dead or moribund mice was positive by polymerase chain reaction assay for the gene for the C. perfringens a toxin, but actual toxin production was not determined. The disease in this mouse colony was ameliorated by increasing the fat and calorie content of the diet of lactating dams, which each received 1 g peanut butter every 48 h.
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Adequate pain control is necessary for optimal postsurgical recovery and humane treatment of laboratory and companion animals. Opioid drugs are currently the most potent analgesic agents available in human and veterinary medicine.... more
Adequate pain control is necessary for optimal postsurgical recovery and humane treatment of laboratory and companion animals. Opioid drugs are currently the most potent analgesic agents available in human and veterinary medicine. Long-acting formulations of opioid drugs confer several important advantages over standard pharmaceutical preparations, especially for use in animals. A long-acting formulation of oxymorphone hydrochloride was produced by encapsulation into liposomes. Liposome-encapsulated (LE) oxymorphone was tested in a rat model of visceral postoperative pain. Rats were given one subcutaneous injection of LE oxymorphone (1.2 or 1.6 mg/kg of body weight) or standard oxymorphone (0.3 mg/kg) at the time of intestinal transection or resection. A single administration of LE oxymorphone hydrochloride was as effective for relief of postoperative pain in rats (P = 0.18), as were multiple (q4 h or q8 h) injections of 0.3 mg/kg of the standard pharmaceutical preparation. The rats...
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To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG). Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing... more
To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG). Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg. Randomized cross-over design. Each dog was given either 4.0 mg kg(-1) of ASG-oxymorphone or 8.0 mg kg(-1) of ASG-hydromorphone SC on separate occasions with a 3-month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC-MS and pharmacokinetic parameters were calculated using commercial software and non-compartmental methods. Serum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG-oxymorphone was 7.5 ng mL(-1) ; Cmax for ASG-hydromorphone was 5.7 ng mL(-1) . Oxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.
Research Interests:
Research Interests:
Psychopharmacology, Animal Behavior, Mass Spectrometry, Reward, Female, and 15 moreAnimals, Blood sampling, Male, Liposomes, High Performance Liquid Chromatography, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Rhesus Monkey, Rhesus macaques, Motor Performance, Macaca Mulatta, Side Effect, Delayed-Action Preparations, Hydromorphone, Extended release, and Motor Skills
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ABSTRACT A delayed-release formulation of liposome-encapsulated oxymorphone was produced using a novel dehydration–rehydration technique. The purpose of this study was to (i) compare the analgesic properties of this preparation with those... more
ABSTRACT A delayed-release formulation of liposome-encapsulated oxymorphone was produced using a novel dehydration–rehydration technique. The purpose of this study was to (i) compare the analgesic properties of this preparation with those of repeated injections of standard oxymorphone in rats with post-operative visceral pain and (ii) determine whether liposome-encapsulated oxymorphone differed from standard oxymorphone in duration of the effect.Visceral pain was elicited in approximately 300 g Sprague–Dawley rats by intestinal resection performed under isoflurane anesthesia. Rats were monitored with pulse oximetry; mean anesthesia time (35 ± 10 minutes) did not differ between the groups. Rats were randomly divided into two groups: Group 1 received 1.2 mg kg−1 liposome-encapsulated oxymorphone SC once at skin closure and 0.2 mL of saline SC every 4 hours; Group 2 received 0.2 mL liposome-encapsulated sucrose SC once at skin closure and 0.3 mg kg−1 standard oxymorphone SC every 4 hours. In both groups, a behavioral ethogram for pain score (grooming, porphyrin staining, body position) was recorded every 4 hours for 48 hours after surgery. Observers were blinded to the treatment. Body weight, food consumption, and urine output were recorded daily for 7 days after anesthetic recovery. Data were analyzed using anova, with significance at p &lt; 0.05.Based on the behavioral pain score, a single injection of liposome-encapsulated oxymorphone was as effective for relief of post-surgical visceral pain in rats as multiple (every 4 hours) injections of standard oxymorphone administered over a 48 hour period (p = 0.18). In rats, given one dose of liposome-encapsulated oxymorphone, the mean body weight change from day 0 to day 7 was +9.4 g, whereas rats given multiple injections of standard oxymorphone had a mean body weight change of −3.6 g over this time (p &lt; 0.01). Mean daily food consumption was significantly less in rats given multiple injections of standard oxymorphone (p &lt; 0.05). There was no difference between groups in urine production.In conclusion, a single dose of liposome-encapsulated oxymorphone was effective in treating visceral pain in rats. Rats treated with liposome-encapsulated oxymorphone had improved recovery, based on body weight changes and food consumption, compared with rats treated with multiple doses of standard oxymorphone. Liposome-encapsulated oxymorphone offered advantages including provision of effective analgesia, prolonged dosing intervals, and minimal handling stress.