Dr. Miller is a Board Certified Veterinary Ophthalmologist and a Clinical Professor at the School of Veterinary Medicine, University of Wisconsin-Madison. His research and clinical interests focus on glaucoma in animals and, recently, he has worked extensively with non-human primate models of glaucoma.
Observation of Silicone Oil Within the Vitreous and Sclera Following Intravitreal Administration of Biotherapeutics Using Insulin Syringes in Cynomolgus Monkeys.
Toxicol Pathol. 2020 Dec 04;:192623320966543
Authors: Huet F, Miller J, Miller PE, Hayden C, Glick JJ, Bentley A, De Benedetto C, McPherson LE, Turner OC
Silicone oil droplets have been reported in the eyes of human patients following intravitreous (IVT) injections with several marketed biotherapeutic products. Intravitreous administration of a novel biotherapeutic in a 14-week cynomolgus monkey study using insulin syringes was associated with 2, non-test-article-related phenomena: "vitreous floater/clear sphere" on indirect ophthalmoscopy and intrascleral "foreign material near injection track" on histopathology. Retrospective analysis of 81 other preclinical studies of IVT administration of novel biotherapeutics found a greater frequency of clear spheres in monkey IVT studies using insulin syringes and formulations containing polysorbate. We were able to correlate microscopic findings of clear circular to oval areas in the sclera near the injection track with an energy-dispersive X-ray spectroscopy (EDS) signal for silicon at the same location in the sclera. These observations provide further evidence that silicone lubricant in insulin syringes/needles is the source of clear spheres noted in the vitreous and foreign material noted near the injection track in the sclera. Although considered inert and toxicologically insignificant, silicone deposition within the eye should form part of the risk-benefit equation in a clinical setting.
PMID: 33272095 [PubMed - as supplied by publisher]
Medical anti-glaucoma therapy: Beyond the drop.
Vet Ophthalmol. 2020 Nov 09;:
Authors: Miller PE, Eaton JS
Barriers to effective medical therapy are numerous and include difficulties with effective and sustained control of intraocular pressure (IOP) and adherence to prescribed anti-glaucoma drop regimens. In an effort to circumvent these challenges, a number of new anti-glaucoma therapies with sustained effects have emerged. Methods for sustained delivery of prostaglandin analogs are being intensely investigated and many are in human clinical trials. Intracameral devices include the following: Allergan's Durysta™ Bimatoprost SR, Envisia Therapeutics' ENV515 travoprost implant, Glaukos' iDose™ , Ocular Therapeutix's OTX-TIC travoprost implant, and Santen's polycaprolactone implant with PGE2-derivative DE-117. Other prostaglandin-based technologies include Allergan's bimatoprost ring (placed in the conjunctival fornix), Ocular Therapeutics' OTX-TP intracanalicular travoprost implant, subconjunctival latanoprost in a liposomal formulation, and the PGE2 derivative PGN 9856-isopropyl ester that is applied to the periorbital skin. Exciting breakthroughs in gene therapy include using viral vectors to correct defective genes such as MYOC or to modulate gonioimplant fibrosis, CRISPR technology to edit MYOC or to alter aquaporin to reduce aqueous humor production, and siRNA technology to silence specific genes. Stem cell technology can repopulate depleted tissues or, in the case of Neurotech's Renexus® NT-501 intravitreal implant, serve as a living drug delivery device that continuously secretes neurotrophic factors. Other unique approaches involve nanotechnology, nasal sprays that deliver drug directly to the optic nerve and noninvasive alternating current stimulation of surviving cells in the optic nerve. Over time these modalities are likely to challenge the preeminent role that drops currently play in the medical treatment of glaucoma in animals.
PMID: 33164328 [PubMed - as supplied by publisher]
Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.
Sci Rep. 2020 May 06;10(1):7692
Authors: Abi-Gerges N, Indersmitten T, Truong K, Nguyen W, Ratchada P, Nguyen N, Page G, Miller PE, Ghetti A
Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect (sarcomere shortening) and generating multi-parameter data to profile different mechanisms of action based on cluster analysis of a set of 12 contractility parameters. We report that 17 positive and 9 negative inotropes covering diverse mechanisms of action exerted concentration-dependent increases and decreases in sarcomere shortening, respectively. Interestingly, the multiparametric readout allowed for the differentiation of inotropes operating via distinct mechanisms. Hierarchical clustering of contractility transient parameters, coupled with principal component analysis, enabled the classification of subsets of both positive as well as negative inotropes, in a mechanism-related mode. Thus, human cardiomyocyte contractility model could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for the correction of heart failure.
PMID: 32376974 [PubMed - in process]
The West coast regional safety pharmacology society meeting update: Filling translational gaps in safety assessment.
J Pharmacol Toxicol Methods. 2019 May 08;:106582
Authors: Abi-Gerges N, McMahon C, Vargas H, Sager P, Chui R, Stevens D, Davila J, Schaub JR, Wu JC, Del Rio C, Mathes C, Miller PE, Burns-Naas LA, Ghetti A
The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia. A variety of scientific topics were presented by speakers, covering a broad variety of topics in the fields of safety risk assessment; from pro-arrhythmia and contractility risk evaluation, to models of heart failure and seizure in-a-dish; and discovery sciences; from stem cells and precision medicine, to models of inherited cardiomyopathy and precision cut tissue slices. The present review summarizes the highlights of the presentations and provides an overview of the high level of innovation currently underlying many frontiers in safety pharmacology.
PMID: 31077805 [PubMed - as supplied by publisher]
Label-free imaging of atherosclerotic plaques using third-harmonic generation microscopy.
Biomed Opt Express. 2018 Jan 01;9(1):214-229
Authors: Small DM, Jones JS, Tendler II, Miller PE, Ghetti A, Nishimura N
Multiphoton microscopy using laser sources in the mid-infrared range (MIR, 1,300 nm and 1,700 nm) was used to image atherosclerotic plaques from murine and human samples. Third harmonic generation (THG) from atherosclerotic plaques revealed morphological details of cellular and extracellular lipid deposits. Simultaneous nonlinear optical signals from the same laser source, including second harmonic generation and endogenous fluorescence, resulted in label-free images of various layers within the diseased vessel wall. The THG signal adds an endogenous contrast mechanism with a practical degree of specificity for atherosclerotic plaques that complements current nonlinear optical methods for the investigation of cardiovascular disease. Our use of whole-mount tissue and backward scattered epi-detection suggests THG could potentially be used in the future as a clinical tool.
PMID: 29359098 [PubMed]
MEASURING INTRAOCULAR PRESSURE IN WHITE'S TREE FROGS (LITORIA CAERULEA) BY REBOUND TONOMETRY: COMPARING DEVICE, TIME OF DAY, AND MANUAL VERSUS CHEMICAL RESTRAINT METHODS.
J Zoo Wildl Med. 2017 Jun;48(2):413-419
Authors: Hausmann JC, Krisp A, Sladky K, Miller PE, Mans C
Ocular diseases reported in frogs include uveitis and glaucoma, which are associated with changes in intraocular pressure (IOP). The objectives of this study were to characterize the normal IOP for White's tree frogs ( Litoria caerulea ) using two types of rebound tonometers, and to assess whether time of day or method of restraint affected IOP. Eighteen conscious, unrestrained, ophthalmologically normal frogs were used to measure IOP using TonoVet® and TonoLab® tonometers, at three time points during the day. In a subset of 12 frogs, IOP was measured while under manual restraint using the TonoVet. Anesthesia was induced in 9 frogs using two different concentrations of MS-222 (0.5 g/L and 2 g/L) in order to evaluate for changes in IOP with the TonoVet. Mean (± SD) IOP values for the TonoLab (16.8 ± 3.9 mm Hg) were significantly higher than TonoVet values (14.7 ± 1.6 mm Hg; P < 0.01). TonoVet IOP values did not significantly change with time of day. TonoLab values were significantly lower in the evening (1600-1800; 14.5 ± 3.1 mm Hg), compared with morning and midday measurements (0800-1000 and 1200-1400; 18.0 ± 3.8 mm Hg; P < 0.01). Manually restrained frogs had significantly lower IOP (13.4 ± 1.5 mm Hg) compared with unrestrained frogs (15.3 ± 1.2 mm Hg; P < 0.01). Chemical restraint did not cause significant changes in IOP. Intraocular pressure can be measured with both types of rebound tonometers in White's tree frogs, but time of day and manual restraint can affect IOP values.
PMID: 28749263 [PubMed - in process]
Determination of a No-Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Dutch Belted Rabbits.
Invest Ophthalmol Vis Sci. 2017 Mar 01;58(3):1545-1552
Authors: Bantseev V, Miller PE, Bentley E, Schuetz C, Streit TM, Christian BJ, Farman C, Booler H, Thackaberry EA
Purpose: The purpose of this study was to characterize the inflammatory response and determine a no-observable effect level (NOEL) in rabbit eyes after endotoxin intravitreal (ITV) injection.
Methods: Fifty-three naïve male Dutch Belted rabbits were treated with a single 50-μL ITV injection ranging from 0.01 to 0.75 endotoxin units/eye (EU/eye) and monitored for up to 42 days post treatment. Ophthalmic examination included slit-lamp biomicroscopy and indirect ophthalmoscopy. Laser flare photometry was performed in a subset of animals. On days 2, 8, 16, and 43, a subset of animals was necropsied and eyes processed for histopathological evaluation.
Results: Intravitreal injection of endotoxin at ≥0.05 EU/eye resulted in a dose-related anterior segment inflammation response. No aqueous flare or cell response was noted in the 0.01 EU/eye dose group. A more delayed posterior segment response characterized by vitreal cell response was observed beginning on day 5, peaking on day 9, and decreasing starting on day 16 that persisted at trace to a level of 1+ on day 43. Microscopy findings of infiltrates of minimal mixed inflammatory cells in the vitreous and subconjunctiva and proteinaceous fluid in the anterior chamber and/or vitreous were observed in eyes given ≥0.1 EU/eye.
Conclusions: We defined the NOEL for ITV endotoxin to be 0.01 EU/eye, suggesting that the vitreal cavity is more sensitive to the effects of endotoxin than the anterior segment and aqueous chamber. These data highlight the importance of assessing endotoxin level in intravitreal formulations, as levels as low as 0.05 EU/eye may confound the safety evaluations of intravitreal therapeutics in rabbits.
PMID: 28282486 [PubMed - in process]
Evaluation of potential risk factors for development of primary angle-closure glaucoma in Bouviers des Flandres.
J Am Vet Med Assoc. 2017 Jan 01;250(1):60-67
Authors: Dubin AJ, Bentley E, Buhr KA, Miller PE
OBJECTIVE To evaluate potential risk factors for development of primary angle-closure glaucoma (PACG) in Bouviers des Flandres. DESIGN Prospective, observational study. ANIMALS 98 Bouviers des Flandres. PROCEDURES All dogs underwent slit-lamp biomicroscopy, indirect ophthalmoscopy, gonioscopy, applanation tonometry, streak retinoscopy, and A-scan, B-scan, and high-resolution ultrasonography. Iridocorneal angles and degree of pectinate ligament dysplasia sheeting were graded, and an angle index was mathematically derived for each eye on the basis of these values. Ciliary clefts evaluated by high-resolution ultrasonography were classified as open, narrow, or closed. Owners were contacted by telephone 7 to 9 years after the initial examination to determine whether dogs had a subsequent diagnosis of PACG. Relationships between previously recorded variables and the development of PACG were evaluated by logistic regression methods. Available pedigrees were reviewed to assess genetic relationships among affected dogs. RESULTS 9 of 92 (9.8%) dogs with follow-up information available developed PACG. An angle index < 1 and presence of a narrow or closed ciliary cleft in 1 or both eyes were each significantly associated with development of PACG. Odds of developing PACG for dogs with an angle index < 1 (indicating marked reduction in outflow capacity through the iridocorneal angle), a narrow or closed ciliary cleft in > 1 eye, or both findings were 13, 20, and 28 times those for dogs that did not have these findings, respectively. All dogs that developed PACG shared 1 common male sire or grandsire. CONCLUSIONS AND CLINICAL RELEVANCE Several anatomic factors were significant risk factors for development of PACG in this population of dogs. Results also suggested a genetic component for the disease.
PMID: 28001106 [PubMed - in process]
Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability.
Front Physiol. 2017;8:597
Authors: Britton OJ, Abi-Gerges N, Page G, Ghetti A, Miller PE, Rodriguez B
Background:In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae. Methods and Results:Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and IKr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening. Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs.
PMID: 28868038 [PubMed]
Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae.
Front Physiol. 2017;8:1109
Authors: Qu Y, Page G, Abi-Gerges N, Miller PE, Ghetti A, Vargas HM
To assess drug-induced pro-arrhythmic risk, especially Torsades de Pointe (TdP), new models have been proposed, such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs). Previously we evaluated the electrophysiological profile of 15 reference drugs in hESC-CMs and hiPSC-CMs for their effects on intracellular AP and extracellular field potential, respectively. Our findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting TdP risk. To expand our knowledge with mature human cardiac tissues for drug-induced pro-arrhythmic risk assessment, human ventricular trabeculae (hVT) from ethically consented organ donors were used to evaluate the effects of the same 15 drugs (8 torsadogenic, 5 non-torsadogenic, and 2 discovery molecules) on AP parameters at 1 and 2 Hz. Each drug was tested blindly with 4 concentrations in duplicate trabeculae from 2 hearts. To identify the pro-arrhythmic risk of each drug, a pro-arrhythmic score was calculated as the weighted sum of percent drug-induced changes compared to baseline in various AP parameters, including AP duration and recognized pro-arrhythmia predictors such as triangulation, beat-to-beat variability and incidence of early-afterdepolarizations, at each concentration. In addition, to understand the translation of this preclinical hVT AP-based model to clinical studies, a ratio that relates each testing concentration to the human therapeutic unbound Cmax (Cmax) was calculated. At a ratio of 10, for the 8 torsadogenic drugs, 7 were correctly identified by the pro-arrhythmic score; 1 was mislabeled. For the 5 non-torsadogenic drugs, 4 were correctly identified as safe; 1 was mislabeled. Calculation of sensitivity, specificity, positive predictive value, and negative predictive value indicated excellent performance. For example, at a ratio of 10, scores for sensitivity, specificity, positive predictive value and negative predictive values were 0.88, 0.8, 0.88 and 0.8, respectively. Thus, the hVT AP-based model combined with the integrated analysis of pro-arrhythmic score can differentiate between torsadogenic and non-torsadogenic drugs, and has a greater predictive performance when compared to human SC-CM models.
PMID: 29354071 [PubMed]
Calibration of the TonoVet and Tono-Pen Vet tonometers in the porcine eye.
Vet Ophthalmol. 2016 Nov 24;:
Authors: Lewin AC, Miller PE
OBJECTIVE: The pig has an increasingly important role in ocular drug delivery models, but the most accurate tonometer in this species is unknown. The purpose of this study was to evaluate the accuracy of TonoVet and Tono-Pen Vet tonometers in the ex vivo porcine eye.
PROCEDURE: Four freshly enucleated normal porcine eyes were cannulated with two 25-gauge needles; one connected via tubing to a mercury manometer calibrated continuous physiologic recorder and the other connected to a reservoir of lactated Ringer's solution on an adjustable stand. Triplicate IOP readings were taken with the TonoVet and then the Tono-Pen Vet at 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80 mmHg.
RESULTS: Linear regression showed strong linear trends for both the TonoVet (r(2) = 0.969) and Tono-Pen Vet (r(2) = 0.983). The TonoVet slightly underestimated IOP at lower pressures and slightly overestimated IOP at higher pressures (y = 1.092x - 4.0, where y = tonometer reading, x = manometer reading, and 4.0 = intercept). The Tono-Pen Vet consistently underestimated IOP (y = 0.773x - 2.1). These differences were statistically significant (P = <0.001, one-way repeated-measures ANOVA).
CONCLUSION: As in other species, both the TonoVet and Tono-Pen Vet tonometers do not measure true IOP in the porcine eye; however, the TonoVet more closely approximated true IOP in the normal porcine eye than the Tono-Pen Vet and may be the tonometer of choice for this species.
PMID: 27882675 [PubMed - as supplied by publisher]
Ocular toxicity of AUY922 in pigmented and albino rats.
Toxicol Appl Pharmacol. 2016 Oct 15;309:55-62
Authors: Roman D, VerHoeve J, Schadt H, Vicart A, Walker UJ, Turner O, Richardson TA, Wolford ST, Miller PE, Zhou W, Lu H, Akimov M, Kluwe W
AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, β-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.
PMID: 27576608 [PubMed - in process]
Bilateral Uveitis and Hyphema in a Catalina Macaw (Ara ararauna × Ara macao ) With Multicentric Lymphoma.
J Avian Med Surg. 2016 Jun;30(2):172-8
Authors: Hausmann JC, Mans C, Gosling A, Miller JL, Chamberlin T, Dunn JR, Miller PE, Sladky KK
A 20-year-old, female Catalina macaw (Ara ararauna × Ara macao ) was presented with bilateral uveitis and hyphema. The hyphema initially improved with 0.12% prednisolone acetate ophthalmic drops (1 drop OU q4h for 7 days), but the hyphema recurred after the drops were tapered. The bird subsequently developed inappetance, weight loss, regurgitation, and lethargy and was euthanatized 24 days after initial presentation. Necropsy revealed marked splenomegaly and hepatomegaly, with significant mucosal ulcerations of the proventriculus and petechiation associated with both kidneys. Histopathologic examination revealed multicentric lymphoma, with neoplastic cells observed in ocular, splenic, hepatic, renal, proventricular, intestinal, pancreatic, and choanal tissue. Neoplastic lymphocytes effaced the iris, ciliary body, and the choroid of the eyes, and neoplastic lymphocytes were attached to the corneal endothelium and infiltrated the sclera, episclera, and conjunctivae. Immunohistochemical results indicated that the neoplastic lymphocytes were CD3(+) and CD79a(-), which is consistent with T-cell lymphoma.
PMID: 27315386 [PubMed - indexed for MEDLINE]
α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors.
Gut. 2016 Feb 17;
Authors: Castro J, Harrington AM, Garcia-Caraballo S, Maddern J, Grundy L, Zhang J, Page G, Miller PE, Craik DJ, Adams DJ, Brierley SM
OBJECTIVE: α-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown.
DESIGN: We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined γ-aminobutyric acid receptor B (GABABR) and voltage-gated calcium channel (CaV2.2, CaV2.3) expression in human and mouse DRG neurons.
RESULTS: Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABABR did not. Human DRG neurons expressed GABABR and its downstream effector channels CaV2.2 and CaV2.3. Mouse colonic DRG neurons exhibited high GABABR, CaV2.2 and CaV2.3 expression, with upregulation of the CaV2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABABR antagonist prevented Vc1.1-induced inhibition, whereas blocking both CaV2.2 and CaV2.3 caused inhibition comparable with Vc1.1 alone.
CONCLUSIONS: Vc1.1-mediated activation of GABABR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABABR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.
PMID: 26887818 [PubMed - as supplied by publisher]
Human ex-vivo action potential model for pro-arrhythmia risk assessment.
J Pharmacol Toxicol Methods. 2016 Sep-Oct;81:183-95
Authors: Page G, Ratchada P, Miron Y, Steiner G, Ghetti A, Miller PE, Reynolds JA, Wang K, Greiter-Wilke A, Polonchuk L, Traebert M, Gintant GA, Abi-Gerges N
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.
PMID: 27235787 [PubMed - in process]
Clinical Signs and Diagnosis of the Canine Primary Glaucomas.
Vet Clin North Am Small Anim Pract. 2015 Nov;45(6):1183-212
Authors: Miller PE, Bentley E
The diagnosis of glaucoma is highly dependent on a working understanding of the clinical signs and available diagnostic procedures. Clinical signs may be attributable to increased intraocular pressure and/or complex alterations in the physiology or molecular biology of the anterior segment, retinal ganglion cells, and optic nerve. Many diagnostic procedures seek to more fully characterize these alterations and to identify which clinical features increase the risk of overt primary angle closure glaucoma (PACG) occurring. Considerable progress has been made in identifying the anatomic features that predispose an eye to PACG, and in elucidating the role of reverse pupillary block.
PMID: 26456752 [PubMed - in process]
Evaluation of rebound tonometry in red-eared slider turtles (Trachemys scripta elegans).
Vet Ophthalmol. 2014 Jul;17(4):261-7
Authors: Delgado C, Mans C, McLellan GJ, Bentley E, Sladky KK, Miller PE
OBJECTIVE: To evaluate feasibility and accuracy of intraocular pressure (IOP) measurement by rebound tonometry in adult red-eared slider turtles and determine the effects of manual and chemical restraint on IOP.
ANIMAL STUDIED: Seventeen adult red-eared slider turtles.
PROCEDURES: Intraocular pressure was measured with TonoLab® and TonoVet® tonometers in conscious, unrestrained turtles. To evaluate the effects of manual restraint, turtles were restrained by digital pressure on the rostral head or proximal neck. The effect of two chemical restraint protocols (dexmedetomidine, ketamine, midazolam [DKM] and dexmedetomidine, ketamine [DK] subcutaneously) on IOP was evaluated. Triplicate TonoLab® and TonoVet® readings were compared with direct manometry in three ex vivo turtle eyes.
RESULTS: TonoLab® correlated better with manometry at IOPs < 45 mmHg than TonoVet® (linear regression slopes of 0.89 and 0.30, respectively). Mean (±SD) IOP in unrestrained conscious turtles was significantly lower (P < 0.01) with TonoLab® (10.02 ± 0.66 mmHg) than with TonoVet® (11.32 ± 1.57 mmHg). Manual neck restraint caused a significant increase in IOP (+6.31 ± 5.59 mmHg), while manual rostral head restraint did not. Both chemical restraint protocols significantly reduced IOP (DKM: −1.0 ± 0.76 mmHg; DK: −1.79 ± 1.17) compared with measurements in conscious unrestrained turtles.
CONCLUSIONS: Chemical and manual neck restraint affected IOP. Rostral head restraint had no significant effect on IOP and is, therefore, recommended as the appropriate restraint technique in red-eared slider turtles. TonoLab® measurements estimated actual IOP more accurately, within physiologic range, than measurements obtained using the TonoVet®.
PMID: 25097909 [PubMed - indexed for MEDLINE]
Investigation of ocular events associated with taprenepag isopropyl, a topical EP2 agonist in development for treatment of glaucoma.
J Ocul Pharmacol Ther. 2014 Jun;30(5):429-39
Authors: Yanochko GM, Affolter T, Eighmy JJ, Evans MG, Khoh-Reiter S, Lee D, Miller PE, Shiue MH, Trajkovic D, Jessen BA
PURPOSE: Taprenepag isopropyl is an EP2 receptor agonist that is in development for the treatment of glaucoma. Iritis, photophobia, and increased corneal thickness observed in a Phase 2 clinical trial with taprenepag isopropyl were not previously observed in topical ocular toxicity studies in rabbits and dogs. In vivo studies using cynomolgus monkeys and in vitro models were used to elucidate the mechanisms underlying these ocular events.
METHODS: Monkeys were dosed daily for 28 days in 1 eye with taprenepag and in the other with vehicle control. Complete ophthalmic examinations were performed at baseline and weekly thereafter. Serial sections of eyes were examined histopathologically at the end of the study. Recovery after the discontinuation of taprenepag was assessed for 28 days in the monkeys in the high-dose group. In vitro studies evaluated cell viability, paracellular permeability, and cytokine induction with human corneal epithelial or endothelial cell cultures.
RESULTS: Monkeys demonstrated a dose-related incidence of iritis and increased corneal thickness that resolved within 28 days of discontinuing taprenepag. There was no evidence in vivo of taprenepag toxicity to the corneal endothelium or epithelium. Cell viability of stratified epithelial cells was primarily affected by excipients and was similar to Xalatan(®). The viability of HCEC-12 cells was not affected by taprenepag at concentrations up to 100 μM.
CONCLUSIONS: The lack of in vivo or in vitro endothelial cytotoxicity and the reversibility of the increase in corneal thickness and iritis in the monkey provide confidence to permit further clinical development of taprenepag.
PMID: 24720348 [PubMed - indexed for MEDLINE]
The effect of topical latanoprost on anterior segment anatomic relationships in normal dogs.
Vet Ophthalmol. 2013 Sep;16(5):370-6
Authors: Tsai S, Almazan A, Lee SS, Li H, Conforti P, Burke J, Miller PE, Robinson MR
OBJECTIVE: Topical latanoprost 0.005% is commonly used in dogs with primary angle closure glaucoma (PACG), and marked miosis has been reported in the literature. To further explore the effect of topical latanoprost on anterior segment anatomy, we performed iridocorneal angle biometrics in normal beagle dogs.
METHODS: Thirty-five normal female beagle dogs were assessed using anterior segment optical coherence tomography (AS-OCT). One eye of each dog was scanned with the AS-OCT in the superotemporal quadrant. One drop of latanoprost 0.005% was applied topically, and the OCT scan was repeated 30 min later. Images were imported into ImageJ, and pupil diameter, anterior chamber angle, angle opening distance, angle recess area (ARA), anterior chamber hemifield, and anterior chamber depth were measured.
RESULTS: A single drop of latanoprost resulted in marked miosis, anterior bowing of the peripheral iris, narrowing of the iridocorneal angle, and shallowing of the anterior chamber. The anterior segment parameters demonstrated a significant reduction (P-value ≤ 0.001) from baseline following latanoprost with the exception of the ARA (P = 0.07).
CONCLUSIONS: Latanoprost significantly decreases pupil diameter and narrows the iridocorneal angle in normal female beagle dogs. Therefore, the utility of latanoprost as a prophylactic treatment for PACG in fellow eyes may be limited. Studies using quantitative iridocorneal angle measurements in goniodysgenic dogs are warranted to understand the changes in iridocorneal angle morphology that occur in PACG in response to topical application of latanoprost.
PMID: 23227993 [PubMed - indexed for MEDLINE]
Iridocorneal angle measurements in mammalian species: normative data by optical coherence tomography.
Vet Ophthalmol. 2013 Mar;16(2):163-6
Authors: Almazan A, Tsai S, Miller PE, Lee SS, Vilupuru AS, Burke JA, Robinson MR
Objective Gonioscopy provides limited quantitative information to compare the iridocorneal anatomy across different species. In addition, the anatomic relationships by histologic examination are altered during processing. As a result, the comparative anatomy of the iridocorneal angle across several mammalian species was evaluated by Optical Coherence Tomography (OCT). Methods Cats, beagle dogs, minipigs, owl monkeys, cynomolgus monkeys, and rhesus monkeys (n = 6 or 7 per species) were evaluated. Imaging was performed using the OCT. The anterior chamber angle (ACA), angle opening distance (AOD), and the angle recess area (ARA) were evaluated. Results AC angle: cat (63 ± 6°) > owl monkey (54 ± 4°) > beagle dog (42 ± 4°) > minipig (40 ± 3°) > rhesus monkey (36 ± 1°) > cynomolgus monkey (34 ± 2°). AOD: cat (3.3 ± 0.5 mm) > owl monkey (2.05 ± 0.2 mm) > beagle dog (1.08 ± 0.1 mm) > rhesus monkey (0.92 ± 0.06 mm) > minipig (0.64 ± 0.04 mm) > cynomolgus monkey (0.43 ± 0.03 mm). ARA: cat (3.5 ± 0.1 mm(2) ) > owl monkey (1.41 ± 0.2 mm(2) ) > dog (0.88 ± 0.1 mm(2) ) > rhesus monkey (0.62 ± 0.06 mm(2) ) > minipig (0.21 ± 0.05 mm(2) ) > cynomolgus monkey (0.15 ± 0.01 mm(2) ). Conclusions This study benchmarks the normative iridocorneal angle measurements across different mammalian species by OCT. These data can be useful to compare iridocorneal angle measurements in disease states as OCT evolves as a common diagnostic tool in veterinary ophthalmic research and practice.
PMID: 22612298 [PubMed - indexed for MEDLINE]
Topical application of 0.005% latanoprost increases episcleral venous pressure in normal dogs.
Vet Ophthalmol. 2012 Mar;15 Suppl 1:71-8
Authors: Tsai S, Miller PE, Struble C, Howard S, Almazan A, Burke JA, Hughes PM, Li H, Conforti P, Lee SS, Robinson MR
INTRODUCTION: Episcleral venous pressure (EVP) has an important role in intraocular pressure (IOP) homeostasis and accounts for more than 70% of the IOP in the normal dog. A frequently used species in glaucoma research is the normotensive dog especially when evaluating the efficacy of prostaglandin analogues and prostamides; however, aqueous humor dynamic studies in normal dogs are lacking, and the effect of 0.005% latanoprost on canine EVP is not known. We sought to determine the effects to the EVP of topically applied 0.005% latanoprost in the normotensive beagle dog.
METHODS: Female beagle dogs (n = 14) were used and each had a normal ophthalmic examination on study entry. EVP was determined using a standard episcleral venomanometer. Animals were dosed in one eye with 0.005% latanoprost, and the effects on EVP were compared with the averaged baseline EVP's determined in the predosing phase and the fellow nondosed eye. The Mixed Model Repeated Measures method was used to analyze the EVP data.
RESULTS: During the dosing phase of the study with topical 0.005% latanoprost, the mean EVPs of dosed eyes were significantly higher than that of nondosed eyes (P < 0.0001).
CONCLUSIONS: The increase in EVP in the dog with exposure to topical 0.005% latanoprost has not been observed in other species that have been studied, such as in the mouse and in humans, where the drug had no significant effect on the EVP. This response may be unique to dogs and suggests that dogs may not fully mimic human aqueous humor dynamics with topical 0.005% latanoprost. Although frequently performed in human studies, EVP should not be regarded to be a constant value in aqueous humor dynamic studies in the normal beagle dog.
PMID: 22129101 [PubMed - indexed for MEDLINE]
Feline glaucoma--a comprehensive review.
Vet Ophthalmol. 2011 Sep;14 Suppl 1:15-29
Authors: McLellan GJ, Miller PE
Cats with glaucoma typically present late in the course of disease. It is likely that glaucoma in cats is under-diagnosed due to its insidious onset and gradual progression, as well as limitations of some commonly used tonometers in this species. Treatment of glaucoma in feline patients presents a clinical challenge, particularly as glaucoma is often secondary to other disease processes in cats. In this review, we consider the clinical features, pathophysiology, and classification of the feline glaucomas and provide current evidence to direct selection of appropriate treatment strategies for feline glaucoma patients.
PMID: 21923820 [PubMed - indexed for MEDLINE]
Effects of topical administration of latanoprost, timolol, or a combination of latanoprost and timolol on intraocular pressure, pupil size, and heart rate in clinically normal dogs.
Am J Vet Res. 2010 Sep;71(9):1055-61
Authors: Smith LN, Miller PE, Felchle LM
OBJECTIVE: To determine effects after topical administration of latanoprost, timolol, or a commercially available latanoprosttimolol combination twice daily on intraocular pressure (IOP), pupil size (PS), and heart rate (HR) in clinically normal dogs.
ANIMALS: 17 clinically normal dogs.
PROCEDURES: A randomized controlled clinical trial was performed with a treatment (n=9) and saline (0.9% NaCl) solution group (8). Each dog in the treatment group received 3 treatments (latanoprost, timolol, and the latanoprost-timolol combination), with a 14-day washout period between treatments. Baseline values were established on day 1 of each treatment period. On days 2 through 5, drugs were administered topically every 12 hours to 1 eye of each dog in the treatment group. In both groups, IOP PS, and HR were measured at 0, 2, 4, 6, 8, and 9 hours on days 2 and 5.
RESULTS: Eyes treated with latanoprost or the latanoprost-timolol combination had a significant decrease in IOP and a significantly smaller PS, compared with results for dogs receiving only timolol or dogs in the saline solution group. Timolol and the latanoprost-timolol combination both significantly lowered HR, compared with HR following administration of latanoprost and the saline solution.
CONCLUSIONS AND CLINICAL RELEVANCE: Topical administration of latanoprost alone was as effective at lowering IOP as was administration of the latanoprost-timolol combination when both were given every 12 hours to clinically normal dogs. Timolol, either alone or in combination with latanoprost, appeared to have little or no effect on IOP in clinically normal dogs but was associated with a reduction in HR.
PMID: 20807145 [PubMed - indexed for MEDLINE]
Surgical extraction of an intraocular infection of Parelaphostrongylus tenuis in a horse.
J Am Vet Med Assoc. 2010 Jul 15;237(2):196-9
Authors: Reinstein SL, Lucio-Forster A, Bowman DD, Eberhard ML, Hoberg EP, Pot SA, Miller PE
CASE DESCRIPTION: A 4-year-old Hanoverian gelding was evaluated because of a mobile worm-like structure in the right eye.
CLINICAL FINDINGS: Ophthalmologic examination of the right eye revealed a white, thin, coiled, mobile parasite, which was presumed to be a nematode, located in the ventral portion of the anterior chamber of the eye; there also were vitreal strands located temporally and inferiorly near the margin of the pupil. Results of ophthalmologic examination of the left eye were unremarkable.
TREATMENT AND OUTCOME: The horse was treated with a neomycin-polymyxin B-dexamethasone ophthalmic solution applied topically (1 drop, q 8 h) to the right eye and penicillin V potassium (22,000 U/kg [10,000 U/lb], IV, q 6 h). The horse was anesthetized. A stab incision was made in the cornea, and a viscoelastic agent was infused around the parasite. The parasite was extracted via the incision by use of an iris hook and tying forceps. The horse had an uncomplicated recovery from the procedure and retained vision in the right eye. Gross and microscopic examination was used to identify the parasite as an adult metastrongyloid nematode consistent with a fully developed male Parelaphostrongylus tenuis.
CLINICAL RELEVANCE: To the authors' knowledge, this is the first report of intraocular parelaphostrongylosis in a horse. This report provided evidence that vision could be retained after treatment for intraocular P tenuis infection in a horse.
PMID: 20632794 [PubMed - indexed for MEDLINE]