Browsing by Author "Davis, Jennifer Lynn"
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- Aqueous humor concentration and prostaglandin E2 suppression efficacy of topically applied ophthalmic ketorolac 0.5% and diclofenac 0.1% solutions in dogs with cataractWaler, Kayla A. (Virginia Tech, 2020-06-01)Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, anti-pyretic and anti-inflammatory properties in both human and veterinary patients. Topical ophthalmic NSAIDs are commonly employed in the management of intraocular inflammation (uveitis), corneoconjunctival inflammatory disease and pre-operatively to prevent intraoperative miosis during cataract surgery. Despite their routine application in these clinical scenarios, little is known regarding the corneal penetration and relative anti-inflammatory efficacy of the available topical ophthalmic NSAIDs in the dog. Decisions regarding which of these agents to employ are therefore based upon factors such as cost and ease of acquisition as opposed to established efficacy. Objectives: To investigate the relative intraocular penetration and anti-inflammatory efficacy of two commonly utilized topical ophthalmic NSAIDs in dogs, diclofenac 0.1% and ketorolac 0.5%. Animals: Twenty-two client owned dogs (22 operated eyes) presenting to the VTH ophthalmology service for routine cataract surgery for mature or hypermature cataract. Methods: Subjects were randomized to be treated with either topical ketorolac 0.5% or topical diclofenac 0.1% ophthalmic solutions at specified times in the 24-hour period pre-operatively. Aqueous humor samples were obtained intra-operatively and stored for subsequent evaluation of drug concentrations and prostaglandin E2 (PGE2) concentrations via ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) and enzyme-linked immunoassay (ELISA) analysis, respectively. Results: Median aqueous humor drug concentrations were significantly higher in dogs treated with ketorolac 0.5% (1311.6 ng/mL) compared to those treated with diclofenac 0.1% (284.9 ng/mL). There was no significant difference in aqueous humor PGE2 concentrations between the two treatment groups. No significant association was determined between aqueous humor drug concentration and PGE2 concentration. There was no significant association between diabetic status and aqueous humor drug concentration or PGE2 concentration in either group. Conclusions and clinical importance: This study suggests that topical ketorolac 0.5% and diclofenac 0.1% are efficacious in decreasing aqueous humor PGE2 concentrations and are equally suitable for use based on their comparable anti-inflammatory profiles. The results of these assays provide clinically relevant information regarding intraocular penetration and anti-inflammatory efficacy of these medications in dogs with cataract.
- The Clinical Pharmacology of Acetaminophen in Adult HorsesMercer, Melissa Ann (Virginia Tech, 2022-08-18)Non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay of the management of pain and inflammation associated with musculoskeletal disorders and systemic inflammation in horses. The most utilized NSAIDs in equine practice are non-selective cyclooxygenase (COX) inhibitors, such as flunixin meglumine and phenylbutazone, which act through global inhibition of prostaglandin synthesis and release. While non-selective COX inhibitors are effective as anti-inflammatory agents, they are mired with complications with prolonged or high-dose use, particularly in critically ill patients. Therefore, non-selective COX-inhibitors have been displaced by selective COX-2 inhibitors for many practitioners due to the perceived reduced risk of gastrointestinal complications. It should be noted, however, that the use of COX-2 selective inhibitors in horses is not without risk. Due to the potential for significant adverse events in horses with critical illness treated with traditional NSAIDs, there is clinical need for safe, and effective anti-inflammatories and anti-pyretics for administration in these patients. The studies presented in this dissertation explore the pharmacokinetics, efficacy, and safety of acetaminophen in adult horses for use in musculoskeletal pain and pyrexia. In the first study, the pharmacokinetics and efficacy of oral acetaminophen at two different doses (20 mg/kg and 30 mg/kg) were examined in an experimentally induced lameness model and the analgesic efficacy of acetaminophen was compared to placebo and the non-selective COX inhibitor phenylbutazone. Acetaminophen when administered at 30 mg/kg produced a more rapid onset of greater improvement in subjective lameness scores and heart rate compared to other treatments in this model, and therefore would be more suitable as a monotherapy than acetaminophen dosed at 20 mg/kg. Acetaminophen dosed at 30 mg/kg resulted in a more rapid improvement in lameness scores than phenylbutazone at 2.2 mg/kg and was equivalent to phenylbutazone in lameness score reduction. However, results of this study necessitated further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg orally every 12 hours to determine clinical utility. In the second study, the pharmacokinetics, efficacy, and safety of oral acetaminophen (30 mg/kg) were examined in adult horses with naturally occurring chronic lameness. In that study, following 21 days of twice daily oral dosing at 30 mg/kg, acetaminophen was found to be safe with no evidence of gastric ulceration or hepatopathy in horses. Acetaminophen at 30 mg/kg twice daily for 21 days provided transient improvement in subjective and objective lameness evaluation when compared to baseline evaluation; however, the study concluded that acetaminophen may not be suitable as a monotherapy for management of moderate to severe orthopedic pain in horses In the third study, the pharmacokinetics and efficacy of oral acetaminophen (30 mg/kg) was examined in adult horses with experimentally induced endotoxemia when compared to placebo and the nonselective COX inhibitor flunixin meglumine. That study found that acetaminophen was superior to placebo and not statistically different from flunixin meglumine in reducing rectal temperature in adult horses with experimentally induced endotoxemia and may be an option for antipyresis in clinical cases, particularly when administration of traditional NSAIDs is contraindicated. Furthermore, acetaminophen administered at 30 mg/kg orally to adult horses with experimentally induced endotoxemia is an effective antipyretic but is unlikely to provide any alteration in systemic inflammatory response.
- Investigating MCE Chemical Library Drugs for Combinational Therapies for Clinical Aspergillus fumigatus isolatesBurns, Nicolas Dale (Virginia Tech, 2023-12-20)Aspergillus fumigatus is a globally present pathogen capable of inflicting debilitating and life-threatening opportunistic infections in individuals, primarily those who are immunocompromised. Diagnosing A. fumigatus infections is often difficult, leading to a delay in treatment which can greatly impact patient outcomes. Furthermore, our lessening of antifungal development combined with increasing resistance generates a feasible scenario where only last resort options are viable. This has prompted the World Health Organization (WHO) to declare this pathogen a "critical priority" due to increased resistance and rising mortality rates. Azoles are utilized as primary treatment options for Aspergillus fumigatus infections such as voriconazole (VRC), itraconazole (ITC), and posaconazole (POS) with a reserve of Amphotericin B (AmB). In the past two decades, the emergence of resistance to azoles has contributed to a 90% mortality rate in resistant cases globally. In this report, we investigated the MedChem Express (MCE) Drug Repurposing Compound Library (4,226 compounds) in conjunction with itraconazole at 0.06 µg/mL against A. fumigatus CDC #738. After the initial screening, we identified compounds known to be antifungals or antiseptics and deselected them. The remaining thirty selected compounds were evaluated through published literature and clinical trial data to determine those candidates with favorable characteristics/properties. Criteria for candidate selection consisted of evaluating the compounds; plasma concentration peak, the time to reach peak, protein binding, oral availability, and drug class. Six candidates were ranked the highest of the previous round –surprisingly 50% of those compounds were HIV drugs, cobicistat, elvitegravir, lopinavir. The remaining three selected compounds are penfluridol, rilapladib, and rolapitant. The combination of itraconazole (ITC), posaconazole (POS), and voriconazole (VRC), with the identified compounds demonstrated promising amounts of synergy, in resistant and susceptible isolates. Further investigation revealed novel properties of ITC and POS when in combination with our compounds of interest. Rilapladib was able to reverse POS, ITC, and VRC resistant strain(s) to a sensitive profile. Growth kinetic assays demonstrate potent anti-germination properties not seen before in the sub-inhibitory doses of azoles. This work demonstrates that high-throughput screening as a viable technique to identify robust antifungal synergizers, allowing for tenable translation to a clinical setting.
- Pharmacokinetics and pulmonary distribution of Draxxin® (tulathromycin) in healthy adult horsesLeventhal, Hannah Rani (Virginia Tech, 2021-10-13)The objective of this study was to determine the pharmacokinetics and tolerance of tulathromycin (Draxxin®; 2.5 mg/kg once) after intramuscular (IM), subcutaneous (SC), and slow intravenous (IV) administration to six adult horses. A three-phase design and 4-week washout period were used. Drug concentrations in blood and bronchoalveolar lavage (BAL) samples were determined by ultra-performance liquid chromatography tandem mass spectrometry and pharmacokinetic parameters calculated using noncompartmental analysis. Following SC and IM administration, all horses exhibited sweating, discomfort, and periods of recumbency. As signs were more severe after SC administration this route was only used in 3/6 horses. Intravenous administration of tulathromycin was well tolerated in all horses. Mean bioavailability was 99.4% IM and 115% SC. Mean maximum plasma concentration was 645 ng/ml IM and 373 ng/ ml SC. Mean half-life was 59.8 h, 54.8 h, and 57.9 h for IV, IM, and SC administration, respectively. Mean clearance was 3.25 ml/kg/min, and mean volume of distribution was 16.8 L/kg following IV administration. Drug was detectable in plasma and BAL samples for 120 h following all routes; however, adverse effects may prevent IM use and SC use is not recommended. Tulathromycin may be a practical and affordable antibacterial for use in adult equine patients.
- Pharmacokinetics and Safety of Acetaminophen in Adult HorsesMercer, Melissa Ann (Virginia Tech, 2018-10-15)Due to the detrimental side effects of NSAID administration, such as gastrointestinal ulceration and renal papillary necrosis, there is a profound need for clinical pain relief in horses with long term orthopedic disease whereby gastrointestinal side effects are obviated. Acetaminophen is one of the most commonly used analgesic drugs in humans, and is readily available as an inexpensive generic over-the-counter preparation. Acetaminophen has a number of mechanisms of action that differ from NSAIDs, including actions on the serotonergic, opioid, endocannabinoid and lipoxygenase pathways. These alternate pathways may provide greater efficacy against chronic or neuropathic pain in equine patients. Acetaminophen was preferred by physicians over COX-2 and nonselective NSAIDs, even when those drugs were coupled with proton-pump inhibitors to reduce gastrointestinal side effects; due to cost considerations and the occurrence of adverse side effects from those drugs. In horses, acetaminophen has been reported to be efficacious as an adjunct treatment for laminitis in one pony, and was an effective analgesic agent when combined with NSAIDs in a model of inducible foot pain. However, no studies have been performed to validate a dose-response curve in horses. A study recently completed by our group demonstrated rapid absorption following oral administration of acetaminophen. Reported human therapeutic plasma concentrations were achieved within 30 minutes of administration, with no clinical or clinicopathologic evidence of adverse side effects after two weeks of repeated dosing. Dose simulation trials indicate that a change in dosage schedule may be required in order to provide adequate plasma concentrations.
- Pharmacokinetics of a high-concentration formulation of buprenorphine (Simbadol®) in male dogsHansford, Jeremy Dustin (Virginia Tech, 2021-07-28)Objective: To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine. Study design: Prospective, randomized, crossover study. Animals: A total of six healthy male intact Beagle dogs, 9–13 months of age and weighing 10.3 ± 1.4 kg (mean ± standard deviation). Methods: Dogs were randomized to be administered buprenorphine (0.12 mg kg−1; Simbadol, 1.8 mg mL−1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry. Results: A 3-compartment model with zero or biphasic rapid and slow first order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg−1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute−1 kg−1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minutes delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239) %. Calculated terminal half-life was 963 minutes. Conclusions and clinical relevance: The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues.
- The Pharmacokinetics of Firocoxib after Multiple Oral Doses to Neonatal FoalsHovanessian, Natasha (Virginia Tech, 2012-07-05)The purpose of this study was to determine the safety and pharmacokinetic profile of firocoxib in healthy neonatal foals. Foals are more sensitive to the side effects of nonsteroidal anti-inflammatory drugs, (NSAIDs), particularly due to immature renal clearance mechanisms and ulcerogenic effects on gastric mucosa. Firocoxib, a novel second generation NSAID, is reported to have reduced side effects due to its COX-2 selectivity. The pharmacokinetic profile of firocoxib in neonates has not been established, making reliable dosing difficult. We hypothesized that firocoxib given per os at the labeled dose to neonatal foals would be absorbed and not be associated with clinically significant adverse events. Seven healthy American Quarter Horse foals of mixed gender were administered 0.1mg/kg firocoxib orally q24h for nine consecutive days, commencing at 36h of age. Blood samples were collected for firocoxib analysis using high pressure liquid chromatography with fluorescence detection at 0 (dose #1 only), 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours after doses #1, 5 and 9. For all other doses (2, 3, 4, 6, 7 and 8) blood was collected immediately prior to the next dose (24 hour trough). Elimination samples (36, 48, 72, 96, 120 and 144 hours) were collected after dose #9. Safety was assessed via physical examinations, changes in body weight, gastroscopy, complete blood count, serum biochemistry and urinalysis. Firocoxib was rapidly absorbed following oral administration with minimal accumulation after repeat dosing. After the initial dose, an average peak serum concentration (Cmax) of 89.50 ° 53.36 ng/mL (mean ° SD) was achieved (Tmax) in 0.54 ° 0.65 hours. Steady state was obtained after approximately 4 doses and the average maximum concentration (Cavg) in serum was 39.1 ° 8.4 ng/mL. After the final dose, the mean terminal half-life (T½?») was 10.46 ° 4.97 hours. Firocoxib was not detected in plasma 72 hours after the final dose (<2ng/mL). Bioavailability could not be determined as currently, there is no accompanying intravenous dose of firocoxib for this age group to permit the calculation. No significant abnormalities were noted on blood work, urinalysis or gastroscopy. This study demonstrated that firocoxib is absorbed after oral administration in neonatal foals with no observable adverse effects after multiple doses.
- Single dose pharmacokinetics of pimobendan in healthy horsesJula, Catherine Antonia (Virginia Tech, 2024-08-27)Few drugs are available to treat congestive heart failure and other cardiac diseases in horses. Pimobendan is an inodilator drug approved as Vetmedin® for treatment of canine cardiac disease. Previous research shows that pimobendan increases heart rate and contractility following intravenous administration in horses. The pharmacokinetics of oral pimobendan have not been investigated in horses. The hypothesis of this study was that pimobendan would be absorbed following oral administration to healthy adult horses and reach concentrations known to be therapeutic in other species. Additional objectives were to compare the absorption of compounded pimobendan capsules (C) and suspension (S) to Vetmedin® (V) and determine the effects of sample site on plasma drug concentrations in a pilot study using two horses. These two horses received C, S, or V (0.5 mg/kg via oral syringe, once) following a minimum 10 hour fast, using a crossover design with a minimum 1-week washout period. Samples were collected simultaneously from lateral thoracic and jugular catheters before and after drug administration at predetermined time points. Differences between formulation and sample site were analyzed by one-way ANOVA. After evaluation of the data from the initial 2 horses, an additional 4 horses received pimobendan, in the form of Vetmedin tablets® (V), in a similar manner. Only jugular samples were collected at the same predetermined time points. Plasma concentrations were determined by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pharmacokinetic parameters determined by noncompartmental analysis. No significant differences were noted between formulations or sample site (P < 0.05). Concentrations in compounded formulations were 88%(S) and 90%(C) of label. For V, mean (±SD) maximum plasma concentration (Cmax) was 4.96 ± 2.13 ng/mL at 2.17 ± 0.98 hours, and area under the curve (AUC0-∞) was 22.1 ± 8.8*ng/mL. Concentration of the active metabolite of pimobendan, o-desmethyl-pimobendan, was below the limit of detection (0.07ng/mL) for all samples. At 0.5mg/kg orally, pimobendan plasma concentrations were considerably lower than reported in dogs and other species. There was no evidence of oral transmucosal absorption. Pimobendan was poorly absorbed in horses, regardless of formulation, and appears unlikely to have clinical effects.
- Small Therapeutic Peptides: In vitro pharmacokinetics of alpha-carboxyl terminus 11 peptide in rat plasmaTasdemiroglu, Yagmur (Virginia Tech, 2021-06-04)Cardiovascular diseases affect one third of the U.S. population and are the number one cause of death globally. Acute myocardial infarction is one of the most catastrophic cardiovascular diseases that permanently alters patient's lives. Small molecule drugs, surgery, medical devices and lifestyle changes are the current treatment methods that only address symptoms and fail to cure cardiovascular disorders. Small therapeutic peptides are emerging methods to treat diseases ranging from cancer to auto-immune disorders. Due to their nature, they are non-toxic, non-immunogenic, biocompatible and highly target specific. However, because of their small size and lack of tertiary structure, they have a very short half-life. Alpha-carboxyl terminus 11 peptide (αCT11) is a 9 amino acid long small peptide that has shown to promote left ventricular function recovery when mouse hearts are perfused with the peptide prior to an ischemia-reperfusion injury. This study investigates the in vitro pharmacokinetics of αCT11 in rat plasma in the presence of protease and phosphatase inhibitor cocktails to provide a method to delay its degradation and to understand the degradation pattern of the peptide in vitro. The effect of time, temperature, presence of inhibitors and sex are investigated. Results have shown that while sex does not have a significant effect on αCT11 degradation, time and temperature significantly promote its degradation. Utilization of inhibitors also leads to a pronounced delay in αCT11 degradation, as the amount of αCT11 remaining in plasma increases from almost undetectable to 15-16% upon introduction of inhibitors. These results indicate that αCT11 degradation can be delayed significantly when inhibitor cocktails are used, bringing αCT11 closer to being used in a clinical setting to address ischemia-reperfusion injuries.