Publications by authors named "William R Ravis"

13 Publications

  • Page 1 of 1

Clinical Feasibility and Airway Deposition of Nebulized Voriconazole in Healthy Horses.

J Equine Vet Sci 2020 11 3;94:103246. Epub 2020 Sep 3.

Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL. Electronic address:

Voriconazole (VRC) is a potential treatment for pneumomycosis in horses. The objectives of this study were to determine if the delivery of Vfend using a Flexineb nebulizer produced clinically significant [VRC] in lower airways. The hypothesis was that [VRC] after delivery by nebulization would be greater in the pulmonary epithelial lining fluid than plasma. A secondary objective was to determine [VRC] in upper airways through the collection of nasopharyngeal wash (NPW) samples. Voriconazole solution [Vfend-6.25 mg/mL, 100 (n = 2), 200 (n = 3), 500 (n = 1) mg] was nebulized once in 6 healthy geldings. Clinical responses, duration of nebulization, and [VRC] at various time points (up to 8 hours) in plasma, bronchoalveolar lavage fluid (BALF) supernatant and cell pellet, and NPW samples were recorded. Voriconazole (Vfend-6.25 mg/mL, 200 mg) was nebulized in 5 additional, healthy geldings, and [VRC] was measured in NPW samples pre- and postnebulization at time points up to 8 hours. The antifungal activity of BALF and NPW samples was determined using agar disk diffusion. Concentrations of voriconazole were below detection in plasma, BALF supernatant, and cell pellets for all time points and doses except the BALF cell pellet (0.4 μg/g) immediately after nebulization of 500 mg. For 5 horses, administered 200 mg of Vfend, mean [VCR] in NPW at the end of nebulization and 1, 6, and 8 hours postnebulization were: 30.8 ± 29, 1.0 ± 0.84, 0.2 ± 0.19, and 0.34 ± 0.67 μg/mL, respectively. Only NPW samples obtained immediately postnebulization showed antifungal activity. A nebulized Vfend solution is not recommended for the treatment of pneumomycosis in horses.
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http://dx.doi.org/10.1016/j.jevs.2020.103246DOI Listing
November 2020

Pharmacokinetics of multivesicular liposomal encapsulated cytarabine when administered subcutaneously in dogs.

J Vet Intern Med 2020 Jul 22;34(4):1563-1569. Epub 2020 May 22.

Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA.

Background: Prolonged cytotoxic concentrations of cytarabine (CA) are required for maximum cytotoxicity. DepoCyt is a human liposomal cytarabine (LC) product that lasts longer in plasma and CSF compared with free CA (FC). The use of LC has not been evaluated in dogs.

Objectives: To perform a LC pharmacokinetic (PK) study when administered SC in dogs.

Animals: Five healthy female beagles.

Methods: Three-period, 3-treatment, nonblinded, randomized, and crossover design, including a pilot study. LC was administered at 50 mg/m SC and FC was administered at 25 and 50 mg/m SC and IV. Plasma CA concentrations were measured until 240, 72, and 8 hours after SC LC, SC FC, and IV FC administration, respectively. CA plasma concentrations were quantitated by ultra-high-performance liquid chromatography with mass spectrometry (MS/MS) detection and concentration-time profiles were evaluated by noncompartmental analysis.

Results: Subcutaneous LC administration resulted in a maximum plasma concentration of 26.3 to 59.78 ng/mL, time to reach maximum plasma concentration of 2 hours, area under the concentration-time curve to last measurable concentration of 669.3 to 1126 h × ng/mL, and plasma bioavailability (%F) of 19.6% to 31.3%. The PK profiles of FC after SC and IV administration differed when compared with LC.

Conclusions And Clinical Importance: In healthy dogs, SC LC administration at 50 mg/m results in measurable plasma CA concentrations, is apparently safe and well tolerated, but does not result in prolonged cytotoxic plasma concentrations. Poor absorption of LC prevented establishment of a complete LC PK profile.
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http://dx.doi.org/10.1111/jvim.15809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379012PMC
July 2020

Microemulsion and Microporation Effects on the Genistein Permeation Across Dermatomed Human Skin.

AAPS PharmSciTech 2018 Nov 23;19(8):3481-3489. Epub 2018 Aug 23.

Department of Drug Discovery and Development, Auburn University, Auburn, Alabama, 36849, USA.

This study reports the microemulsion (ME) effects on the permeation of genistein across normal (intact) and microporated human skin. The genistein formulation was optimized to know the stable ME region in the pseudo-ternary phase diagrams and to maximize the skin permeation and retention of genistein. The phase diagrams were constructed with different oil phases, surfactants, and their combinations. The influence of formulation factors on the permeation through intact and microporated human skin was determined. Based on its wide ME region, as well as permeation enhancement effects, oleic acid was used as an oil phase with various surfactants and co-surfactants to further maximize the ME region and skin permeation. The water content in the formulation played an important role in the ME stability, droplet size, and flux of genistein. For example, the ME with 20% water exhibited 4- and 9-fold higher flux as compared to the ME base (no water) and aqueous suspension, respectively. Likewise, this formulation had demonstrated 2- and 4-fold higher skin retention as compared to the ME base (no water) and aqueous suspension, respectively. The skin microporation did not significantly increase the skin permeation of genistein from ME formulations. The ME composition, water content, and to a lesser extent the ME particle size played a role in improving the skin permeation and retention of genistein.
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http://dx.doi.org/10.1208/s12249-018-1150-9DOI Listing
November 2018

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

Hepatology 2018 03 30;67(3):1003-1013. Epub 2018 Jan 30.

University of Texas, Southwestern Medical Center, Dallas, TX.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] μg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting.

Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).
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http://dx.doi.org/10.1002/hep.29621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826861PMC
March 2018

Pharmacokinetics and absorption of paromomycin and gentamicin from topical creams used to treat cutaneous leishmaniasis.

Antimicrob Agents Chemother 2013 Oct 22;57(10):4809-15. Epub 2013 Jul 22.

Auburn University, Auburn, Alabama, USA.

This study evaluated the pharmacokinetics of topical creams containing 15% paromomycin ("paromomycin alone") and 15% paromomycin plus 0.5% gentamicin (WR 279,396) in patients with cutaneous leishmaniasis. The investigational creams were applied topically to all lesions once daily for 20 days. Plasma samples were analyzed for simultaneous quantitation of paromomycin and gentamicin isomers and total gentamicin. Pharmacokinetic parameters for gentamicin could not be calculated because detectable levels were rarely evident. After one application, the paromomycin area under the concentration-time curve from 0 to 24 h (AUC0-24) was 2,180 ± 2,621 ng · h/ml (mean ± standard deviation [SD]) for the paromomycin-alone group and 975.6 ± 1,078 ng · h/ml for the WR 279,396 group. After 20 days of application, the paromomycin AUC0-24 and maximum concentration of drug (Cmax) were 5 to 6 times greater than those on day 1 for both treatment groups. For the paromomycin-alone group, the AUC0-24 was 8,575 ± 7,268 ng · h/ml and the Cmax was 1,000 ± 750 ng/ml, compared with 6,037 ± 3,956 ng · h/ml and 660 ± 486 ng/ml for the WR 279,396 group, respectively. Possibly due to large intersubject variability, no differences (P ≥ 0.05) in the AUC0-24 or Cmax were noted between treatment or between sites on day 1 or 20. The percentage of dose absorbed on day 20 was 12.0% ± 6.26% and 9.68% ± 6.05% for paromomycin alone and WR 279,396, respectively. Paromomycin concentrations in plasma after 20 days of application were 5 to 9% of those after intramuscular administration of 15 mg/kg of body weight/day to adults for the systemic treatment of visceral leishmaniasis. Effective topical treatment of cutaneous leishmaniasis appears to be possible with limited paromomycin and gentamicin systemic absorption, thus avoiding drug accumulation and toxicity. (The work described here has been registered at ClinicalTrials.gov under registration no. NCT01032382 and NCT01083576.).
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http://dx.doi.org/10.1128/AAC.00628-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811440PMC
October 2013

Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model.

Drug Deliv 2010 Apr;17(3):145-51

407 Walker Building, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.

The efficacy of n-lauryl-beta-D-maltopyranoside, (dodecylmaltoside, DDM) as a permeability-enhancer for tiludronate and cromolyn (BCS Class III, water-soluble compounds with oral bioavailability < 5%) was evaluated in Caco-2 cell monolayers and rat intestinal sacs. In Caco-2 cells samples were collected over a 5-h period and transepithelial resistance (TEER) was measured concurrently. In rat intestinal sacs, samples of the test compounds and marker (Lucifer Yellow) were collected over a 40 min period; accumulation in the serosal fluid and intestinal tissue was measured. At lower concentration DDM had no effect on cromolyn permeability and a marginal increase was observed at higher concentration. Tiludronate permeability in the presence of DDM showed greater enhancement as compared to cromolyn. At higher concentration DDM appeared to cause permanent damage to the cell monolayer (irreversible change in TEER). In the intestinal tissue, DDM caused increased tissue accumulation of test compounds. This indicated that transport was not restricted to the paracellular route and damage to the intestinal tissue could not be ruled out. Based on the results obtained in this study it can be concluded that at concentrations that are non-toxic DDM appears to have a limited use to improve the oral absorption of cromolyn and tiludronate.
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http://dx.doi.org/10.3109/10717541003604882DOI Listing
April 2010

Gefitinib-cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies.

Drug Dev Ind Pharm 2009 Sep;35(9):1113-20

Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

Background: Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs).

Methods: Phase solubility studies of gefitinib with hydroxypropyl betaCD (HPbetaCD) and randomly methylated betaCD (RMbetaCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC).

Results: Gefitinib formed stable complexes with HPbetaCD and RMbetaCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M(-1) for HPbetaCD and RMbetaCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an A(N) type of phase-solubility diagrams, whereas gefitinib and HPbetaCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in A(P)-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPbetaCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC.

Conclusion: Gefitinib formed stable inclusion complexes with HPbetaCD and RMbetaCD, and the solubility and dissolution rate of the drug was significantly increased.
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http://dx.doi.org/10.1080/03639040902783074DOI Listing
September 2009

Improved delivery of cromolyn from oral proliposomal beads.

Int J Pharm 2008 Jun 6;358(1-2):128-36. Epub 2008 Mar 6.

Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.

Proliposomal bead formulations for improved oral delivery of cromolyn (BCS Class III compound) were formulated. Phospholipid (distearylphosphatidylcholine)-cholesterol-surfactant (Tween 80/sodium cholate) systems were spray-coated on beads containing cromolyn sodium and the dosage forms were characterized for vesicle formation and encapsulation efficiency. Delivery of cromolyn sodium from this novel dosage form was evaluated across the Caco-2 and everted rat intestinal sac model. Spontaneous formation of vesicles upon dilution of beads was observed. Enhancement in cromolyn transport was higher with phospholipids-surfactant proliposomal formulations compared to surfactant-free lipid formulations or pure surfactant solutions, most significant enhancement being with formulations with low surfactant concentration. No evidence of cellular damage to Caco-2 monolayers (e.g. significant decrease in the TEER) or change in transport and tissue accumulation of a marker molecule in the intestinal tissue model was observed. This indicated enhancement of transport via transcellular routes and not due to the modulation of the tight junctions or cell disruption. Results suggest that phospholipids-surfactant proliposomal beads offer a good potential for improved oral delivery of cromolyn.
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http://dx.doi.org/10.1016/j.ijpharm.2008.02.026DOI Listing
June 2008

Lack of pharmacokinetic interaction between St. John's wort and prednisone.

Ann Pharmacother 2007 Nov 9;41(11):1819-24. Epub 2007 Oct 9.

College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, USA.

Background: St. John's wort (SJW) is a popular dietary supplement involved in numerous dietary supplement-drug interactions with prescription and non-prescription drugs. The supplement has been shown to affect the metabolism of various CYP3A4 substrates. The CYP3A4 pathway mediates the metabolism of a large number of drug entities, including the corticosteroids prednisone and prednisolone.

Objective: To examine the effects of long-term SJW administration on the pharmacokinetics of prednisone and its reversible metabolite prednisolone in male subjects.

Methods: Eight male subjects participated in this single-dose study. The pharmacokinetics of prednisone and prednisolone were evaluated before and after 28 days of SJW administration. Plasma corticosteroid concentrations were determined using a normal phase high-performance liquid chromatography assay. Model-independent methods were used to evaluate corticosteroid pharmacokinetics.

Results: Twenty-eight days of SJW treatment resulted in no significant alterations in the pharmacokinetic parameters for prednisone or prednisolone. Oral administration of prednisone resulted in prednisone mean +/- SD area under the curves (AUCs) of 115.89 +/- 39.52 microg x h/L prior to SJW treatment and 128.76 +/- 32.71 microg x h/L after 28 days of treatment. Prednisolone mean AUCs were 714.19 +/- 153.29 microg x h/L before SJW administration and 700.74 +/- 89.68 microg x h/L after treatment.

Conclusions: Concurrent administration of SJW had no significant effect on the single-dose pharmacokinetics of prednisone or metabolic prednisolone in male subjects.
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http://dx.doi.org/10.1345/aph.1K316DOI Listing
November 2007

Effects of St. John's wort supplementation on ibuprofen pharmacokinetics.

Ann Pharmacother 2007 Feb 6;41(2):229-34. Epub 2007 Feb 6.

College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.

Background: St. John's wort is a popular herbal supplement that has been involved in various herb-drug interactions. Experimental findings suggest that the supplement may impact CYP2C9 metabolism. CYP2C9 is responsible for the irreversible metabolism of ibuprofen.

Objective: To examine the effect of 3 weeks of St. John's wort administration on the stereoselective pharmacokinetics of ibuprofen.

Methods: Eight male subjects participated in this study. The single-dose pharmacokinetics of ibuprofen were evaluated before and after 21 days of St. John's wort administration. Plasma ibuprofen concentrations were determined, using a stereoselective, reversed-phase HPLC assay. Model independent methods were used to evaluate the pharmacokinetics of each ibuprofen enantiomer. Data were analyzed by 2 way ANOVA testing and confidence interval testing.

Results: S(+)-ibuprofen mean +/- SD AUC and maximum concentration (C(max)) values were 131.6 +/- 26.8 microg x h/mL and 31.8 +/- 7.33 microg/mL, respectively, for control samples and 122.4 +/- 32.9 microg x h/mL and 33.6 +/- 7.83 microg/mL, respectively, after St. John's wort treatment. R(-)-ibuprofen mean AUC and C(max) values were 85.1 +/- 26.6 microg x h/mL and 28.4 +/- 8.72 microg/mL, respectively, for control samples and 87.7 +/- 30.1 microg x h/mL and 30.0 +/- 8.97 microg/mL, respectively, for St. John's wort treatment samples. St. John's wort administration resulted in no significant effects on the C(max) and AUC of either stereoisomer. A 31% decrease in S(+)-ibuprofen mean residence time (p = 0.02) was observed.

Conclusions: St. John's wort administration for 21 days had no apparent clinically important impact on the single-dose pharmacokinetic parameters of S(+)- and R(-)-ibuprofen. Although St. John's wort treatment appears to significantly reduce the mean residence time of S-ibuprofen, no ibuprofen dose adjustments appear warranted when the drug is administered orally with St. John's wort, due to the lack of significant change observed in ibuprofen AUC and C(max) for either enantiomer.
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http://dx.doi.org/10.1345/aph.1H602DOI Listing
February 2007

Pharmacokinetics of eplerenone after single and multiple dosing in subjects with and without renal impairment.

J Clin Pharmacol 2005 Jul;45(7):810-21

Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.

The influence of renal impairment on the pharmacokinetics of eplerenone following single and multiple dosing was evaluated. Subjects (n = 64) were stratified based on creatinine clearance values as follows: renal impairment (mild, moderate, severe), hemodialysis, and normal matches. Subjects received a single dose of eplerenone 100 mg on day 1 and then received 100 mg once daily on days 3 to 8. There were no statistically significant differences between any of the renal impairment groups and their matched-normal groups for area under the curve (AUC), C(max), or CL/F or CL/F/WT following either single or multiple dosing (P > or = .093). The inactive metabolite and inactive ring-opened form displayed greater AUCs in renal impairment. Hemodialysis removed approximately 10% of the eplerenone dose. Eplerenone 100 mg once daily was well tolerated in all groups. Considering that renal function had no significant effects on eplerenone CL/F and that eplerenone metabolites are inactive, no dose adjustment appears necessary in patients with renal dysfunction.
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http://dx.doi.org/10.1177/0091270005275894DOI Listing
July 2005

Pharmacokinetics of subcutaneous selenium in adult llamas.

Vet Ther 2004 ;5(4):272-8

Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, 36849, USA.

Selenium (Se) deficiency disease has been described in camelids and only clinical data is available for administration of parenteral Se supplements. This study investigated the pharmacokinetic effects of subcutaneous Se injection (0.1 mg/kg) in llamas fed a diet adequate in Se. Absorption of Se was rapid with peak whole blood Se concentration at the first sampling time. Significant differences in whole blood Se concentration from before injection of Se were not found past 2 days after Se injection. Parenteral Se is unlikely to have a long-term effect on whole blood Se concentration in llamas fed adequate dietary Se.
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March 2005

Delivery of didanosine from enteric-coated, sustained-release bioadhesive formulation.

Drug Deliv 2003 Jan-Mar;10(1):47-50

Department of Pharmacal Sciences, School of Pharmacy, Auburn University, Auburn, Alabama, USA.

The aim of our study is to assess the release characteristics, in vitro permeation, and stability of an enteric-coated, bioadhesive, sustained-release formulation of didanosine (ddI). Enteric-coated tablets of ddI, containing Polyox WSRN-303 and Methocel K4M, were prepared using hydroxypropylmethylcellulose phthalate (HPMCP 5.5). The enteric-coated formulation was resistant to dissolution in 0.1 N HCl solution but dissolved within 10 min (+/-2 min) in pH 7.4 phosphate buffered saline. The release profiles were linear with square root time. Stability studies indicate that the formulations were stable at 4 degrees C, room temperature, and 40 degrees C upon storage for 6 months. Polyox WSRN-303 tablets exhibited a higher ddI permeation ratio across live intestinal tissue compared with conventional tablets. Enteric-coated, sustained-release, bioadhesive tablets deliver ddI in small doses and at the same time prevent acid-induced degradation and hence hold a potential to improve ddI's oral bioavailability.
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http://dx.doi.org/10.1080/713840322DOI Listing
August 2003