Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs

Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs Suk-kyu Koh, Jong-Woo Jeong, Seo-In Choi, Rae-Man Kim, Tae-Sung Koo, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-403597/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Furosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal patients, which leads to noncompliance, especially during long-term administration. The oral disintegrating film (ODF) has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The objective of this study was to research the pharmacokinetic and pharmacodynamics (PK/PD) profiles of furosemide after intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered a single dose (2 mg/kg) of furosemide via each route using a cross-over design. Results: The most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. The maximum plasma concentration of furosemide was higher and the elimination half-life and time at maximum concentration were slightly lower after FS-ODF administration than after OUT administration. In the blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h), whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF). Conclusions: These results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (<10 kg) or cats, for the management of congestive heart failure. Large Animal Medicine Small Animal Medicine Canine Furosemide Loop diuretic Oral film Tablet Conventional administration Congestive heart failure Diuresis Noncompliance Figures Figure 1 Figure 2 Figure 3 Background Furosemide, a diuretic commonly used in veterinary and human medicine, is recommended as first-line therapy in the management of congestive heart failure (CHF) ( 1 , 2 ). It is used in animals for the treatment of pulmonary edema, udder edema, hypercalciuric nephropathy, uremia, and hypertension. Additionally, it reduces the incidence of sterile hemorrhagic cystitis associated with cyclophosphamide administration in dogs and is used as adjunctive therapy in hyperkalemia ( 2 – 10 ). The PK/PD properties of loop diuretics, including furosemide after IV and PO administration, have been well investigated in both human and veterinary medicine ( 5 , 8 , 11 – 14 ). Furosemide decreases the absorption of electrolytes in the luminal surface of the thick ascending loop of Henle via the deactivation of the Na + -K + -2Cl − cotransporter. Thus, this drug increases the renal excretion of sodium, potassium, chloride, and water ( 8 ). Additionally, furosemide causes renal venodilation, increases glomerular filtration rate, increases renal blood flow, and decreases peripheral resistance. Furthermore, furosemide activates the renin-angiotensin-aldosterone-system and sympathetic nervous system ( 15 – 17 ). Although furosemide increases renin secretion, owing to its effects on the nephron, increases in sodium and water retention do not occur ( 8 ). The conventional routes of furosemide administration are intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (PO). Unless an acute heart failure event occurs, PO administration is indicated in most cases that require long-term use in stable patients ( 8 , 9 , 18 ). The onset time (IV, 5 min), elimination half-life (IV, 1–1.5 h), duration (IV, 3–6 h), and peak urine output (IV and SC, 1 h; PO, 2 h) of furosemide have been shown in previous experiments in dogs ( 8 ). However, some owners have difficulty administering oral tablet medications, which leads to noncompliance, especially with drugs that require long-term administration. Particularly with cats, it is often difficult to administer pills or capsules. Beyond the conventional administration routes and formulations, studies have been conducted to identify options with similar efficacy that can be easily administered. For human cardiac disease, these studies have led to the development of the sildenafil citrate sublingual tablet to treat pulmonary arterial hypertension, nitroglycerin ointment to treat CHF, transdermal tulobuterol patch for bronchodilation, and transdermal beta-blocker (bisoprolol) patch to reduce postoperative atrial fibrillation ( 19 – 22 ). The oral disintegrating film (ODF) offers several benefits especially in children, including easy administration via a non-invasive route, fast dissolution, and no risk of choking ( 23 ), that also can be utilized in veterinary medicine. Moreover, sublingual and oral furosemide administration differ in pharmacokinetic and pharmacodynamic (PK/PD) results in humans ( 11 ); the sublingual route may provide therapeutic advantages over the oral route, especially in patients with CHF. In veterinary medicine, there is a study on the diuretic effect of furosemide according to the IV, SC, PO, and constant rate infusion (CRI) routes in dogs ( 18 ). The study on furosemide administration using sublingual bioadhesive film showed ex vivo mucoadhesion using the buccal mucosa and permeability using the tongue excised from slaughtered pigs ( 24 ). And the alternative route of administration of furosemide have not been reported except for a study that the therapeutic effect of the transdermal application of furosemide to cats is negligible compared to that after oral and IV administration ( 7 ). However, there are no announced studies on alternative administration routes in dogs. Despite there is a need for formulations that can be safely administered to and easily absorbed by animals, ODFs for use in dogs (especially small dogs) and cats have not been developed. The purpose of this study was to compare the PKs and diuretic effect of furosemide after newly developed furosemide-loaded ODF (FS-ODF), conventional oral commercial tablet, and IV administration. The first objective of this study was to develop a suitable film applicable containing furosemide, which provide advantages over conventional administration routes in veterinary medicine. The second objective of this study was to compare the PKs and diuretic effect of furosemide after newly developed furosemide-loaded ODF (FS-ODF), conventional oral commercial tablet, and IV administration. We hypothesized that the newly developed FS-ODF would have similar drug when compared to oral tablets of the same dose. Results Based on previous studies, film-forming agent and other excipients, including the plasticizer, solubilizer, disintegrant, sweetener, and solvent, were investigated for the most suitable agent and sodium alginate was selected to form the ODF. Table 1 Formulation of FS-ODF. Purpose of use Formulation (mg) Acitive ingredient Furosemide 20 Film forming agent Sodium alginate 14 Plasticizer Glycerin 4 PEG 400 4 Solubilizer Tween 80 1 Sweetener D-Sorbitol 1 Disintegrant Crospovidone 6 Total weight (mg) 50 The FS-ODF was prepared using the formulation shown in Table 1 . Each FS-ODF had a size of 2 × 3 cm 2 and weight of each film is 50 mg. This film had a homogeneous surface with some turbidity (Fig. 1). The mean weight of the film and drug content were 51.75 ± 2.25 mg and 97.63% ± 1.87%, respectively (Table 2 ). The disintegration time was 33.5 ± 4.5 s in water and the bending count, which represents tensile strength, was 4.4 ± 0.5. Table 2 Characterization of FS-ODF. Film properties FS-ODF Weight (mg) 51.75 ± 2.25 Drug Content (%) 97.63 ± 1.87 Disintegration Time (s) 33.5 ± 4.5 Bending Count 4.4 ± 0.5 Results are presented as mean ± SD (n = 5) In the dissolution test, FS-ODF showed a pH-dependent curve (Fig. 2). The dissolution rate at pH 4.0 (96.75%) and pH 6.8 (98.48%) was higher than that at pH 1.2 (3.54%) after 60 min. The dissolution rate at pH 1.2 was less than 10% after 120 min. However, FS-ODF reached complete dissolution of more than 95% at pH 4.0 and pH 6.8 within 60 min. Table 3 Pharmacokinetic parameters of furosemide (2 mg/kg) based on route of administration in beagle dogs. Pharmacokinetic parameters IV OUT FS-ODF P OUT vs. FS-ODF C max (µg/mL) 6.30 ± 0.78 (6.46) 0.61 ± 0.31 (0.69) 0.81 ± 0.81 (0.58) 0.619 T max (h) 0.083 (0.083) 1.05 ± 0.45 (1) 0.65 ± 0.29 (0.75) 0.130 T 1/2 (h) 2.07 ± 0.76 (1.63) 3.46 ± 1.82 (2.86) 2.65 ± 0.77 (2.46) 0.602 MRT (h) 0.90 ± 0.25 (0.78) 4.76 ± 1.59 (3.99) 3.36 ± 0.77 (3.45) 0.128 AUC inf (µg·h/mL) 2.74 ± 0.25 (2.60) 1.62 ± 0.77 (1.77) 1.28 ± 0.70 (1.36) 0.493 AUC last (µg·h/mL) 2.67 ± 0.26 (2.56) 1.27 ± 0.49 (1.53) 1.14 ± 0.64 (1.11) 0.734 F (%) 100 59.06 ± 27.95 (64.74) 46.91 ± 25.49 (50.01) 0.493 C max , maximum plasma concentration; T max , time at the maximum concentration; T 1/2 , elimination half-life, MRT, mean residence time; AUC inf , area under the curve from time zero to time of infinity measurable concentration; AUC last , area under the curve from time zero to time of last measurable concentration; F,fraction of oral dose absorbed(= bioavailability), expressed as a percentage; IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. Results are presented as mean ± SD (median). (*), values are significantly different (P < 0.05); (**) values are significantly different (P < 0.01). The dose of furosemide via all three routes was well-tolerated in all dogs. The vital signs on physical examination and behavior did not change during the study period. PK data of furosemide after the three routes of administration are summarized in Table 3 and presented in Fig. 3. No significant differences were detected between the orally uncoated tablet (OUT) and FS-ODF. In our study, the PK results of plasma furosemide showed a mean C max of 6.3 µg/mL (IV), 0.61 µg/mL (OUT), and 0.81 µg/mL (FS-ODF), mean AUC last of 2.67 µg·h/mL (IV), 1.27 µg·h/mL (OUT), and 1.14 µg·h/mL (FS-ODF), and mean T 1/2 of 2.07 h (IV), 3.46 h (OUT), and 2.65 h (FS-ODF). A higher maximum plasma concentration (C max ) and lower elimination half-life (T 1/2 ) of furosemide were observed when administered via the IV route than when administered via the OUT and FS-ODF routes. After FS-ODF administration, the C max of furosemide was 33% higher, whereas the area under the curve from time zero to time of last measurable concentration (AUC last ), time at maximum concentration (T max ), and T 1/2 were 10%, 39%, and 23% lower, respectively, than those after OUT administration. Table 4 Hematocrit and biochemistry profile following single dose of furosemide (2 mg/kg) administration. Baseline Time (h) 1 2 4 6 8 Hematocrit(%) IV 40.46 ± 9.43 41.36 ± 5.43 38.52 ± 6.84 39.06 ± 7.43 39.02 ± 6.01 40.22 ± 5.35 OUT 38.98 ± 4.18 39.10 ± 3.16 38.52 ± 3.50 38.64 ± 3.75 38.72 ± 4.04 40.12 ± 3.94 FS-ODF 41.94 ± 5.19 41.02 ± 6.17 40.20 ± 6.48 41.44 ± 4.21 41.58 ± 6.30 40.54 ± 7.81 BUN (mg/dL) IV 17.10 ± 6.33 17.50 ± 5.60 ** 17.20 ± 5.57 ** 16.72 ± 5.25 16.20 ± 5.21 15.94 ± 5.23 OUT 21.84 ± 9.99 20.82 ± 9.12 ** 20.22 ± 8.99 19.04 ± 7.96 17.52 ± 6.25 16.60 ± 5.83 FS-ODF 18.96 ± 6.39 18.68 ± 6.15 ** 18.16 ± 6.10 17.30 ± 5.90 ** 16.14 ± 5.28 * 15.41 ± 4.72 * Cr (mg/dL) IV 0.72 ± 0.24 0.68 ± 0.19 0.68 ± 0.24 0.68 ± 0.19 0.72 ± 0.13 0.68 ± 0.23 OUT 0.72 ± 0.29 0.70 ± 0.25 0.68 ± 0.23 0.66 ± 0.23 0.68 ± 0.16 0.66 ± 0.18 FS-ODF 0.72 ± 0.13 0.74 ± 0.19 0.68 ± 0.22 0.70 ± 0.19 0.72 ± 0.19 0.70 ± 0.20 Total protein (mg/dL) IV 5.90 ± 0.36 6.32 ± 0.29** 6.18 ± 0.36** 6.10 ± 0.30* 6.04 ± 0.25 6.04 ± 0.34* OUT 5.74 ± 0.29 6.02 ± 0.25** 6.10 ± 0.38** 6.10 ± 0.31* 5.94 ± 0.34 6.00 ± 0.29* FS-ODF 6.06 ± 0.18 6.30 ± 0.10** 6.38 ± 0.18** 6.26 ± 0.17* 6.30 ± 0.20 6.34 ± 0.05* Data are described as mean ± SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film; BUN, Blood urea nitrogen; Cr, Creatinine. The p-values are significantly different (*p < 0.05, **p < 0.01) compared to the baseline. The plasma concentration of total protein was significantly increased 4 h after IV, 1–4 h after OUT, and 2–4 h after FS-ODF administration compared to the baseline. However, the plasma blood urea nitrogen (BUN) concentration was significantly decreased 1–2 h after IV and 4–8 h after FS-ODF administration compared to the baseline. The plasma concentrations of creatinine and hematocrit were not significantly different compared to the baseline at any time point (Table 4 ). Moreover, the serum potassium concentration was significantly decreased 1–6 h after IV and OUT and 1–8 h after FS-ODF administration, and the serum chloride concentration was significantly decreased 2 h after IV and OUT administration. Compared to that at the baseline, the serum sodium concentration did not change significantly over time (Table 5 ). Additionally, the indirect systolic blood pressure was not different among application routes nor time points. Table 5 Serum electrolyte concentration following furosemide (2 mg/kg) administration. Baseline Time (h) 1 2 4 6 8 Serum sodium excretion (mmol) IV 151.26 ± 4.06 148.14 ± 1.46 148.04 ± 1.13 150.60 ± 2.10 147.74 ± 4.79 148.52 ± 1.30 OUT 150.34 ± 2.62 153.56 ± 7.59 150.14 ± 1.48 149.12 ± 1.08 151.92 ± 5.29 149.84 ± 1.44 FS-ODF 150.94 ± 2.97 155.20 ± 9.26 150.06 ± 2.12 148.98 ± 6.06 153.46 ± 9.29 148.56 ± 1.09 Serum potassium excretion (mmol) IV 4.48 ± 0.15 4.19 ± 0.17 * 3.97 ± 0.29 ** 4.12 ± 0.29 ** 4.04 ± 0.31 ** 4.15 ± 0.42 OUT 4.51 ± 0.34 4.43 ± 0.41 * 3.97 ± 0.14 ** 4.05 ± 0.23 ** 4.04 ± 0.28 ** 4.05 ± 0.27 FS-ODF 4.43 ± 0.32 4.08 ± 0.36 ** 3.92 ± 0.28 ** 4.09 ± 0.37 ** 4.13 ± 0.41 * 4.05 ± 0.23 * Serum chloride excretion (mmol) IV 110.66 ± 4.20 106.46 ± 1.41 105.96 ± 1.33 * 107.64 ± 2.01 104.34 ± 4.25 106.36 ± 0.80 OUT 110.28 ± 3.38 111.56 ± 8.26 107.52 ± 1.61 * 105.88 ± 0.58 107.76 ± 3.43 106.50 ± 1.35 FS-ODF 110.22 ± 3.30 112.74 ± 7.69 106.84 ± 1.82 106.04 ± 4.56 109.96 ± 7.89 106.20 ± 1.08 Results are presented as mean ± SD. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. The p-values are significantly different (*p < 0.05, **p < 0.01) compared to the baseline. The hourly urine output (HUO) and accumulated urinary output are shown in Table 6 . The HUO was increased significantly compared to the baseline in each group. The HUO peak of IV administration was high and early, whereas that of OUT and FS-ODF administration was broader and appeared later. The HUO was increased 1 h after IV administration, then returned to the baseline level after 4 h. The HUO for OUT and FS-ODF was increased 1–2 h after administration and returned to the baseline level after 6 h. The mean duration of diuresis until the return to baseline levels after IV, OUT, and FS-ODF administration was 4.1 h, 5.72 h, and 5.24 h, respectively. Similar value of HUO were observed between OUT and FS-ODF during the initial 2 h after administration. The total urine output was 24.65 mL/kg, 30.9 mL/kg, and 25.4 mL/kg during 8 h after IV, OUT, and FS-ODF administration, respectively. The urine-specific gravity (USG) and urine electrolyte excretion per hour (UEEH) are shown in Table 7 . The USG was significantly decreased after administration in all groups but returned to the baseline after 8 h. The UEEH was significantly increased 1–2 h after administration in all groups. The peak times of sodium and chloride UEEH were 1 h, 2 h, and 2 h, whereas those of potassium UEEH were 1 h, 1 h, and 2 h, after IV, OUT, and FS-ODF administration, respectively. Table 6 Hourly urine output and cumulative urine output after furosemide administration via different routes. Baseline Time (h) 1 2 4 6 8 Hourly urinary output (ml/h) IV 8.45 ± 2.82 147.20 ± 34.05 ** 74.60 ± 15.61 ** 9.70 ± 3.93 7.10 ± 3.11 6.20 ± 3.68 OUT 16.40 ± 22.28 88.80 ± 94.10 ** 128.80 ± 51.09 ** 34.30 ± 16.90 13.50 ± 5.51 6.60 ± 4.59 FS-ODF 12.66 ± 6.97 71.40 ± 41.93 * 121.20 ± 61.49 * 18.0 ± 8.96 9.40 ± 4.48 6.70 ± 2.31 Accumulatedurinary output (ml) IV 13.0 ± 4.53 160.20 ± 37.16 ** 234.80 ± 47.07 ** 254.20 ± 51.28 ** 268.4 ± 57.05 ** 288.6 ± 55.76 ** OUT 26.20 ± 32.22 115.0 ± 124.80 ** 243.80 ± 151.63 ** 312.40 ± 139.36 ** 339.4 ± 135.60 ** 359.8 ± 134.75 ** FS-ODF 27.0 ± 16.90 98.40 ± 41.97 * 219.60 ± 89.41 ** 255.60 ± 91.68 ** 274.40 ± 87.68 ** 293.60 ± 99.60 ** Data are described as mean ± SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating. The p-values are significantly different (*p < 0.05, **p < 0.01) compared to the baseline. Table 7 Urine-specific gravity and urine electrolyte excretion after furosemide (2 mg/kg) administration. Baseline Time (h) 1 2 4 6 8 Urine-specific gravity IV 1.040 ± 0.010 1.012 ± 0.002 ** 1.007 ± 0.001 ** 1.011 ± 0.002 ** 1.020 ± 0.004 * 1.030 ± 0.007 OUT 1.039 ± 0.009 1.032 ± 0.015 ** 1.012 ± 0.006 ** 1.010 ± 0.003 ** 1.017 ± 0.006 * 1.022 ± 0.007 FS- ODF 1.045 ± 0.007 1.022 ± 0.013 * 1.009 ± 0.002 ** 1.014 ± 0.005 ** 1.020 ± 0.010 * 1.025 ± 0.009 * Urine sodium excretion per hour (mmol/h) IV 0.64 ± 0.56 17.75 ± 7.21 ** 8.70 ± 3.52 ** 0.95 ± 0.47 0.52 ± 0.21 0.35 ± 0.21 OUT 0.95 ± 1.05 11.13 ± 11.67 ** 18.88 ± 10.01 ** 3.77 ± 1.77 1.22 ± 0.52 0.44 ± 0.22 FS- ODF 0.93 ± 0.56 8.63 ± 4.63 * 17.18 ± 12.01 * 1.96 ± 0.94 0.78 ± 0.24 0.48 ± 0.11 Urine potassium excretion per hour (mmol/h) IV 0.31 ± 0.16 3.51 ± 1.17 ** 1.11 ± 0.32 ** 0.21 ± 0.10 0.16 ± 0.06 0.16 ± 0.11 OUT 0.92 ± 1.12 4.48 ± 4.48 ** 2.46 ± 1.24 ** 0.63 ± 0.26 0.33 ± 0.18 0.14 ± 0.06 FS- ODF 0.79 ± 0.53 2.40 ± 0.67 * 2.70 ± 1.38 * 0.41 ± 0.21 0.24 ± 0.13 0.16 ± 0.06 Urine chloride excretion per hour (mmol/h) IV 0.43 ± 0.11 11.43 ± 3.04 ** 5.72 ± 1.33 ** 0.72 ± 0.33 0.32 ± 0.12 0.19 ± 0.08 ** OUT 1.04 ± 1.29 8.48 ± 9.14 ** 10.29 ± 4.41 ** 2.63 ± 1.36 0.84 ± 0.38 0.25 ± 0.09 ** FS- ODF 0.76 ± 0.47 4.89 ± 2.62 * 9.60 ± 5.21 * 1.39 ± 0.62 0.53 ± 0.23 0.30 ± 0.09 Data are described as mean ± SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. The p-values are significantly different (*p < 0.05, **p < 0.01) compared to the baseline. Discussion To the authors’ knowledge, this study is the first to compare the PK/PD parameters of IV, OUT and ODF administration of furosemide in dogs. Among the conventional routes of furosemide administration, PO administration is the most common route for long-term management in veterinary patients with CHF ( 8 , 9 ). However, in the case of home care, oral tablet administration may be limited by low patient cooperation and it is difficult to use other traditional administration routes, such as IM, SC, and IV. For this reason, we did research into alternative routes that could actually be applied to veterinary medicine. Usually, ODFs disintegrate within 1 min in the oral cavity owing to contact with the saliva, which results in rapid absorption and drug bioavailability. Furthermore, when administered via buccal or sublingual routes, there are advantages of high permeability and bypassing first-pass metabolism ( 23 ). In this study, the ODF dissolved in the mouths of dogs quickly without water, which indicates that the ODF formulation is beneficial with regard to rapid dissolution, absorption, and ease of drug administration in veterinary patients. Therefore, a low-dose FS-ODF formulation for small animals was developed. Based on our research results, sodium alginate decided to use as film-forming agent containing furosemide. Then, 20 mg of furosemide (a high ratio; 40%, w/w) was loaded per sheet, which was cut depending on the body weight of the dog to reach a dose of 2 mg/kg. These physical specifications were achieved for convenience of use in small animals, such as small dogs (< 10 kg) or cats ( 25 ). The small and uniform particles of furosemide in the final preparation suspension enabled the homogeneous and desirable film surface and might have reduced weight variation and content loss ( 26 ). The formulation was optimized, with a disintegration time of less than 40 s, owing to the presence of crospovidone as a disintegrant. Rapid disintegration to small particles in the mouth is an essential property to ensure the good usability of a film ( 27 ). Moreover, the bending count was in an acceptable range and showed the flexibility of the film. Overall, FS-ODF had suitable film properties in terms of appearance, drug content, disintegration time, and tensile strength. In the dissolution test, FS-ODF showed a pH-dependent curve because furosemide has a highly pH-dependent solubility. Furosemide is a weak acid (pKa = 3.48) with a carboxylic acid functional group and its aqueous solubility increases as the pH increases from 0.18 mg/mL (pH 2.3) to 13.36 mg/mL (pH 10.0) ( 28 ). Thus, in this study, the dissolution rate was in the order of pH 6.8 > pH 4.0 > > pH 1.2 within 60 min. FS-ODF showed immediate-release on the curve (Fig. 2), with high dissolution rates at pH 4.0 and pH 6.8 owing to the rapid disintegration time of less than 1 min. Therefore, FS-ODF was sufficient, in terms of disintegration time and dissolution rate, for administration to small animals. In dogs and humans, the diuretic effect caused by furosemide continues for 3 h after IV injection. The concentration of furosemide initially exceeds the number of Na + -K + -2Cl − cotransporters in the loop of Henle after IV administration and are excreted in the urine. Thereafter, the furosemide concentration declines under therapeutic concentrations ( 29 – 31 ). Additionally, the bioavailability of furosemide is different depending on the administration method. For example, when administered orally, the first-pass effect, related to the extent of gastrointestinal absorption and metabolism, plays a major role in the bioavailability of furosemide. Also, the first-pass effect varies by species and individual. The diuretic effect of furosemide after PO administration has a slower onset than that after IV and SC administration ( 32 ). Furthermore, the bioavailability of furosemide is approximately 77% in dogs and 60–65% in humans after PO administration ( 8 , 13 , 29 ). The bioavailability of furosemide after IV administration is greater than that after PO administration, and the diuretic effect continues 1–2 h after IV injection. Moreover, the absorption of furosemide is influenced by the pH and the existence of binding proteins in the stomach ( 18 , 33 , 34 ). Although furosemide is slowly absorbed in the small intestine, it is absorbed rapidly in the stomach because of the acid environment. The absorption of furosemide in the gastrointestinal tract of patients with CHF may be lower than normal ( 35 ). Generally, in patients with CHF, absorption delay may be the result of increased motility, reduced perfusion, or mucosal edema of intestine ( 36 , 37 ). The PKs of furosemide determine the therapeutic effect, entry rate of drug into the blood and urine, and onset and duration of effects, all of which are altered by the method of administration ( 18 , 29 , 30 ). Both OUT and FS-ODF administration showed a slower onset and a longer elimination half-life than IV administration. Previous studies have shown a half-life of 0.5–1 h after IV administration, whereas the half-life has been reported as 30 min in the major disposition phase and approximately 7 h in the slow elimination phase after PO administration in dogs ( 5 , 6 , 38 ). According to another PK/PD study in healthy beagle dogs, the half-life after PO administration in dogs is 3 h, which is similar to the results of the present study ( 39 ). In the body, furosemide moves across the renal tubule from the plasma to the lumen of the nephron; thus, furosemide acting on henle’s loop of renal tubule should have a short duration of effects if its half-life is short ( 7 ). After IV administration, the C max was slightly higher than that after OUT or FS-ODF administration, whereas the T 1/2 and T max were slightly lower. These results appear to be owing to the initial high blood concentration and rapid elimination of furosemide after IV administration. In addition to the route of administration of the drug, it should also be considered that the half-life of drugs is affected by many factors, including illness status, age, and other physiological variables ( 40 ). The present study demonstrates that the PKs after the administration of FS-ODF are similar to those after that of OUT in healthy dogs. Furthermore, after IV administration, the HUO was significantly increased and peaked after 1 h, then decreased gradually to baseline levels. This result was similar to the predicted PK result of the IV route ( 8 ). The HUO of OUT and FS-ODF routes were significantly increased after 1–2 h and peaked after 2 h. Therefore, FS-ODF and OUT resulted in a similar HUO during the initial 2 h after administration The duration of diuresis (time until return to baseline level after furosemide administration) after OUT and FS-ODF administration was similar at 5 h. Additionally, UEEHs were increased during the initial 2 h after administration in all groups. Based on HUO, USG, and UEEH results, FS-ODF has equivalent aquaretic, natriuretic, kaliuretic, chloriuretic, and diuretic effects to conventional OUT. This study has a few limitations, which may be overcome by further research. First, additional studies using different doses and repeating doses are needed because we used only a single dose of furosemide (2 mg/kg). Second, we only used five healthy intact beagle dogs. Additional studies should be conducted in more dog patients with CHF, renal failure, and delayed intestinal absorption. Third, there is a need to study the administration of this drug by ODF in various animals, including cats. Conclusion In this study, we developed an ODF for small animals that showed similar PK/PD results to OUT administration. Collectively, the results of this study suggest that the FS-ODF formulation can be used as an alternative to oral tablets in animal patients with heart failure and volume overload. Therefore, it would be helpful to owners of small dogs and cats that refuse conventional oral medications owing to the potential benefits of easy administration and convenient dosage form. Methods Animals Five clinically healthy adult beagle dogs (three intact males and two intact females) dogs from a research colony at the College of Veterinary Medicine of Chungnam National University were included in this study. The animals were 5–9 years of age and weighed 10–13 kg. All dogs were normal on physical examination, including systemic blood pressure measurement with a Doppler device, and within normal ranges on complete blood count, serum biochemistry panel, serum electrolytes, and urinalysis. Animals were housed in cages and fed commercial food (SUNGBO Pet Healthcare, Seoul, South Korea) twice daily. Water was provided ad libitum. This study was approved by the Institutional Animal Care and Use Committee (IACUC) at Chungnam National University (approval number, CNU-01189). After the study, all dogs were adopted as companion animals. Preparation of FS-ODF The FS-ODFs were prepared by a simple, easy solvent-casting method that required no special equipment (41). For lab-scale preparation, as the batch size was 15 FS-ODFs, the amount of formulation for 15 FS-ODFs was weighed and used (Table 1). Furosemide and two plasticizers were dissolved in 4.5 mL of ethanol, heated in 80 °C chambers for 30 min. This solution was transferred to a 40 °C chamber to reach temperature equilibrium (Solution A). The other excipients, including the film-forming agent, solubilizer, and sweetener, were dissolved in 10.5 mL of water and the disintegrant was suspended. This aqueous solution was transferred to 40 °C chambers to reach temperature equilibrium (Solution B). Solution A was added to Solution B and the mixture was stirred at room temperature (22-24 °C) for 30 min to obtain a uniform suspension. This suspension was sonicated for 10 min for degassing. The amount of suspension equivalent to 10.60 films on an area basis was placed on a Petri dish (9 cm in diameter) and dried in 80 °C chambers for 40–45 min. The formed film was peeled off and cut to a predetermined size of 2 × 3 cm 2 . Characterization of FS-ODF Disintegration Time One FS-ODF was placed on a petridish (9 cm diameter) with 15 mL of 37 ℃ water. The time to disintegrate completely was measured by visual observation (42). The absence of any significant floating fragments was considered to be the completion of disintegration. Bending Count The bending count measured by the number of times it took to split when the film was folded in half repeatedly with two fingers. Weight and Drug Content The prepared FS-ODF was weighed using balance and transferred into 30 mL dilution solution (0.05N NaOH solution) in 50 mL volumetric flask and dissolved with vortexing. Then, the dilution solution was added to be total volume. This solution of 2 mL was transferred to 100 mL volumetric flask and the dilution solution was added to be total volume. The final solution was filtered with syringe filter (0.45 ㎛) and the filtrate was analyzed by the below HPLC method. HPLC Condition The HPLC analysis of furosemide in the samples was conducted using a Waters 2695 HPLC system (Waters, Milford, MA, USA) equipped with a UV-Vis detector (Waters 2487, Waters, Milford, MA, USA). Furosemide was analyzed using the reverse column with C18, 5 μm, 4.5 mm × 25 cm (Shiseido, Tokyo, Japan). The mobile phase consisted of water, tetrahydrofuran, and acetic acid (70:30:1, v/v/v). The HPLC analysis was performed with a flow rate of 1.2 mL/min. The injected volume of the sample was 20 μL, and UV detection was monitored at 272 nm (43). Data acquisition and processing were carried out using the Waters LC Solution software. Dissolution Test The dissolution test was performed using the USP (35) dissolution apparatus II at pH 1.2 (0.1 N HCl/NaCl buffer), pH 4.0 (acetate buffer), pH 6.8 (phosphate buffer) with the media volume of 900 mL at 37.0 ± 0.5 °C. The rotational speed was adjusted to 50 rpm. The prepared FS-ODF containing furosemide 20 mg in a sample was placed into a dissolution vessel with a sinker (44). At each predetermined interval, the aliquot (5 mL) of the medium was collected and filtered through a membrane filter (pore size: 0.45 µm). The concentration of furosemide in the filtrate was determined using the above HPLC method. Study design This study was performed using a single-dose, randomized, 3-way crossover design. Three methods of furosemide administration were used in each subject with at least 7-day washout period between each experiment. Animals were fasted for 12 hours before the administration of furosemide and had a free access to water during the experiment. Each (random) animals received a furosemide of 2 mg/kg via intravenous (IV), orally uncoated tablet (OUT), furosemide-loaded orally disintegrating film (FS-ODF) routes: (1) Furosemide 2 mg/kg IV, (2) OUT formulation of furosemide 2 mg/kg orally, (3) FS-ODF formulation 2 mg/kg orally. Injections and OUT formulation of furosemide were purchased from handok Pharm. Co. (Seoul, South Korea). For oral administration, furosemide OUT and FS-ODF formulation were cut according to body weight of each dog. Also, 22-Gauge IV catheter was used in the cephalic vein for the IV injections. All dogs were not received other medications before experiment and during the washout period. Sample collection Blood samples were collected at 0 (serving as baseline), 5, 15, 30, 45, 60, 120, 240, 360, 480 minutes in each administration routes. All blood samples were obtained from the jugular vein with 23-Gauge 5mL syringe. These samples were immediately divided into heparinized tubes for biochemical test, plain tubes for electrolyte analysis and EDTA-K2 tube for hematocrit. Heparinized plasma and serum were separated after centrifugation at 3,000 x g for 15 minutes and stored at −20 °C until analysis. A complete blood count, BUN, creatinine (Cr), plasma total protein and serum electrolytes were measured. The urine samples were collected at 0 (serving as baseline), 1, 2, 4, 6, 8 hours in each administration routes. In line with previous studies, the bladder was initially emptied 2 hours before baseline and then collected in 2 hours to calculate baseline hourly urine output (HUO) before furosemide administration. An indwelling 6-8 Fr balloon Foley catheter was placed into the urinary bladder at the initiation of each experiment and the bladder was emptied for urine volume measured at each time point. Urine sample was centrifuged (1500 × g, 10 min) and the supernatant was collected to verify urine-specific gravity and the concentrations of sodium, potassium and chloride. Complete blood count was measured by ADVIA 2120i (SIEMENS corporation, Munich, Germany) and biochemistry were measured by Mindray BS-300 (Bio-Medical Electronics Co., Ltd, Shenzhen, China). Electrolyte concentrations in plasma and urine sample were measured by EasyLyte PLUS (MEDICA corporation, Bedford, USA). Quantification of furosemide in plasma Plasma concentration of furosemide were determined by HPLC-MS/MS system. To prepare appropriate assay samples, plasma samples were processed with acetonitrile to induce precipitation of plasma protein. More details as follows; firstly, 15 µL of plasma or calibrator sample were treated with 155 µL of 0.11 µg/mL ibuprofen (internal standard, IS) in acetonitrile. And then, sample mixtures were vigorously shaken by vortex mix for 15 minutes. Finally, sample mixtures were separated into supernatant and precipitant pellet by centrifugation at 17,600 g for 15 minutes. Standard samples were prepared by spiking of 5 µL working solution (as furosemide; 0, 30, 100, 300, 1,000, 3,000, 10,000, 30,000, and 100,000 ng/mL in acetonitrile) into 45 µL of blank plasma. For a sample analysis, 130 µL of supernatant were transferred into sample vials, and 5 µL of processed sample was directly injected into HPLC separation system. Furosemide and IS were separated by Agilent 1100 HPLC system. Chromatographic separation was conducted on Agilent ZORBAX ® phase phenyl column (5 µm, 2.1 x 50 mm) by 6 mM ammonium formate in 40% acetonitrile solution. After a separation, both analytes were detected by triple quadrupole mass spectrometer (AB SCIEX API4000 QTRAP®). Furosemide and IS were monitored under electrospray ionization negative mode as multiple reaction monitoring, which mass to charge ratio of 329.08 - to 284.80 - for furosemide and 205.05 - to 161.10 - for IS, respectively. Peak areas integration and quantification were automatically conducted by using Analyst software® (AB Sciex) 1.6.2. Concentration-response of furosemide was linear at ranges from 30 ng/mL to 10 µg/mL. Pharmacokinetic analysis Temporal profiles of furosemide in beagle were analyzed with via non-compartmental model using Phoenix WinNonlin 6.2. (Pharsight, USA). The following pharmacokinetic parameters were calculated and compared based on the route of administration: C max , half-life time, AUCs, CL, V ss , bioavailability (BA). The elimination rate constant (k e ) was determined by linear regression of the semi-log portion of the elimination phase. The elimination half-life (T 1/2 ) was calculated by dividing 0.693 with k e . The area under the plasma concentration versus time curve from time zero to infinity (AUC inf ) and the area under the respective first moment time curve from time zero to infinity (AUMC inf ) were calculated based on the linear-trapezoidal method. To estimate the elimination clearance (CL) and volume of distribution at steady state (V ss ), a moment analysis was conducted. In more detail, CL was gained by dividing administered dose with AUC inf . V ss was obtained by multiply CL with MRT, which division of AUMC inf by AUC inf . BAs of film and tablet groups were calculated from the dose normalized AUC PO /AUC IV , respectively. Statistical methods All data were expressed as mean and standard deviation values. Normality test was conducted with Kolmogorov-Smirnov test and pharmacokinetic parameters were an independent t -test. Because the study aimed to compare orally uncoated tablet with orally disintegrating film, only the differences between these two formulations of administration were statistically analyzed. Comparisons between baseline (0h) and various time phases after drug administration were analyzed statistically using the paired t -test. A P -value < 0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS 25 (SPSS Inc., Chicago, IL, USA). Abbreviations IV: Intravenous; CRI: constant-rate infusion; SC: subcutaneous; PO: oral; OUT: orally uncoated tablet; ODF: orally disintegrating film; FS-ODF: furosemide loaded-orally disintegrating film; BUN: blood urea nitrogen; Cr: creatinine; HUO: hourly urine output; PK/PD: pharmacokinetic and pharmacodynamics; PK: pharmacokinetics; HPLC-MS/MS: High-performance liquid chromatography-tandem mass spectrometry; HPLC: High-performance liquid chromatography; C max : maximum plasma concentration ; T max : time at the maximum concentration;T 1/2 : elimination half-life; AUC inf : area under the curve from time zero to time of infinity measurable concentration; AUC last : area under the curve from time zero to time of last measurable concentration; F: fraction of oral dose absorbed; MRT: mean residence time; USG: urine specific gravity; UEEH: urinary electrolytes excretion per hour Declarations Ethics approval and consent to participate This study was approved by the Institutional Animal Care and Use Committee at Chungnam National University (Approval number: CNU-01189). All methods were carried out in accordance with relevant guidelines and regulations. Consent for publication Not applicable. Availability of data and materials The data for figures, tables, and material used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Not applicable. Authors' contributions KSK performed the clinical procedures and data analysis and interpretation and drafted the manuscript. JWJ performed pharmacokinetic analysis and contributed to statistical analysis. SIC contributed to scientific discussions and helped clinical procedures. RMK prepared and characterized FS-ODFs. TSK participated in the study design and revised the manuscript. KHJ developed and provided film materials used for study. KWS were responsible for the study design and academic direction and contributed to revising, editing, and writing of manuscript. All authors have read and approved the final manuscript. Acknowledgements This manuscript is written based on the Master’s thesis of author Suk-Kyu Koh. This research with the support of “Cooperative Research Program of Center for Companion Animal Research (Project No. PJ140452): Rural Development Administration, Republic of Korea. References Hori Y, Ohshima N, Kanai K, Hoshi F, Itoh N, Higuchi S. Differences in the duration of diuretic effects and impact on the renin-angiotensin-aldosterone system of furosemide in healthy dogs. J Vet Med Sci. 2010;72(1):13-8. 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Biopharm Drug Dispos. 1986;7(6):537-47. Sleeper MM, O'Donnell P, Fitzgerald C, Papich MG. Pharmacokinetics of furosemide after intravenous, oral and transdermal administration to cats. J Feline Med Surg. 2018:1098612X18805879. Plumb DC. Furosemide, In: Plumb DC. ed. Veterinary Drug Hand-book. 9th ed. . 2018:pp. 726-31. MD. K. Management of heart failure, In: Kittleson MD, Kienle RD. eds. Small Animal Cardiovascular Medicine. St Louis: Mosby. 1998:pp.149-94. GERALD J. YAKATAN DDM, JEAN SCHOLLER, WM. J. NOVICK, Jr., and JAMES T. DOLUISIO. Absorption, Distribution, Metabolism, and Excretion of Furosemide in Dogs and Monkeys I Analytical Methodology, Metabolism, and Urinary Excretion. Journal of Pharmaceutical Sciences. 1976;Vol. 65(No.10):pp.1456-60. Haegeli L, Brunner-La Rocca HP, Wenk M, Pfisterer M, Drewe J, Krahenbuhl S. Sublingual administration of furosemide: new application of an old drug. Br J Clin Pharmacol. 2007;64(6):804-9. Benet LZ. Pharmacokinetics/pharmacodynamics of furosemide in man: a review. J Pharmacokinet Biopharm. 1979;7(1):1-27. El-Sayed MG, Atef M, El-Gendi AY, Youssef SA. Disposition kinetics of furosemide in dogs. Arch Int Pharmacodyn Ther. 1981;253(1):4-10. Miyazaki H, Hirai J, Taneike T. The Pharmacokinetics and Pharmacodynamics of Furosemide in Anesthetized Dogs with Normal and Experimentally Decreased Renal-Function. Japanese Journal of Veterinary Science. 1990;52(2):265-73. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med. 1985;103(1):1-6. Hori Y, Katou A, Tsubaki M, Kanai K, Nakao R, Hoshi F, et al. Assessment of diuretic effects and changes in plasma aldosterone concentration following oral administration of a single dose of furosemide or azosemide in healthy dogs. Am J Vet Res. 2008;69(12):1664-9. 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Transdermal Tulobuterol Patch, a Long-Acting beta(2)-Agonist. Allergol Int. 2012;61(2):219-29. Okamura H, Arakawa M, Miyagawa A, Adachi H. Incidence of postoperative atrial fibrillation in transdermal beta-blocker patch users is lower than that in oral beta-blocker users after cardiac and/or thoracic aortic surgery. Gen Thorac Cardiovasc Surg. 2019;67(12):1007-13. Karki S, Kim H, Na SJ, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian J Pharm Sci. 2016;11(5):559-74. De Caro V, Ajovalasit A, Sutera FM, Murgia D, Sabatino MA, Dispenza C. Development and Characterization of an Amorphous Solid Dispersion of Furosemide in the Form of a Sublingual Bioadhesive Film to Enhance Bioavailability. Pharmaceutics. 2017;9(3). Vondrak B, Barnhart S. Dissolvable films: dissolvable films for flexible product format in drug delivery. 2008. Borges AF, Silva C, Coelho JFJ, Simoes S. Oral films: Current status and future perspectives I - Galenical development and quality attributes. J Control Release. 2015;206:1-19. Shoukri RA, Ahmed IS, Shamma RN. In vitro and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets. Eur J Pharm Biopharm. 2009;73(1):162-71. Devarakonda B, Otto DP, Judefeind AA, Hill RA, de Villiers MM. Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes. Int J Pharmaceut. 2007;345(1-2):142-53. Branch RA, Roberts CJ, Homeida M, Levine D. Determinants of response to frusemide in normal subjects. Br J Clin Pharmacol. 1977;4(2):121-7. Kaojarern S, Day B, Brater DC. The time course of delivery of furosemide into urine: an independent determinant of overall response. Kidney Int. 1982;22(1):69-74. van Meyel JJ, Smits P, Russel FG, Gerlag PG, Tan Y, Gribnau FW. Diuretic efficiency of furosemide during continuous administration versus bolus injection in healthy volunteers. Clin Pharmacol Ther. 1992;51(4):440-4. Kim EJ, Han KS, Lee MG. Gastrointestinal first-pass effect of furosemide in rats. J Pharm Pharmacol. 2000;52(11):1337-43. Doungngern T, Huckleberry Y, Bloom JW, Erstad B. Effect of Albumin on Diuretic Response to Furosemide in Patients with Hypoalbuminemia. Am J Crit Care. 2012;21(4):280-6. Farless LB, Steil N, Williams BR, Bailey FA. Intermittent subcutaneous furosemide: parenteral diuretic rescue for hospice patients with congestive heart failure resistant to oral diuretic. Am J Hosp Palliat Care. 2013;30(8):791-2. Ansel HC ALJ, Popovich NG. Pharmaceutical Dosage Forms and Drug Delivery Systems. 7th ed. Philadelphia: Lippin-cott Willams & Wilkins. 1999:pp. 60-100. Ponto LL, Schoenwald RD. Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part II). Clin Pharmacokinet. 1990;18(6):460-71. Brater DC. Pharmacokinetics of loop diuretics in congestive heart failure. Br Heart J. 1994;72(2 Suppl):S40-3. Yakatan GJ, Maness DD, Scholler J, Johnston JT, Novick WJ, Jr., Doluisio JT. Plasma and tissue levels of furosemide in dogs and monkeys following single and multiple oral doses. Res Commun Chem Pathol Pharmacol. 1979;24(3):465-82. Pelligand L, Guillot E, Geneteau A, Guyonnet J, Magnier R, Elliott J, et al. Population Pharmacokinetics and Pharmacodynamics Modeling of Torasemide and Furosemide After Oral Repeated Administration in Healthy Dogs. Front Vet Sci. 2020;7:151. Raj Kumar Goel PS, Shazia, Sanjay Khanna, Rakesh Kumar Dixit. Clinical Significance of Half Life of Drugs. International Journal of Pharmacotherapy. 2014;4(1):6-7. Lee Y, Kim K, Kim M, Choi DH, Jeong SH. Orally disintegrating films focusing on formulation, manufacturing process, and characterization. Journal of Pharmaceutical Investigation. 2017;47(3):183-201. Kim B-S, Park G-T, Park M-H, Shin YG, Cho C-W. Preparation and evaluation of oral dissolving film containing local anesthetic agent, lidocaine. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 17 Jun, 2021 Reviews received at journal 17 Jun, 2021 Reviewers agreed at journal 09 Jun, 2021 Reviews received at journal 04 Jun, 2021 Reviewers agreed at journal 28 May, 2021 Reviewers invited by journal 10 May, 2021 Editor assigned by journal 07 May, 2021 Editor invited by journal 16 Apr, 2021 Submission checks completed at journal 16 Apr, 2021 First submitted to journal 08 Apr, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-403597","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":21638773,"identity":"5f82a395-8a3b-4fc8-9000-2550e5f5d049","order_by":0,"name":"Suk-kyu Koh","email":"","orcid":"","institution":"Chungnam National University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suk-kyu","middleName":"","lastName":"Koh","suffix":""},{"id":21638774,"identity":"0a77abd6-d27f-4893-8362-b9f486067cbe","order_by":1,"name":"Jong-Woo Jeong","email":"","orcid":"","institution":"Chungnam National University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jong-Woo","middleName":"","lastName":"Jeong","suffix":""},{"id":21638775,"identity":"93aba529-7044-4fd2-9413-f79b0b78dbd6","order_by":2,"name":"Seo-In Choi","email":"","orcid":"","institution":"Chungnam National University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Seo-In","middleName":"","lastName":"Choi","suffix":""},{"id":21638776,"identity":"0644598c-51cb-4820-b334-e9a3f4c3a2ab","order_by":3,"name":"Rae-Man Kim","email":"","orcid":"","institution":"Inje University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rae-Man","middleName":"","lastName":"Kim","suffix":""},{"id":21638777,"identity":"aeb33875-85ea-45fc-a9f5-be3f8d850dbe","order_by":4,"name":"Tae-Sung Koo","email":"","orcid":"","institution":"Chungnam National University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tae-Sung","middleName":"","lastName":"Koo","suffix":""},{"id":21638778,"identity":"04176d07-5670-4eca-8252-c804334e7689","order_by":5,"name":"Kwang-Hyung Cho","email":"","orcid":"","institution":"Inje University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kwang-Hyung","middleName":"","lastName":"Cho","suffix":""},{"id":21638779,"identity":"025e7c57-8d5f-4a01-825b-e965605632be","order_by":6,"name":"Kyoung-Won Seo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYBACCTBZAeMeIFrLGZK1MLaRokVyRvrDBx/n1eUZHGB++IHhzD3CWqQlcowNZ247XGxwgM1YguFGMWEtctI5bNK82w4kbjjAYMbA8CGBGC3pz3/zzqkDamH/RpwWaekEM2beBmagFh6gLTeI0CI5/42x5IxjhxNnHuYplkg4Q4QWiTPHH374UFOX2He8feOHD8eI0IIAzEBMkoZRMApGwSgYBbgBANYjOelu+aMUAAAAAElFTkSuQmCC","orcid":"","institution":"Seoul National University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kyoung-Won","middleName":"","lastName":"Seo","suffix":""}],"badges":[],"createdAt":"2021-04-09 02:58:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-403597/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-403597/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":8194423,"identity":"fd95f9f9-36cc-497a-a0cf-f8a286201c4b","added_by":"auto","created_at":"2021-04-19 21:52:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1003308,"visible":true,"origin":"","legend":"Title: Representative appearance of furosemide-loaded orally disintegrating film\nLegend: No content ","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-403597/v1/6191e2c08daf37654bf0f410.jpg"},{"id":8194424,"identity":"62f7b14e-5063-4833-b137-67643d9a1477","added_by":"auto","created_at":"2021-04-19 21:52:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":92530,"visible":true,"origin":"","legend":"Title: Dissolution profiles of furosemide-loaded orally disintegrating film at pH 1.2, pH 4.0, pH 6.8. (n=4)\nLegend: No content","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-403597/v1/b8cc3cd1d4e47970730a696e.jpg"},{"id":8194425,"identity":"b2fe2a01-011d-4723-834e-d9c6a98d3f70","added_by":"auto","created_at":"2021-04-19 21:52:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":480786,"visible":true,"origin":"","legend":"Title: Mean plasma furosemide concentration for each group. \nLegend: (A) Comparison of time course change in plasma concentration following 2 mg/kg furosemide administration in intravenously (IV), orally uncoated tablet (OUT) and furosemide-loaded orally disintegrating film (FS-ODF) group. (B) OUT and FS-ODF are represented by a line graph in figure 3 (A). See Table 3 for pharmacokinetic constant. Values presented as mean ± SD. IV, (●); OUT, (□); FS-ODF, (◇)","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-403597/v1/ed4e053467eff4fbc8c9699d.jpg"},{"id":13687527,"identity":"50d0553b-2336-40a6-8d4c-bbcbac0ebacb","added_by":"auto","created_at":"2021-09-17 12:20:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":572301,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-403597/v1/5b81f289-f8c3-4554-ad82-8f56859159fb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs","fulltext":[{"header":"Background","content":" \u003cp\u003eFurosemide, a diuretic commonly used in veterinary and human medicine, is recommended as first-line therapy in the management of congestive heart failure (CHF) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). It is used in animals for the treatment of pulmonary edema, udder edema, hypercalciuric nephropathy, uremia, and hypertension. Additionally, it reduces the incidence of sterile hemorrhagic cystitis associated with cyclophosphamide administration in dogs and is used as adjunctive therapy in hyperkalemia (\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The PK/PD properties of loop diuretics, including furosemide after IV and PO administration, have been well investigated in both human and veterinary medicine (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurosemide decreases the absorption of electrolytes in the luminal surface of the thick ascending loop of Henle via the deactivation of the Na\u003csup\u003e+\u003c/sup\u003e-K\u003csup\u003e+\u003c/sup\u003e-2Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e cotransporter. Thus, this drug increases the renal excretion of sodium, potassium, chloride, and water (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Additionally, furosemide causes renal venodilation, increases glomerular filtration rate, increases renal blood flow, and decreases peripheral resistance. Furthermore, furosemide activates the renin-angiotensin-aldosterone-system and sympathetic nervous system (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Although furosemide increases renin secretion, owing to its effects on the nephron, increases in sodium and water retention do not occur (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe conventional routes of furosemide administration are intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (PO). Unless an acute heart failure event occurs, PO administration is indicated in most cases that require long-term use in stable patients (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The onset time (IV, 5 min), elimination half-life (IV, 1\u0026ndash;1.5 h), duration (IV, 3\u0026ndash;6 h), and peak urine output (IV and SC, 1 h; PO, 2 h) of furosemide have been shown in previous experiments in dogs (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, some owners have difficulty administering oral tablet medications, which leads to noncompliance, especially with drugs that require long-term administration. Particularly with cats, it is often difficult to administer pills or capsules. Beyond the conventional administration routes and formulations, studies have been conducted to identify options with similar efficacy that can be easily administered. For human cardiac disease, these studies have led to the development of the sildenafil citrate sublingual tablet to treat pulmonary arterial hypertension, nitroglycerin ointment to treat CHF, transdermal tulobuterol patch for bronchodilation, and transdermal beta-blocker (bisoprolol) patch to reduce postoperative atrial fibrillation (\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe oral disintegrating film (ODF) offers several benefits especially in children, including easy administration via a non-invasive route, fast dissolution, and no risk of choking (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), that also can be utilized in veterinary medicine. Moreover, sublingual and oral furosemide administration differ in pharmacokinetic and pharmacodynamic (PK/PD) results in humans (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e); the sublingual route may provide therapeutic advantages over the oral route, especially in patients with CHF. In veterinary medicine, there is a study on the diuretic effect of furosemide according to the IV, SC, PO, and constant rate infusion (CRI) routes in dogs (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The study on furosemide administration using sublingual bioadhesive film showed \u003cem\u003eex vivo\u003c/em\u003e mucoadhesion using the buccal mucosa and permeability using the tongue excised from slaughtered pigs (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). And the alternative route of administration of furosemide have not been reported except for a study that the therapeutic effect of the transdermal application of furosemide to cats is negligible compared to that after oral and IV administration (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). However, there are no announced studies on alternative administration routes in dogs. Despite there is a need for formulations that can be safely administered to and easily absorbed by animals, ODFs for use in dogs (especially small dogs) and cats have not been developed.\u003c/p\u003e \u003cp\u003eThe purpose of this study was to compare the PKs and diuretic effect of furosemide after newly developed furosemide-loaded ODF (FS-ODF), conventional oral commercial tablet, and IV administration.\u003c/p\u003e \u003cp\u003e The first objective of this study was to develop a suitable film applicable containing furosemide, which provide advantages over conventional administration routes in veterinary medicine. The second objective of this study was to compare the PKs and diuretic effect of furosemide after newly developed furosemide-loaded ODF (FS-ODF), conventional oral commercial tablet, and IV administration. We hypothesized that the newly developed FS-ODF would have similar drug when compared to oral tablets of the same dose.\u003c/p\u003e "},{"header":"Results","content":"\u003cp\u003eBased on previous studies, film-forming agent and other excipients, including the plasticizer, solubilizer, disintegrant, sweetener, and solvent, were investigated for the most suitable agent and sodium alginate was selected to form the ODF.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eFormulation of FS-ODF.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePurpose of use\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eFormulation (mg)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAcitive ingredient\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFurosemide\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFilm forming agent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSodium alginate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePlasticizer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGlycerin\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePEG 400\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSolubilizer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTween 80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSweetener\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eD-Sorbitol\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDisintegrant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCrospovidone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eTotal weight (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe FS-ODF was prepared using the formulation shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Each FS-ODF had a size of 2 \u0026times; 3 cm\u003csup\u003e2\u003c/sup\u003e and weight of each film is 50 mg. This film had a homogeneous surface with some turbidity (Fig.\u0026nbsp;1). The mean weight of the film and drug content were 51.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25 mg and 97.63% \u0026plusmn; 1.87%, respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The disintegration time was 33.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 s in water and the bending count, which represents tensile strength, was 4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacterization of FS-ODF.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFilm properties\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight (mg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51.75\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDrug Content (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97.63\u0026thinsp;\u0026plusmn;\u0026thinsp;1.87\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDisintegration Time (s)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBending Count\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\"\u003eResults are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (n\u0026thinsp;=\u0026thinsp;5)\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the dissolution test, FS-ODF showed a pH-dependent curve (Fig.\u0026nbsp;2). The dissolution rate at pH 4.0 (96.75%) and pH 6.8 (98.48%) was higher than that at pH 1.2 (3.54%) after 60 min. The dissolution rate at pH 1.2 was less than 10% after 120 min. However, FS-ODF reached complete dissolution of more than 95% at pH 4.0 and pH 6.8 within 60 min.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePharmacokinetic parameters of furosemide (2 mg/kg) based on route of administration in beagle dogs.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePharmacokinetic parameters\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP\u003c/p\u003e\n\u003cp\u003eOUT vs. FS-ODF\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e(\u0026micro;g/mL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78 (6.46)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.61\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31 (0.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81 (0.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.619\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e(h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.083 (0.083)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29 (0.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.130\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT\u003csub\u003e1/2\u003c/sub\u003e(h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76 (1.63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.46\u0026thinsp;\u0026plusmn;\u0026thinsp;1.82 (2.86)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77 (2.46)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.602\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMRT (h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 (0.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.76\u0026thinsp;\u0026plusmn;\u0026thinsp;1.59 (3.99)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77 (3.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.128\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAUC\u003csub\u003einf\u003c/sub\u003e(\u0026micro;g\u0026middot;h/mL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 (2.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77 (1.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70 (1.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.493\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAUC\u003csub\u003elast\u003c/sub\u003e(\u0026micro;g\u0026middot;h/mL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 (2.56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49 (1.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64 (1.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.734\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eF (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59.06\u0026thinsp;\u0026plusmn;\u0026thinsp;27.95 (64.74)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46.91\u0026thinsp;\u0026plusmn;\u0026thinsp;25.49 (50.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.493\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eC\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration; T\u003csub\u003emax\u003c/sub\u003e, time at the maximum concentration; T\u003csub\u003e1/2\u003c/sub\u003e, elimination half-life, MRT, mean residence time; AUC\u003csub\u003einf\u003c/sub\u003e, area under the curve from time zero to time of infinity measurable concentration; AUC\u003csub\u003elast\u003c/sub\u003e, area under the curve from time zero to time of last measurable concentration; F,fraction of oral dose absorbed(=\u0026thinsp;bioavailability), expressed as a percentage; IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. Results are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (median). (*), values are significantly different (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05); (**) values are significantly different (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe dose of furosemide via all three routes was well-tolerated in all dogs. The vital signs on physical examination and behavior did not change during the study period.\u003c/p\u003e\n\u003cp\u003ePK data of furosemide after the three routes of administration are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and presented in Fig.\u0026nbsp;3. No significant differences were detected between the orally uncoated tablet (OUT) and FS-ODF. In our study, the PK results of plasma furosemide showed a mean C\u003csub\u003emax\u003c/sub\u003e of 6.3 \u0026micro;g/mL (IV), 0.61 \u0026micro;g/mL (OUT), and 0.81 \u0026micro;g/mL (FS-ODF), mean AUC\u003csub\u003elast\u003c/sub\u003e of 2.67 \u0026micro;g\u0026middot;h/mL (IV), 1.27 \u0026micro;g\u0026middot;h/mL (OUT), and 1.14 \u0026micro;g\u0026middot;h/mL (FS-ODF), and mean T\u003csub\u003e1/2\u003c/sub\u003e of 2.07 h (IV), 3.46 h (OUT), and 2.65 h (FS-ODF). A higher maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e) and lower elimination half-life (T\u003csub\u003e1/2\u003c/sub\u003e) of furosemide were observed when administered via the IV route than when administered via the OUT and FS-ODF routes. After FS-ODF administration, the C\u003csub\u003emax\u003c/sub\u003e of furosemide was 33% higher, whereas the area under the curve from time zero to time of last measurable concentration (AUC\u003csub\u003elast\u003c/sub\u003e), time at maximum concentration (T\u003csub\u003emax\u003c/sub\u003e), and T\u003csub\u003e1/2\u003c/sub\u003e were 10%, 39%, and 23% lower, respectively, than those after OUT administration.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eHematocrit and biochemistry profile following single dose of furosemide (2 mg/kg) administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eTime (h)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eHematocrit(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.46\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;9.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.36\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.52\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.84\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.06\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.02\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.22\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.98\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.52\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.64\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.72\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.12\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.94\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.94\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.02\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.44\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.58\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.54\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eBUN\u003c/p\u003e\n\u003cp\u003e(mg/dL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.50\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.60\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.57\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.72\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.94\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.84\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;9.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.82\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;9.12\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.22\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;8.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.52\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.96\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.68\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.15\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.16\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.30\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.90\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.14\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.28\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.41\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.72\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eCr\u003c/p\u003e\n\u003cp\u003e(mg/dL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003cp\u003eprotein\u003c/p\u003e\n\u003cp\u003e(mg/dL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.90\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.32\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.29**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.18\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.36**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.30*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.34*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.74\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.02\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.25**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.38**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.31*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.94\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.00\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.29*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.06\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.30\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.10**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.38\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.18**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.26\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.17*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.30\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.34\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.05*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eData are described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film; BUN, Blood urea nitrogen; Cr, Creatinine. The p-values are significantly different (*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the baseline.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe plasma concentration of total protein was significantly increased 4 h after IV, 1\u0026ndash;4 h after OUT, and 2\u0026ndash;4 h after FS-ODF administration compared to the baseline. However, the plasma blood urea nitrogen (BUN) concentration was significantly decreased 1\u0026ndash;2 h after IV and 4\u0026ndash;8 h after FS-ODF administration compared to the baseline. The plasma concentrations of creatinine and hematocrit were not significantly different compared to the baseline at any time point (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Moreover, the serum potassium concentration was significantly decreased 1\u0026ndash;6 h after IV and OUT and 1\u0026ndash;8 h after FS-ODF administration, and the serum chloride concentration was significantly decreased 2 h after IV and OUT administration. Compared to that at the baseline, the serum sodium concentration did not change significantly over time (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Additionally, the indirect systolic blood pressure was not different among application routes nor time points.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSerum electrolyte concentration following furosemide (2 mg/kg) administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eTime (h)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eSerum\u003c/p\u003e\n\u003cp\u003esodium\u003c/p\u003e\n\u003cp\u003eexcretion\u003c/p\u003e\n\u003cp\u003e(mmol)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151.26\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.14\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e147.74\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.52\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150.34\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e153.56\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150.14\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e149.12\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151.92\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e149.84\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150.94\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e155.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;9.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e150.06\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.98\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e153.46\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;9.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e148.56\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eSerum\u003c/p\u003e\n\u003cp\u003epotassium\u003c/p\u003e\n\u003cp\u003eexcretion (mmol)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.48\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.19\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.17\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.97\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.29\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.12\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.29\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.31\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.15\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.51\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.43\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.41\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.97\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.14\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.05\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.23\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.28\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.05\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.43\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.08\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.36\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.92\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.28\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.09\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.37\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.13\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.41\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.05\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.23\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eSerum\u003c/p\u003e\n\u003cp\u003echloride\u003c/p\u003e\n\u003cp\u003eexcretion (mmol)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e110.66\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.46\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105.96\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.33\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107.64\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e104.34\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.36\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e110.28\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e111.56\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;8.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107.52\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.61\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105.88\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e107.76\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.50\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e110.22\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112.74\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.84\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.04\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e109.96\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;7.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;1.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eResults are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. The p-values are significantly different (*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the baseline.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe hourly urine output (HUO) and accumulated urinary output are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e. The HUO was increased significantly compared to the baseline in each group. The HUO peak of IV administration was high and early, whereas that of OUT and FS-ODF administration was broader and appeared later. The HUO was increased 1 h after IV administration, then returned to the baseline level after 4 h. The HUO for OUT and FS-ODF was increased 1\u0026ndash;2 h after administration and returned to the baseline level after 6 h. The mean duration of diuresis until the return to baseline levels after IV, OUT, and FS-ODF administration was 4.1 h, 5.72 h, and 5.24 h, respectively. Similar value of HUO were observed between OUT and FS-ODF during the initial 2 h after administration. The total urine output was 24.65 mL/kg, 30.9 mL/kg, and 25.4 mL/kg during 8 h after IV, OUT, and FS-ODF administration, respectively. The urine-specific gravity (USG) and urine electrolyte excretion per hour (UEEH) are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e. The USG was significantly decreased after administration in all groups but returned to the baseline after 8 h. The UEEH was significantly increased 1\u0026ndash;2 h after administration in all groups. The peak times of sodium and chloride UEEH were 1 h, 2 h, and 2 h, whereas those of potassium UEEH were 1 h, 1 h, and 2 h, after IV, OUT, and FS-ODF administration, respectively.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab6\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eHourly urine output and cumulative urine output after furosemide administration via different routes.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eTime (h)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eHourly\u003c/p\u003e\n\u003cp\u003eurinary\u003c/p\u003e\n\u003cp\u003eoutput\u003c/p\u003e\n\u003cp\u003e(ml/h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.45\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e147.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;34.05\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;15.61\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.70\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.10\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;3.68\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;22.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88.80\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;94.10\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e128.80\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;51.09\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34.30\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;16.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.50\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;5.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.66\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;6.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;41.93\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;61.49\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.0\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;8.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.70\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eAccumulatedurinary\u003c/p\u003e\n\u003cp\u003eoutput\u003c/p\u003e\n\u003cp\u003e(ml)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.0\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e160.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;37.16\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e234.80\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;47.07\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e254.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;51.28\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e268.4\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;57.05\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e288.6\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;55.76\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.20\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;32.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e115.0\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;124.80\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e243.80\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;151.63\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e312.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;139.36\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e339.4\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;135.60\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e359.8\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;134.75\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-ODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.0\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;16.90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;41.97\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e219.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;89.41\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e255.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;91.68\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e274.40\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;87.68\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e293.60\u003c/p\u003e\n\u003cp\u003e\u0026plusmn;\u0026thinsp;99.60\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eData are described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating. The p-values are significantly different (*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the baseline.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab7\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUrine-specific gravity and urine electrolyte excretion after furosemide (2 mg/kg) administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003eTime (h)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUrine-specific\u003c/p\u003e\n\u003cp\u003egravity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.040 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.010\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.012 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.007 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.011 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.020 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.030 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.039 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.032 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.015\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.012 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.006\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.010 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.003\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.017 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.006\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.022 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-\u003c/p\u003e\n\u003cp\u003eODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.045 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.022 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.013\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.009 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.014 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.005\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.020 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.010\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.025 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.009\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUrine sodium\u003c/p\u003e\n\u003cp\u003eexcretion per\u003c/p\u003e\n\u003cp\u003ehour (mmol/h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.64 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.75 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e7.21\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.70 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e3.52\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.95 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.95 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.13 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e11.67\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.88 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e10.01\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.77 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.22 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.44 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-\u003c/p\u003e\n\u003cp\u003eODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.93 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.63 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e4.63\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.18 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e12.01\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.96 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.78 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.48 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUrine potassium excretion per\u003c/p\u003e\n\u003cp\u003ehour (mmol/h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.51 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.17\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.11 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.32\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.92 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.48 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e4.48\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.46 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.24\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.63 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-\u003c/p\u003e\n\u003cp\u003eODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.79 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.40 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.67\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.70 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.38\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.24 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eUrine chloride\u003c/p\u003e\n\u003cp\u003eexcretion per\u003c/p\u003e\n\u003cp\u003ehour (mmol/h)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.43 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e3.04\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.72 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.33\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.72 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.08\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOUT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.04 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.48 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e9.14\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.29 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e4.41\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.63 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e1.36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.84 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.09\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFS-\u003c/p\u003e\n\u003cp\u003eODF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.89 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e2.62\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.60 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e5.21\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.39 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.53 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30 \u0026plusmn;\u003c/p\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eData are described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD values. IV, intravenous; OUT, orally uncoated tablet; FS-ODF, furosemide-loaded orally disintegrating film. The p-values are significantly different (*p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the baseline.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the authors\u0026rsquo; knowledge, this study is the first to compare the PK/PD parameters of IV, OUT and ODF administration of furosemide in dogs. Among the conventional routes of furosemide administration, PO administration is the most common route for long-term management in veterinary patients with CHF (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). However, in the case of home care, oral tablet administration may be limited by low patient cooperation and it is difficult to use other traditional administration routes, such as IM, SC, and IV. For this reason, we did research into alternative routes that could actually be applied to veterinary medicine.\u003c/p\u003e\n\u003cp\u003eUsually, ODFs disintegrate within 1 min in the oral cavity owing to contact with the saliva, which results in rapid absorption and drug bioavailability. Furthermore, when administered via buccal or sublingual routes, there are advantages of high permeability and bypassing first-pass metabolism (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). In this study, the ODF dissolved in the mouths of dogs quickly without water, which indicates that the ODF formulation is beneficial with regard to rapid dissolution, absorption, and ease of drug administration in veterinary patients. Therefore, a low-dose FS-ODF formulation for small animals was developed.\u003c/p\u003e\n\u003cp\u003eBased on our research results, sodium alginate decided to use as film-forming agent containing furosemide. Then, 20 mg of furosemide (a high ratio; 40%, w/w) was loaded per sheet, which was cut depending on the body weight of the dog to reach a dose of 2 mg/kg. These physical specifications were achieved for convenience of use in small animals, such as small dogs (\u0026lt;\u0026thinsp;10 kg) or cats (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e). The small and uniform particles of furosemide in the final preparation suspension enabled the homogeneous and desirable film surface and might have reduced weight variation and content loss (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e). The formulation was optimized, with a disintegration time of less than 40 s, owing to the presence of crospovidone as a disintegrant. Rapid disintegration to small particles in the mouth is an essential property to ensure the good usability of a film (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e). Moreover, the bending count was in an acceptable range and showed the flexibility of the film. Overall, FS-ODF had suitable film properties in terms of appearance, drug content, disintegration time, and tensile strength.\u003c/p\u003e\n\u003cp\u003eIn the dissolution test, FS-ODF showed a pH-dependent curve because furosemide has a highly pH-dependent solubility. Furosemide is a weak acid (pKa\u0026thinsp;=\u0026thinsp;3.48) with a carboxylic acid functional group and its aqueous solubility increases as the pH increases from 0.18 mg/mL (pH 2.3) to 13.36 mg/mL (pH 10.0) (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e). Thus, in this study, the dissolution rate was in the order of pH 6.8\u0026thinsp;\u0026gt;\u0026thinsp;pH 4.0\u0026thinsp;\u0026gt;\u0026thinsp;\u0026gt;\u0026thinsp;pH 1.2 within 60 min. FS-ODF showed immediate-release on the curve (Fig.\u0026nbsp;2), with high dissolution rates at pH 4.0 and pH 6.8 owing to the rapid disintegration time of less than 1 min. Therefore, FS-ODF was sufficient, in terms of disintegration time and dissolution rate, for administration to small animals.\u003c/p\u003e\n\u003cp\u003eIn dogs and humans, the diuretic effect caused by furosemide continues for 3 h after IV injection. The concentration of furosemide initially exceeds the number of Na\u003csup\u003e+\u003c/sup\u003e-K\u003csup\u003e+\u003c/sup\u003e-2Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e cotransporters in the loop of Henle after IV administration and are excreted in the urine. Thereafter, the furosemide concentration declines under therapeutic concentrations (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAdditionally, the bioavailability of furosemide is different depending on the administration method. For example, when administered orally, the first-pass effect, related to the extent of gastrointestinal absorption and metabolism, plays a major role in the bioavailability of furosemide. Also, the first-pass effect varies by species and individual. The diuretic effect of furosemide after PO administration has a slower onset than that after IV and SC administration (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). Furthermore, the bioavailability of furosemide is approximately 77% in dogs and 60\u0026ndash;65% in humans after PO administration (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e). The bioavailability of furosemide after IV administration is greater than that after PO administration, and the diuretic effect continues 1\u0026ndash;2 h after IV injection. Moreover, the absorption of furosemide is influenced by the pH and the existence of binding proteins in the stomach (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e). Although furosemide is slowly absorbed in the small intestine, it is absorbed rapidly in the stomach because of the acid environment. The absorption of furosemide in the gastrointestinal tract of patients with CHF may be lower than normal (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e). Generally, in patients with CHF, absorption delay may be the result of increased motility, reduced perfusion, or mucosal edema of intestine (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe PKs of furosemide determine the therapeutic effect, entry rate of drug into the blood and urine, and onset and duration of effects, all of which are altered by the method of administration (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). Both OUT and FS-ODF administration showed a slower onset and a longer elimination half-life than IV administration. Previous studies have shown a half-life of 0.5\u0026ndash;1 h after IV administration, whereas the half-life has been reported as 30 min in the major disposition phase and approximately 7 h in the slow elimination phase after PO administration in dogs (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). According to another PK/PD study in healthy beagle dogs, the half-life after PO administration in dogs is 3 h, which is similar to the results of the present study (\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn the body, furosemide moves across the renal tubule from the plasma to the lumen of the nephron; thus, furosemide acting on henle\u0026rsquo;s loop of renal tubule should have a short duration of effects if its half-life is short (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). After IV administration, the C\u003csub\u003emax\u003c/sub\u003e was slightly higher than that after OUT or FS-ODF administration, whereas the T\u003csub\u003e1/2\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e were slightly lower. These results appear to be owing to the initial high blood concentration and rapid elimination of furosemide after IV administration. In addition to the route of administration of the drug, it should also be considered that the half-life of drugs is affected by many factors, including illness status, age, and other physiological variables (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e). The present study demonstrates that the PKs after the administration of FS-ODF are similar to those after that of OUT in healthy dogs.\u003c/p\u003e\n\u003cp\u003eFurthermore, after IV administration, the HUO was significantly increased and peaked after 1 h, then decreased gradually to baseline levels. This result was similar to the predicted PK result of the IV route (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). The HUO of OUT and FS-ODF routes were significantly increased after 1\u0026ndash;2 h and peaked after 2 h. Therefore, FS-ODF and OUT resulted in a similar HUO during the initial 2 h after administration\u003c/p\u003e\n\u003cp\u003eThe duration of diuresis (time until return to baseline level after furosemide administration) after OUT and FS-ODF administration was similar at 5 h. Additionally, UEEHs were increased during the initial 2 h after administration in all groups. Based on HUO, USG, and UEEH results, FS-ODF has equivalent aquaretic, natriuretic, kaliuretic, chloriuretic, and diuretic effects to conventional OUT.\u003c/p\u003e\n\u003cp\u003eThis study has a few limitations, which may be overcome by further research. First, additional studies using different doses and repeating doses are needed because we used only a single dose of furosemide (2 mg/kg). Second, we only used five healthy intact beagle dogs. Additional studies should be conducted in more dog patients with CHF, renal failure, and delayed intestinal absorption. Third, there is a need to study the administration of this drug by ODF in various animals, including cats.\u003c/p\u003e"},{"header":"Conclusion","content":" \u003cp\u003eIn this study, we developed an ODF for small animals that showed similar PK/PD results to OUT administration. Collectively, the results of this study suggest that the FS-ODF formulation can be used as an alternative to oral tablets in animal patients with heart failure and volume overload. Therefore, it would be helpful to owners of small dogs and cats that refuse conventional oral medications owing to the potential benefits of easy administration and convenient dosage form.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eAnimals \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive clinically healthy adult beagle dogs (three intact males and two intact females) dogs from a research colony at the College of Veterinary Medicine of Chungnam National University were included in this study. The animals were 5\u0026ndash;9 years of age and weighed 10\u0026ndash;13 kg. All dogs were normal on physical examination, including systemic blood pressure measurement with a Doppler device, and within normal ranges on complete blood count, serum biochemistry panel, serum electrolytes, and urinalysis. Animals were housed in cages and fed commercial food (SUNGBO Pet Healthcare, Seoul, South Korea) twice daily. Water was provided ad libitum. This study was approved by the Institutional Animal Care and Use Committee (IACUC) at Chungnam National University (approval number, CNU-01189). After the study, all dogs were adopted as companion animals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePreparation of FS-ODF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe FS-ODFs were prepared by a simple, easy solvent-casting method that required no special equipment (41). For lab-scale preparation, as the batch size was 15 FS-ODFs, the amount of formulation for 15 FS-ODFs was weighed and used (Table 1). Furosemide and two plasticizers were dissolved in 4.5 mL of ethanol, heated in 80 \u0026deg;C chambers for 30 min. This solution was transferred to a 40 \u0026deg;C chamber to reach temperature equilibrium (Solution A). The other excipients, including the film-forming agent, solubilizer, and sweetener, were dissolved in 10.5 mL of water and the disintegrant was suspended. This aqueous solution was transferred to 40 \u0026deg;C chambers to reach temperature equilibrium (Solution B). Solution A was added to Solution B and the mixture was stirred at room temperature (22-24 \u0026deg;C) for 30 min to obtain a uniform suspension. This suspension was sonicated for 10 min for degassing. The amount of suspension equivalent to 10.60 films on an area basis was placed on a Petri dish (9 cm in diameter) and dried in 80 \u0026deg;C chambers for 40\u0026ndash;45 min. The formed film was peeled off and cut to a predetermined size of 2 \u0026times; 3 cm\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacterization of FS-ODF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisintegration Time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne FS-ODF was placed on a petridish (9 cm diameter) with 15 mL of 37 ℃ water. The time to disintegrate completely was measured by visual observation (42). The absence of any significant floating fragments was considered to be the completion of disintegration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBending Count\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe bending count measured by the number of times it took to split when the film was folded in half repeatedly with two fingers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWeight and Drug Content\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prepared FS-ODF was weighed using balance and transferred into 30 mL dilution solution (0.05N NaOH solution) in 50 mL volumetric flask and dissolved with vortexing. Then, the dilution solution was added to be total volume. This solution of 2 mL was transferred to 100 mL volumetric flask and the dilution solution was added to be total volume. The final solution was filtered with syringe filter (0.45 ㎛) and the filtrate was analyzed by the below HPLC method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHPLC Condition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe HPLC analysis of furosemide in the samples was conducted using a Waters 2695 HPLC system (Waters, Milford, MA, USA) equipped with a UV-Vis detector (Waters 2487, Waters, Milford, MA, USA). Furosemide was analyzed using the reverse column with C18, 5 \u0026mu;m, 4.5 mm \u0026times; 25 cm (Shiseido, Tokyo, Japan). The mobile phase consisted of water, tetrahydrofuran, and acetic acid (70:30:1, v/v/v). The HPLC analysis was performed with a flow rate of 1.2 mL/min. The injected volume of the sample was 20 \u0026mu;L, and UV detection was monitored at 272 nm (43). Data acquisition and processing were carried out using the Waters LC Solution software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissolution Test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dissolution test was performed using the USP (35) dissolution apparatus II at pH 1.2 (0.1 N HCl/NaCl buffer), pH 4.0 (acetate buffer), pH 6.8 (phosphate buffer) with the media volume of 900 mL at 37.0 \u0026plusmn; 0.5 \u0026deg;C. The rotational speed was adjusted to 50 rpm. The prepared FS-ODF containing furosemide 20 mg in a sample was placed into a dissolution vessel with a sinker (44). At each predetermined interval, the aliquot (5 mL) of the medium was collected and filtered through a membrane filter (pore size: 0.45 \u0026micro;m). The concentration of furosemide in the filtrate was determined using the above HPLC method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed using a single-dose, randomized, 3-way crossover design. Three methods of furosemide administration were used in each subject with at least 7-day washout period between each experiment. Animals were fasted for 12 hours before the administration of furosemide and had a free access to water during the experiment.\u003c/p\u003e\n\u003cp\u003eEach (random) animals received a furosemide of 2 mg/kg via intravenous (IV), orally uncoated tablet (OUT), furosemide-loaded orally disintegrating film (FS-ODF) routes: (1) Furosemide 2 mg/kg IV, (2) OUT formulation of furosemide 2 mg/kg orally, (3) FS-ODF formulation 2 mg/kg orally.\u003c/p\u003e\n\u003cp\u003eInjections and OUT formulation of furosemide were purchased from handok Pharm. Co. (Seoul, South Korea). For oral administration, furosemide OUT and FS-ODF formulation were cut according to body weight of each dog. Also, 22-Gauge IV catheter was used in the cephalic vein for the IV injections. All dogs were not received other medications before experiment and during the washout period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood samples were collected at 0 (serving as baseline), 5, 15, 30, 45, 60, 120, 240, 360, 480 minutes in each administration routes. All blood samples were obtained from the jugular vein with 23-Gauge 5mL syringe. These samples were immediately divided into heparinized tubes for biochemical test, plain tubes for electrolyte analysis and EDTA-K2 tube for hematocrit. Heparinized plasma and serum were separated after centrifugation at 3,000 x g for 15 minutes and stored at \u0026minus;20 \u0026deg;C until analysis. A complete blood count, BUN, creatinine (Cr), plasma total protein and serum electrolytes were measured.\u003c/p\u003e\n\u003cp\u003eThe urine samples were collected at 0 (serving as baseline), 1, 2, 4, 6, 8 hours in each administration routes. In line with previous studies, the bladder was initially emptied 2 hours before baseline and then collected in 2 hours to calculate baseline hourly urine output (HUO) before furosemide administration. An indwelling 6-8 Fr balloon Foley catheter was placed into the urinary bladder at the initiation of each experiment and the bladder was emptied for urine volume measured at each time point. Urine sample was centrifuged (1500 \u0026times; g, 10 min) and the supernatant was collected to verify urine-specific gravity and the concentrations of sodium, potassium and chloride.\u003c/p\u003e\n\u003cp\u003eComplete blood count was measured by ADVIA 2120i (SIEMENS corporation, Munich, Germany) and biochemistry were measured by Mindray BS-300 (Bio-Medical Electronics Co., Ltd, Shenzhen, China). Electrolyte concentrations in plasma and urine sample were measured by EasyLyte PLUS (MEDICA corporation, Bedford, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantification of furosemide in plasma\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlasma concentration of furosemide were determined by HPLC-MS/MS system. To prepare appropriate assay samples, plasma samples were processed with acetonitrile to induce precipitation of plasma protein. More details as follows; firstly, 15 \u0026micro;L of plasma or calibrator sample were treated with 155 \u0026micro;L of 0.11 \u0026micro;g/mL ibuprofen (internal standard, IS) in acetonitrile. And then, sample mixtures were vigorously shaken by vortex mix for 15 minutes. Finally, sample mixtures were separated into supernatant and precipitant pellet by centrifugation at 17,600 g for 15 minutes. Standard samples were prepared by spiking of 5 \u0026micro;L working solution (as furosemide; 0, 30, 100, 300, 1,000, 3,000, 10,000, 30,000, and 100,000 ng/mL in acetonitrile) into 45 \u0026micro;L of blank plasma. For a sample analysis, 130 \u0026micro;L of supernatant were transferred into sample vials, and 5 \u0026micro;L of processed sample was directly injected into HPLC separation system.\u003c/p\u003e\n\u003cp\u003eFurosemide and IS were separated by Agilent 1100 HPLC system. Chromatographic separation was conducted on Agilent ZORBAX\u003csup\u003e\u0026reg;\u003c/sup\u003e phase phenyl column (5 \u0026micro;m, 2.1 x 50 mm) by 6 mM ammonium formate in 40% acetonitrile solution.\u003c/p\u003e\n\u003cp\u003eAfter a separation, both analytes were detected by triple quadrupole mass spectrometer (AB SCIEX API4000 QTRAP\u0026reg;). Furosemide and IS were monitored under electrospray ionization negative mode as multiple reaction monitoring, which mass to charge ratio of 329.08\u003csup\u003e-\u003c/sup\u003e to 284.80\u003csup\u003e-\u003c/sup\u003e for furosemide and 205.05\u003csup\u003e-\u003c/sup\u003e to 161.10\u003csup\u003e-\u003c/sup\u003e for IS, respectively.\u003c/p\u003e\n\u003cp\u003ePeak areas integration and quantification were automatically conducted by using Analyst software\u0026reg; (AB Sciex) 1.6.2. Concentration-response of furosemide was linear at ranges from 30 ng/mL to 10 \u0026micro;g/mL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePharmacokinetic analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTemporal profiles of furosemide in beagle were analyzed with via non-compartmental model using Phoenix WinNonlin 6.2. (Pharsight, USA). The following pharmacokinetic parameters were calculated and compared based on the route of administration: C\u003csub\u003emax\u003c/sub\u003e, half-life time, AUCs, CL, V\u003csub\u003ess\u003c/sub\u003e, bioavailability (BA). The elimination rate constant (k\u003csub\u003ee\u003c/sub\u003e) was determined by linear regression of the semi-log portion of the elimination phase. The elimination half-life (T\u003csub\u003e1/2\u003c/sub\u003e) was calculated by dividing 0.693 with k\u003csub\u003ee\u003c/sub\u003e. The area under the plasma concentration versus time curve from time zero to infinity (AUC\u003csub\u003einf\u003c/sub\u003e) and the area under the respective first moment time curve from time zero to infinity (AUMC\u003csub\u003einf\u003c/sub\u003e) were calculated based on the linear-trapezoidal method. To estimate the elimination clearance (CL) and volume of distribution at steady state (V\u003csub\u003ess\u003c/sub\u003e), a moment analysis was conducted. In more detail, CL was gained by dividing administered dose with AUC\u003csub\u003einf\u003c/sub\u003e. V\u003csub\u003ess\u003c/sub\u003e was obtained by multiply CL with MRT, which division of AUMC\u003csub\u003einf\u003c/sub\u003e by AUC\u003csub\u003einf\u003c/sub\u003e. BAs of film and tablet groups were calculated from the dose normalized AUC\u003csub\u003ePO\u003c/sub\u003e/AUC\u003csub\u003eIV\u003c/sub\u003e, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data were expressed as mean and standard deviation values. Normality test was conducted with Kolmogorov-Smirnov test and pharmacokinetic parameters were an independent \u003cem\u003et\u003c/em\u003e-test. Because the study aimed to compare orally uncoated tablet with orally disintegrating film, only the differences between these two formulations of administration were statistically analyzed. Comparisons between baseline (0h) and various time phases after drug administration were analyzed statistically using the paired \u003cem\u003et\u003c/em\u003e-test. A \u003cem\u003eP\u003c/em\u003e-value \u0026lt; 0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS 25 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIV: Intravenous; CRI: constant-rate infusion; SC: subcutaneous; PO: oral; OUT: orally uncoated tablet; ODF: orally disintegrating film; FS-ODF: furosemide loaded-orally disintegrating film; BUN: blood urea nitrogen; Cr: creatinine; HUO: hourly urine output; PK/PD: pharmacokinetic and pharmacodynamics; PK: pharmacokinetics; HPLC-MS/MS: High-performance liquid chromatography-tandem mass spectrometry; HPLC: High-performance liquid chromatography; C\u003csub\u003emax\u003c/sub\u003e: maximum plasma concentration ; T\u003csub\u003emax\u003c/sub\u003e: time at the maximum concentration;T\u003csub\u003e1/2\u003c/sub\u003e: elimination half-life; AUC\u003csub\u003einf\u003c/sub\u003e: area under the curve from time zero to time of infinity measurable concentration; AUC\u003csub\u003elast\u003c/sub\u003e: area under the curve from time zero to time of last measurable concentration; F: fraction of oral dose absorbed; MRT: mean residence time; USG: urine specific gravity; UEEH: urinary electrolytes excretion per hour\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Animal Care and Use Committee at Chungnam National University (Approval number: CNU-01189). All methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data for figures, tables, and material used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKSK performed the clinical procedures and data analysis and interpretation and drafted the manuscript.\u003c/p\u003e\n\u003cp\u003eJWJ performed pharmacokinetic analysis and contributed to statistical analysis.\u003c/p\u003e\n\u003cp\u003eSIC contributed to scientific discussions and helped clinical procedures.\u003c/p\u003e\n\u003cp\u003eRMK prepared and characterized FS-ODFs.\u003c/p\u003e\n\u003cp\u003eTSK participated in the study design and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eKHJ developed and provided film materials used for study.\u003c/p\u003e\n\u003cp\u003eKWS were responsible for the study design and academic direction and contributed to revising, editing, and writing of manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript is written based on the Master\u0026rsquo;s thesis of author Suk-Kyu Koh. This research with the support of \u0026ldquo;Cooperative Research Program of Center for Companion Animal Research (Project No. PJ140452): Rural Development Administration, Republic of Korea.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHori Y, Ohshima N, Kanai K, Hoshi F, Itoh N, Higuchi S. Differences in the duration of diuretic effects and impact on the renin-angiotensin-aldosterone system of furosemide in healthy dogs. J Vet Med Sci. 2010;72(1):13-8.\u003c/li\u003e\n\u003cli\u003eYancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e61.\u003c/li\u003e\n\u003cli\u003eBiddle TL, Yu PN. 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Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes. Int J Pharmaceut. 2007;345(1-2):142-53.\u003c/li\u003e\n\u003cli\u003eBranch RA, Roberts CJ, Homeida M, Levine D. Determinants of response to frusemide in normal subjects. Br J Clin Pharmacol. 1977;4(2):121-7.\u003c/li\u003e\n\u003cli\u003eKaojarern S, Day B, Brater DC. The time course of delivery of furosemide into urine: an independent determinant of overall response. Kidney Int. 1982;22(1):69-74.\u003c/li\u003e\n\u003cli\u003evan Meyel JJ, Smits P, Russel FG, Gerlag PG, Tan Y, Gribnau FW. Diuretic efficiency of furosemide during continuous administration versus bolus injection in healthy volunteers. Clin Pharmacol Ther. 1992;51(4):440-4.\u003c/li\u003e\n\u003cli\u003eKim EJ, Han KS, Lee MG. Gastrointestinal first-pass effect of furosemide in rats. J Pharm Pharmacol. 2000;52(11):1337-43.\u003c/li\u003e\n\u003cli\u003eDoungngern T, Huckleberry Y, Bloom JW, Erstad B. Effect of Albumin on Diuretic Response to Furosemide in Patients with Hypoalbuminemia. Am J Crit Care. 2012;21(4):280-6.\u003c/li\u003e\n\u003cli\u003eFarless LB, Steil N, Williams BR, Bailey FA. Intermittent subcutaneous furosemide: parenteral diuretic rescue for hospice patients with congestive heart failure resistant to oral diuretic. Am J Hosp Palliat Care. 2013;30(8):791-2.\u003c/li\u003e\n\u003cli\u003eAnsel HC ALJ, Popovich NG. Pharmaceutical Dosage Forms and Drug Delivery Systems. 7th ed. Philadelphia: Lippin-cott Willams \u0026amp; Wilkins. 1999:pp. 60-100.\u003c/li\u003e\n\u003cli\u003ePonto LL, Schoenwald RD. Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part II). Clin Pharmacokinet. 1990;18(6):460-71.\u003c/li\u003e\n\u003cli\u003eBrater DC. Pharmacokinetics of loop diuretics in congestive heart failure. Br Heart J. 1994;72(2 Suppl):S40-3.\u003c/li\u003e\n\u003cli\u003eYakatan GJ, Maness DD, Scholler J, Johnston JT, Novick WJ, Jr., Doluisio JT. Plasma and tissue levels of furosemide in dogs and monkeys following single and multiple oral doses. Res Commun Chem Pathol Pharmacol. 1979;24(3):465-82.\u003c/li\u003e\n\u003cli\u003ePelligand L, Guillot E, Geneteau A, Guyonnet J, Magnier R, Elliott J, et al. Population Pharmacokinetics and Pharmacodynamics Modeling of Torasemide and Furosemide After Oral Repeated Administration in Healthy Dogs. Front Vet Sci. 2020;7:151.\u003c/li\u003e\n\u003cli\u003eRaj Kumar Goel PS, Shazia, Sanjay Khanna, Rakesh Kumar Dixit. Clinical Significance of Half Life of Drugs. International Journal of Pharmacotherapy. 2014;4(1):6-7.\u003c/li\u003e\n\u003cli\u003eLee Y, Kim K, Kim M, Choi DH, Jeong SH. Orally disintegrating films focusing on formulation, manufacturing process, and characterization. Journal of Pharmaceutical Investigation. 2017;47(3):183-201.\u003c/li\u003e\n\u003cli\u003eKim B-S, Park G-T, Park M-H, Shin YG, Cho C-W. Preparation and evaluation of oral dissolving film containing local anesthetic agent, lidocaine. Journal of Pharmaceutical Investigation. 2017;47(6):575-81.\u003c/li\u003e\n\u003cli\u003eUSP Convention Inc. R-v, Maryland, USA. United States Pharmacopoeia XXIX2006. 1497 p.\u003c/li\u003e\n\u003cli\u003eKim DH, Kim JY, Kim AM, Maharjan P, Ji YG, Jang DJ, et al. Orlistat-loaded solid SNEDDS for the enhanced solubility, dissolution, and in vivo performance. Int J Nanomed. 2018;13:7095-106.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Canine, Furosemide, Loop diuretic, Oral film, Tablet, Conventional administration, Congestive heart failure, Diuresis, Noncompliance","lastPublishedDoi":"10.21203/rs.3.rs-403597/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-403597/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eFurosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal patients, which leads to noncompliance, especially during long-term administration. The oral disintegrating film (ODF) has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The objective of this study was to research the pharmacokinetic and pharmacodynamics (PK/PD) profiles of furosemide after intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered a single dose (2 mg/kg) of furosemide via each route using a cross-over design.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. The maximum plasma concentration of furosemide was higher and the elimination half-life and time at maximum concentration were slightly lower after FS-ODF administration than after OUT administration. In the blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h), whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThese results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (\u0026lt;10 kg) or cats, for the management of congestive heart failure.\u003c/p\u003e","manuscriptTitle":"Pharmacokinetics and Diuretic Effect of Furosemide after Single Intravenous, Oral Tablet, and Newly Developed Oral Disintegrating Film Administration in Healthy Beagle Dogs","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-19 21:52:31","doi":"10.21203/rs.3.rs-403597/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-06-18T03:11:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-17T11:03:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"beb1e927-f769-4782-918b-9ac350f17dcd","date":"2021-06-09T09:01:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-06-04T20:12:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f3c70ac3-ade2-464f-80ee-b6f7f45b44c8","date":"2021-05-28T11:05:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-05-10T16:45:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-05-07T09:38:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-04-16T14:51:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-04-16T09:39:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Veterinary Research","date":"2021-04-09T02:45:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c59101a0-05bc-45d8-8206-52de111d51bf","owner":[],"postedDate":"April 19th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3727468,"name":"Large Animal Medicine"},{"id":3727469,"name":"Small Animal Medicine"}],"tags":[],"updatedAt":"2021-08-17T05:29:07+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-19 21:52:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-403597","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-403597","identity":"rs-403597","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}