Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in... more Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in postoperative care. It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. In this study, we aimed to quantify the pharmacokinetics of APAP and its metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), after a single oral and intravenous (IV) administration of 30 mg/kg of propacetamol to six healthy adult Labrador dogs according to a 2 × 2 crossover study. The analyses were performed using a validated HPLC-MS/MS method. PS and PG exposures were higher than that of APAP, while NAPQI concentrations were constantly below the detection limit of the analytical method. IV propacetamol administration produced 30% more APAP than oral administration. However, propacetamol released a significantly lower amount of active moiety in dogs than in humans. The propacetamol dose administered in this study did not produce plasma APAP concentrations above the threshold sufficient to provide analgesia in adult humans (4 μg/mL). In conclusion, direct IV injection of APAP instead of propacetamol might be a better clinical option for pain relief in dogs.
Journal of Veterinary Pharmacology and Therapeutics, Nov 27, 2019
It is generally accepted that alterations in physiology status could affect drug pharmacokinetics... more It is generally accepted that alterations in physiology status could affect drug pharmacokinetics. Diseased animals are frequently reported to have different absorption, distribution, metabolism, and excretion when compared to normal animals (Curry & Whelpton, 2011). However, differences in physiological status in healthy animals can also affect pharmacokinetics (Modric & Martinez, 2011). Females in particular undergo constant changes in their physiological status accompanying gestation and lactation (Bengtsson, Jacobsson, Luthman, & Franklin, 1997). In line with this, several studies have reported that lactation could affect pharmacokinetics of certain drugs (
American Journal of Animal and Veterinary Sciences, Feb 1, 2018
Demontis. This open access article is distributed under a Creative Commons Attribution (CC-BY) 3.... more Demontis. This open access article is distributed under a Creative Commons Attribution (CC-BY) 3.0 license.
Journal of Veterinary Pharmacology and Therapeutics, Jun 25, 2018
Goats produce meat and milk and are therefore potentially important livestock species, especially... more Goats produce meat and milk and are therefore potentially important livestock species, especially in developing countries where they are often of economic significance (Dubeuf, Morand-Fehr, & Rubino, 2004). More recent, goats are also emerging companion animals, which exhibit strong similarities with other companion animals such as dogs and horses in human-directed communicative behavior (Nawroth, 2017). When working with goats, selecting a rational analgesic protocol is essential for veterinarians to facilitate procedures such as assisted parturition and dehorning and to prevent unwanted outcomes including the need for forceful restraint. Disbudding is a procedure commonly performed on juvenile goats to facilitate safe management, and this is painful and can induce extreme stress with excitement (Nfor, Chan, Kere, & Peh, 2016). Although there is motivation for safety and animal welfare reasons, economic considerations limit analgesic use and there are only a small number of licensed drugs available for use in goats. Metamizole (dipyrone, MET) is a nonopioid analgesic prodrug, which exerts antipyretic, anti-inflammatory, spasmolytic, and analgesic properties through the activation of the opioid and cannabinoid
Journal of Veterinary Pharmacology and Therapeutics, Dec 7, 2016
Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market... more Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single‐dose, two‐period crossover). The first study group A (n = 3) received a single IV dose of grapiprant at 2 mg/kg dissolved in ethanol. Group B (n = 3) received a single IV injection of ethanol (equivalent volume to grapiprant volume) at the same site. The second study group C (n = 3) received a single SC dose of meloxicam at 0.5 mg/kg. Group D (n = 3) received a single SC injection of 15% ethanol (equivalent volume to grapiprant volume) at the same site. After a 2‐week washout period, the groups were rotated and the experiments repeated. Blood samples (0.7 mL) were collected from the right ear artery at assigned times and grapiprant plasma concentrations determined by a validated HPLC‐FL method. Three hours prior to administration of the drugs, inflammation was induced by SC injection of lambda carrageenan (200 μL, 3% in physiological saline) under the plantar surface of the right hind paw. At a similar time to the blood collection, an infrared thermal stimuli (40 °C) was applied to the plantar surface of the rabbits’ hindlimbs to evaluate the thermal withdrawal latency (TWL). The thermal antinociceptive effect was expressed as maximum possible response (% MPR). Grapiprant plasma concentrations were detectable up to the 10‐h time point (concentration range 17–7495 ng/mL). The grapiprant‐treated group showed a significant increase in TWL from 1 h and up to 10 h after drug administration compared to the control. In contrast, the meloxicam group showed a significant increase in TWL from 4 up to 10 h after drug administration, compared to control. The maximal MPR% was not statistically different between the grapiprant and meloxicam group from 4 to 8 h, while significant differences were shown at 1, 1.5, 2, 10 and 24 h. Given these findings, grapiprant appears to be an attractive option for antinociception in rabbits, due to its rapid onset and extended duration of effect.
Polish Journal of Veterinary Sciences, Jul 26, 2023
Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It ... more Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is currently marketed for human use in Asian countries for the treatment of asthma, cerebrovascular disorders and ocular allergies. Ibudilast has also been found to have an analgesic action for neuropathic pain at doses 5-10 times higher than those used in asthma therapy. Six healthy Labrador dogs were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, cross-over design (2x2 Latin-square). Dogs in group 1 (n=3) were fasted for at least 10 hours overnight before the beginning of the experiment and 4 h following dosing while dogs in group 2 (n=3) received food ad libitum. During the first phase, each dog in group 1 and 2 received a single dose of 5 mg/kg ibudilast administered orally. After 1-week washout period the groups were rotated and the experiment was repeated. The analytical method, validated for dog plasma, was shown to be linear in the range 0.10-20 µg/mL. The limit of detection (LOD) and quantification (LOQ) were 0.03 and 0.1 µg/mL, respectively. No behavioural or health alterations were observed in the animals during or after the study. Ibudilast was detectable in plasma for up to 24 h showing a wide variability between animals. Although no statistically significant differences were observed in the present study between the fed and fasted states, examination of the raw data suggests that an effect may be present. The wide degree of variation observed in area under the curve (AUC) suggests that the investigation of population pharmacokinetic modelling is warranted.
1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel o... more 1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.
The aim of this study was to assess the pharmacokinetic profile of LFX in sheep after intravenous... more The aim of this study was to assess the pharmacokinetic profile of LFX in sheep after intravenous (IV) and oral (PO) administration of 2 mg/kg LFX once a day for 5 days and to evaluate its tissue depletion in the muscles, heart, liver, lungs, and kidneys. Twenty healthy female sheep were randomly divided into two equal groups. Each group was further randomly subdivided into two equal subgroups (n = 5). Group 1 was used for blood collection and underwent a crossover design (2 × 2 Latin square). Group 2 was randomly subdivided into two equal subgroups (n = 5) for IV and PO route respectively, and used for tissue collection. A single sheep was sacrificed at each time point and the organs were harvested. Samples were analyzed using a validated HPLC method with fluorescence detection. LFX administered orally was rapidly absorbed with a peak plasma concentration of 2866 ± 239 ng/mL and an absolute oral bioavailability of 114 ± 27.7%. The pharmacokinetic estimates were comparable between PO and IV administration. According to the pharmacokinetic/pharmacodynamic surrogate index (area under the curve / minimum inhibitory concentration) of 100-125, LFX has the potential to be an effective treatment for infections caused by bacteria with a MIC of 0.049-0.061 μg/mL. LFX was detected for up to 48 h in all the tissues samples. The kidney had the highest LFX concentration after IV and PO administration. The AUC tissue/plasma ratio was lower than 1 in all tissues indicating absence of LFX tissue accumulation.
Journal of Veterinary Pharmacology and Therapeutics, Jan 27, 2015
In reptiles, administration of opioid drugs has yielded unexpected results with respect to analge... more In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. The aims of this study were to assess the pharmacokinetic/pharmacodynamic (PK/PD) properties of tramadol and its active metabolite M1 and to evaluate the effect of the renal portal system on the PK/PD parameters in yellow-bellied slider turtles. Turtles (n = 19) were randomly assigned to four treatment groups, according to a masked, single-dose, four-treatment, unpaired, four-period crossover design. Group A (n = 5) received a single i.m. dose of tramadol (50 mg/mL) at 10 mg/kg in the proximal hindlimb. Group B (n = 5) received the same i.m. dose but in the forelimb. Groups C (n = 5) and D (n = 4) received a single i.m. injection of saline (NaCl 0.9%) of equivalent volume to the volumes of tramadol injected in the hind- and forelimb, respectively. Groups were rotated (1-month washout period) until the completion of the crossover study. Tramadol plasma concentrations were evaluated by a validated HPLC-FL method. An infrared thermal stimulus was applied to the plantar surface of the turtles' hindlimbs to evaluate the thermal withdrawal latency (TWL). The two PK profiles of tramadol differed in the first 2 h following administration, but overlapped in the elimination phases. The metabolite M1 was formed in both the treatment groups, showing similar pharmacokinetic trends, although the amount of M1 was significantly higher (20%) in the hindlimb vs. forelimb group. Turtles given tramadol in the hind- and forelimb showed a significant increase in TWL over the periods of 0.5-48 and 8-48 h, respectively. The calculated % maximal possible response (% MPR) was low (about 24%). The PK/PD correlations between M1 plasma concentrations vs. % MPR appeared to show a counterclockwise hysteresis loop shape.
Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, ... more Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs in some countries. MT is rapidly hydrolyzed to the active primary metabolite 4methyl-amino-antipyrine (MAA). MAA is formed in much larger amounts compared to other minor metabolites. Among the other secondary metabolites, 4-amino-antipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after administration of 25 mg/kg MT by intravenous (IV) and intramuscular (IM) routes in healthy donkeys. Six jennies were randomly allocated to two equally sized treatment groups according to a 2x2 crossover study. Blood was collected at predetermined times within 24 hours and plasma was analysed by a validated HPLC UV method. Plasma concentrations of MAA after IV and IM administrations of MT were detectable from 5 minutes to 10 hours in all the donkeys. Plasma concentrations of AA were detectable from 5 minutes to 8 hours, but in smaller amounts. C max (P < 0.01), AUC 0-last , AUC 0-∞ , AUMC 0-last and MRT (P < 0.05) were statistically different between the IV and IM groups. The AUC IM /AUC IV ratio of MAA was 1.37. The AA concentrations were lower than those found for MAA. The AA plasma vs time curves profiles after the two routes of administration of MT were variable (within the groups) and different (between the groups). T max , λz and AUC 0-last were found to be statistically different between the groups (P < 0.05). The AUC IM AA/AUC IV AA ratio was 2.26.
Drugs that provide effective analgesia in cats are limited. The aim of the present study was to i... more Drugs that provide effective analgesia in cats are limited. The aim of the present study was to investigate the pharmacokinetics of the novel atypical drug tapentadol (TAP) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) injection in six healthy cats using a 3x3 Latin square crossover study design. The dose rate used was 5 mg/kg and the concentrations of TAP in plasma were evaluated using high-performance liquid chromatography. Some adverse effects including salivation, agitation and panting, were noted, especially following IV administration. In all three administration groups, TAP concentrations were detectable in plasma for up to 8 h. Bioavailability for each route was almost complete, accounting for 94% and 90% after IM and SC administrations, respectively. Drug absorption was faster after IM than SC administration (0.25 h vs. 0.63 h). The half-life of the terminal portion of the plasma concentration curve was not significantly different between the three routes of administrations (2-3 h). TAP appears to have some variation in its pharmacokinetic features in cats compared to other animal species. Further studies are needed to evaluate whether TAP would be suitable for use in cats that are experiencing moderate to severe pain, but are sensitive to the adverse effects of commonly prescribed opioids.
American Journal of Animal and Veterinary Sciences, 2019
Vilazodone (VLZ) is an antidepressant agent approved in 2011 by Food and Drug Administration (FDA... more Vilazodone (VLZ) is an antidepressant agent approved in 2011 by Food and Drug Administration (FDA) for the treatment of major depressive syndromes. Its chemical structure derives from trazodone which is used as an off-label drug for dogs and cats in order to induce sedation and reduce anxiety, behavioural and pre-and post-operative stress. VLZ could be a potentially useful compound in reducing severe anxiety responses in pet animals. The aim of the present research was to develop and validate a method to quantify VLZ in rabbit plasma. A 500 µL aliquot of rabbit control plasma was added to 50 µL of IS (0.1 ug/mL) and 100 µL of NaOH 0.1M. Then 1 mL of Et 2 O:EtOAc (70:30 v/v) was added and the sample, shaken and centrifuged. The organic layer was transferred into a clean polypropylene vial. This procedure was repeated twice. The combined supernatants were evaporated under nitrogen at 40°C and reconstituted with 100 µL of mobile phase. 50 µL of this latter solution was injected onto HPLC-FL. The mobile phase consisted of Na 2 HPO 4 (0.02M, pH 5):ACN (67:33 v/v) at a flow rate of 1 mL/min. The analytical column (C18) was maintained at 40°C. Excitation and emission wavelengths were set at 353 and 486 nm, respectively. Times of retention of VLZ and IS were 3.26±0.09 and 4.70±0.08 minutes, respectively. The recovery of VLZ was about 83%. Limits of quantification and detection were 0.005 µg/mL and 0.001 µg/mL, respectively. This method was verified by determining VLZ concentration in rabbit plasma after a 1 mg/kg single IV administration. The analysis of samples allowed the calculation of the main pharmacokinetic parameters. In conclusion, the present research was able to quantify VLZ in rabbit plasma after VLZ administration. This method might have application for pharmacokinetic or toxicological studies.
Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in... more Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in postoperative care. It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. In this study, we aimed to quantify the pharmacokinetics of APAP and its metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), after a single oral and intravenous (IV) administration of 30 mg/kg of propacetamol to six healthy adult Labrador dogs according to a 2 × 2 crossover study. The analyses were performed using a validated HPLC-MS/MS method. PS and PG exposures were higher than that of APAP, while NAPQI concentrations were constantly below the detection limit of the analytical method. IV propacetamol administration produced 30% more APAP than oral administration. However, propacetamol released a significantly lower amount of active moiety in dogs than in humans. The propacetamol dose administered in this study did not produce plasma APAP concentrations above the threshold sufficient to provide analgesia in adult humans (4 μg/mL). In conclusion, direct IV injection of APAP instead of propacetamol might be a better clinical option for pain relief in dogs.
Journal of Veterinary Pharmacology and Therapeutics, Nov 27, 2019
It is generally accepted that alterations in physiology status could affect drug pharmacokinetics... more It is generally accepted that alterations in physiology status could affect drug pharmacokinetics. Diseased animals are frequently reported to have different absorption, distribution, metabolism, and excretion when compared to normal animals (Curry & Whelpton, 2011). However, differences in physiological status in healthy animals can also affect pharmacokinetics (Modric & Martinez, 2011). Females in particular undergo constant changes in their physiological status accompanying gestation and lactation (Bengtsson, Jacobsson, Luthman, & Franklin, 1997). In line with this, several studies have reported that lactation could affect pharmacokinetics of certain drugs (
American Journal of Animal and Veterinary Sciences, Feb 1, 2018
Demontis. This open access article is distributed under a Creative Commons Attribution (CC-BY) 3.... more Demontis. This open access article is distributed under a Creative Commons Attribution (CC-BY) 3.0 license.
Journal of Veterinary Pharmacology and Therapeutics, Jun 25, 2018
Goats produce meat and milk and are therefore potentially important livestock species, especially... more Goats produce meat and milk and are therefore potentially important livestock species, especially in developing countries where they are often of economic significance (Dubeuf, Morand-Fehr, & Rubino, 2004). More recent, goats are also emerging companion animals, which exhibit strong similarities with other companion animals such as dogs and horses in human-directed communicative behavior (Nawroth, 2017). When working with goats, selecting a rational analgesic protocol is essential for veterinarians to facilitate procedures such as assisted parturition and dehorning and to prevent unwanted outcomes including the need for forceful restraint. Disbudding is a procedure commonly performed on juvenile goats to facilitate safe management, and this is painful and can induce extreme stress with excitement (Nfor, Chan, Kere, & Peh, 2016). Although there is motivation for safety and animal welfare reasons, economic considerations limit analgesic use and there are only a small number of licensed drugs available for use in goats. Metamizole (dipyrone, MET) is a nonopioid analgesic prodrug, which exerts antipyretic, anti-inflammatory, spasmolytic, and analgesic properties through the activation of the opioid and cannabinoid
Journal of Veterinary Pharmacology and Therapeutics, Dec 7, 2016
Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market... more Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single‐dose, two‐period crossover). The first study group A (n = 3) received a single IV dose of grapiprant at 2 mg/kg dissolved in ethanol. Group B (n = 3) received a single IV injection of ethanol (equivalent volume to grapiprant volume) at the same site. The second study group C (n = 3) received a single SC dose of meloxicam at 0.5 mg/kg. Group D (n = 3) received a single SC injection of 15% ethanol (equivalent volume to grapiprant volume) at the same site. After a 2‐week washout period, the groups were rotated and the experiments repeated. Blood samples (0.7 mL) were collected from the right ear artery at assigned times and grapiprant plasma concentrations determined by a validated HPLC‐FL method. Three hours prior to administration of the drugs, inflammation was induced by SC injection of lambda carrageenan (200 μL, 3% in physiological saline) under the plantar surface of the right hind paw. At a similar time to the blood collection, an infrared thermal stimuli (40 °C) was applied to the plantar surface of the rabbits’ hindlimbs to evaluate the thermal withdrawal latency (TWL). The thermal antinociceptive effect was expressed as maximum possible response (% MPR). Grapiprant plasma concentrations were detectable up to the 10‐h time point (concentration range 17–7495 ng/mL). The grapiprant‐treated group showed a significant increase in TWL from 1 h and up to 10 h after drug administration compared to the control. In contrast, the meloxicam group showed a significant increase in TWL from 4 up to 10 h after drug administration, compared to control. The maximal MPR% was not statistically different between the grapiprant and meloxicam group from 4 to 8 h, while significant differences were shown at 1, 1.5, 2, 10 and 24 h. Given these findings, grapiprant appears to be an attractive option for antinociception in rabbits, due to its rapid onset and extended duration of effect.
Polish Journal of Veterinary Sciences, Jul 26, 2023
Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It ... more Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is currently marketed for human use in Asian countries for the treatment of asthma, cerebrovascular disorders and ocular allergies. Ibudilast has also been found to have an analgesic action for neuropathic pain at doses 5-10 times higher than those used in asthma therapy. Six healthy Labrador dogs were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, cross-over design (2x2 Latin-square). Dogs in group 1 (n=3) were fasted for at least 10 hours overnight before the beginning of the experiment and 4 h following dosing while dogs in group 2 (n=3) received food ad libitum. During the first phase, each dog in group 1 and 2 received a single dose of 5 mg/kg ibudilast administered orally. After 1-week washout period the groups were rotated and the experiment was repeated. The analytical method, validated for dog plasma, was shown to be linear in the range 0.10-20 µg/mL. The limit of detection (LOD) and quantification (LOQ) were 0.03 and 0.1 µg/mL, respectively. No behavioural or health alterations were observed in the animals during or after the study. Ibudilast was detectable in plasma for up to 24 h showing a wide variability between animals. Although no statistically significant differences were observed in the present study between the fed and fasted states, examination of the raw data suggests that an effect may be present. The wide degree of variation observed in area under the curve (AUC) suggests that the investigation of population pharmacokinetic modelling is warranted.
1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel o... more 1. The aim of the study was to evaluate the pharmacokinetics (PKs) of tapentadol (TAP), a novel opioid analgesic, in laying hens after intravenous (IV) and oral (PO) administration and to quantify the concentrations of TAP residues in eggs. 2. Twenty healthy laying hens were divided into three groups: A (n = 6), B (n = 6) and C (n = 8). The study was conducted in two phases. Groups A and B received TAP by IV and PO routes at the dose of 1 and 5 mg/kg, respectively. 3. No visible adverse effects were observed after administration of the drug. TAP plasma concentrations were detectable up to 4 h following administration. Following IV administration, TAP plasma concentrations were only higher than the minimal effective concentration (148 ng/ml) reported for humans for 1 h. After single PO administration, plasma concentrations of TAP would not conform to software algorithms and the PK parameters were not calculated. TAP concentration following multiple PO doses at 5 mg/kg for 5 d was found to be higher and more persistent (12 h vs. 7 h) in yolk compared with albumen. 4. This is the first PK study on the novel atypical opioid TAP in laying hens. Further studies are required to investigate the analgesic efficacy and actual effective plasma concentration of TAP in this species.
The aim of this study was to assess the pharmacokinetic profile of LFX in sheep after intravenous... more The aim of this study was to assess the pharmacokinetic profile of LFX in sheep after intravenous (IV) and oral (PO) administration of 2 mg/kg LFX once a day for 5 days and to evaluate its tissue depletion in the muscles, heart, liver, lungs, and kidneys. Twenty healthy female sheep were randomly divided into two equal groups. Each group was further randomly subdivided into two equal subgroups (n = 5). Group 1 was used for blood collection and underwent a crossover design (2 × 2 Latin square). Group 2 was randomly subdivided into two equal subgroups (n = 5) for IV and PO route respectively, and used for tissue collection. A single sheep was sacrificed at each time point and the organs were harvested. Samples were analyzed using a validated HPLC method with fluorescence detection. LFX administered orally was rapidly absorbed with a peak plasma concentration of 2866 ± 239 ng/mL and an absolute oral bioavailability of 114 ± 27.7%. The pharmacokinetic estimates were comparable between PO and IV administration. According to the pharmacokinetic/pharmacodynamic surrogate index (area under the curve / minimum inhibitory concentration) of 100-125, LFX has the potential to be an effective treatment for infections caused by bacteria with a MIC of 0.049-0.061 μg/mL. LFX was detected for up to 48 h in all the tissues samples. The kidney had the highest LFX concentration after IV and PO administration. The AUC tissue/plasma ratio was lower than 1 in all tissues indicating absence of LFX tissue accumulation.
Journal of Veterinary Pharmacology and Therapeutics, Jan 27, 2015
In reptiles, administration of opioid drugs has yielded unexpected results with respect to analge... more In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. The aims of this study were to assess the pharmacokinetic/pharmacodynamic (PK/PD) properties of tramadol and its active metabolite M1 and to evaluate the effect of the renal portal system on the PK/PD parameters in yellow-bellied slider turtles. Turtles (n = 19) were randomly assigned to four treatment groups, according to a masked, single-dose, four-treatment, unpaired, four-period crossover design. Group A (n = 5) received a single i.m. dose of tramadol (50 mg/mL) at 10 mg/kg in the proximal hindlimb. Group B (n = 5) received the same i.m. dose but in the forelimb. Groups C (n = 5) and D (n = 4) received a single i.m. injection of saline (NaCl 0.9%) of equivalent volume to the volumes of tramadol injected in the hind- and forelimb, respectively. Groups were rotated (1-month washout period) until the completion of the crossover study. Tramadol plasma concentrations were evaluated by a validated HPLC-FL method. An infrared thermal stimulus was applied to the plantar surface of the turtles&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; hindlimbs to evaluate the thermal withdrawal latency (TWL). The two PK profiles of tramadol differed in the first 2 h following administration, but overlapped in the elimination phases. The metabolite M1 was formed in both the treatment groups, showing similar pharmacokinetic trends, although the amount of M1 was significantly higher (20%) in the hindlimb vs. forelimb group. Turtles given tramadol in the hind- and forelimb showed a significant increase in TWL over the periods of 0.5-48 and 8-48 h, respectively. The calculated % maximal possible response (% MPR) was low (about 24%). The PK/PD correlations between M1 plasma concentrations vs. % MPR appeared to show a counterclockwise hysteresis loop shape.
Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, ... more Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine and dogs in some countries. MT is rapidly hydrolyzed to the active primary metabolite 4methyl-amino-antipyrine (MAA). MAA is formed in much larger amounts compared to other minor metabolites. Among the other secondary metabolites, 4-amino-antipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after administration of 25 mg/kg MT by intravenous (IV) and intramuscular (IM) routes in healthy donkeys. Six jennies were randomly allocated to two equally sized treatment groups according to a 2x2 crossover study. Blood was collected at predetermined times within 24 hours and plasma was analysed by a validated HPLC UV method. Plasma concentrations of MAA after IV and IM administrations of MT were detectable from 5 minutes to 10 hours in all the donkeys. Plasma concentrations of AA were detectable from 5 minutes to 8 hours, but in smaller amounts. C max (P < 0.01), AUC 0-last , AUC 0-∞ , AUMC 0-last and MRT (P < 0.05) were statistically different between the IV and IM groups. The AUC IM /AUC IV ratio of MAA was 1.37. The AA concentrations were lower than those found for MAA. The AA plasma vs time curves profiles after the two routes of administration of MT were variable (within the groups) and different (between the groups). T max , λz and AUC 0-last were found to be statistically different between the groups (P < 0.05). The AUC IM AA/AUC IV AA ratio was 2.26.
Drugs that provide effective analgesia in cats are limited. The aim of the present study was to i... more Drugs that provide effective analgesia in cats are limited. The aim of the present study was to investigate the pharmacokinetics of the novel atypical drug tapentadol (TAP) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) injection in six healthy cats using a 3x3 Latin square crossover study design. The dose rate used was 5 mg/kg and the concentrations of TAP in plasma were evaluated using high-performance liquid chromatography. Some adverse effects including salivation, agitation and panting, were noted, especially following IV administration. In all three administration groups, TAP concentrations were detectable in plasma for up to 8 h. Bioavailability for each route was almost complete, accounting for 94% and 90% after IM and SC administrations, respectively. Drug absorption was faster after IM than SC administration (0.25 h vs. 0.63 h). The half-life of the terminal portion of the plasma concentration curve was not significantly different between the three routes of administrations (2-3 h). TAP appears to have some variation in its pharmacokinetic features in cats compared to other animal species. Further studies are needed to evaluate whether TAP would be suitable for use in cats that are experiencing moderate to severe pain, but are sensitive to the adverse effects of commonly prescribed opioids.
American Journal of Animal and Veterinary Sciences, 2019
Vilazodone (VLZ) is an antidepressant agent approved in 2011 by Food and Drug Administration (FDA... more Vilazodone (VLZ) is an antidepressant agent approved in 2011 by Food and Drug Administration (FDA) for the treatment of major depressive syndromes. Its chemical structure derives from trazodone which is used as an off-label drug for dogs and cats in order to induce sedation and reduce anxiety, behavioural and pre-and post-operative stress. VLZ could be a potentially useful compound in reducing severe anxiety responses in pet animals. The aim of the present research was to develop and validate a method to quantify VLZ in rabbit plasma. A 500 µL aliquot of rabbit control plasma was added to 50 µL of IS (0.1 ug/mL) and 100 µL of NaOH 0.1M. Then 1 mL of Et 2 O:EtOAc (70:30 v/v) was added and the sample, shaken and centrifuged. The organic layer was transferred into a clean polypropylene vial. This procedure was repeated twice. The combined supernatants were evaporated under nitrogen at 40°C and reconstituted with 100 µL of mobile phase. 50 µL of this latter solution was injected onto HPLC-FL. The mobile phase consisted of Na 2 HPO 4 (0.02M, pH 5):ACN (67:33 v/v) at a flow rate of 1 mL/min. The analytical column (C18) was maintained at 40°C. Excitation and emission wavelengths were set at 353 and 486 nm, respectively. Times of retention of VLZ and IS were 3.26±0.09 and 4.70±0.08 minutes, respectively. The recovery of VLZ was about 83%. Limits of quantification and detection were 0.005 µg/mL and 0.001 µg/mL, respectively. This method was verified by determining VLZ concentration in rabbit plasma after a 1 mg/kg single IV administration. The analysis of samples allowed the calculation of the main pharmacokinetic parameters. In conclusion, the present research was able to quantify VLZ in rabbit plasma after VLZ administration. This method might have application for pharmacokinetic or toxicological studies.
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Papers by Mario Giorgi