Pharmacokinetics of enflicoxib in dogs: Effects of prandial state and repeated administration.
Ontology highlight
ABSTRACT:
SUBMITTER: Homedes J
PROVIDER: S-EPMC9291756 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5- fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration.ResultsIn three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, non-compartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed.ConclusionsLong term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy.
| S-EPMC8218522 | biostudies-literature
Project description:Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3 day washout and resumed daily treatment for 10 days (until Day 14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5-1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 administrations at the highest dose. At higher doses (≥0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day 1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modeled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ≥0.3 mg/kg, higher doses should be limited to 3-5 days to avoid supra-clinical effects in high responders.
| S-EPMC7199743 | biostudies-literature
Project description:Intranasal ketamine has recently gained interest in human medicine, not only for its sedative, anaesthetic or analgesic properties, but also in the management of treatment resistant depression, where it has been shown to be an effective, fast acting alternative treatment. Since several similarities are reported between human psychiatric disorders and canine anxiety disorders, intranasal ketamine could serve as an alternative treatment for anxiety disordered dogs. However, to the authors knowledge, intranasal administration of ketamine and its pharmacokinetics have never been described in dogs. Therefore, this study aimed to examine the pharmacokinetics, absolute bioavailability and tolerability of intranasal ketamine administration compared with intravenous administration. Seven healthy, adult laboratory Beagle dogs were included in this randomized crossover study. The dogs received 2 mg/kg body weight ketamine intravenously (IV) or intranasally (IN), with a two-week wash-out period. Prior to ketamine administration, dogs were sedated intramuscularly with dexmedetomidine. Venous blood samples were collected at fixed times until 480 min post-administration and ketamine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. Cardiovascular parameters and sedation scores were recorded at the same time points. Non-compartmental pharmacokinetic analysis revealed a rapid (Tmax = 0.25 ± 0.14 h) and complete IN bioavailability (F = 147.65 ± 49.97%). Elimination half-life was similar between both administration routes (T1/2el IV = 1.47 ± 0.24 h, T1/2el IN = 1.50 ± 0.97 h). Heart rate and sedation scores were significantly higher at 5 and 10 min following IV administration compared to IN administration, but not at the later time-points.
| S-EPMC6957157 | biostudies-literature
Project description:BackgroundThe inclusion of dexmedetomidine (DEX) within a balanced general anaesthesia protocol is effective in improving the clinical outcome and recovery quality of anaesthesia in horses. This study aimed to determine the pharmacokinetic profile of DEX following repeated subcutaneous (SC) administration at 2 µg/kg every 60 min till the end of the procedure in comparison to intravenous constant rate infusion (CRI) at 1 µg/kg/h in anaesthetized horses undergoing diagnostic procedures up to the end of the diagnostic procedure.ResultsIn the CRI and SC groups DEX maximum concentrations (Cmax) were 0.83 ± 0.27 ng/mL and 1.14 ± 0.71 ng/mL, respectively, reached at a time (Tmax) of 57.0 ± 13.4 min and 105.5 ± 29.9 min. Mean residence time to the last measurable concentration (MRTlast) was 11.7 ± 6.2 and 55.8 ± 19.7 min for the CRI group and SC groups, respectively. The apparent elimination half-life was 18.0 ± 10.0 min in the CRI group and 94.8 ± 69.8 min for the SC group, whereas the area under the curve (AUC0-last) resulted 67.7 ± 29.3 and 83.2 ± 60.5 min*ng/mL for CRI and SC group, respectively. Clearance was 16.26 ± 8.07 mL/min/kg for the CRI group. No signs of adverse effects were recorded in both groups.ConclusionsThe pharmacokinetic profile of DEX following repeated SC administration in anaesthetized horses was comparable to intravenous CRI administration during the intranaesthetic period and beneficial during the recovery phase from general anaesthesia. The SC route could be considered as an alternative to CRI for improving the recovery quality of equine patients undergoing general anaesthesia.
| S-EPMC10709979 | biostudies-literature
Project description:BackgroundGlucocorticoids are used for a variety of purposes in veterinary medicine but often are associated with clinically important adverse effects. Polyuria and polydipsia are the most frustrating adverse effects noted by owners.ObjectiveTo determine whether administration of desmopressin ameliorates polyuria and polydipsia associated with prednisolone administration.AnimalsSeven healthy adult Walker Hounds.MethodsProspective hypothesis testing study. Daily water intake and urine specific gravity (USG) were measured in dogs under 4 separate sequential conditions: no medications (C), prednisolone only (P), prednisolone and desmopressin (PD), and prednisolone after discontinuation of desmopressin (PAD).ResultsWhen compared to baseline, 6 of 7 dogs became polydipsic after administration of prednisolone (0.5 mg/kg PO q12h). When desmopressin (5 μg/dog SC q12h) was administered to dogs receiving prednisolone, significant decreases in water intake and serum sodium concentration occurred, and USG increased significantly.Conclusions and clinical importanceAdministration of desmopressin to dogs receiving prednisolone significantly decreased water intake and serum sodium concentration, and increased USG. Our results suggest that, in some dogs, desmopressin ameliorates the most important adverse effect of prednisolone noted by owners, but that hyponatremia is an important complication associated with desmopressin use.
| S-EPMC8478070 | biostudies-literature
Project description:AimsTo verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference.MethodsThis was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022.ResultsAfter administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR10%max≈11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated.ConclusionsThe PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile.Clinical trial registrationClinicaltrials.gov, identifier NCT04975022.
| S-EPMC10411801 | biostudies-literature
Project description:ObjectivesThyronamines are decarboxylated and deiodinated metabolites of thyroid hormones (THs). Of all possible thyronamine variants, only 3-iodothyronamine (3-T1AM) and iodine-free thyronamine (T0AM) have been detected in vivo. While intensive research has been done on the (patho-)physiological action of 3-T1AM, the role of T0AM has been studied less intensively.Study designWe determined whether a single pharmacological dose (50 mg/kg, i.p.) or repeated administration (5 mg/kg/day, i.p., for 7 days) of T0AM affects metabolism, cardiovascular function, or thermoregulation in male C57BL/6J mice. Since selenium (Se) is important for proper TH function and Se metabolism is affected by TH, we additionally analyzed Se concentrations in liver, serum, and kidney using total reflection X-ray analysis.ResultsA single injection of T0AM had no effect on heart rate, temperature, or activity as assessed by radio telemetry. Likewise, daily administration of T0AM did not alter body weight, food or water intake, heart rate, blood pressure, brown adipose tissue thermogenesis, or body temperature, and no significant differences in hepatic glycogen content or mRNA expression of genes involved in cardiovascular function or metabolic control were determined. Also, the X-ray analysis of Se concentrations revealed no significant changes. However, hepatic T0AM was significantly increased in the treated animals.ConclusionsIn summary, our data demonstrate that T0AM elicits no obvious metabolic, cardiovascular, or thermoregulatory activities in mice. As T0AM does also not interfere with TH or Se metabolism, we conclude that the deiodination of 3-T1AM to T0AM constitutes an efficient inactivation mechanism, terminating the actions of the more powerful precursor.
| S-EPMC5836237 | biostudies-literature
Project description:Alcoholic liver disease (ALD) has become a critical global public health issue worldwide. Tartary buckwheat extracts exhibit potential therapeutic effects against ALD due to its antioxidant and anti-inflammatory activities. However, in vivo pharmacokinetics and metabolite identification of tartary buckwheat extracts have not been clearly elucidated. Accordingly, the current manuscript aimed to investigate pharmacokinetics and to identify novel metabolites in beagle dogs following oral co-administration of tartary buckwheat extracts and ethanol. To support pharmacokinetic study, a simple LC-MS/MS method was developed and validated for simultaneous determination of quercetin and kaempferol in beagle dog plasma. The conjugated forms of both analytes were hydrolyzed by ?-glucuronidase and sulfatase followed by liquid-liquid extraction using methyl tert-butyl ether. In addition, another effective approach was established using advanced ultrafast liquid chromatography coupled with a Q-Exactive hybrid quadrupole orbitrap high resolution mass spectrometer to identify the metabolites in beagle dog biological samples including urine, feces, and plasma. The pharmacokinetic study demonstrated that the absolute oral bioavailability for quercetin and kaempferol was determined to be 4.6% and 1.6%, respectively. Oral bioavailability of quercetin and kaempferol was limited in dogs probably due to poor absorption, significant first pass effect, and biliary elimination, etc. Using high resolution mass spectrometric analysis, a total of nine novel metabolites were identified for the first time and metabolic pathways included methylation, glucuronidation, and sulfation. In vivo pharmacokinetics and metabolite identification results provided preclinical support of co-administration of tartary buckwheat extracts and ethanol in humans.
| S-EPMC6836259 | biostudies-literature
Project description:Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.
| S-EPMC2811070 | biostudies-other
Project description:Background and objectiveDexmedetomidine is a potent agonist of α2-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing.MethodsNon-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion.ResultsThe absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals.ConclusionsOur final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.
| S-EPMC7658092 | biostudies-literature