Benazepril increases feed intake and body weight in healthy growing cats.
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Administration, Oral↗
Biomedical subjects
J N King
Publications and source records attributed to J N King.
Pharmacokinetic/pharmacodynamic modelling of the disposition and effect of benazepril and benazeprilat in cats.
The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14C-benazeprilat and oral 14C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 approximately 1.0 h; Cl approximately 0.125 L/kg/h), elimination being principally biliary ( approximately 85%) rather than urinary ( approximately 15%). Nevertheless, inhibition of ACE was long-lasting (t1/2 16-23 h) due to high affinity binding of benazeprilat to ACE (Kd approximately 3.5 mmol/L, IC50 approximately 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).
Administration, Oral↗
Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of benazepril in cats.
The effect of renal insufficiency was studied on the pharmacokinetics (PK) and pharmacodynamics (PD) of the angiotensin-converting enzyme (ACE) inhibitor benazepril in cats. The active metabolite of benazepril, benazeprilat, is eliminated principally ( approximately 85%) via biliary excretion in cats. A total of 20 control animals and 32 cats with moderate renal insufficiency induced by partial nephrectomy were used. Assessments were made at steady state after treatment with placebo or benazepril (0.25-2 mg/kg) once daily for a minimum of 10 days. The PK endpoint was the AUC (0-->24 h) of total plasma benazeprilat. The PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP, DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex vivo assay. Renal function was assessed by glomerular filtration rate (GFR), measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As compared with control animals, the renal insufficient cats had a 78% reduction in GFR (0.57 +/- 0.41 mL/min kg), increased plasma creatinine (2.7 +/- 1.0 mg/dL), urea (44.0 +/- 11.9 mg/dL) and ACE activity, and moderately increased blood pressure (SBP 171.8 +/- 5.1 mmHg) (all parameters P < 0.05). Renal insufficient cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and ACE, and higher GFR values as compared with placebo-treated animals. There were no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according to the degree of renal insufficiency in cats receiving benazepril. It is concluded that no dose adjustment of benazepril is necessary in cats with moderate renal insufficiency.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacokinetics of clomipramine in dogs following single-dose intravenous and oral administration.
OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose. ANIMALS: 6 male and 6 female Beagles. PROCEDURES: Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Time to peak plasma concentrations of clomipramine and desmethylclomipramine following oral administration was 1.2 hours. For clomipramine, after IV administration, elimination half-life was 5 hours, mean residence time was 3 hours, and plasma clearance was 1.4 L/h/kg. Values for mean residence time and terminal half-life following oral administration were similar to values obtained following IV administration, and systemic bioavailability was approximately 20% for clomipramine and 140% for desmethylclomipramine, indicating fast absorption of clomipramine from the gastrointestinal tract and extensive first-pass metabolism. Administration of clomipramine with food did not alter the area under the concentration versus time curve for desmethylclomipramine but resulted in a 25% increase for clomipramine. Clomipramine and desmethylclomipramine were extensively bound (> 96%) to serum proteins. There were no significant differences in area under the concentration versus time curve between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that there should not be any clinically important differences in efficacy regardless of whether clomipramine is administered with or without food.
Administration, Oral↗
Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration.
OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ANIMALS: 9 male and 9 female Beagles. PROCEDURES: Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Dose-related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethylclomipramine in dogs.
Administration, Oral↗
Effects of clomipramine hydrochloride on heart rate and rhythm in healthy dogs.
OBJECTIVE: To determine the effects of clomipramine hydrochloride on heart rate and rhythm in dogs. ANIMALS: 17 healthy Beagles. PROCEDURES: In experiment 1, 8 dogs received placebo or clomipramine (20 mg/kg of body weight, q 24 h, PO) for 7 days in a 2-way crossover design. In experiment 2, 9 dogs were evaluated for 48 hours before and 24 hours after oral administration of clomipramine (4 or 12 mg/kg) in a 2-way crossover design. Electrocardiogram and heart rate were monitored continuously by use of telemetry. RESULTS: A significant diurnal rhythm in heart rate was detected; minimum values were recorded at night. Administration of 20 mg of clomipramine/kg induced a significant reduction in heart rate, with peak effect achieved approximately 12 hours after dosing. Administration of 4 or 12 mg of clomipramine/kg did not result in significant changes in heart rate. Sinoatrial and second-degree atrioventricular block and ventricular escape beats were observed during periods of slow heart rate in more dogs that received clomipramine (3 to 4 of 8 dogs), compared with dogs that received placebo (1 to 2 of 8 dogs), but this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE: Short-term administration of clomipramine induced benign cardiovascular effects in dogs rather than the potentially dangerous arrhythmias or tachycardia reported following administration of tricyclic antidepressants to humans. Precautions regarding cardiovascular effects may not be needed for the use of clomipramine in healthy dogs.
Animals↗
Benazeprilat disposition and effect in dogs revisited with a pharmacokinetic/pharmacodynamic modeling approach.
The pharmacokinetic disposition of benazeprilat, an angiotensin-converting enzyme (ACE) inhibitor (ACEI), was assessed with a nonlinear binding model in dogs. A single oral benazepril dose, a single i.v. benazeprilat dose, or a daily oral dose of benazepril for 14 consecutive days was administered. The activity of benazeprilat was assessed by measuring plasma ACE inhibition with an ex vivo assay. Benazeprilat data were fitted to equations corresponding to a monocompartmental model with a volume equal to the extracellular space ( approximately 0.2 l/kg) in which a fraction of benazeprilat was nonlinearily bound to ACE with both a saturable tissue and nontissue binding. The half-life of benazeprilat elimination determined from this physiologically based model was 39 +/- 6 min. The estimated maximal binding capacity of benazeprilat to ACE was approximately 23.5 nmol/kg, 90% of which was tissular. The estimated equilibrium constant of dissociation (K(d)) of benazeprilat to ACE was 2.7 to 4.5 nM. IC(50) values were one order of magnitude lower than K(d) values (i.e., approximately 0.27 nM). The nonlinear disposition of benazeprilat raised several issues and it was concluded that the benazeprilat concentration profile was only relevant to definition of an optimal dosage regimen if the appropriate kinetic model was used to interpret the plasma data.
Administration, Oral↗
Plasma angiotensin converting enzyme activity and pharmacokinetics of benazepril and benazeprilat in cats after single and repeated oral administration of benazepril.HCl.
The plasma pharmacokinetics of benazepril and its active metabolite, benazeprilat, were determined in cats after oral administration of benazepril.HCl at dosages of 0.25, 0.5 and 1.0 mg/kg as a single dose (n = 5 per group) and after once daily application for 8 days (n = 6 per group). Pharmacodynamics were assessed by measurement of plasma angiotensin converting enzyme (ACE) activity. After single administration of benazepril.HCl, maximum benazepril concentrations were recorded at the first sample (2 h) and declined relatively rapidly with an elimination half life (t1/2) of 1.4 h. Highest benazeprilat concentrations were recorded at the first sample (2 h) in most cats and declined biphasically with half lives of each phase of 2.4 and 27.7 h. With repeated administration, plasma benazeprilat concentrations accumulated slightly with accumulation ratios (R) of 1.46, 1.36 and 1.24 for the 0.25, 0.5 and 1.0 mg/kg dosages of benazepril.HCl, respectively (median value of 1.36 for all dosages). All three dosages of benazepril.HCl caused marked inhibition of plasma ACE activity in all cats. The maximum effect (Emax, % inhibition of ACE as compared to baseline) was > or = 98% after single and 100% with repeated administration. The duration of action of benazepril.HCl was long, with > 87% (single) and > 90% (repeat) inhibition of plasma ACE persisting 24 h after dosing. Benazepril.HCl was well tolerated in all animals. Dosages of 0.25-1.0 mg/kg benazepril.HCl once daily are recommended for clinical testing in cats.
Administration, Oral↗
Pharmacokinetics of the angiotensin-converting-enzyme inhibitor, benazepril, and its active metabolite, benazeprilat, in dog.
1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inhibitor benazepril were evaluated in eight healthy Beagle dogs. Benazepril was administered orally at a dosage of 7.5 mg (about 0.5 mg/kg) both as a single dose and then once daily for 14 consecutive days. The prodrug, benazepril, and its active metabolite, benazeprilat, were measured in plasma using a gas chromatography mass-spectrometry method with mass-selective detection. 2. Benazepril appeared quickly in the plasma (tmax 0.5 h) and was rapidly eliminated by metabolism to benazeprilat. Peak benazeprilat concentrations were attained later (tmax 1.25 h) and declined biphasically with a rapid elimination phase (t1/2 lambda 1 1.1 and 1.7 h after single and the last repeated dose respectively) followed by a terminal elimination phase (t1/2 lambda z 11.7 and 19.0 h after single and repeated dose respectively). The mean residence time for benazeprilat was 15.2 h after the single dose and 17.4 h after the 14th dose. 3. Repeated administration of benazepril produced moderate bioaccumulation of benazeprilat; the ratio of AUC[0-->24 h]'s after the 14th dose as compared with the single dose was 1.47, equivalent to a half-life for accumulation (t1/2acc) of 14.6 h. Steady-state benazeprilat concentrations at peak (Cmax) and trough (Cmin) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both single doses and at steady-state, benazepril produced inhibition of ACE activity in all dogs that was maximal at peak effect (Emax = 100%) and long-lasting (> 85% inhibition was present at 24 h). The long duration of action of benazepril on plasma ACE is due to the presence of the terminal elimination phase of benazeprilat, even though most of the metabolite is rapidly eliminated from the plasma.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacokinetics of the active metabolite of benazepril, benazeprilat, and inhibition of plasma angiotensin-converting enzyme activity after single and repeated administrations to dogs.
Plasma pharmacokinetic variables of benazeprilat, the active metabolite of the angiotensin-converting enzyme (ACE) inhibitor benazepril, were evaluated in healthy Beagles. Benazeprilat was administered IV at a dosage of 0.5 mg/kg of body weight (n = 9). The elimination of half-life of benazeprilat was 3.5 hours, although an additional terminal phase was observed in some dogs. Vehicle (gelatin capsules) or benazepril at dosages of 0.125, 0.25, 0.5, or 1.0 mg/kg was administered orally as a single administration, then once daily for 15 consecutive days (n = 5 or 6/group). Peak benazeprilat concentrations were rapidly attained by 2 hours. Benazeprilat concentrations accumulated moderately with repeated administration, with a peak concentration that was 23% higher and an area under the concentration-time curve that was 34% higher after the 15th dose of benazepril, compared with values after a single dose. The effective half-life for accumulation for all 4 dosages was 12 hours. Steady-state concentrations at 2 hours after administration were achieved after a median (range) of 1 (1 to 6) dose(s). Pharmacodynamic variables were assessed by measurements of plasma ACE activity after oral administration of benazepril or vehicle. All dosages of benazepril caused profound inhibition of ACE, with rapid onset of activity (time to peak effect, 2 hours) and long duration of action (single administration of all 4 doses induced inhibition of ACE that was significantly different from the value in the control [vehicle-treated] dogs for all time points between 1 and 30 hours). Maximal inhibition at all time points was induced by the 0.25-mg/kg dosage at a single administration and with the lowest dosage tested (0.125 mg/kg) at steady state. At steady state, the 0.25-mg/kg dosage caused (mean +/- SEM) 96.9 +/- 2.0% inhibition of ACE activity at maximal effect and 83.6 +/- 4.2% at trough effect (24 hours after dosing), indicating minimal variation in peak/trough effect. Steady-state inhibition of ACE activity at both peak and trough drug effect was achieved after 1 to 4 doses. The data indicate that benazepril is a potent and long-acting ACE inhibitor in dogs.
Administration, Oral↗
Bidirectional chiral inversion of the enantiomers of the nonsteroidal antiinflammatory drug oxindanac in dogs.
The nonsteroidal antiinflammatory drug oxindanac exists as two enantiomers, with most of its pharmacological activity residing in the (S)-isomer. The behavior of its enantiomers was investigated in dogs. Bidirectional inversion occurred in heparinised plasma and blood, with a ratio of enantiomers [S:R] of 7.3:1 being achieved at equilibrium after incubation for 24 h at 37 degrees C. There was no detectable inversion of either isomer in plasma incubated at 4 degrees C for up to 8 h or in aqueous solution at 37 degrees C for up to 36 h. Bidirectional inversion also occurred in vivo, with a ratio of plasma AUC (0 infinity)s [S:R] of 8.1:1. The ratio of enantiomers reached equilibrium within 2 hr following (S)- or rac-oxindanac, and within 8 h following (R)-oxindanac. Elimination t1/2s of the isomers were the same (R, 12.1 h, S, 13.3 h). There were no differences in the ratio of enantiomers following oral or intravenous application, suggesting that a systemic site for inversion was predominant. Although concentrations of the respective isomers were similar at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac, AUC (0 infinity)s differed due to the delay in reaching equilibrium. The extent of inversion to the (S)-isomer was 100, 73.2, and 60.7% after administration of (S)-, rac-, and (R)-oxindanac, respectively. Although pharmacological activity might be equivalent at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac; efficacy at early time points should be superior in the order (S) > racemate > (R).(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Detection of malignancy-associated metabolites in the sera of cancer patients by electron capture gas chromatography.
A reliable test that detects malignancy and indicates response to therapy is needed. Frequency-pulsed electron-capture gas-liquid chromatography (FPEC-GLC), a selective analytical technique that is sensitive to 15 fmol quantities of metabolites, was used to analyse derivatised acidic chloroform extracts of sera from patients with biopsy-proven cancer, non-malignant infectious and non-infectious disease, and healthy controls. Two peaks designated P1 and P10, not found in serum from healthy controls (n = 7) or patients with non-malignant disease (n = 85), were detected in biopsy-proven samples (n = 52) from cancer patients. P1 and P10 were later shown by chemical and mass spectral studies to be carboxylic acids. When one or both of these peaks were detected in the sera of non-treated patients they were always associated with malignancy. In patients responding to therapy, a reduction or disappearance of these peaks was observed. Further, it was noted that P10 persisted or increased in sera of patients with progressive cancer not responding to therapy. We conclude that this test has potential in diagnosis and for following the response of the disease to therapy.
Adenocarcinoma↗
High performance liquid chromatography and pharmacokinetics of the non-steroidal anti-inflammatory drug oxindanac in calves.
A high-performance liquid chromatographic method for the determination of the non-steroidal anti-inflammatory drug, oxindanac, in calf plasma is described. Recoveries over the concentration range 0.375 to 62.5 micrograms/ml were 90.2-107.8% with interassay coefficients of variation of 2.1-22.3%. The limit of detection was estimated as 0.10 micrograms/ml and the limit of quantification calculated to be 0.24 micrograms/ml in a 1 ml plasma sample. This method was used to establish the pharmacokinetics following intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administration to calves of oxindanac at a dose rate of 2 mg/kg. The elimination t1/2 was long (t1/2 21.2 h after i.v. injection) and absorption was rapid (t1/2a 0.072 h) and complete (F > 100%) following i.m. administration. Bioavailability was incomplete (F = 66.6%) following p.o. administration to calves that had been fed on milk, and Wagner-Nelson analysis revealed two absorption phases (t1/2's 0.20 and 1.9 h). Oxindanac produced long-lasting inhibition of serum TxB2 production, with mean Emax values (% inhibition) of 96.8, 94.1 and 81.3 following i.v., i.m. and p.o. administration, respectively. A single i.v. or i.m. injection of 2 mg/kg oxindanac will probably be active in calves for at least 36-48 h.
Administration, Oral↗
Correlation between the pharmacokinetics of oxindanac and inhibition of serum thromboxane B2 in calves.
The pharmacokinetics and pharmacodynamics of the non-steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The elimination t1/2 was constant in the dose range 0.5 to 4 mg/kg (20.2-22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB2, an index of platelet cyclo-oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB2 fitted in all cases a sigmoidal Emax equation. There were no significant differences in the estimates for ED50 (1.6-1.9 micrograms/ml), Hill constant (1.3-2.7) or Emax between the doses used in the in vivo studies or when blood was spiked with oxindanac in vitro. Plots of inhibition of serum TxB2 vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal Emax plot generated in vitro. These data were not significantly different from the results produced in vivo. It is concluded that oxindanac causes reversible inhibition of platelet cyclo-oxygenase in calves. Its inhibition of serum TxB2 can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal Emax enzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.
Animals↗
MR 'hot nose sign' and 'intravascular enhancement sign' in brain death.
Three cases of MR with gadopentetate dimeglumine in patients diagnosed with cerebral death are presented. Observation of an MR "hot nose sign" and an "intravascular enhancement sign" provided additional imaging support in the clinical diagnosis of brain death. The MR findings in brain death include: 1) transtentorial and foramen magnum herniation, 2) absent intracranial vascular flow void, 3) poor gray matter/white matter differentiation, 4) no intracranial contrast enhancement, 5) carotid artery enhancement (intravascular enhancement sign), and 6) prominent nasal and scalp enhancement (MR hot nose sign). Additional modalities for confirming brain death are discussed.
Adult↗
Preoperative spinal angiography for lateral extracavitary approach to thoracic and lumbar spine.
PURPOSE: To establish the safety, efficacy, and value of preoperative angiography in the surgical management of thoracic and lumbar spine disease, in which it is important to avoid injury to the artery of Adamkiewicz or other vessels that supply the spinal cord. METHODS: Sixty-one patients were evaluated primarily using digital subtraction angiography, low-osmolar or nonionic contrast agents, selective catheterization limited to the region of disease, and careful angiographic techniques. RESULTS: Two minor (small hematomas of the groin) and no major complications of angiography were encountered. Arterial supply to the spinal cord was identified in 22 patients. In 17 patients (77%), the arterial supply was in the region of planned surgery. In each of these patients the surgical approach was altered, either by dictating the use of a posterior surgical approach (four patients) or by altering the side of the lateral extracavitary approach (13 patients). CONCLUSION: Spinal angiography is a safe preoperative examination for thoracic and lumbar spine surgery. It is specifically useful when the lateral extracavitary surgical approach to spinal cord decompression and fusion (which predictably interrupts the terminal end-arterial blood supply to the spinal cord, if present) is planned.
Adolescent↗
The use of intradermal carrageenan in calves to estimate the dose of oxindanac, a nonsteroidal anti-inflammatory drug.
A simple and humane model of inflammation, induced by the intradermal injection of 0.3 mL of sterile 2% carrageenan, was characterized in calves by measuring the volume of skin swelling plus histological analysis of skin biopsies. Carrageenan produced a biphasic increase in skin swelling, with an early edematous response followed by a more chronic cellular infiltrate. The swelling and sensitivity to pressure observed in the early response were suitable for testing the antiedematous and analgesic activity of a new nonsteroidal anti-inflammatory drug (NSAID), oxindanac. Pretreatment with intravenous oxindanac at doses from 0.5 to 8.0 mg/kg reduced the volume of swelling and this reached statistical significance (p < 0.05) at 2 mg/kg. The ED50 and ED90 values for inhibition of the peak swelling volume (4 h) were estimated to be 1 mg/kg and 2 mg/kg, respectively. These compare with an ED90 of 2.0 mg/kg for inhibition of serum TxB2 production, an index of platelet cyclo-oxygenase activity. The dose of oxindanac required for antiedematous activity correlated, therefore, with maximal inhibition of serum TxB2. The analgesic activity of oxindanac reached no clear maximum response, but statistically significant difference (p < 0.05) from placebo was reached with doses of 2 mg/kg and above. It is concluded that intradermal carrageenan produced a simple, humane and useful model for dose estimation of a new NSAID in calves.
Animals↗