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PubMed1983

Effect of forebrain lesions on response to chronic intraventricular angiotensin II.

We previously reported that chronic (10 days) intracerebroventricular (ivt) infusion of angiotensin II (ANG II) into conscious rabbits produced a significant rise in mean arterial pressure (MAP), water intake (WI), and urinary sodium excretion (UNaV), and a significant fall in plasma sodium (PNa) and potassium (PK) concentrations. Urinary potassium excretion (UKV) and body fluid volume were not changed significantly. In the present experiments, similar chronic infusions were carried out in intact rabbits and in rabbits with an electrolytic lesion placed in the anteroventral third cerebral ventricle (AV3V) region. Integrity of the AV3V area is essential for normal expression of a variety of acute physiological responses to ANG II injected into the brain. In rabbits with AV3V lesions, chronic ivt infusion of ANG II did not significantly alter MAP, but WI and fractional UNaV increased, and PNa decreased in a manner identical to that of sham-lesioned control rabbits. Plasma and extracellular fluid volumes increased, and body weight and food intake decreased in all rabbits during ANG II infusion, but to a slightly greater extent in the AV3V-lesioned rabbits. We conclude that an intact AV3V region is crucial for the hypertensive effect of chronic ivt fusions of ANG II in the rabbit but is not necessary for most of the fluid and electrolyte alterations associated with such infusions.

Angiotensin II↗

PubMed1988

Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever.

Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E2 and thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE2 elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE2 formation, and their effect was also manifest during the latent period of the fever. The PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE2, on the other hand, was higher in animals pretreated with probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE2, TXB2 levels did not change during the fever to intravenous endotoxin. TXB2 rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA2 analog (ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (ONO-11120;2 micrograms ivt) did not interfere with endotoxin fever. These findings strongly support a causative role for PGE2 in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA2.

Animals↗

PubMed1992

Electrophysiologic effects of magnesium sulfate infusion in patients with cardiac conduction defects.

We report the electrocardiographic and electrophysiologic effects of magnesium (Mg) sulfate infusion in 25 normomagnesemic patients (16 men and 9 women, aged 22-74 years; mean +/- SD, 60.4 +/- 11.9) with different cardiac conduction impairments. Ten patients had chronic ischemic heart disease, two had idiopathic dilated cardiomyopathy, two had hypertensive heart disease, three had valvular heart disease, five had sclerodegenerative heart disease and three had no clinical evidence of cardiac disease. Five patients had trifascicular block [first degree atrioventricular (A-V) block+right bundle branch block (RBBB)+left anterior hemiblock (LAH)], eight had bifascicular block (6 RBBB+LAH, 2 first degree A-V block+RBBB), four had isolated first degree A-V block and eight had bundle branch block [5 RBBB, 3 left bundle branch block (LBBB)]. Before and during Mg infusion (50 mg/min/60 min) we evaluated the A-V (P-R), intraatrial (P-A), suprahisian (A-H), infrahisian (H-V) conduction times, electrical ventricular systole (Q-T), Q-T index (Q-Tc) intraventricular conduction time (QRS) and heart rate. At the end of infusion the P-R, P-A, A-H, H-V increased from 215.4 +/- 36.6, 33.6 +/- 9.1, 112.8 +/- 37.3, 69.0 +/- 12.8 ms to 217.6 +/- 37.1 (p less than 0.002), 33.8 +/- 9.4 (NS), 114.2 +/- 38.1 (p less than 0.005), 69.6 +/- 13.3 (NS) ms. QRS complex did not change (125 +/- 16.9 ms).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

[Evoked potentials in the sacred baboon: long-term follow-up of intracerebroventricular infusion of nerve growth factor].

INTRODUCTION AND OBJECTIVE: It is well known that in aged animals cognitive deficit occurs, homologous with that occurring in Alzheimer's disease in humans, and as has been shown in others species, this may be attenuated by administration of nerve growth factor (NGF). Therefore the basic aim of this study was to make an electrophysiological evaluation of the repercussion that there might be after long-term administration of this neurotropin in the sacred baboon (Papio hamadryas) comparing aged with young animals. MATERIAL AND METHODS: We studied a six year old male and a 39 year old female, after sedation. Long-term intraventricular administration of NGF was carried out using a continuous infusion pump, at a dose of 2.1 micrograms/kg/day. Recordings were made before installing the pump and 1, 3 and 6 months after insertion. A Neuropack Four-mini set for evoked potentials (Nihon Kohden) was used to record auditory evoked potentials from the brain stem and visual evoked potentials due to flash. RESULTS AND CONCLUSION: In both animals there were modifications of their electrophysiological responses. These reached a maximum after one month, more markedly in the older animal and this could possibly be related to the neuromodulator effect of NGF.

Animals↗

PubMed2005

Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Animals↗

PubMed1980

Effect of intraventricular serotonin on the plasma cortisol response to restraint stress in unanesthetized sheep.

Serotonin infused into a lateral ventricle of unanesthetized sheep reduced the response of the hypothalamic-pituitary-adrenal axis to restraint stress. However, the attenuation of the adrenal response by serotonin was of only limited duration, suggesting that pharmacological manipulation of serotonin would not be effective in altering the adrenal response to stress.

Animals↗

PubMed2004

The effects of changes in loading conditions and modulation of inotropic state on the myocardial performance index: comparison with conductance catheter measurements.

AIM: The myocardial performance index (MPI), or Tei index, has been shown to be useful in the assessment of global myocardial performance. There are few invasive data however, which examine its load dependence or sensitivity to acute changes in contractile function. The purpose of this study was therefore to study formally the effect of clinically relevant changes in these parameters in an animal model. METHODS AND RESULTS: We examined 10 Yorkshire pigs using echocardiographic assessment and simultaneous measurements of intraventricular pressure and volume by conductance catheterization. With dobutamine infusion, there was no significant change in the MPI (0.26+/-0.13-0.22+/-0.11; p=0.42), but dP/dtmax increased significantly (1001+/-240-1569+/-532 mm Hg/s, p<0.001). Afterload increase (40% change in ventricular pressure) and preload reduction (20% change in ventricular volume) were associated with significant increases in the MPI (0.26+/-0.13-0.49+/-0.20; p<0.005 and 0.26+/-0.13-0.51+/-0.20; p<0.001, respectively) without any significant change in maximal elastance (Ees). CONCLUSIONS: The MPI, or Tei index, is significantly affected by acute changes in loading conditions but is unable to consistently detect acute changes in contractile function.

Animals↗

PubMed2001

Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours.

As the systemic administration of etoposide is effective in the treatment of relapsed and metastatic brain tumours, a pilot trial was designed to study the feasibility of intraventricular administration of etoposide in such patients. 14 patients aged 2.1 to 33.2 years were treated with intraventricular etoposide simultaneously with either oral or intravenous chemotherapy with trofosfamide or carboplatin and etoposide. In 59 courses (1-12/patient) 0.5 mg etoposide was administered daily via an indwelling subcutaneous reservoir for 5 consecutive days every 2-5 weeks over a period of 0-11 months. During 15 courses in 5 patients serial CSF samples were obtained and etoposide levels were determined by reversed-phase HPLC. Side effects included transient headache and bacterial meningitis, each during 2 courses. Pharmacokinetic data analysis in the CSF (11 courses, 4 patients) revealed a terminal half-life of 7.4+/-1.2 hours and an AUC of 25.0 +/- 9.5 microg h ml(-1)(mean +/- standard deviation). The volume of distribution at steady state and total clearance exhibited a large interindividual variability with mean values of 0.16 l and 0.46 ml min(-1)respectively. Intraventricularly administered etoposide is well tolerated. CSF peak levels exceed more than 100-fold those achieved with intravenous infusions. Further studies should be focused on optimizing the dose and schedule and on determining the effectiveness of intraventricularly administered etoposide.

Adolescent↗

PubMed1986

Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection.

Neurons in the rat medial septum (MS) and vertical limb of the diagonal band of Broca (VDB) undergo a rapid and severe cell death after transection of their dorsal projection to the hippocampus by aspiration of the ipsilateral fimbria fornix and supracallosal striae. By 2 weeks posttransection, the extent of neuronal loss was 50% of the total neurons and 70% of the cholinergic neurons in the MS and 30% of the total neurons and 40% of the cholinergic neurons in the VDB. We hypothesized that (i) the death was due to the loss of a hippocampus-derived neuronotrophic factor, and (ii) exogenous nerve growth factor (NGF) might provide trophic support to the MS/VDB cholinergic neurons, in light of recent reports that the septal diagonal band cholinergic neurons are responsive to NGF and that NGF is present and produced in the hippocampus. In the present study, we attempted to prevent the transection-induced neuronal death by continuous infusion of exogenous 7S NGF (1 microgram/wk) through an intraventricular cannula device. We report here that NGF treatment significantly reduces both the total neuronal and cholinergic neuronal death found 2 weeks after fimbria fornix transection; there was a sparing of 50% of the neurons in the MS and essentially 100% of those in the VDB that otherwise would have died. We conclude that NGF also has a protective effect on noncholinergic neurons since calculations indicate that 80% of the NGF-affected neurons are noncholinergic.

Animals↗

PubMed1992

Time course of intraventricular pressure change in a canine model of hydrocephalus: its relationship to sagittal sinus elastance.

Hydrocephalus was induced in adult greyhounds by intracisternal kaolin. Intraventricular pressure (IVP) was monitored in the conscious animal for 2 weeks using a small implantable sensor, and the time-course of IVP change was characterized. Intraventricular pressure increased significantly within 36 h of kaolin infusion and gradually subsided to normal values within 1 week. Enlargement of the lateral ventricles was not observed during the early phase of intracranial hypertension (less than 2 days). Evolving hydrocephalus and intracranial hypertension increased the elasticity (dP/dV) of the sagittal sinus. This effect was statistically significant (p < 0.05) and is possibly reversible in the acute stage. Normotensive hydrocephalus (1 and 2 weeks after kaolin) was associated with an irreversible increase in resistance to outflow (i.e., increased sagittal sinus elasticity). Sagittal sinus venography of animals with obvious ventricular enlargement (at least 1 week after kaolin) showed development of venous collaterals and atypical outflow pathways.

Animals↗

PubMed1985

GABAergic inhibition of hypertonic saline-induced vasopressin-dependent hypertension.

Previous studies have shown that hypotension produced by drugs facilitating gamma-aminobutyric acid (GABA) transmission was caused by a decrease in sympathetic nervous system outflow. We attempted to determine if GABA agonists and GABA uptake inhibitors could also lower arterial pressure that was elevated by increasing the secretion of endogenous vasopressin. GABA and nipecotic acid, an uptake inhibitor of GABA, were administered intraventricularly to determine the cardiovascular effects of these agents in nephrectomized rats made acutely hypertensive with hypertonic saline. A 2-hr i.v. infusion of hypertonic saline (3.0 mEq/ml) increased arterial pressure from 119 +/- 2 to 157 +/- 2 mm Hg. Intraventricular administration of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid produced a peak decrease in blood pressure of 0 +/- 0, 30 +/- 4 and 22 +/- 3 mm Hg, respectively. In nephrectomized rats receiving an equal volume of isotonic saline (0.15 mEq/ml), infused i.v. arterial pressure did not change. In these animals, central infusions of artificial cerebrospinal fluid, 100 micrograms of GABA and 175 micrograms of nipecotic acid decreased blood pressure only 1 +/- 1, 13 +/- 2 and 8 +/- 3 mm Hg, respectively. Further experiments utilizing nephrectomized rats infused with hypertonic saline were designed to determine the mechanism for the augmented depressor response produced by these agents. Elimination of the contribution of vasopressin to arterial pressure with a vascular vasopressin antagonist reduced the depressor responses produced by 100 micrograms of GABA and 175 micrograms of nipecotic acid to 10 +/- 3 and 8 +/- 3 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminobutyrates↗

PubMed1998

Lateral ventricular injections of the NK3 agonist senktide affect salt taste-elicited responses.

Central injections of the selective tachykinin NK3 receptor agonist senktide (SENK) suppresses salt appetite. Also, following SENK, intraoral infusions of hypertonic NaCl elicit fewer ingestive taste reactivity responses and more aversive responses than following intraventricular injections of isotonic saline. This pattern of taste reactivity results suggest that SENK affects the oral stimulating properties of salt taste. Before accepting this interpretation, however, alternative explanations need to be examined. The following experiments evaluated whether the effects of intraventricular SENK injection on taste reactivity could be due to: 1) a general oral motor impairment that reduces ingestive responding to tastes (Experiment 1) or; 2) SENK having aversive consequences (Experiment 2). In Experiment 1, the effects of intraventricular injections of SENK (200 ng) on taste reactivity responses to 0.5 M NaCl and 0.1 M sucrose were measured in sodium deficient rats. Intraoral infusions of 0.5 M NaCl elicited fewer ingestive taste reactivity responses following SENK than injections of isotonic saline in sodium deficient rats. Sucrose continued to elicit the same high number of ingestive taste reactivity responses following intraventricular injections of isotonic saline and SENK. Thus, SENK did not cause a general decrease in ingestive responding. A conditioned taste aversion test was employed in Experiment 2 to determine if SENK had aversive consequences. Rats were given 30 min access to alanine (0.3 M) and were then administered either lithium chloride (LiCl) or intraventricular injections of SENK (200 ng) on three consecutive days. Rats avoided alanine that was paired with LiCl, but those rats that had alanine paired with SENK showed no avoidance of the taste even after three pairings. These results replicate findings that intraventricular injections of the NK3 agonist SENK decreases the palatability of NaCl (as measured by taste reactivity) and suggest that its effect on NaCl-elicited taste reactivity is not due to the treatment causing a motor impairment or malaise.

Animals↗

PubMed1979

Thyrotropin-releasing hormone stimulates release of arginine vasopressin and oxytocin in vivo.

The effects of TRH upon neurohypophyseal hormone release were studied in conscious rabbits. Intravenous infusion of 250 nm/kg TRH had no significant effect on either arginine vasopressin (AVP) or oxytocin (OT) release, but a 5-fold greater dose led to significant increases in plasma levels of both AVP and OT and behavioral arousal. Intraventricular injection of 3 nm TRH produced significant elevations of both plasma AVP and OT, with even greater effects on behavior than after iv infusion. The maximal hormone response to intraventricular injection was observed considerably earlier than that for iv injection and the response occurred after an almost 1000-fold lower dose of TRH. Neither artificial cerebrospinal fluid vehicle nor the inactive analogue D-tyrosine2 TRH (p-Glu-d-Tyr-Proamide) had any effect on neurohypophyseal hormone release or on behavior. MK-771 [L-N-(2-oxopiperidin-6-YL-carbonyl)-L-histidyl-L-thiazolidine-4-carboxamide], a TRH analog with enhanced central nervous system effects, had effects on AVP and OT release comparable to equimolar doses of TRH. TRH stimulates release of both AVP and OT after both intraventricular and iv injection, and these effects may be independent of behavioral activation.

Animals↗

PubMed1971

Influence of the duration of experimental fever on salicylate antipyresis in the rabbit.

1. Steady state fever has been produced in rabbits with a priming injection followed by a sustaining infusion of homologous plasma containing endogenous pyrogen (EP). This fever appears to last as long as the infusion continues.2. Intravenous salicylate given 1 h after the start of the EP infusion produced only a small antipyretic effect. The same dose of salicylate given 4 h after the start of an EP infusion resulted in rapid and progressive defervescence. Intermediate antipyretic responses were obtained when salicylate was administered intravenously 2 and 3 h after the start of an EP infusion.3. Less than 1% of the systemic dose, when injected into a lateral cerebral ventricle, produced a significantly smaller response at 1 h than at 4 h after the start of an EP infusion. At both these times the fall in temperature following the intraventricular salicylate injection was dose dependent, but the slope of the dose-response line was significantly steeper at 4 h than at 1 hour.4. It is suggested that salicylates produce their antipyretic effects by antagonizing the action of EP within the nervous system, and that the hypothalamic EP concentration falls during the course of an EP infusion.

Animals↗

PubMed2000

Effects of intravenous amiodarone on ventricular refractoriness, intraventricular conduction, and ventricular tachycardia induction.

AIMS: Intravenous amiodarone has recently emerged as an important drug for the acute treatment of ventricular tachyarrhythmias. However, electrophysiological actions and the efficacy of the drug in the suppression of ventricular tachycardia inducibility have not yet been fully established. The present study was designed to address these issues. METHODS AND RESULTS: The study group consisted of 18 patients (all males, mean age 75 +/- 14 years), who underwent electrophysiological study due to a history of sustained ventricular tachyarrhythmia or syncope with non-sustained ventricular tachycardia detected on ambulatory ECG monitoring. The effects of 5 mg.kg(-1) or 10 mg.kg(-1) of intravenous amiodarone on (1) ventricular refractoriness (QTc interval, right ventricular effective refractory period and monophasic action potential duration), (2) intraventricular conduction (paced-QRS and signal-averaged QRS duration), and (3) ventricular tachycardia inducibility, were examined. The drug had no significant effect on ventricular refractoriness. However, a relatively small but significant slowing of intraventricular conduction was seen (paced-QRS duration: 182 +/- 27 ms vs 191 +/- 28 ms, P<0.0007; 183 +/- 32 ms vs 195 +/- 33 ms, P<0.0007; and 177 +/- 21 ms vs 192 +/- 24 ms, P<0.003, at the cycle lengths of 600, 500 and 400 ms, respectively). This effect was more evident during extrasystolic beats than during stable pacing (for example, at the cycle length of 600 ms, the magnitude of amiodarone-induced lengthening of QRS duration was 23.9 +/- 17.6 ms vs 9.7 +/- 7.2 ms, P<0.009, respectively). Intravenous amiodarone did not prevent induction of sustained ventricular tachycardia in any of five patients inducible at baseline. Of six patients with non-sustained ventricular tachycardia, five had sustained ventricular tachycardia or fibrillation induced after amiodarone infusion. CONCLUSION: Intravenous amiodarone does not prolong ventricular refractoriness, slows intraventricular conduction and may facilitate inducibility of sustained ventricular arrhythmias.

Aged↗

PubMed1995

A comparison between effects of intraventricular insulin and intraperitoneal lithium chloride on three measures sensitive to emetic agents.

When low doses of insulin are infused directly into the third ventricle, rats reduce their food intake and lose weight. To determine whether these effects could be due to malaise induced by the treatment, the effects of intraventricular insulin were compared to the effects of the emetic agent lithium chloride to condition a taste aversion, to stimulate oxytocin secretion, and to reduce sodium appetite in response to furosemide treatment. For all three of these measures, lithium chloride treatment had a predictable effect compared to controls. Specifically, lithium caused a significant taste aversion, elevated plasma oxytocin, and attenuated sodium appetite. However, lithium did not produce a significant change in food intake or body weight. On the other hand, intraventricular insulin treatment did cause a significant reduction in body weight yet had no effect on these indices of malaise in the rat. These data are consistent with the hypothesis that intraventricular insulin does not reduce food intake and body weight by producing malaise but rather serves as a negative feedback signal of body adiposity to the central nervous system.

Animals↗

PubMed1980

Effects of mild hyperkalemia on conduction velocity and effective refractory period in various parts of the dog heart in situ.

Effects of mild hyperkalemia on conduction velocity, effective refractory periods (ERPs) and sinus rate were studied on 16 anesthetized dogs, using endocavitary His bundle recordings, the extrastimulus method and standard electrocardiogram. Six dogs were placed under acetylcholine infusion (300 micrograms/kg/min) (ACh group), 10 received atropine sulfate 0.2 mg/kg intravenously (atropine group). Intraventricular conduction time, ventricular ERP and QRS duration of the EKG were studied on 7 other open-chested dogs (ventricular group). During a 60 min potassium chloride infusion (0.025 mmol/kg/min, 30 min, then 0.05 mmol/kg/min, 30 min), following observations were made: - In the ACh group, AV node conduction time (A-H interval) decreased by 20% and AV node ERP by 17%, whereas, in the atropine group, the former parameter was not affected and atrial ERP increased by 29%. - At the same time, sinus rate increased in the ACh group and was unaffected in the atropine group. - Conduction times in atrial contractile tissue (S-A interval), His-Purkinje system (H-V interval) and ventricular contractile tissue, like ventricular ERP, exhibited no variation or very slight, occasionally biphasic variations under both conditions. These results can be accounted for by an "anticholinergic" effect of mild hyperkalemia which is discussed.

Animals↗

PubMed1982

Studies on acute toxicity and drug levels of citalopram in the dog.

Electrocardiographic and haemodynamic changes have been studied in conscious dogs after a sublethal oral dose (20 mg . kg-1) of citalopram. Furthermore, the effects of continuous intravenous infusion of citalopram (10 mg . kg-1 per hour) have been studied in conscious and anesthetized dogs. The findings have been related to plasma levels of citalopram. Severe convulsive attacks occurred in conscious dogs after infusion of 21.3 or 26.5 mg . kg-1 and after the oral dose. The convulsions were successfully treated with diazepam. In contrast convulsions were not seen in the anesthetized dogs. They died from respiratory arrest after infusion of 42.2 or 61.3 mg . kg-1. Atrioventricular and intraventricular conduction was unchanged and electrocardiographic changes were negligible. Sinus tachycardia which could be reversed by diazepam and moderate haemodynamic changes were seen. Since no electrocardiographic changes were seen in conscious dogs even during pauses in the convulsive seizure it is concluded that citalopram does not exert cardiotoxic effects in the dog. Good correlation was found between general clinical findings and citalopram levels in plasma. Conscious dogs were exposed to drug levels exceeding those of the average patient by a factor of about 20, while anesthetized dogs had considerable higher concentrations.

Administration, Oral↗