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Biomedical subjects

D D Denson

Publications and source records attributed to D D Denson.

At least 73 records · Page 4Linked to original sources
PubMed1983

Comparison of neural blockade and pharmacokinetics after subarachnoid lidocaine in the rhesus monkey. II: Effects of volume, osmolality, and baricity.

The effects of volume, osmolality, and baricity on lidocaine spinal anesthesia in the rhesus monkey were studied. Changes in neural blockade, physical properties of cerebrospinal fluid, and arterial pharmacokinetics associated with variations in injectate composition were assessed. Wide ranges of volume, baricity, and osmolality were studied using 1, 2, and 5% lidocaine prepared in either sterile water or 7.5% dextrose. Minimal changes in neural blockade were found in the ranges of osmolality and baricity studied, although 5% lidocaine in sterile water resulted in significantly shorter complete recovery times for both sensory and motor block when compared to other solutions. Samples of cerebrospinal fluid obtained after injection of lidocaine showed increases or decreases in specific gravity and osmolality depending on the physical properties of the solution injected. No differences in elimination phase pharmacokinetics were found with any of the lidocaine solutions. Rates of systemic absorption increased with decreasing osmolality. Osmotic potentiation of lidocaine spinal anesthesia could not be demonstrated.

Anesthesia, Spinal↗
PubMed1983

Continuous perineural infusion of bupivacaine for prolonged analgesia: pharmacokinetic considerations.

The pharmacokinetic parameters for 50 patients undergoing continuous extravascular perineural bupivacaine infusions for the treatment of their chronic pain were studied. The total plasma clearance (CL), volume of distribution (Vz), and elimination rate (lambda z) were estimated from two blood samples. These parameters were compared to values obtained from the actual mono-exponential decay curve at the termination of infusion. Estimated and actual pharmacokinetic parameters were found to be in excellent agreement. No evidence of accumulation was seen even after 5 days of continuous infusion. Steady states (Css) were found to be independent of the infusion site. This study demonstrates a wide margin of safety during continuous perineural bupivacaine infusions at dosages used in our study, e.g., up to 30 mg/h in normal patients. Such patients do not require determination of serum bupivacaine concentration to monitor the changes in dosages necessary for adequate clinical effect. On the other hand, in patients with renal or hepatic dysfunction, altered clearance rates are expected. In such patients, monitoring of serum bupivacaine concentrations is necessary to determine the range of dosages available for adjustment to provide adequate clinical effect and prevent systemic toxicity. This study demonstrates that two blood samples drawn at 3-5 h after the start of infusion and at steady state are sufficient to accurately determine the clearance rate for a patient. Safe management is then possible using this clearance to calculate the range of dosages permissible for that patient during continuous perineural infusion. Steady-state concentrations estimated from clearances were found to be in excellent agreement with the steady-state concentrations actually measured for a given infusion rate.

Brachial Plexus↗
PubMed1982

Neural blockade and pharmacokinetics following subarachnoid lidocaine in the rhesus monkey. I. Effects of epinephrine.

A sensitive and reliable animal model for the objective physiologic and pharmacokinetic evaluation of spinal anesthesia has been developed. Using this model, spinal anesthesia using lidocaine (30 mg) in 7.5% dextrose with and without epinephrine was compared. Epinephrine did not alter the degree or duration of time to achieve maximum motor block. However, epinephrine did significantly increase the time for complete motor recovery. A significantly higher dermatome level of sensory block was achieved in the epinephrine-containing solutions, as well as a significantly longer time for complete recovery. This reflects a latent effect of epinephrine, as the time for two-segment regression was independent of epinephrine. Pharmacokinetic analysis showed no effect of epinephrine on absorption and elimination constants. The maximum plasma concentration and time to reach maximum plasma concentration were equal with and without epinephrine.

Anesthesia, Spinal↗
PubMed1980

Kinetics of local anesthetic esters and the effects of adjuvant drugs on 2-chloroprocaine hydrolysis.

A rapid, reliable method for the determination of 2-chloroprocaine in serum was developed. The method, using double-beam ultraviolet spectroscopy, provides rapid, accurate analysis of 2-chloroprocaine in the range of 5.5 to 111 microM (1.5--30 microgram/ml), as documented by comparison with the accepted gas chromatographic procedure. The contribution of 4-amino-2-chlorobenzoic acid, the principal metabolite of 2-chloroprocaine, to the total absorbance at 300 nm was examined and found to be negligible. Using the ultraviolet spectrophotometric method, values of the Michaelis-Menton constant (Km) and maximal reaction velocity (Vmax) for hydrolysis of procaine and 2-chloroprocaine by homozygous typical, heterozygous, and homozygous atypical plasma cholinesterase were determined. The Kms for the three genotypes were 5.0, 6.2, and 14.7 microM, respectively, for procaine, and 8.2, 17, and 103 microM, respectively for 2-chloroprocaine. The Vmaxs for the three genotyps were similar for all esters. Vmax for procaine was 18.6 +/- 0.9 nmol/min/ml serum, while Vmax for 2-chloroprocaine was 98.4 +/- 2.1 nmol/min/ml serum. At high concentrations, 2-chloroprocaine acts as an inhibitor of its hydrolysis. The inhibitory effects of lidocaine, bupivacaine, neostigmine, and succinyldicholine on 2-chloroprocaine hydrolysis for homozygous typical and atypical variants, respectively, were studied. Competitive inhibition was demonstrated for all four drugs. However, at clinically significant concentrations, only neostigmine and bupivacaine produced high degrees of inhibition. The competitive inhibition constants (K1) for the typical and atypical variants, respectively, were 3.3 +/- 0.3 microM and 15.1 +/- 4.8 microM for neostigmine, and 4.2 +/- 0.3 microM and 36.9 +/- 9.8 microM for bupivacaine.

Adjuvants, Pharmaceutic↗
PubMed1979

Localized fluoride release from fluorine-carrying polyphosphonates.

Fluoride release from fluorine-carrying copolymers of vinylphosphonate induced by calcium apatite and tooth enamel has been investigated. Fluoride ions were determined potentiometrically in the study of calcium hydroxyapatite, and Auger spectroscopy was used to study the fluoride release to enamel. The adsorbed copolymer of vinylphosphonic acid and vinylphosphonyl thiofluoride was shown to release fluoride to calcium hydroxyapatite and to enamel. The oxygen analog has shown a similar behavior with calcium hydroxyapatite, but not with tooth enamel. The results suggest a potential application of such copolymers as caries preventive agents which combine the effects of polyphosphonates and of fluoride ions.

Adsorption↗
PubMedDate not supplied

A comparison of intravenous and subarachnoid lidocaine pharmacokinetics in the rhesus monkey.

A comparative study between intravenous and subarachnoid lidocaine in the rhesus monkey was conducted in an effort to compare the kinetics of lidocaine in the monkey with reported intravenous human data, and to determine the rate and extent of systemic absorption of lidocaine following subarachnoid injection. Each animal received an intravenous and subarachnoid treatment in an effort to determine the fraction of drug absorbed. Pharmacokinetic parameters were calculated for each animal based on arterial blood concentrations of lidocaine. In the case of the intravenous data, a standard two-compartment model was used. Subarachnoid injections were evaluated by fitting data to an extravascular one-compartment model and by analog computer fitting of the blood level data to an extravascular two-compartment model. Data for both intravenous and subarachnoid injection were also analysed independent of compartment model. The intravascular parameters, alpha and beta, were in excellent agreement with those reported for man.

Anesthesia, Spinal↗
PubMedDate not supplied

First-pass elimination of lidocaine in the rabbit after peroral and rectal route of administration.

Lidocaine shows pronounced first-pass metabolism upon peroral administration in man (about 30 per cent peroral bioavailability). Since the rectal bioavailability is about 65 per cent in man it is assumed that some drug is directly absorbed into systemic circulation by-passing the liver. In rats peroral bioavailability is about 8 per cent whereas rectal bioavailability is about 100 per cent. This indicates that the rat is not a suitable model to study rectal lidocaine dosage forms. The purpose of this study was to investigate lidocaine disposition and bioavailability in rabbits after peroral and rectal administration. The peroral bioavailability in rabbits was found to be about 6 per cent and the rectal bioavailability is about 33 per cent. The results indicate that the rabbit is a suitable model for the study of systemic absorption of rectal lidocaine dosage forms.

Administration, Oral↗
PubMedDate not supplied

Use of a limited physiologic model to explain target organ toxicity of bupivacaine as a function of route of administration.

A physiologic model to describe bupivacaine uptake by and elimination from brain and heart was developed. Preliminary validation of the model was accomplished by comparing concentration data predicted by the model with those determined in rabbits. The model was modified to examine similarities and differences following intravenous and epidural administration of 150 mg of bupivacaine in humans. Simulations illustrated why rapid cardiovascular and central nervous system toxicity occurs following intravenous administration and is absent when an identical dose is administered epidurally. A slow continuous intravenous infusion of bupivacaine was simulated to examine the possibility that brain and heart concentrations would continue to accumulate reaching toxic concentrations in the absence of blood concentrations associated with bupivacaine toxicity.

Animals↗
PubMedDate not supplied

Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects.

The pharmacokinetic properties of hydromorphone in healthy young male subjects were studied after i.v., peroral, and rectal administration. After i.v. administration the following pharmacokinetic parameters were found: elimination half-life 2.36 +/- 0.5 h, hepatic extraction ratio 0.51, apparent volume of distribution 2.9 +/- 1.3 L kg-1 and volume of central compartment 0.23 +/- 0.2 L kg-1. The absolute bioavailability after peroral administration was 50.7 +/- 29.8 per cent, and that after rectal administration was 33 +/- 22 per cent.

Administration, Oral↗
PubMedDate not supplied

Continuous intravenous infusion of methadone for control of burn pain.

Seventeen patients with acute, severe burns were treated with a two-stage continuous, intravenous infusion of methadone to control pain. An initial loading infusion was run for 2 hours at 0.1 mg/kg/hr of methadone; then a maintenance infusion was continued at 0.01 mg/kg/hr of methadone. Median visual analog scale scores were 70% pain relief after the 2-hour loading infusion and 80% after 24 hours. Cardiovascular parameters were stable. There was a significant decrease in the respiratory rate of the patients. It appears that continuous intravenous methadone is an effective analgesic agent for the patient with acute, severe burns. Administration of the drug should be on an individualized basis with conservative dosing in a well-monitored environment because somnolence and respiratory depression can occur.

Adult↗
PubMedDate not supplied

Enantiomer-specific effects of an intravenously administered arrhythmogenic dose of bupivacaine on neurons of the nucleus tractus solitarius and the cardiovascular system in the anesthetized rat.

BACKGROUND AND OBJECTIVE: This investigation was designed to determine whether the effects on the cell firing rate (CFR) at the nucleus tractus solitarius (NTS) and on the cardiovascular system, which are associated with a toxic dose of bupivacaine, have an enantiomer-specific component. METHODS: Adult Sprague-Dawley rats were anesthetized with chloral hydrate, and a femoral artery and vein were cannulated. After the cranial surface was exposed, a 3-mm hole was drilled 2 mm caudal and 1.5 mm lateral with respect to lambda for placement of a 1-microns tungsten microelectrode. Cells of the NTS were located 6-6.5 mm from the brain surface, and CFR was continuously recorded. Lead II electrocardiogram and arterial blood pressure were also recorded. Twenty-four animals received either d- or l-bupivacaine (2 mg/kg) in random order. RESULTS: Cell firing rates decreased from 21 +/- 13 to 0 +/- 0 impulses/second (p < 0.001) at 34 +/- 15 seconds after the injection of d-bupivacaine. Cell firing rates decreased from 22 +/- 17 to 2 +/- 4 impulses/second (p < 0.01) at 68 +/- 45 seconds after injection of l-bupivacaine. In addition to the decreases in blood pressure and heart rate that were found, all animals exhibited an inversion in electrical axis beginning within 2-3 seconds after bupivacaine administration. Mild bradycardia was noted in four of the animals receiving the l-bupivacaine, whereas severe bradycardia was observed in all animals receiving d-bupivacaine. Most important, this severe bradycardia was accompanied by progressive hypotension. In addition, all animals receiving d-bupivacaine became apneic and died, whereas all animals receiving l-bupivacaine continued to breathe and all but two of the animals survived. CONCLUSIONS: Data in the current report support the hypothesis that effects of bupivacaine on neurons of the NTS and on the cardiovascular system have an enantiomer-specific component.

Anesthesia↗
PubMedDate not supplied

Tourniquet pain: the response to the maintenance of tourniquet inflation on the upper extremity of volunteers.

This investigation examined the effect of three factors--tourniquet width, tourniquet inflation pressure, and application of the tourniquet to the left or right extremity--on the intensity of tourniquet pain and duration of tourniquet inflation, as well as the circulatory effects associated with maintenance of inflation of a pneumatic tourniquet on an upper extremity of 12 healthy, unmedicated volunteers. All subjects manifested a time-dependent circulatory response to maintenance of tourniquet inflation, characterized by increases in heart rate and systolic and diastolic blood pressure. The mean duration of tourniquet inflation was 34 +/- 13 minutes (mean +/- SD). No difference was demonstrated with respect to the width of the tourniquet, the tourniquet inflation pressure, or the application of the tourniquet to the left or right extremity on the intensity of pain or the duration of tourniquet inflation.

Arm↗
PubMedDate not supplied

Alkalinization of chloroprocaine for epidural anesthesia: effects of pCO2 at constant pH.

Increasing the pH of 2% chloroprocaine (CP) with sodium bicarbonate to pH 7.7 hastens the onset of epidural analgesia. The purpose of the present study was to determine the effect of pCO2 on the onset of epidural analgesia with CP buffered to a constant pH 7.7. Four groups consisting of ten patients each were studied: C, control, commercial CP (pH 4.35); B, CP buffered with sodium bicarbonate (pH 7.7); T, CP buffered with tromethamine (pH 7.7), and BT, CP buffered with sodium bicarbonate and tromethamine (pH 7.7). All epidural catheters were placed at the L2-3 or L3-4 interspace using a loss-of-resistance technique with air with each patient in a sitting position. The pH and pCO2 of each local anesthetic solution were measured as well as the onset and duration of analgesia. The study groups did not differ with respect to demography or entry characteristics. There were intergroup differences in the pCO2 values of the study solutions as follows: Group 1 (C), 11.8 +/- 1.5 mmHg; 2 (B), 113.0 +/- 1.4 mmHg; 3 (T), 3.0 +/- 0.3 mmHg, and 4 (BT), 74.1 +/- 1.0 mmHg, respectively. The time to the onset of analgesia was significantly faster in Group 2 (B; 2.7 +/- 0.8 minute), while the onset of analgesia was significantly slower for Group 3 (T; 5.4 +/- 0.4 minute) than either Group 1 (C; 4.2 +/- 0.8 minute) or Group 4 (BT; 3.4 +/- 0.3 minute). Regression analysis revealed that the onset times of the buffered solutions were significantly related to pCO2 (r2 = 0.81).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Effects of an intravenously administered arrhythmogenic dose of bupivacaine at the nucleus tractus solitarius in the conscious rat.

This study was designed to further investigate the CNS-mediated cardiovascular toxicity of local anesthetics and to determine any effect of anesthesia on the firing rate of cells in the nucleus tractus solitarius (NTS) of conscious animals. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. A femoral artery and vein were cannulated. A 3-mm hole was then drilled for placement of a unidirectional microdrive. The animal was removed from the stereotactic instrument, and EKG electrodes, pressure transducer and the microdrive containing a 1-micron tungsten electrode were attached. Animals were then placed in a canvas sling for recovery from the anesthetic. Cells of the NTS were located and cell firing rate (CFR) was continuously recorded. None of the animals exhibited any sign of discomfort upon recovery from anesthesia. CFRs decreased from 19 +/- 13 to 4 +/- 4 impulses/second at 20 +/- 16 seconds after the IV injection of bupivacaine (p less than 0.01). Maximum decreases in blood pressures were 26 +/- 15% of control and occurred at 32 +/- 14 seconds after the injection of bupivacaine. The maximum decrease in heart rate was 38 +/- 16% and occurred at 13 +/- 10 seconds after the injection of bupivacaine. Maximum heart rate changes occurred significantly earlier than maximum decreases in CFR (p less than 0.01). On the other hand, maximum blood pressure changes occurred significantly later than maximum decreases in CFR (p less than 0.01). The data reported here demonstrate that conscious animals respond similarly to animals anesthetized with chloral hydrate with respect to the medullary effect of local anesthetics.

Animals↗