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Biomedical subjects

D D Denson

Publications and source records attributed to D D Denson.

At least 55 records · Page 3Linked to original sources
PubMed1987

Comparison of continuous epidural infusion of a local anesthetic and administration of systemic narcotics in the management of pain after total knee replacement surgery.

Continuous bupivacaine epidural analgesia was compared with conventional methods of systemic analgesic administration in the management of postoperative pain in 30 patients for 3 days following total knee replacement surgery. Patients given continuous epidural analgesia had significantly better pain relief (visual analogue scale, global evaluation), needed significantly fewer supplementary analgesics, and had significantly fewer side effects. In the epidural group, sensory block averaged six dermatomes on day 1 and four dermatomes on day 3. The number of patients with complete (or almost complete) motor block of the lower limbs decreased from eight on day 1 to five on day 3. The mean dosage of bupivacaine decreased from 21.0 +/- 5.7 (SD) mg/hr on day 1 to 15.1 +/- 8.5 mg/hr on day 3. No signs of accumulation of or toxic reactions to bupivacaine were seen.

Adolescent↗
PubMed1987

Meperidine pharmacokinetics following intravenous, peroral and buccal administration in beagle dogs.

The pharmacokinetics of meperidine was studied in Beagle dogs following intravenous, peroral and buccal administration of a meperidine hydrochloride solution. The elimination half-life after I.V., P.O. and buccal routes was 0.75 +/- 0.14 hours, 0.93 +/- 0.18 hours and 0.36 +/- 0.10 hours, respectively. The volume of distribution and total clearance following I.V., P.O. and buccal administration were 2.41 +/- 0.34 L/kg and 42.5 +/- 8.9 ml/min/kg, 2.84 +/- 1.24 L/kg and 34.6 +/- 7.8 ml/min/kg, 1.01 +/- 0.52 L/kg and 34.7 +/- 8.0 ml/min/kg, respectively. The absolute bioavailability after P.O. and buccal administration was 11.0 +/- 6.8% and 11.9 +/- 6.6%, respectively. This paper discusses the observed low bioavailabilities on hypothesis of hepatic and lung first-pass effect. A hypothesis is presented to explain the delayed onset of absorption following buccal administration.

Administration, Buccal↗
PubMed1987

Comparison of pharmacokinetic parameters determined by four different methods.

Pharmacokinetic evaluation was performed using RESID, NONLIN84, KINPAK and AUC-RPP programs for a crossover hydromorphone study involving I.V., P.O. and rectal administration in humans. It was observed that when the curve fitting was difficult by using compartment model dependent methods, pharmacokinetic parameters could still be estimated by compartment model independent analysis.

Administration, Oral↗
PubMed1987

Rectal bioavailability of lidocaine in the dog: evaluation of first-pass elimination.

The disposition of lidocaine was studied in beagle dogs after I.V., P.O. and rectal administration. Lidocaine HCl solution was used for the I.V. and P.O. studies. For rectal administration 3 gels were prepared: 1) lidocaine base in a hydrophilic vehicle, 2) lidocaine HCl in a hydrophilic vehicle, and 3) lidocaine base in a lipophilic vehicle. The gels were administered 3 cm deep in the rectum. Additionally, the gel of lidocaine HCl in a hydrophilic vehicle was also administered 10 cm deep in the rectum. No significant differences between I.V. and all extravascular administrations were observed for terminal half-life, total clearance and apparent volume of distribution. The systemic bioavailability after P.O. was 31%, and between 32% and 53% for the rectal dosage forms. The lidocaine base in lipophilic vehicle had the lowest systemic availability, the lowest peak concentration and the longest time to peak, whereas the lidocaine HCl in a hydrophilic vehicle, inserted 10 cm deep into the rectum, had the highest systemic bioavailability, highest peak concentration and shortest time to peak. The dog seems to be an excellent model for evaluation of peroral and rectal first-pass elimination.

Administration, Rectal↗
PubMed1986

The effect of nonesterified fatty acids and progesterone on bupivacaine protein binding.

We examined the influence of elevations in levels of nonesterified fatty acids (NEFAs) and progesterone concentrations on bupivacaine protein binding. The addition of NEFAs to isolated binding proteins of bupivacaine (alpha 1-acid glycoprotein and serum albumin) resulted in an increased binding to alpha 1-acid glycoprotein and an inconsistent decrease in binding to serum albumin. The NEFA alteration in the binding of bupivacaine to isolated proteins, however, only restored the isolated protein binding to normal whole serum levels. An elevated progesterone concentration in whole serum did not alter the binding of bupivacaine. It appears from our results that increases in either NEFA or progesterone concentrations do not account for the observed decrease in bupivacaine protein binding in the term parturient.

Adult↗
PubMed1986

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone.

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.

Anesthetics, Local↗
PubMed1986

Differential effect of plasma protein binding of bupivacaine on its in vivo transfer into the brain and salivary gland of rats.

The effect of plasma protein binding of bupivacaine on its transfer into brain and salivary gland was studied using bovine serum albumin, human alpha 1-acid glycoprotein (AAG) and human serum. The in vivo brain extraction and salivary gland extraction of [3H] bupivacaine relative to [14C]butanol were determined with an intracarotid injection technique used on rats. The brain extraction varied inversely with the bovine serum albumin (0-7.5%) and AAG (0-3.0 mg/ml) concentrations. The salivary extraction only slightly varied inversely with the AAG concentration, whereas no significant effects of bovine albumin binding on salivary gland uptake were observed. The in vivo percentage of exchangeable drug in brain or salivary gland capillaries was severalfold greater than the in vitro percentage of unbound drug. The percent values of free drug, brain exchangeable drug and salivary exchangeable drug were 12 +/- 1, 81 +/- 7 and 93 +/- 18% for umbilical cord serum, 8.6 +/- 1.1, 73 +/- 6 and 103 +/- 3% for normal human serum, 5.9 +/- 0.5, 60 +/- 4 and 89 +/- 3% for serum of rheumatoid arthritis patients and 5.0 +/- 0.2, 45 +/- 2 and 83 +/- 3% for serum of metastatic cancer patients. These data indicate that bupivacaine is not transported through the brain capillary wall, i.e., the blood-brain barrier, from the bovine albumin-bound pool, but bupivacaine is partially available for transfer from the circulating AAG-bound pool. However, both bovine albumin-bound and AAG-bound bupivacaine are readily available for transport through salivary gland capillaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The influence of diazepam on the pharmacokinetics of intravenous and epidural bupivacaine in the rhesus monkey.

Pretreatment of patients with diazepam has been reported to reduce the plasma half-life of epidurally administered bupivacaine. The concentrations of bupivacaine used to estimate its plasma half-life may be influenced by input into the vascular system (rate and extent of absorption from the epidural space) and disposition (distribution and elimination). We conducted a study in Rhesus monkeys in which the input function was known and the influence of intravenous diazepam on the disposition of intravenous bupivacaine could be delineated. Results indicated no differences in the primary pharmacokinetic parameters (i.e., total clearance and volume of distribution) for the disposition of bupivacaine. To determine whether the apparent disparity between these results and a previous study might be due to a diazepam-induced alteration in the input function, the influence of intravenous diazepam or saline on the mean absorption time of epidurally administered bupivacaine was also studied in monkeys. Epidural bupivacaine was completely absorbed whether the animals received intravenous saline or intravenous diazepam. No significant differences in pharmacokinetic parameters were found between animals pretreated with intravenous saline or intravenous diazepam and receiving an epidural injection of bupivacaine. The mean residence time of bupivacaine in the body (P less than 0.01) and plasma elimination half-life (P less than 0.005) were significantly longer after epidural administration than after intravenous administration. Intravenous diazepam does not alter the pharmacokinetics of intravenously or epidurally administered bupivacaine.

Absorption↗
PubMed1986

Cardiovascular toxicity of local anesthetics: an alternative hypothesis.

The current study examined the possibility that high local anesthetic concentrations within the central nervous system could contribute to the toxic cardiovascular effects observed clinically after an accidental intravenous injection. Equal numbers of molecules of lidocaine (1.6 microliter of a 2% solution) and bupivacaine (1.0 microliter of a 4% solution) were injected at three vasomotor and cardioactive areas in the rat medulla by means of a 28-gauge hypodermic needle and a microsyringe. These areas were the C1 region, the intermediolateral column (IML), and the nucleus tractus solitarius (NTS). Both lidocaine and bupivacaine at C1 significantly decreased mean arterial pressure and, at IML, resulted in significant bradycardia and hypotension. At NTS, both lidocaine and bupivacaine caused significant bradycardia and hypotension, which were accompanied by ventricular arrhythmias in 55% of the animals. In all animals in whom ventricular arrhythmias were associated with lidocaine, the arrhythmias spontaneously reverted to normal sinus rhythm. In 50% of animals developing ventricular arrhythmias after bupivacaine, the arrhythmias resulted in death. Using an equal number of molecules of lidocaine and bupivacaine, all three regions studied demonstrated that bupivacaine was 2-4 times more potent than lidocaine in producing cardiovascular effects. These data demonstrate that direct application of local anesthetics within the medullary region of the central nervous system can result in hypotension, bradycardia, and ventricular arrhythmias similar to what may be seen in humans after accidental intravenous injections of local anesthetics. Moreover, the sites and mechanisms of action appear to be identical for bupivacaine and lidocaine. Thus bupivacaine does not appear to be an aberrant local anesthetic, as some have suggested, but rather produces more profound effects related to its potency and physicochemical properties.

Animals↗
PubMed1984

Influence of bupivacaine on mepivacaine protein binding.

To elucidate the mechanism of any drug displacement interaction, we examined the protein binding of mixtures of mepivacaine and bupivacaine in serum and solutions of albumin or alpha 1-acid glycoprotein. Protein binding data with mepivacaine alone were best described by a model with one class of binding site and a partitioning constant in serum and by a model with one class of binding site in both isolated protein solutions. Binding affinity of mepivacaine in serum was reduced in the presence of bupivacaine. Displacement of mepivacaine by bupivacaine was observed when an alpha 1-acid glycoprotein solution was studied. Classic competitive inhibition was demonstrated. Bupivacaine reduced mepivacaine binding to albumin, but the degree of displacement was not significant. When administered simultaneously, these two amino-amide local anesthetics interact synergistically to produce a higher than expected free concentration of mepivacaine. This interaction increases the risk of toxicity.

Binding, Competitive↗
PubMed1984

Bupivacaine protein binding in the term parturient: effects of lactic acidosis.

The effects of lactic acidosis on bupivacaine serum protein binding was studied in a group of term parturients and a group of nonpregnant female control subjects. Groups were matched in age and health. Distribution characteristics of bupivacaine in pregnancy were determined. Bupivacaine protein binding was best characterized by the model for two classes of binding sites in all studies. The parturients exhibited a lower capacity for the high-affinity, low-capacity (alpha 1-acid glycoprotein) site and higher affinity for the low-affinity, high-capacity (albumin) site. Lactic acidosis decreased the affinity constant for the high-affinity, low-capacity site in the control group but did not change binding characteristics in the parturients. Free concentration of bupivacaine (Cu) was elevated at low total bupivacaine concentrations (Ct) (less than 10 micrograms/ml). No differences in Cu were detected at concentrations in the cardiotoxic range (greater than 20 micrograms/ml). The Cu values predicted by the estimated binding parameters from in vitro experiments were compared with actual Cu measured in nine parturients at delivery; they correlated significantly (r = 0.94). Distribution changes for bupivacaine in the parturients were consistent with known physiologic changes in body composition associated with pregnancy. Alterations that occur in serum protein binding during pregnancy should not result in increased risk of central nervous system or cardiovascular system toxicity since these alterations do not increase free tissue concentration.

Absorption↗
PubMed1984

The influence of lactic acid on the serum protein binding of bupivacaine: species differences.

Various animal models have been used for studies of bupivacaine cardiovascular toxicity. These studies are difficult to relate to the clinical situation, since the disposition of bupivacaine in the various species is unknown. The serum protein binding of bupivacaine, therefore, was determined in human, sheep, monkey, dog, and rat at physiologic pH using ultrafiltration. Since a mixed acidosis results during a systemic toxicity reaction to bupivacaine, the influences of an acidic pH, resulting from the addition of lactic acid, also was examined. All sera exhibited two classes of binding sites, a high-affinity, low-capacity class (class 1) and a low-affinity, high-capacity class (class 2). When compared to human serum at physiologic pH, a significantly higher (P less than 0.05) affinity constant for the class 1 sites was observed for all species studied, with the exception of the rat. All species studied exhibited a significantly lower (P less than 0.05) capacity for the class 1 sites. The binding parameters of the class 2 sites displayed no significant difference. An acid pH resulted in a decrease in bupivacaine protein binding over the entire concentration range studied for all species, with the exception of the monkey. Monkey serum exhibited no change in bupivacaine binding with a decrease in pH. Since protein binding explains only a portion of the total disposition of bupivacaine, further delineation of each animal model under both acidotic and physiologic conditions needs to be accomplished before the animal studies currently under investigation can be extrapolated to the clinical situation.

Acidosis↗
PubMed1984

Serum bupivacaine concentrations in term parturients following continuous epidural analgesia for labor and delivery.

This study was undertaken to measure the blood concentrations of bupivacaine associated with a single loading dose followed by continuous epidural infusion for the management of the pain of labor and delivery with special reference to the potential for accumulation and toxicity. Four-milliliter venous blood samples were obtained every 15 min following the loading dose until delivery. If inadequate analgesia was observed just prior to delivery, an additional dose of bupivacaine was administered. Bupivacaine concentrations were measured using a double extraction technique followed by gas chromatographic analysis using a nitrogen-specific detector. Clearance, volume of distribution, and rate of absorption were estimated from the blood concentration time data and were 43.39 +/- 11.46 L/h, 67.56 +/- 17.66 L, and 8.97 +/- 3.69 h-1, respectively. Peak serum bupivacaine concentrations were 0.68 +/- 0.14 microgram/ml and occurred 0.58 +/- 0.25 h following administration of the loading dose. The duration of bupivacaine infusion was 3.42 +/- 0.80 h. Serum bupivacaine concentrations at delivery or just prior to administration of a supplemental delivery dose were significantly lower than the peak concentration in all patients (p less than 0.001). Fetal-to-maternal serum concentration ratios were found to be 0.44 +/- 0.16 for the six patients requiring a supplemental delivery dose and 0.44 +/- 0.13 for the six patients receiving bupivacaine only by infusion. The data reported here illustrate that epidural analgesia for labor and delivery achieved using a single 50-mg loading dose followed by a continuous infusion of 12.5 mg/h of bupivacaine will not result in maternal or fetal accumulation or toxicity.

Adult↗
PubMed1984

The influence of diazepam on the serum protein binding of bupivacaine at normal and acidic pH.

Since both bupivacaine and diazepam are highly protein bound, it is possible that a drug displacement interaction could occur, resulting in an increase in free bupivacaine concentration that could exacerbate systemic toxicity. This study was undertaken to characterize the serum binding of diazepam and to evaluate any drug displacement interaction between diazepam and bupivacaine. Human serum obtained from venous blood of normal male and female volunteers was used for measurements of protein binding using an Amicon Micropartition System. Bupivacaine protein binding in the presence of 0, 0.5 and 1.5 microgram/ml diazepam was best described by the model for two classes of binding sites. Neither concentration of diazepam significantly altered the capacity or affinity for either class of bupivacaine binding sites when compared to control. Free concentrations of bupivacaine were statistically identical in the presence of both diazepam concentrations. The complete diazepam binding profile in both serum and isolated human serum albumin was best described by a model describing two classes of binding sites. The effect of an acidic pH on bupivacaine was also independent of diazepam concentration. Diazepam protein binding was not affected by a reduction in pH from 7.4 to 7.0. The data reported here suggest no binding displacement interaction exists between bupivacaine and concomitantly administered diazepam. Thus, administration of diazepam during a toxic reaction associated with bupivacaine should not alter free bupivacaine concentration.

Acidosis↗
PubMed1984

The clinical relevance of the drug displacement interaction between meperidine and bupivacaine.

The effect of meperidine at two clinically relevant concentrations (0.4 and 0.8 microgram/ml) on the serum protein binding of bupivacaine was studied. The serum protein binding profile for meperidine was characterized over a wide concentration range (0.5-100 micrograms/ml). All bupivacaine binding experiments were characterized by a two classes of binding sites model. Bupivacaine binding was independent of added meperidine. Meperidine binding was characterized by a one class of binding sites model and the unbound meperidine concentration was relatively constant over the entire range studied. The capacity and affinity of the meperidine binding site are suggestive of binding primarily to albumin. At clinically encountered meperidine concentrations, no increased toxicity due to an increase in unbound bupivacaine would be expected.

Binding, Competitive↗
PubMed1984

Continuous perineural infusions of bupivacaine for prolonged analgesia--a rapid two-point method for estimating individual pharmacokinetic parameters.

Results of previous studies have shown a 5-10 fold range in the clearance total and half-life of bupivacaine. Since bupivacaine has a narrow therapeutic range and highly variable pharmacokinetic parameters, rapid estimation of the parameters allows early dosage regimen adjustments, and hence, better pain management. The pharmacokinetic parameters in 17 patients were estimated based on two samples drawn within 18 h after initiation of therapy. Based on the estimated parameters, a later sample's concentration was predicted. Results of this study confirm the previously reported large variation in pharmacokinetic parameters. An excellent agreement between actual and predicted concentration was found. The use of this method allows early readjustment in the dosage regimen, resulting in effective pain management without compromising patient safety.

Aged↗
PubMed1984

Pharmacokinetics and neural blockade after subarachnoid lidocaine in the rhesus monkey. III. Effects of phenylephrine.

Using a rhesus monkey model, lidocaine (30 mg) in 7.5% dextrose was compared with lidocaine (30 mg) in 7.5% dextrose containing 1.5 mg of phenylephrine (Neosynephrine). Phenylephrine increased both duration of maximum motor block and time for complete motor recovery. A significantly higher sensory dermatome level and significantly longer time for complete sensory recovery was found when the lidocaine solution contained phenylephrine. Time for two-segment regression of sensory blockade was unaffected by phenylephrine. The slope of the regression phase for motor block was parallel for both treatments, suggesting differences in neural blockade were caused by a more profound initial block when phenylephrine was added. Pharmacokinetic analysis revealed identical absorption and elimination constants. Maximum plasma concentrations of lidocaine and time to reach maximum plasma concentrations were identical with and without phenylephrine. The systemic absorption (fraction of drug absorbed from the subarachnoid space) was complete with and without phenylephrine. No lag times for systemic absorption were found for either treatment. Our data demonstrate that there are no clinically significant differences between phenylephrine and epinephrine when added to lidocaine solutions for spinal anesthesia.

Anesthesia, Spinal↗