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Biomedical subjects

C M Bernards

Publications and source records attributed to C M Bernards.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effect of chronic cocaine exposure on the hemodynamic response to vasopressors in sheep.

BACKGROUND: The purpose of this study was to determine how chronic cocaine exposure affects the hemodynamic response to epinephrine, dopamine, phenylephrine, and ephedrine in awake sheep. METHODS: The hemodynamic response to dopamine (10 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) boluses was determined at baseline before low-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. The hemodynamic response to epinephrine (0.15 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) was determined at baseline before high-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. RESULTS: Chronic cocaine exposure abolished the mean arterial pressure and heart rate responses to dopamine but did not alter the responses to epinephrine, phenylephrine, or ephedrine. CONCLUSION: In awake sheep, chronic cocaine exposure markedly impairs the hemodynamic response to dopamine but not to epinephrine, phenylephrine, or ephedrine.

Animals↗
PubMed1997

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Analysis of Variance↗
PubMed1996

Centrally mediated hemodynamic effects of cocaine in rabbits: the role of local anesthetic actions and biogenic amine re-uptake blockage.

This study sought to identify the central nervous system-mediated cardiovascular effects of cocaine and to determine if these effects result from local anesthetic action or biogenic amine re-uptake blockade. New Zealand rabbits received multiple i.c.v. doses of cocaine, pseudococaine, lidocaine or desipramine while recording blood pressure and heart rate. Moderate dose cocaine produced a decrease in heart rate and mean arterial pressure while the highest dose produced increases in heart rate and blood pressure. Lidocaine and pseudococaine produced dose-dependent increases in blood pressure while desipramine produced decreases in heart rate and mean arterial pressure. In this model, the central nervous system-mediated cardiovascular effects of cocaine are dose-dependent; low doses produced cardiovascular depression while higher doses produced cardiovascular stimulation. The data also suggest that cocaine's local anesthetic effects are responsible for its central nervous system-mediated cardiovascular stimulation, while biogenic amine re-uptake blockade causes cardiovascular depression.

Adrenergic Uptake Inhibitors↗
PubMed1996

Palmitoyl carnitine increases the transmeningeal flux of hydrophilic but not hydrophobic compounds in vitro.

BACKGROUND: Increasing drug penetration through the spinal meninges should improve epidural analgesia/anesthesia by increasing the rate and extent to which epidurally administered drugs redistribute to the spinal cord. Palmitoyl carnitine has been shown to improve drug penetration through the intestinal mucosa. The purpose of this study was to determine whether palmitoyl carnitine improves drug penetration through the spinal meninges. METHODS: The transmeningeal flux of morphine, mannitol, bupivacaine, and sufentanil was determined through the spinal meninges of Macacca nemestrina monkeys before and after addition of palmitoyl carnitine. Flux was determined using a previously established in vitro diffusion cell method. RESULTS: Palmitoyl carnitine significantly increased the transmeningeal flux of mannitol, morphine, and bupivacaine by 942 +/- 102%, 401 +/- 43%, and 12 +/- 4%, respectively. However, palmitoyl carnitine had no significant effect on the transmeningeal flux of sufentanil. The penetration-enhancing effect of palmitoyl carnitine was shown to depend on the dose of palmitoyl carnitine added and on the octanol:buffer distribution coefficient of the study drugs but not on the concentration of the study drug. CONCLUSIONS: The mechanism by which palmitoyl carnitine increases transmeningeal flux is unclear but may be a result of palmitoyl carnitine's ability to decrease packing order of lipid bilayers in the arachnoid mater cell membranes. Regardless of the mechanism, palmitoyl carnitine's ability to selectively increase the transmeningeal flux of hydrophilic compounds in vitro offers the possibility of improving the spinal bioavailability of this group of epidurally administered drugs in vivo.

Analgesia, Epidural↗
PubMed1996

Chronic cocaine administration reversibly increases isoflurane minimum alveolar concentration in sheep.

BACKGROUND: Significant numbers of patients are seen for surgery and anesthesia with a history of chronic cocaine use. However, little is known about how cocaine use influences anesthetic physiology and pharmacology. The purpose of this study was to investigate the effect of chronic cocaine exposure on the minimum alveolar concentration (MAC) of isoflurane in sheep. METHODS: Isoflurane MAC was determined at baseline in 12 sheep using a standard protocol. The animals were subsequently exposed to cocaine for 18 days. Cocaine exposure consisted of a continuous subcutaneous cocaine infusion at 0.2 mg.kg-1.h-1, twice daily 4-mg/kg intravenous boluses and repeated hourly 4 mg/kg cocaine boluses for 8 h on day 18. Minimum alveolar concentration determinations were repeated again on days 15, 18, and on day 28 after 10 days of cocaine abstinence. RESULTS: Compared to baseline MAC (1.53 +/- 0.12%) cocaine exposure significantly increased isoflurane MAC on days 15 (1.91 +/- 0.14%) and 18 (1.78 +/- 0.13%; P = .005). MAC decreased after discontinuation of cocaine and was not different from baseline on day 28 (1.67 +/- 0.11). CONCLUSIONS: In sheep, chronic cocaine exposure resulted in a reversible increase in isoflurane MAC. This finding contrasts with studies of other central nervous system stimulants, which have demonstrated a decrease in MAC after chronic drug exposure.

Anesthetics, Inhalation↗
PubMed1995

Epinephrine is metabolized by the spinal meninges of monkeys and pigs.

BACKGROUND: Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol-O-methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space. METHODS: Spinal meningeal specimens measuring 4 cm2 were obtained from monkeys (M. nemestrina) and farm-bred pigs and were incubated in bicarbonate-buffered mock cerebrospinal fluid. Epinephrine (200 micrograms base) was added at t = 0, and 200 min later, the mock cerebrospinal fluid was collected for metanephrine analysis. In separate experiments, pig meningeal specimens were separated into dura mater, pia-arachnoid mater, and pia mater, and the experiments were repeated to determine which meninx had the greatest COMT activity. RESULTS: Metanephrine was produced by monkey meninges at the rate of 0.47 ng.min-1.cm-2 and by pig meninges at the rate of 0.23 ng.min-1.cm-2 (P > 0.05). The pia-arachnoid meninx produced metanephrine at a greater rate (4.48 +/- 0.46 ng.min-1.mg-1 tissue) than did the pia mater (1.3 +/- 0.15 ng.min-1.mg-1 tissue) or dura mater alone (1.82 +/- 0.23 ng.min-1.mg-1 tissue). CONCLUSIONS: These data demonstrate the functional presence of COMT in the spinal meninges of pigs and monkeys and suggest that the spinal meninges may limit the spinal bioavailability of epidurally or intrathecally administered epinephrine.

Animals↗
PubMed1994

Effect of (hydroxypropyl)-beta-cyclodextrin on flux of morphine, fentanyl, sufentanil, and alfentanil through the spinal meninges of monkey.

Previous studies have demonstrated that (hydroxypropyl)-beta-cyclodextrin behaves as a slow-release reservoir when used as a vehicle for intrathecal administration of opioids. The goal of the current investigation was to determine if (hydroxypropyl)-beta-cyclodextrin might serve as a slow-release vehicle for epidural opioid administration as well. An in vitro diffusion cell model was used to determine the flux of morphine, fentanyl, alfentanil, and sufentanil through the spinal meninges of Macaque nemestrina monkeys in the absence or presence of varying concentrations of (hydroxypropyl)-beta-cyclodextrin. No concentration of cyclodextrin slowed the flux of any of the opioids through the meninges, indicating that (hydroxypropyl)-beta-cyclodextrin will not behave as a slow-release reservoir for these opioids in the epidural space. This finding suggests that the rate-limiting step in opioid transfer was diffusion through the meninges not dissociation of the opioid cyclodextrin complex. However, (hydroxypropyl)-beta-cyclodextrin significantly increased the flux of sufentanil through the meninges. Since sufentanil's hydrophobicity has previously been shown to impede its meningeal flux, this finding suggests that cyclodextrin effectively decreases sufentanil's hydrophobicity by formation of inclusion complexes in the aqueous environments of the spinal meninges.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1994

Effect of needle puncture on morphine and lidocaine flux through the spinal meninges of the monkey in vitro. Implications for combined spinal-epidural anesthesia.

BACKGROUND: Combined spinal-epidural anesthesia is a technique growing in popularity. However, there have been no attempts to investigate the risk of epidural drug reaching the subarachnoid space in high concentration by passing through the meningeal hole left by the spinal needle. This study begins to address this question by quantitating the flux of morphine and lidocaine through the spinal meninges of the monkey in vitro after puncture with three different-sized needles. METHODS: Spinal meningeal tissue from anesthetized monkeys was mounted in a diffusion cell and drug flux was measured through intact tissue and through tissue punctured with a 27-G Whitacre, a 24-G Sprotte, and an 18-G Tuohy needle. RESULTS: The flux of morphine through the meningeal tissue was significantly increased by puncture with each of the study needles. The flux of lidocaine was significantly increased only by puncture with the 24-G Sprotte and 18-G Tuohy needles. The flux of morphine through intact tissue was less than the flux of lidocaine through intact tissue. In contrast, the flux of morphine and lidocaine were the same through tissue punctured with the study needles. The magnitude of the drug flux through the needle puncture was a function of the diameter of the study needle. CONCLUSIONS: Epidural anesthesia after accidental or intentional puncture of the spinal meninges has occasionally resulted in high spinal blocks and total spinal anesthesia. This study suggests that drug movement through the meningeal hole is responsible for this complication and that the risk may be decreased by using the smallest possible needle to puncture the meninges.

Anesthesia, Epidural↗
PubMed1994

Radicular artery blood flow does not redistribute fentanyl from the epidural space to the spinal cord.

BACKGROUND: Epidural opioids must redistribute to the spinal cord to produce analgesia. It has been suggested that opioids may reach the spinal cord via the radicular arterial blood supply. This study was designed to test this hypothesis. METHODS: Microdialysis probes were placed in the lumbar and thoracic spinal cord of six anesthetized pigs and a ligature placed around the thoracic aorta. At t = 0, fentanyl (300 micrograms) was injected into the epidural space and the spinal cord and plasma were sampled over 90 min to determine resultant spinal cord dialysate fentanyl concentrations. At t = 90, the thoracic aorta was occluded to eliminate distal radicular artery blood flow and fentanyl was again injected into the epidural space. The spinal cord was sampled for an additional 90 min to determine spinal cord dialysate fentanyl concentrations. At t = 90 min the aortic cross-clamp was released and spinal cord samples were collected for another 30 min. RESULTS: There was no difference in lumbar spinal cord dialysate concentrations of fentanyl between the control and cross-clamp conditions over the first 20 min after epidural administration. Between 20 and 90 min, lumbar spinal cord fentanyl concentrations were significantly greater during aortic cross-clamp. Fentanyl was not detected in the thoracic cord. CONCLUSIONS: Radicular artery blood supply does not redistribute fentanyl from the epidural space to the spinal cord in this model. However, radicular artery blood flow does play a role in clearing fentanyl from the spinal cord.

Animals↗
PubMed1993

Effect of intracerebroventricular picrotoxin and muscimol on intravenous bupivacaine toxicity. Evidence supporting central nervous system involvement in bupivacaine cardiovascular toxicity.

BACKGROUND: The authors have previously shown that administration of bupivacaine into the cerebral ventricles of rabbits results in CNS-mediated cardiac dysrhythmias and that these CNS-mediated dysrhythmias could be terminated by CNS administration of a drug (midazolam) that enhances GABAergic activity. The goal of the current investigation was to determine whether the CNS-mediated cardiotoxicity that occurs after direct CNS administration of bupivacaine contributes to bupivacaine's cardiovascular toxicity following intravenous administration. METHODS: Three groups of rabbits were pretreated by intracerebroventricular administration of mock CSF (control), muscimol (a GABA agonist), or picrotoxin (a GABA chloride channel blocker). A fourth group received intravenous hexamethonium as a pretreatment. After pretreatment, all groups received intravenous bupivacaine at 1.5 mg.kg-1.min-1 and the bupivacaine dose and plasma concentration at the onset of dysrhythmias and cardiovascular collapse were determined. It was hypothesized that pretreatment with muscimol and hexamethonium would increase the threshold for cardiac dysrhythmias, while pretreatment with picrotoxin would decrease the threshold for dysrhythmias. RESULTS: The bupivacaine plasma concentration required to produce cardiac dysrhythmias was significantly greater in the muscimol and hexamethonium groups compared to control. The bupivacaine plasma concentration at the onset of dysrhythmias was not different from control in the picrotoxin group. The bupivacaine plasma concentration that produced cardiovascular collapse did not differ from control in any of the groups. CONCLUSIONS: It was concluded that the data generally support the hypothesis that bupivacaine-mediated cardiac dysrhythmias are, at least in part, mediated by CNS actions of the drug.

Animals↗
PubMed1993

Flux of morphine, fentanyl, and alfentanil through rabbit arteries in vivo. Evidence supporting a vascular route for redistribution of opioids between the epidural space and the spinal cord.

BACKGROUND: It has been suggested that opioids may move from the epidural space to the spinal cord by way of the spinal radicular arteries. However, there are no data that address this proposed mechanism. The goal of the current study was to determine whether the radicular arterial supply of the spinal cord is a viable route for movement of opioids between the epidural space and spinal cord. METHODS: The carotid and femoral arteries of anesthetized rabbits were exposed, ligated distally, and cannulated proximal to the ligature. A fluid reservoir was placed around the study vessel and filled with saline buffered to pH = 7.4 or 9.0. The study drug (morphine, fentanyl, or alfentanil) and a radiolabeled tracer were added to the reservoir. Blood was collected as it flowed through the arterial segment bathed by the fluid reservoir and analyzed by scintillation counting to determine how much drug diffused through the arterial wall per minute. RESULTS: Relative flux rates through the carotid artery at pH = 7.4 were alfentanil flux > fentanyl > morphine. Increasing the pH to 9.0 resulted in a significant decrease in fentanyl's flux, but no significant change in alfentanil's or morphine's flux. In addition, the data demonstrate a biphasic relationship between octanol:buffer distribution coefficient and transarterial flux rates. CONCLUSIONS: Because the critical step in transporting drug via radicular arteries is diffusion through the radicular artery wall, these data support the idea that drugs may gain direct access to the spinal cord by diffusing into the radicular arteries as they traverse the epidural space en route to the spinal cord.

Alfentanil↗
PubMed1992

Progression of first degree heart block to high-grade second degree block during spinal anaesthesia.

A case is presented in which a patient with pre-existing first degree heart block developed high-grade second degree heart block during spinal anaesthesia. Progression of the block was associated with blockade of cardiac sympathetic neurons induced by spinal anaesthesia. This suggests that patients with pre-existing heart block may be at increased risk for development of higher grade block during spinal anaesthesia.

Adult↗
PubMed1992

Liposome encapsulation prolongs alfentanil spinal analgesia and alters systemic redistribution in the rat.

The effect of liposome encapsulation on the analgesia produced by intrathecally administered alfentanil was examined in the rat. In rats prepared with chronic intrathecal catheters, alfentanil in doses of 1-50 micrograms was administered intrathecally in either saline or in multilamellar liposomes (dipalmitoylphosphatidylcholine and cholesterol). Animals were then tested for analgesia by hot-plate and paw-pressure tests. A second group of animals received intrathecal injections of 30 micrograms alfentanil in saline or liposomes, and blood samples were obtained at 5, 15, 45, and 135 min thereafter for measurement of alfentanil plasma concentrations. The liposome preparation markedly prolonged spinal analgesia in the paw-pressure test and to a lesser extent in the hot-plate test. Neither the time to peak analgesia nor the intensity of analgesia differed between the saline and liposome groups. Liposome encapsulation significantly reduced the peak alfentanil plasma concentration at 5 min and prolonged the period in which low but measurable levels of alfentanil could be measured in plasma. These pharmacokinetic data demonstrate that liposome encapsulation resulted in a slow but prolonged appearance of free alfentanil into a diffusible pool available for uptake into the spinal cord. Consistent with the lower peak plasma concentration of alfentanil, the liposome group demonstrated a significantly lower incidence of catalepsy, indicating less systemic redistribution of alfentanil to supraspinal sites. Liposome encapsulation thus appears to produce a significant reduction in peak plasma concentration with a concomitant reduction in systemic side effects and an increase in the duration of action for a given intrathecal dose of the otherwise rapidly cleared alfentanil.

Alfentanil↗
PubMed1992

Physical and chemical properties of drug molecules governing their diffusion through the spinal meninges.

Drugs administered into the epidural space for selective spinal analgesia must diffuse through the spinal meninges to gain access to their sites of action in the spinal cord. Therefore, knowledge of the physical and chemical properties of drug molecules that govern their diffusion through the meninges is important for understanding the pharmacokinetics of epidural analgesia. To determine the physicochemical properties of drug molecules that govern the rate at which drugs diffuse through the spinal meninges, the authors measured the permeability coefficient of eight different drug molecules through the spinal meninges of the monkey using a previously established in vitro model. We previously reported permeability measurements for four of the molecules used in this study; the other four molecules' permeability measurements are new. The measured permeability coefficient was then correlated with the drugs' molecular weight, molecular surface area, molecular volume, length of the major molecular axis, and octanol:buffer distribution coefficient. We found no relationship between the drugs' permeability coefficients and any measure of drug mass, molecular shape, or molecular size. There was, however, a biphasic relationship between the octanol: buffer distribution coefficient and the drugs' measured permeability coefficients. Drugs that were either very hydrophilic or very hydrophobic had permeability coefficients that were significantly less than drugs of intermediate hydrophobicity. These data suggest that it should be possible to design novel analgesics for which meningeal permeability is maximal.

Animals↗