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Biomedical subjects

C A DiFazio

Publications and source records attributed to C A DiFazio.

At least 37 records · Page 2Linked to original sources
PubMed1986

Prolonged blockade of opioid effect with oral nalmefene.

In a placebo-controlled, double-blind study we evaluated the ability of a single 50 mg oral dose of nalmefene to block the effects of intravenous opioid challenge (2 micrograms/kg fentanyl). Fentanyl-induced respiratory depression (CO2 responsiveness), analgesia (tourniquet ischemia), and subjective effects were totally blocked for 48 hours and showed only minimal breakthrough 72 hours after nalmefene. Plasma concentration-time data for nalmefene indicate good oral bioavailability and a prolonged terminal elimination phase (mean t1/2 11.1 hours). These findings suggest that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy.

Administration, Oral↗
PubMed1986

Prolonged antagonism of opioid action with intravenous nalmefene in man.

To identify the opioid antagonist activity of nalmefene and to determine its duration in man, six healthy male subjects were pretreated on separate days with a saline placebo, 0.5 mg, 1 mg, or 2 mg nalmefene intravenously in a randomized double-blind fashion. Opioid challenges with fentanyl, 2 micrograms/kg, then were administered 1, 2, 4, 6, and 8 h afterward. Respiratory depression was monitored by ventilatory and occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was identified with the submaximal effort tourniquet ischemia test. One hour following placebo pretreatment, the initial fentanyl dose produced marked respiratory depression. Minute ventilation and occlusion pressure at a PCO2 60 mmHg during rebreathing (VE60 and P(0.1)60) were reduced to 29 and 41% of control, respectively. The slopes of the ventilatory and occlusion pressure responses also decreased significantly to 51 and 55% of control. Respiratory effects were similar with all subsequent fentanyl doses. Pretreatment with 2 mg nalmefene completely prevented the subjective and respiratory effects of fentanyl for the entire 8 h of the experiment. Nalmefene, 1 mg, significantly blunted the fentanyl effects for the same period, but VE60 values at 6 and 8 h were depressed significantly (P less than 0.05) to 66 and 61% of control. The antagonist effects of the lowest nalmefene dose, 0.5 mg, persisted for about 4 h, at which time VE60 was 64% of control. Fentanyl administration produced consistent increases in pain tolerance (44-55% above control) throughout the experiment. Nalmefene pretreatment abolished this analgesic response in a dose-related time course that mirrored the respiratory effects almost exactly.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Dose-dependent effects of bupivacaine on rat muscle arterioles.

The dose-dependent actions of bupivacaine on the microvasculature were evaluated by television microscopy in an in vivo rat cremaster muscle preparation. Animals were anesthetized with chloralose and urethane. Mean arterial pressure was measured via a carotid artery cannula; heart rate was calculated from the phasic pressure trace. The cremaster muscle was suffused with a balanced electrolyte solution that was controlled for temperature, pH, PO2, PCO2, and osmolarity to provide a physiologic environment. Internal diameters of fourth-order arterioles were measured with an electronic vernier displayed on the video monitor. Arteriolar diameters were measured every 30 s during a 10-min control period, a 10-min period of topical application of bupivacaine hydrochloride, and a 30-min recovery period. Bupivacaine 10(-1), 10(0), 10(1), and 10(2) micrograms X ml-1 produced progressive vasoconstriction to 82.7 +/- 2.9%, 75.0 +/- 5.6%, 71.0 +/- 7.0%, and 65.7 +/- 9.4% of control (P less than 0.05 for each), respectively. Bupivacaine, 10(3) and 2.5 X 10(3) micrograms X ml-1, did not alter arteriolar diameters significantly, although there was a tendency for vasodilation. In a second group of animals, arteriolar diameters were measured during intravenous bupivacaine infusion that produced stable plasma concentrations of 2.3 +/- 0.2 micrograms X ml-1. Vasoconstriction of 91.4 +/- 2.2%, of control (P less than 0.01) was observed. These results demonstrate that dose-dependent arteriolar constriction occurs even with blood bupivacaine levels that are at the upper limits of those expected to occur during regional anesthesia.

Administration, Topical↗
PubMed1986

Comparison of pH-adjusted lidocaine solutions for epidural anesthesia.

One hundred forty-eight adult patients having epidural anesthesia for cesarean section, postpartum tubal ligation, lower extremity orthopedic procedures, or lithotriptic therapy were assigned to five groups. Group 1 patients were given a commercially prepared 1.5% lidocaine solution with 1:200,000 epinephrine plus 1 ml of normal saline per 10 ml of lidocaine; the solution pH was 4.6. Group 2 patients were given commercially prepared 1.5% lidocaine solution plus 1:200,000 epinephrine, with 1 mEq (1 ml) NaHCO3 per 10 ml of lidocaine; the solution pH was 7.15. Group 3 patients received the commercial solution of 1.5% lidocaine with 1:200,000 epinephrine; the solution pH was 4.55. Group 4 patients were given a mixture of 18 ml of 2% lidocaine with 30 ml of 1.5% lidocaine, both commercially packaged with 1:200,000 epinephrine, plus 1 mEq (1 ml) of NaHCO3 added per 10 ml of solution; the solution pH was 7.2. Group 5 patients received 1.5% plain lidocaine to which epinephrine was added to a final concentration of 1:200,000; the solution pH was 6.35. Times of onset of analgesia (time between the completion of the anesthetic injection and loss of scratch sensation at the right hip (L-2 dermatome] and of surgical anesthesia (time between completion of injection and loss of discomfort following tetanic stimulation produced by a nerve stimulator applied to skin on the right hip) were significantly more rapid in the groups that received the pH-adjusted solutions (groups 4 and 2). Group 4 had the fastest mean onset time, 1.92 +/- 0.17 min, followed by group 2, 3.31 +/- 0.23 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Epidural↗
PubMed1986

Lidocaine pharmacokinetics in children during general anesthesia.

In spite of the increasing use of intravenous lidocaine in the operating room, no pharmacokinetic data exist for intravenous lidocaine in children. We studied ten children, ages 0.5-3 yr, and eight adults to determine lidocaine pharmacokinetics during anesthesia with halothane, nitrous oxide, and oxygen. After induction of anesthesia, tracheal intubation, and insertion of venous and arterial catheters, lidocaine, 1 mg/kg, was infused intravenously over 30 sec. Arterial samples were drawn at 0.5, 1, 2, 4, 5, 10, 15, 30, 60, 90, and 120 min. Plasma was separated and analyzed for lidocaine, using gas chromatography. Plasma concentration vs time data were fitted to a two-compartment model. Using standard formulas, we derived the following data: Children: distribution half-life (t 1/2 alpha) 3.2 min, elimination half-life (t 1/2 beta) 58 min, volume of the central compartment (V1) 0.22 L/kg, volume of distribution (Vd area) 1.1 L/kg, and total plasma clearance (Cl) 11.1 ml X kg-1 X min-1. Adults: t 1/2 alpha 3.6 min, t 1/2 beta 43 min, V1 0.16 L/kg, Vd area 0.71 L/kg, and Cl 9.8 ml X kg-1 X min-1. No significant differences were found between children and adults for all parameters analyzed. We conclude that children older than 6 months of age distribute and eliminate intravenous lidocaine in the same manner as adults.

Adolescent↗
PubMed1985

Brain-stem auditory-evoked potentials during lidocaine infusion in humans.

Auditory brain-stem responses (ABR) were recorded in six healthy male volunteers during intravenous infusion of lidocaine that achieved systemic blood levels similar to those seen with conduction anesthesia and antiarrhythmic therapy. Following an initial loading dose of lidocaine (1 mg/kg), subjects noted prominent tinnitus, perioral numbness, and drowsiness. All of these symptoms except drowsiness abated during continued infusion as blood concentrations reached equilibrium. All subjects noted that the click stimuli used to elicit ABR varied markedly in intensity and character throughout the lidocaine infusion. Although waves I and III were unaffected by lidocaine, wave V exhibited significant decreases in amplitude and increases in latency. Therefore, the more central components of the auditory system seem to be the prominent site of lidocaine's central nervous system effects.

Acoustic Stimulation↗
PubMed1985

Lidocaine constricts or dilates rat arterioles in a dose-dependent manner.

The microvascular effects of varying concentrations of lidocaine were evaluated with the use of videomicroscopy in an in vivo rat cremaster muscle preparation. Animals were anesthetized with chloralose and urethane and breathed room air spontaneously. Mean arterial pressure and heart rate were measured via a carotid artery cannula. The cremaster muscle was suffused with a balanced electrolyte solution and pH, temperature, PO2, PCO2, and osmolarity were controlled. Internal diameters of fourth-order arterioles in the cremaster muscle were measured with an electronic vernier system. In one group of animals (n = 7), arteriolar diameters were measured every 30 s during a 10-min control period, a 10-min period of topical application of lidocaine hydrochloride, and a 10-min recovery period. Lidocaine hydrochloride, 10(0), 10(1), 10(2), 10(3), or 10(4) micrograms X ml-1, produced changes in arteriolar diameters to 88.9 +/- 0.9, 79.0 +/- 1.3, 67.5 +/- 2.4, 60.1 +/- 3.4, and 127.1 +/- 7.2 per cent of control, respectively (P less than 0.001). In a second group of animals (n = 4), fourth-order arteriolar diameters were measured during administration of intravenous lidocaine, 1.2 mg X kg-1 bolus plus 0.3 mg X kg-1 X min-1. Vasoconstriction to 91.3 +/- 0.9% of control was observed (P less than 0.001). These results demonstrate a biphasic dose-dependent response to lidocaine. At lesser concentrations, including those that occur in the plasma of patients during intravenous infusion or nerve blocks, dose-related vasoconstriction occurred. Lidocaine, 10(4) micrograms X ml-1, a concentration similar to that which occurs at the site of injection during infiltration, nerve block, or epidural anesthesia, produced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1985

Analgetic contribution of sufentanil during halothane anesthesia: a mechanism involving serotonin.

Catecholamine and serotonin concentrations in the cord, medulla, and hypothalamus were measured in rats after saline, after sufentanil sufficient to reduce the minimum alveolar concentration (MAC) of halothane by 30% or less, or after sufentanil sufficient to reduce the MAC of halothane by 80% or more. In the cord, high doses of sufentanil resulted in a 13.4% reduction (P less than 0.05) in serotonin concentration compared to saline control and a 17.4% reduction (P less than 0.05) in serotonin concentration compared to low dosages of sufentanil. A 12.8% reduction (P less than 0.05) in medullary serotonin also was observed with high sufentanil compared to low sufentanil. Epinephrine decreased significantly in the hypothalamus at the high sufentanil dose. No other significant differences were found in catecholamine content. The experimental results support the hypothesis that sufentanil may contribute to an analgetic component of general anesthesia by modulating nociception via the release of 5-HT.

Analgesics↗
PubMed1985

Reduction in halothane MAC: comparison of morphine and alfentanil.

The anesthetic potency and effectiveness of alfentanil and morphine were established by determining the effects of increasing drug doses on the alveolar anesthetic requirement of halothane to maintain a constant anesthetic (MAC) level. Six selected doses of alfentanil and four of morphine were administered to groups of mechanically ventilated rats anesthetized with halothane. Alfentanil was given as a loading dose followed by an intravenous infusion of 0.01-100 micrograms X kg-1 X min-1, and morphine was administered as a subcutaneous dose of 4-20 mg/kg. The reduction in halothane requirement after morphine was biphasic, with a rapid linear increase occurring up to an 8 mg/kg subcutaneous dose, followed by a further, slower reduction in halothane requirement after doses of 8-20 mg/kg. At a 20 mg/kg dose, the halothane MAC was reduced approximately 84%. With alfentanil, a curvilinear reduction in halothane MAC occurred up to an alfentanil dose of 15 micrograms X kg-1 X min-1, where a 48% reduction was found. Larger doses produced severe truncal, chest wall, and abdominal rigidity, precluding adequate ventilation and the determination of MAC.

Adjuvants, Anesthesia↗
PubMed1984

Ventilatory and analgesic effects of dezocine in humans.

The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurement, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 +/- 14% above control with the first dose to 70 +/- 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.

Adult↗
PubMed1984

Cardiorespiratory effects of nalbuphine and morphine premedication in adult cardiac surgical patients.

Premedication for cardiac surgical patients attempts to achieve relief of anxiety with minimal or no cardiorespiratory changes. Nalbuphine (NUBAIN) and morphine produced similar decreases in respiratory rate (1-3 breaths per min) and PaO2 (averaging 1.34 kPa), and increases in arterial PaCO2 (averaging 0.56 kPa). Cardiovascular changes were not seen with either agent. A similar degree of sedation and relief of anxiety was achieved with both drugs. Side effects were minimal and infrequent. Nalbuphine produces respiratory depression and sedation without cardiovascular changes which is comparable to an equivalent dose of morphine in patients with either valvular or coronary artery disease.

Carbon Dioxide↗
PubMed1983

The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats.

The anesthetic potency of sufentanil was established by determining its effect on the minimal alveolar anesthetic concentration (MAC) of halothane. Each of eight selected doses of sufentanil was administered to a group of four to five mechanically ventilated rats anesthetized with halothane. Sufentanil was administered as a constant infusion preceded by an intravenous bolus dose that was three times that of the infusion rate per minute. The tail-clamp technique was used to establish control MAC and the MAC of halothane with sufentanil. Increasing sufentanil dosages were nonlinearly related to reductions in the MAC of halothane. A sigmoidal dose-response curve was described. An abrupt, steep response follows the initial upward deflection of the curve with an additional 62% MAC reduction occurring between doses of 1 X 10(-5) mg X kg-1 X min-1 and 1 X 10(-4) mg X kg-1 X min-1. Essentially complete anesthesia was seen at the latter dosage. No significant adverse side effects were seen with sufentanil at doses up to 1 X 10(-2) mg X kg-1 X min-1.

Anesthesia, Inhalation↗
PubMed1983

Anesthetic potency of dezocine and its interaction with morphine in rats.

A new partial agonist-antagonist analgesic drug, dezocine, was evaluated in rats for its anesthetic potency using a MAC-reduction model. Respiratory effects as shown by changes in PaCO2 were also analyzed. A reduction of approximately 50% in cyclopropane MAC was found with doses of 6 mg/kg or more. This is the largest reduction for any drug of this class. PaCO2 levels increased up to 52 mm Hg with doses of dezocine up to 2 mg/kg. No evidence of reversal of respiratory depression or of further respiratory depression was found with increasing dosages. Combining dezocine with morphine resulted in a further reduction in cyclopropane MAC without a significant change in PaCO2. This suggests that dezocine acts primarily on the same receptor (mu) as morphine and that this receptor activity is further modulated by effects of dezocine on a second opioid receptor.

Anesthetics↗
PubMed1982

Cerebral monoamines and lidocaine toxicity in rats.

The effect of alterations in whole brain monoamine content on the plasma lidocaine concentration resulting in seizures was studied in rats. Reductions in brain monoamine content were produced by treatment with one of the following drugs: reserpine, parachlorophenylalanine (PCPA), or alpha methyl paratyrosine (AMPT). Reserpine depleted norepinephrine (NE), and dopamine (DA) by 75 per cent and serotonin (5HT) by 54 per cent; PCPA reduced brain 5HT 56 per cent without changing NE and DA; AMPT reduced brain NE and DA by 54 and 60 per cent, respectively, without altering 5HT content. Treatment with 5-hydroxytryptophan, a serotonin precursor combined with the peripheral decarboxylase inhibitor RO4-4602 increased brain 5HT content by 400 per cent without changes in DA and NE. Whole brain NE concentrations were assayed fluorometrically, DA brain concentrations were assayed by HPLC, and lidocaine concentrations in plasma were determined by gas chromatography. Plasma lidocaine concentrations at the onset of convulsions were found to be elevated significantly only by drugs causing serotonin depletion; increasing to 128 per cent of control with reserpine treatment and 139 per cent of control with PCPA treatment. Depletion of NE and DA had no effect on the lidocaine seizure threshold. Increases in brain 5HT caused a small but not statistically significant decrease to 94 per cent of control in the mean plasma lidocaine concentration at seizure onset.

Animals↗
PubMed1982

The effect of acute phencyclidine administration on cyclopropane requirement (MAC) in rats.

The effect of acute administration of phencyclidine (PCP) on the anesthetic requirement (MAC) was studied in rats. Rats were anesthetized with cyclopropane and MAC determinations were made by the tail-clamp technique. PCP, 2 or 4 mg/kg, subcutaneously, produced a 32 and 42 per cent decrease, respectively, in cyclopropane MAC. The PCP-induced decrease in MAC was not altered by naloxone treatment indicating that an interaction of PCP with opiate mechanisms is unlikely. Central monoamine depletion with reserpine decreased cyclopropane MAC by 20 per cent. In these monoamine-depleted rats, 4 mg/kg PCP produced a further reduction in MAC of 22 per cent. In rats almost totally depleted of catecholamines by pretreatment with reserpine and alpha-methyl-p-tyrosine, a marked (43 per cent) decrease in MAC was observed. The administration of 2 mg/kg PCP, in these catecholamine-depleted rats produced an additional 10 per cent decrease in MAC for a total reduction in MAC of 53 per cent. The effect of PCP in the monoamine- and catecholamine-depleted rats indicates that while an effect on central monoamines may play a part in the mechanism of action of PCP, it is not the sole mode of action of the drug. In patients intoxicated with PCP there is a significant potential for anesthetic overdose as their anesthetic requirement may be much less than would be expected in the nonintoxicated state.

Anesthesia↗
PubMed1982

Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine.

To compare the respiratory depressant and analgesic effects of nalbuphine and morphine, six healthy male subjects were given the drugs as single 0.15-mg/kg doses, and as four successive doses of 0.15 mg/kg. Respiratory depression was monitored by ventilatory and mouth occlusion pressure responses during CO2 rebreathing, while analgesia to experimental pain was tested with the submaximal effort tourniquet ischemia test. When given as single 0.15 mg/kg doses, both drugs significantly increases the threshold and tolerance for experimental pain. The analgesic effect was similar for both drugs at this dosage, as was depression of the ventilatory and occlusion pressure responses to CO2. Morphine administered in multiple doses progressively increased pain tolerance from 30 +/- 13% above control with the first dose of 0.15 mg/kg to 107 +/- 13% above control after the fourth dose (cumulative total 0.60 mg/kg). Nalbuphine produced a 40 +/- 12% increase in pain tolerance with an initial dose of 0.15 mg/kg, but additional increments of nalbuphine did not result in significantly greater analgesia. The increasing morphine dosage was associated with progressive rightward displacements and ultimately decreases in the slope of the CO2 response curves. Nalbuphine produced an initial rightward displacement of the CO2 response curves similar to morphine, but continued administration of the drug did not result in further displacement or changes in slope. These findings demonstrate that nalbuphine, in contrast to morphine, exhibits a ceiling effect for respiratory depression which is paralleled by its limited analgesic effect on experimental pain.

Adult↗