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Biomedical subjects

C E Inturrisi

Publications and source records attributed to C E Inturrisi.

At least 91 records · Page 5Linked to original sources
PubMed1987

A comparison of the effects of a macrobiotic diet and a Western diet on drug metabolism and plasma lipids in man.

We have compared the effects of two dietary regimens with different macronutrient compositions--a macrobiotic diet and a Western diet--on drug metabolism and plasma lipids in seven healthy volunteers. The macrobiotic diet, high in carbohydrate, low in protein and fat, and devoid of animal food sources, was eaten for a ten day control period, as was the Western diet, high in calories, fat, and protein, as well as animal food sources. We determined the influences of these diets on the clearance of orally administered antipyrine, oxazepam, and methadone, as well as on plasma lipids. There was a statistically significant change in antipyrine clearance as well as in plasma LDL-cholesterol and HDL-cholesterol after the dietary periods. This suggests that the influence of dietary changes may have some effect on the clearance of therapeutic drugs. However, this is not universal and is probably important when the drug is highly dependent on the mixed-function oxidase system.

Adult↗
PubMed1987

Chronic opioid antagonist treatment facilitates nonopioid, stress-induced analgesia.

Chronic exposure to opioid antagonists produces increases brain opioid receptors and enhances morphine analgesia. Since opioid antagonists could affect both opioid and nonopioid analgesic systems, the present study evaluated whether chronic opioid antagonist treatment with naltrexone alters the nonopioid analgesia produced by cold-water swims (CWS). Rats were implanted (SC) with two, 30 mg naltrexone pellets. The pellets were removed 8 days later or left in place and rats tested 24 hr later for analgesia (tail-flick) following a 3.5 min CWS or morphine (3 mg/kg, SC). As expected, morphine analgesia was potentiated in rats with naltrexone pellets removed, but was blocked in rats tested with the naltrexone still implanted. In contrast, naltrexone pretreatment potentiated CWS analgesia, irrespective of whether the pellets were removed or left in place. These findings confirm the nonopioid nature of CWS analgesia and indicate that chronic treatment with an opioid antagonist can affect both opioid and nonopioid analgesic mechanisms.

Animals↗
PubMed1987

Analgesic drug therapy in cancer pain: principles and practice.

Drug therapy represents the mainstay of treatment for patients with cancer pain. Non-narcotic, narcotic, and adjuvant analgesics are the commonly used agents. The choice of a specific analgesic drug regimen is dependent on the type of pain and its severity, and the drug must be titrated to the individual needs of the patient.

Analgesics↗
PubMed1987

Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain.

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.

Adult↗
PubMed1987

High-dose naloxone: pharmacokinetics in patients in septic shock.

Naloxone, a commonly used narcotic antagonist, may be beneficial in reversing the hemodynamic alterations seen in septic shock. In normal subjects, naloxone pharmacokinetics are characterized by rapid distribution and elimination. We investigated the pharmacokinetics of high-dose naloxone in four patients with septic shock and multiorgan failure. The pharmacokinetics of naloxone in these patients can be described by a two-compartment model with a rapid alpha distribution similar to that observed in normal humans. However, in these critically ill patients there was virtually no drug elimination as levels were followed for 5 h post-termination of a 6-h infusion of 2.4 mg/kg X h. This dramatic accumulation of naloxone may explain why responses have been reported by others to small doses of naloxone in septic shock patients. No significant side-effects were seen in our patients with plasma naloxone levels as high as 3.78 micrograms/ml. Caution is warranted when one administers naloxone to patients whose ability to eliminate this drug is minimal.

Double-Blind Method↗
PubMed1986

Cerebrospinal fluid pharmacokinetics of intrathecal morphine sulfate and D-Ala2-D-Leu5-enkephalin.

Using an implantable pump system to deliver drugs and sample cerebrospinal fluid (CSF), we assessed rostral redistribution and systemic uptake after intrathecal bolus injection and steady-state infusion of morphine sulfate and the opioid peptide D-Ala2-D-Leu5-enkephalin (DADL) in two patients. Following bolus injection, the mean CSF elimination half-lives for morphine sulfate and DADL were 94 and 115 minutes, respectively. With the catheter tip at L2, the ratio of lumbar to cisternal (L/C) concentrations of morphine sulfate was about 7:1, and with the catheter tip at T10, the L/C ratios of morphine sulfate and DADL were approximately 2:1, indicating that this ratio is dependent in part on the level of intrathecal drug administration. CSF levels of morphine sulfate at steady state were three orders of magnitude higher than those in plasma. The CSF pharmacokinetics of morphine sulfate and DADL are similar, with supraspinal redistribution of these opioids via the CSF likely playing an important role in the generation of analgesia and central nervous system side effects.

Enkephalin, Leucine↗
PubMed1986

A chronic sheep preparation for the study of drug pharmacokinetics in spinal and ventricular CSF.

We describe a sheep preparation utilizing chronic vascular and subarachnoid catheterization and ventriculocisternal perfusion. This preparation allows simultaneous, atraumatic sampling of plasma and CSF after drug administration by the intravenous, intracerebroventricular, or lumbar intrathecal (i.t.) routes in an unanesthesized animal. This sheep preparation provides a convenient means of studying the CSF distribution of exogenous and/or endogenous substances. During intravenous infusion at a rate of 2.2 micrograms/kg/min, morphine appears in cisternal CSF within 15 min. The steady-state plasma concentration and CSF flux (or appearance rate) of morphine was 0.037 and 0.009 micrograms/min, respectively. At steady state, 0.008% of the administered dose appears in CSF/min. The coadministration of morphine, methadone, and [14C]sucrose into the fifth lumbar subarachnoid space is associated with the simultaneous appearance of morphine and [14C]sucrose, but not methadone, in cisternal CSF. The ratio of [14C]sucrose to morphine increased by nearly sevenfold in cisternal CSF, indicating clearance of morphine relative to [14C]sucrose as the compounds ascend in the CSF axis. The simultaneous appearance of morphine and [14C]sucrose in cisternal CSF after lumbar subarachnoid administration indicates that morphine, like sucrose, is distributed within the CSF by bulk flow. This sheep preparation can be used to provide the quantitative data necessary for the development of pharmacokinetic-pharmacodynamic models that relate plasma and CSF concentrations of opiates to their pharmacological effects. These studies will help to provide the pharmacological rationale for the administration of opiates by novel routes for pain management in man.

Animals↗
PubMed1986

Influence of naloxone infusion on analgesia and respiratory depression following epidural morphine.

The influence of two different concentrations of iv naloxone infusion on the analgesia and adverse effects of epidural morphine were compared in a double-blind, placebo-controlled study. Forty-five patients undergoing gallbladder surgery were provided postoperative analgesia by 4 mg epidural morphine; they then received an iv infusion over a 12-h period consisting of either 5 micrograms X kg-1 X h-1 naloxone, 10 micrograms X kg-1 X h-1 naloxone, or saline. Pain relief was assessed by hourly visual analog scoring (VAS) and by direct questioning of the patient. Requirement of additional analgesia was noted. Respiratory frequency was monitored every 15 min and arterial blood gases were analyzed every 2 h for 24 h. Peak expiratory flow (PEF) was recorded 6 and 24 h postoperatively. Steady-state kinetics of naloxone were determined by a modified radioimmunoassay (RIA) method. All patients had good to excellent postoperative pain relief. Naloxone, 5 micrograms X kg-1 X h-1, did not appear to have any effect on epidural morphine analgesia. However, naloxone infusion at the rate of 10 micrograms X kg-1 X h-1 reduced the duration of analgesia by about 25%, and more frequent injections of epidural morphine were required to give effective analgesia. Complete reversal of analgesia was not seen in any patient. A dose-related stimulatory effect on respiratory frequency was noted in the groups receiving naloxone. PaCO2 values also were better in these groups as compared to values in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

I.v. infusion of opioids for cancer pain: clinical review and guidelines for use.

To assess the safety, efficacy, and use of continuous iv infusion (CI) of opioids for cancer pain, we reviewed the clinical experience of 36 patients who received 46 CIs. CI was always preceded by a period of repetitive dosing of opioids. Morphine was used in 36 CIs, methadone in four, hydromorphone in four, oxymorphone in one, and levorphanol in one. Mean doses during CI were the morphine equivalent of 17 mg/hour (range, 0.7-100) at the start, 69 mg/hour (range, 4-480) at the maximum, and 52 mg/hour (range, 1-480) at termination. Pain relief was acceptable during 28 CIs, unacceptable during 17, and unknown during one. There were few toxic effects other than sedation. Twenty-five patients died, 12 resumed im or oral opioids, six continued CI with a different opioid (yielding analgesia in two), and outcome was undetermined in three. This review suggests that (a) CI is safe, (b) analgesia may require rapid escalation of infusion rates, (c) patient response varies and lack of acceptable analgesia may occur in up to one-third, (d) ineffective CI with one drug may be followed by success with another, (e) CI should be preceded by a period of repetitive iv boluses with the same drug, and (f) guidelines can be developed which incorporate pharmacokinetic principles.

Adolescent↗
PubMed1986

Pharmacodynamic supersensitivity and opioid receptor upregulation in the mouse.

The analgesic potency and toxicity (lethality) of morphine were increased 2.5 times after implantation of 7.5-mg s.c. naltrexone pellets in the mouse for 8 days. Implantation for 8 days also resulted in a 41% [3H][D-Ala2-D-Leu5]enkephalin and 55% [3H] [D-Ala2-MePhe4-Gly(ol)5]enkephalin increase in radiolabeled opioid binding in mouse brain relative to placebo-implanted controls. Treatment for 1 day did not produce any significant increases in binding or morphine's analgesic potency. Brain morphine concentrations did not differ after a dose of morphine (8 mg/kg) that produced analgesia in 86% of 8-day naltrexone-treated mice vs. 39% of placebo-treated mice. The increase in the analgesic potency of morphine by chronic naltrexone treatment in the mouse is particularly striking as it is approximately 3 times greater than that observed for the rat. The decrease in the LD50 of morphine after 8 days of naltrexone treatment raises the possibility that the toxicity of opiates may be increased in patients who discontinue naltrexone maintenance treatment and resume opiate abuse.

Animals↗
PubMed1986

Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat.

Subcutaneous implantation of naltrexone pellets is a standard method of producing chronic blockade of opioid receptors. In the present experiments, rats were treated with two, 30-mg naltrexone pellets and the pharmacokinetics and pharmacodynamics examined. This dosing method produced high plasma naltrexone levels (350 ng/ml) by 1 hr which declined over an implant period of 192 hr (24 ng/ml). Approximately 40% of the systemically available naltrexone (15.6 mg) was released in the first 24 hr. A total of 39.8 mg was released over the 192-hr implantation period. At 192 hr after implantation, naltrexone produced a greater than 50-fold shift to the right in the dose-response curve for morphine analgesia relative to placebo-implanted controls. When naltrexone pellets were removed at 192 hr after implantation, morphine analgesia (10 mg/kg) returned with a time course that was inversely related to the elimination of naltrexone. Pharmacokinetic analysis indicated that naltrexone has a terminal elimination half-life of 4.6 hr. Probit analysis revealed a linear plasma level-response relationship for naltrexone antagonism of morphine analgesia with a plasma ED50 of 2.1 ng/ml when plasma morphine levels average 1126 ng/ml. In the rat, s.c. naltrexone pellets are a dosage form that provides a rapid release of systemic drug. The systemic availability of naltrexone continues for at least 192 hr after implantation. The high potency of naltrexone permits continued antagonism of morphine even when the systemic availability of naltrexone from the pellets has greatly diminished.

Animals↗
PubMed1985

CSF distribution of morphine, methadone and sucrose after intrathecal injection.

The lumbar to cisternal CSF distribution of morphine and methadone were compared to C-14 sucrose, a standard marker of CSF bulk flow, after lumbar subarachnoid injections in a sheep preparation. Morphine appeared and peaked simultaneously with C-14 sucrose in cisternal CSF at 90 to 190 minutes. The mean peak cisternal CSF morphine concentrations were sustained for 30-40 minutes, and averaged 148 ng/ml, representing 0.3% of the administered dose. Methadone was not detectable in cisternal CSF up to 240-300 minutes after lumbar subarachnoid administration. The C-14 sucrose/morphine ratio was increased an average of 6.7 times in cisternal CSF as compared to the ratio of the two compounds injected into the lumbar subarachnoid space. These studies demonstrate that morphine, a hydrophilic opioid, given intrathecally moves rostrally and appears in cisternal CSF by bulk flow. Furthermore the rostral redistribution of morphine is associated with the clearance of morphine from CSF. Methadone, a lipophilic opioid, appears to be completely cleared from CSF before it reaches the cisterna magna. These pharmacokinetic studies support a contribution of supraspinal sites to the analgesic and adverse effects produced by morphine given by spinal routes of administration. In contrast methadone appears to exert its effects predominantly at spinal sites.

Animals↗
PubMed1985

Increased analgesic potency of morphine and increased brain opioid binding sites in the rat following chronic naltrexone treatment.

Implantation of rats with prolonged-release naltrexone pellets increased both morphine's analgesic potency in the tailflick assay and radiolabeled opioid binding in the brain. The increases in both radiolabeled opioid binding and morphine potency were time-dependent. Implantation for 24 hours did not increase binding, whereas increases of approximately 45% were seen following 8 days of implantation. Similarly, morphine's analgesic potency, measured as ED50 values, was increased by 50% following 8 days of exposure to naltrexone while a 24 hour exposure had no significant effect.

Animals↗
PubMed1985

The graded and quantal nature of opioid analgesia in the rat tailflick assay.

Opioid agonists routinely increase the latency to respond in the rodent tailflick assay. The nature of this effect was investigated in 5 experiments using several parametric variations and routes of administration. Morphine and methadone were found to produce both quantal and graded effects in all experiments. In cases where quantal effects were observed, the majority of animals also responded in a graded manner during subsequent testing. The increase in latency to respond in the tailflick assay produced by opioid agonists is not accurately characterized as predominantly quantal.

Animals↗
PubMed1985

Epidural and intrathecal opiates: cerebrospinal fluid and plasma profiles in patients with chronic cancer pain.

We studied the cerebrospinal fluid (CSF) and plasma concentration-time profiles of morphine, methadone, and beta-endorphin after lumbar epidural or intrathecal injection in 17 patients with cancer. After epidural injection, all three drugs reached peak levels in lumbar CSF within 34 minutes that were 50 to 1300 times higher than free drug concentrations in plasma. The rate of decline of CSF levels correlated with drug lipid solubility (methadone [t1/2 = 73 minutes] greater than morphine [126 minutes] greater than beta-endorphin [317 minutes]). Plasma levels were comparable with those after intragluteal injection of the same dose. In four patients given intrathecal morphine or methadone, CSF at the C1-2 level contained high levels of morphine as early as 1 hour after injection, but levels of methadone were lower or undetectable. Three of 17 patients reported improved analgesia initially, but none were improved at 2 weeks after chronic therapy. We conclude that analgesia induced by intrathecal or epidural morphine injections is caused by drug acting at both spinal and supraspinal sites. The use of spinal opiates such as morphine is of limited value in patients whose pain is not adequately managed by high systemic doses of morphine-like drugs.

Adult↗
PubMed1985

Pharmacokinetics and pharmacodynamics of subcutaneous morphine pellets in the rat.

The pharmacokinetics and drug release characteristics of a standard, widely available s.c. morphine pellet were examined in the rat, together with antinociceptive (tailflick) effects and physical dependence. Over a 72-hr implant period one, two or three 75-mg morphine pellets released 12.5, 22.6 and 27.6 mg of morphine, respectively. Mean plasma morphine concentration after two morphine pellets reached a peak at 4 to 6 hr, then declined to a mean apparent steady-state level of 210 ng/ml at 36 hr that was maintained until the pellets were removed at 72 hr. The antinociceptive action of two morphine pellets peaked at 4 to 6 hr and had returned to predrug base-line values by 36 hr. After pellet removal, the plasma elimination kinetics of morphine were biexponential with a terminal T1/2 of 8.3 hr. The plasma morphine concentration declined 85% before the onset of significant weight loss could be measured. Peak abstinence weight loss was dose-related and was significantly correlated with both plasma morphine levels just before withdrawal and total dose of morphine absorbed over the 72-hr implant. These studies indicate that the release of morphine from s.c. implanted pellets in the rat is characterized by an initially higher rate of release (dose dumping effect) over the first 24 hr followed by a very constant release from 36 to 72 hr after implantation. The pharmacodynamic consequences of these dosage characteristics are the rapid development of tolerance and maintenance of physical dependence during the period of the implant.

Animals↗
PubMed1984

Role of opioid analgesics.

The clinical pharmacology of the narcotic-type analgesics is discussed in depth. Relative analgesic potency, peak and duration of analgesia, oral potency, and adverse effects are reviewed, With an emphasis on the clinical application of this knowledge. The differences among psychologic dependence, physical dependence, and tolerance are carefully delineated. Guidelines are provided for using narcotic-type analgesics in the management of patients with cancer.

Administration, Oral↗