Biomedical subjects

C E Inturrisi

Publications and source records attributed to C E Inturrisi.

At least 73 records · Page 4Linked to original sources

PubMed1992

Treatment of opioid-induced constipation with oral naloxone: a pilot study.

Opioids cause constipation by binding to specific opioid receptors in the enteric and central nervous systems. First-pass glucuronidation limits systemic bioavailability of oral naloxone. This study was designed to determine if oral naloxone could reverse opioid-induced constipation without precipitating abstinence or recrudescence of pain in opioid-dependent individuals. Concentrations of unmetabolized and total naloxone, including naloxone glucuronide, were measured by radioimmunoassay. A dose-related increase in symptoms of laxation resulted in all three opioid-dependent patients studied that paralleled the increase in active and total naloxone plasma levels. Withdrawal symptoms occurred with plasma naloxone area under the plasma concentration-time curves above 550 ng.min/ml and with dosing intervals less than 3 hours. Peak plasma levels did not predict withdrawal. Oral naloxone ameliorates opioid-induced constipation in opioid-dependent persons. Titration of dose to a maximum of 12 mg at least 6 hours apart may be needed to avoid adverse reactions.

Adult↗

PubMed1992

The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function.

Morphine-6-glucuronide is a metabolite of morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of morphine-6-glucuronide in patients with renal insufficiency has been implicated in morphine toxicity, the contribution of the metabolite to morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of morphine and morphine-6-glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of morphine-6-glucuronide:morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean morphine-6-glucuronide:morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that morphine-6-glucuronide contributes to morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when morphine is used clinically.

Adult↗

PubMed1991

Preproenkephalin mRNA and enkephalin in normal and denervated adrenals in the Syrian hamster: comparison with central nervous system tissues.

The distribution and characteristics of preproenkephalin (PPenk) mRNA and enkephalin-containing (EC) peptides are compared in CNS and adrenal tissues from Syrian hamsters and Sprague-Dawley rats. Total cellular RNA extracts from both rat and hamster tissues produce a single hybridization band of PPenk mRNA of approximately 1500 bases when analyzed by Northern blot hybridization. Quantitation by solution hybridization reveals that in the hamster the highest levels of PPenk mRNA are found in adrenal (16.3 +/- 1.4 pg equivalents/micrograms RNA (mean +/- S.E.M.)) and striatum (13.3 +/- 0.7), followed by hypothalamus (0.8 +/- 0.2), and hippocampus (0.4 +/- 0.2). In the rat the highest levels of PPenk mRNA are in the striatum (35 +/- 2 pg/micrograms RNA) followed by the hypothalamus (3.0 +/- 0.5), hippocampus (0.3 +/- 0.1) and adrenal (0.18 +/- 0.04). Thus, the rank order of abundance of PPenk mRNA is similar in these CNS tissues for rat and hamster. The hamster adrenal levels are more than 90-fold greater than those of the rat. The abundance of EC peptides in both hamster and rat tissues mirror the rank order found with PPenk mRNA. Hamster adrenal contains the highest level of EC peptides (441 +/- 37 pmol/mg protein (mean +/- S.E.M.)) which is more than 400-fold greater than that of the rat adrenal and 8- to 12-fold greater than that found in rat and hamster striatum or hypothalamus. Both size exclusion chromatography and Western blot analysis indicate that EC peptides in hamster adrenal are predominantly large proenkephalin-like peptides with approximately 6 copies of Met- and 1 copy of Leu-enkephalin and that included in their number is a prominent EC peptide with a molecular weight of 34 kDa. Unilateral denervation of the hamster adrenal results in a time-dependent ipsilateral decrease in EC peptide and PPenk mRNA levels. Thus, by day 8 postsurgery, PPenk mRNA levels have declined by an average of 80% while EC peptides are reduced by 68% when compared to the innervated contralateral adrenal. These results demonstrate the great abundance of PPenk mRNA and EC peptides in the hamster adrenal. They also demonstrate the apparent need for transsynaptic impulse activity to maintain the high steady-state levels of PPenk and EC peptides. These characteristics of the hamster adrenal system provide opportunities for physiological and pharmacological investigations of the regulation of proenkephalin gene expression.

Adrenal Glands↗

PubMed1991

Chronic nausea and morphine-6-glucuronide.

Morphine-6-glucuronide is an active metabolite of morphine that has analgesic properties and is measurable in the plasma and cerebrospinal fluid of patients treated with this opioid. Decreased clearance of the compound has been observed in patients with renal insufficiency, and this has been associated with an increase in the ratio of morphine-6-glucuronide to morphine. Clinical effects from accumulation of morphine-6-glucuronide have not been described with the exception of case reports in which patients with renal failure were noted to develop opioid toxicity with high plasma levels of the metabolite and low levels of the parent drug. We describe a patient who experienced chronic nausea and an episode of confusion while treated with a small, stable dose of oral morphine in the setting of mild renal insufficiency. Relatively high levels of morphine-6-glucuronide were measured and all symptoms resolved promptly as the concentration of this metabolite declined. This case provides suggestive evidence that morphine-6-glucuronide can produce clinically significant effects in patients with mild renal insufficiency.

Adenocarcinoma↗

PubMed1991

Chronic morphine therapy for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations.

Morphine-6-glucuronide (M-6-G) is an active metabolite that may contribute to the clinical effects produced by systemic administration of morphine. To help clarify the extent to which M-6-G may cross the blood-brain barrier and exert effects, we employed high-performance liquid chromatography with electrochemical detection to measure the concentrations of M-6-G and morphine in the plasma and either ventricular (three patients) or lumbar (eight patients) CSF of cancer patients receiving chronic morphine therapy. The mean ratio of morphine in ventricular CSF:morphine in plasma was 0.71; the same ratio for M-6-G was only 0.077. The average molar ratio of M-6-G: morphine in ventricular CSF was 0.207, and the average molar ratio in plasma was 1.89. Although sampling problems render the lumbar CSF results less reliable, they were very similar. Thus, plasma contained approximately twice as much M-6-G as morphine, whereas CSF contained only one-fifth to one-third as much. These data confirm that M-6-G in plasma is distributed into CSF, but to a far lesser extent than morphine. They help explain animal data demonstrating much higher potency of M-6-G on administration into CSF than systemic administration and indicate that the degree to which M-6-G contributes to morphine effects in humans remains an unresolved question.

Adult↗

PubMed1991

Transsynaptic activity regulates proenkephalin and tyrosine hydroxylase gene expression and the response to reserpine in the hamster adrenal.

Transsynaptic neurogenic activity and reserpine are two signals that cause the proenkephalin (Penk) gene to alter the levels of preproenkephalin (PPenk) mRNA and enkephalin-containing (EC) peptides. In the Syrian hamster adrenal, but not in rat adrenal, both of these signals appear to be positive activators of Penk gene expression. The separate and combined effects of reserpine and denervation on EC peptides and catecholamine systems were investigated in the adrenal of the hamster, a species with relatively high medullary PPenk mRNA and EC peptide levels. Unilateral adrenal denervation resulted in a rapid decrease in PPenk mRNA levels of 54% after 2 days, and by 11 days 90% of Penk mRNA had disappeared. After 4 days both EC peptide and PPenk mRNA levels fell in parallel, whereas total RNA and soluble protein levels were unchanged. Denervation had no effect on TH mRNA levels until 8 days after surgery, and after 11 days both TH mRNA and catecholamine levels had decreased by 35-45%. Reserpine produced a dose- and time-dependent depletion of EC peptides and catecholamines. One day after 5 mg/kg reserpine (given subcutaneously on each of 2 consecutive days), EC peptides were reduced by 80%, norepinephrine by 79%, and epinphrine by greater than 95%. By 4 days after treatment, EC peptides and catecholamines slightly exceeded or had returned to control (concurrent vehicle treatment) values. PPenk mRNA levels, as measured by solution hybridization, were doubled (206 +/- 17%, mean +/- standard error) by day 4. Tyrosine hydroxylase (TH) mRNA levels were increased nearly 7-fold (686 +/- 71%) 24 hr after the first reserpine dose and declined thereafter. Northern blot analysis demonstrated that reserpine did not alter the size of either PPenk or TH mRNAs. Size exclusion chromatography showed a small (20%) reserpine-induced increase in processing of high molecular weight Penk-like peptides. The effects of reserpine, which increases PPenk mRNA, EC peptides, and TH mRNA, were completely blocked by unilateral denervation, whereas the contralateral innervated gland showed the expected responses. The co-localized EC peptide and catecholamine systems, as reflected in their mRNAs, respond differently in both time sequence and magnitude to reserpine and to denervation. Our results support a critical role, in vivo, for transsynaptic mechanisms in the maintenance of the high levels of Penk gene expression in this species and for the positive activation (mediated by reflex neurogenic stimulation) of reserpine on Penk and TH gene expression.

Adrenal Glands↗

PubMed1990

Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain.

To determine the relationship between changes in plasma methadone concentration and pharmacodynamic effects, plasma methadone profiles and pharmacodynamics (analgesia and sedation) were measured during and after the continuous infusion of methadone for 180 to 270 minutes in 15 patients with pain caused by cancer. An increase in plasma methadone concentration resulted in a rapid increase in pain relief or sedation. The estimates of values of 50% of maximum effect (Css50) for pain relief and sedation obtained with a pharmacokinetic-pharmacodynamic model varied tenfold to twentyfold among patients; the mean Css50 value for pain relief (0.359 +/- 0.158 [SD] micrograms/ml) was virtually the same as the mean Css50 value for sedation (0.336 +/- 0.205 [SD] micrograms/ml). Similarly, the mean gamma (slope function) for pain relief (4.4 +/- 3.8 [SD]) and sedation (5.8 +/- 5.4 [SD]) did not differ. Examination of hysteresis plots of data obtained during the infusion and for 4 to 5 hours after cessation of the infusion revealed a very rapid equilibration between plasma methadone values and the sites mediating pain relief. There was no indication of the development of tolerance to the pharmacodynamic effects of methadone during the study. This report describes a method for quantitating the pharmacokinetic-pharmacodynamic relationships of the desirable and undesirable effects of opioid analgesics.

Adult↗

PubMed1989

Management of cancer pain. Pharmacology and principles of management.

The pain of the vast majority of patients with cancer can be controlled with the use of analgesic drugs. Pharmacokinetic and clinical studies have provided the basis for guidelines for the pharmacologic management of cancer pain. The fundamental concept underlying these guidelines is individualization of therapy, which has as its goal the maximization of pain relief and the minimization of adverse drug effects. This article presents these guidelines and discusses the pharmacologic properties and adverse effects of analgesic drugs commonly used in the treatment of cancer pain. Also reviewed are methods for avoiding and treating the adverse effects of analgesics.

Analgesics↗

PubMed1989

Opioid receptor upregulation and supersensitivity in mice: effect of morphine sensitivity.

Mice of the Swiss-Webster strain obtained from two suppliers (Taconic, Charles River) were found to differ in their sensitivity to morphine. Mice from Taconic were approximately two-fold more sensitive to the analgesic and lethal effects of morphine compared to the Charles River mice. In a third strain, C3H/HEN, morphine was found to be more than 2.5 times more potent in producing analgesia than in the Charles River mice. Binding studies showed that the Taconic mice and C3H/HEN mice had approximately 40% and 60%, respectively, more specific [3H]naloxone binding sites in brain than did the less sensitive Charles River mice. When treated with chronic naltrexone for 8 days the analgesic potency of morphine was increased by approximately 90% for both Swiss-Webster mice and by 20% for the C3H/HENs. [3H]Naloxone binding was increased by 45-50% in the Swiss-Webster strains, but by only 33% in C3H/HEN mice. These data indicate that receptor upregulation is directly related to increases in morphine potency. Further, these findings suggest that initial sensitivity to morphine can determine the degree of functional supersensitivity and relative receptor upregulation produced by chronic opioid antagonist treatment.

Analgesia↗

PubMed1989

Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite.

Morphine-6 beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To define more fully the importance of this compound in morphine action, we have compared the analgesic actions of morphine and its 6 beta-glucuronide metabolite after both peripheral and central administration. Given s.c., morphine-6 beta-glucuronide elicited analgesia with an effect approximately twice that of morphine due, in part, to its long duration of action and also inhibited gastrointestinal motility. Both actions were easily reversed by naloxone (s.c.). However, when injected either i.c.v. or intrathecally, morphine-6 beta-glucuronide was approximately 90- and 650-fold more potent an analgesic than morphine, respectively. Whereas morphine in these studies was equipotent at both levels of the neuraxis as an analgesic, the 6 beta-glucuronide was approximately 5-fold more effective at the level of the spinal cord than supraspinally. The mu 1-selective antagonist naloxonazine blocked the analgesic effect of systemic and i.c.v. morphine-6 beta-glucuronide much as it blocked morphine, implying a role for mu1 receptors in these actions. Like morphine, morphine-6 beta-glucuronide analgesia after intrathecal injection was not sensitive to naloxonazine, suggesting a mu2 mechanism within the spinal cord. Together, these results imply that morphine-6 beta-glucuronide elicited its analgesic actions through the same receptor mechanisms as morphine. Mice highly tolerant to morphine after implantation of morphine pellets showed cross-tolerance to morphine-6 beta-glucuronide (s.c.). The high potency of morphine-6 beta-glucuronide strongly suggests that this metabolite plays an important role in morphine's actions.

Analgesia↗

PubMed1988

Characterization of enkephalins in rat adrenal medullary explants.

In the rat, removal of depolarizing stimuli to the adrenal medulla by surgical denervation in vivo or by explanting adrenal medullae has been shown to dramatically increase preproenkephalin mRNA, and enkephalin-containing (EC) peptides. To further elucidate the cellular basis of these effects and the role of transsynaptic influences on post-translational processing, we have defined the time course, and characterized EC peptides in rat adrenal medullary explants in control and depolarized states. The rise in EC peptides begins after 1 day in culture and reaches a peak at 4-7 days. Although the onset of the increase in EC peptides in culture is delayed by 12-24 h compared to the changes seen in vivo, following surgical denervation, the time course of peak and duration is remarkably similar. Size exclusion chromatography (SEC) revealed that the major species of newly appearing EC peptides in explanted glands is a high molecular weight peptide of approximately 18,000 with a Met-/Leu-enkephalin ratio of approximately 6. These results suggest that proenkephalin, the initial precursor of the EC peptide family, is the major EC peptide that accumulates in rat adrenal medullary explants. A low-molecular weight EC peptide, found by high-performance liquid chromatography to be free Met-enkephalin, is a minor component of the culture induced increase in EC peptides. Culturing of medullae in the presence of depolarizing concentrations of K+ prevents the accumulation of the proenkephalin-like EC peptides and free enkephalins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗

PubMed1988

Morphine-induced immunomodulation is not related to serum morphine concentrations.

Morphine pellets produced atrophy of the spleen and thymus and affected mitogen-induced lymphocyte proliferation in mice as characterized by marked suppression of concanavalin A-induced blastogenesis at 48 h, and mild stimulation at 120 h. Morphine blood levels in these animals indicated that changes in the immunomodulatory effects of morphine over time were not related to dramatic shifts in circulating morphine. Enclosure of the pellet in nylon mesh did not alter blood levels or morphine-induced immunomodulation.

Animals↗

PubMed1988

Modification of the response to opioid and nonopioid drugs by chronic opioid antagonist treatment.

Chronic exposure to opioid antagonists increases the analgesic actions of opioids such as morphine. In the present studies, morphine's analgesic potency was increased (supersensitivity) following an 8 day subcutaneous naltrexone implant in mice, but not following a 1 day implant. Supersensitivity was maximal 24hr following the 8 day implant and declined linearly and had returned to control levels by 120hr. Implantation of naltrexone pellets for 8 days was found to increase the relative analgesic potency of methadone by 120%, while the lethal potency of cocaine was slightly (19%), but significantly, decreased. In contrast, identical treatment did not alter the potency of the benzodiazepine alprazolam to induce ataxia.

Alprazolam↗

PubMed1988

Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE.

Chronic treatment with opioid antagonists increases the potency of opioid agonists and produces an increase in brain opioid binding sites. In the present study, 8 day treatment with naltrexone blocked morphine and DADLE analgesia for the entire treatment period and increased mu 1, mu 2 and delta opioid receptor binding sites in mouse brain. mu 1 and mu 2 binding were increased by 81 and 67%, respectively, while delta binding was increased by 31%. Consistent with these binding changes, the potency of ICV morphine to produce analgesia was increased by over 3-fold, while the potency of ICV DADLE was increased by only 1.7. These findings indicate that relative increases in opioid receptor subtypes agree with pharmacodynamic studies on potency changes of opioid agonists.

Animals↗

PubMed1988

Sublingual absorption of selected opioid analgesics.

Ongoing interest in the improvement of pain management with opioid analgesics had led to the investigation of sublingual opioid absorption. The present report determined the percent absorption of selected opioid analgesics from the oral cavity of normal subjects under conditions of controlled pH and swallowing when a 1.0 ml aliquot of the test drug was placed under the tongue for a 10-minute period. Compared with morphine sulfate at pH 6.5 (18% absorption), buprenorphine (55%), fentanyl (51%), and methadone (34%) were absorbed to a significantly greater extent (p less than 0.05), whereas levorphanol, hydromorphone, oxycodone, heroin, and the opioid antagonist naloxone were not. Overall, lipophilic drugs were better absorbed than were hydrophilic drugs. Plasma morphine concentration-time profiles indicate that the apparent sublingual bioavailability of morphine is only 9.0% +/- 11.9% (SD) of that after intramuscular administration. In the same subjects the estimated sublingual absorption was 22.4% +/- 9.2% (SD), indicating that the sublingual absorption method may overestimate apparent bioavailability. When the oral cavity was buffered to pH 8.5, methadone absorption was increased to 75%. Thus, an alkaline pH microenvironment that favors the unionized fraction of opioids increased sublingual drug absorption. Although absorption was found to be independent of drug concentration, it was contact time dependent for methadone and fentanyl but not for buprenorphine. These results indicate that although the sublingual absorption and apparent sublingual bioavailability of morphine are poor, the sublingual absorption of methadone, fentanyl, and buprenorphine under controlled conditions is relatively high.

Administration, Sublingual↗

PubMed1988

Glucocorticoid regulation of enkephalins in cultured rat adrenal medulla.

The effect of dexamethasone on enkephalin-containing (EC) peptide levels and preproenkephalin mRNA levels was determined in adrenal medullary explants (glands) from sham and hypophysectomized (hypox) rats. Culture for 4 days in serum-free medium without dexamethasone resulted in a 13- and 4-fold increase in EC peptide levels in sham and hypox glands, respectively. The addition of dexamethasone (10(-5) M) produced a 20- to 26-fold increase in EC peptides in sham and hypox glands. In serum free medium, hypox glands showed a concentration dependent increase in EC peptides with the ED50 for dexamethasone equal to 5.7 x 10(-7) M. Since the glucocorticoid antagonist RU486 partially blocked the rise in EC peptides in sham glands, it appears that the increase in EC peptides in sham glands in the absence of dexamethasone is a result of a higher concentration of endogenous corticosterone in sham compared to hypox glands. Dexamethasone resulted in a 6-fold increase in preproenkephalin mRNA in hypox glands cultured for 2 days. This increase was approximately proportional to the increase in EC peptides seen at 4 days. In serum free medium progesterone, testosterone, and deoxycorticosterone failed to increase EC peptides in hypox glands. These results indicate that glucocorticoid treatment is required for maximal proenkephalin gene expression and EC peptide biosynthesis in cultured glands.

Adrenal Medulla↗

PubMed1987

Morphine-6-glucuronide, a potent mu agonist.

The 3- and the 6-glucuronides of morphine have been examined in binding studies and in vivo. The 3-glucuronide had poor affinity in all binding studies whereas the 6-glucuronide potently labeled mu, but not delta or kappa receptors with affinities similar to morphine. Microinjections of the 3-glucuronide directly into the periaqueductal gray were without effect. The 6-glucuronide, on the other hand, was up to 20-fold more potent than morphine following microinjections in the same region. High doses of the 6-glucuronide produced profound seizure activity. All 6-glucuronide actions were sensitive to the opiate antagonist naloxone.

Animals↗

PubMed1987

Regulation of rat adrenal medullary enkephalins by glucocorticoids.

Opioid peptides and their precursors of the proenkephalin family are found in the chromaffin cells of the rat adrenal medulla in low quantities. However, if the gland is denervated, there is a 10 to 20-fold increase in enkephalin-containing (EC) peptides consisting mostly of the precursor proenkephalin. The denervation-induced rise in medullary EC peptides is blocked by hypophysectomy, and partially reinstated by corticosterone, dexamethasone or ACTH treatment. In the intact rat, intermediate doses of corticosterone or dexamethasone reduce the denervation-induced increase in EC peptides, while a high dose of dexamethasone restores this response. These results indicate that glucocorticoids exert a permissive effect in vivo on the denervation-induced stimulation of EC peptide biosynthesis.

Adrenal Medulla↗