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Biomedical subjects

C E Inturrisi

Publications and source records attributed to C E Inturrisi.

At least 109 records · Page 6Linked to original sources
PubMed1984

The pharmacokinetics of heroin in patients with chronic pain.

We measured blood concentrations of heroin and its active metabolites, 6-acetylmorphine and morphine, serially in 11 patients with chronic pain (9 of whom had cancer) after intravenous injection, intravenous infusion, intramuscular injection, and an oral dose of heroin hydrochloride. Parenteral heroin provided measureable blood levels of heroin, 6-acetylmorphine, and morphine. Blood levels of heroin and 6-acetylmorphine reached their maximal concentrations within minutes and were cleared rapidly. The mean half-life of heroin (+/- S.D.) after intravenous injection or infusion was only 3.0 +/- 1.3 minutes, and the mean clearance of heroin from the blood at apparent steady state was 30.8 +/- 2.1 ml per kilogram of body weight per minute. Morphine levels rose more gradually, and morphine was cleared much more slowly. Oral administration of heroin resulted in measurable blood levels of morphine but not of heroin or 6-acetylmorphine. The amount of circulating morphine provided by an oral dose of heroin was only 79 per cent of that available from an equal amount of morphine. We conclude that heroin is a pro-drug that serves to determine the distribution of its active metabolites. Parenteral heroin is rapidly converted to 6-acetylmorphine, which contributes to rapid pain relief. Oral heroin is converted to morphine and appears to be an inefficient means of providing morphine to the systemic circulation.

Administration, Oral↗
PubMed1984

Constraints on the tailflick assay: morphine analgesia and tolerance are dependent upon locus of tail stimulation.

In three experiments, the locus of tail stimulation in the tailflick assay was found to be an important parameter in determining morphine action. Rats were intravenously infused (Experiment I), injected with morphine subcutaneously (Experiment II), or implanted subcutaneously with morphine pellets (Experiment III). Analgesia was evaluated periodically following drug administration using the tailflick test and 3 adjacent 1 in. tail areas. In all three experiments, the distal tail section was more sensitive to the analgesic effects of morphine than more proximal sections. In Experiments I and III, tolerance to the effects of morphine developed more slowly at the distal tail location. These results indicate that the locus of stimulation in the tailflick assay can profoundly affect the development of analgesia and tolerance to morphine.

Analgesics↗
PubMed1984

Methadone induced physical dependence in the rat.

Although the morphine withdrawal syndrome has been well described in the rat, a syndrome having similar characteristics has not been demonstrated following chronic methadone treatment. In this study we describe the behavioral effects produced by naloxone (4 mg/kg sc) following 72 hours of continuous iv infusion of methadone, (12.2 micrograms/kg/min), morphine (12.2 to 97.9 micrograms/kg/min) or saline. The cessation of methadone or morphine but not saline treatment followed by naloxone resulted in graded signs including wet dog shakes, escape attempts, self-stimulation and body weight loss and quantal signs including diarrhea, ear blanching, exophthalmos, ptosis, tachypnea and teeth chattering. These results indicate that this mode of methadone administration produces physical dependence characterized by a morphine-like withdrawal syndrome in the rat.

Animals↗
PubMed1984

Chronic vascular catheterization in the rat: comparison of three techniques.

Rats were implanted with an indwelling vascular cannula in the jugular vein, femoral artery or carotid artery, and evaluated for postsurgical weight changes and cannula patency. Complete details for surgical methods and materials are presented for each procedure. Over a 14 day period, the carotid artery procedure produced the most profound weight loss, while the jugular vein implantation was followed by minimal changes in body weight. Weight loss was intermediate for the femoral artery group. Body weight had returned to, or was above presurgical weight at 2, 4 and 6 days postsurgery for the jugular, femoral and carotid catheterizations, respectively. By 14 days following implantation 83%, 67% and 50% of the femoral, carotid and jugular cannulas, respectively, were patent. We conclude that for long-term sampling of blood in the rat, the femoral artery catheterization procedure is preferable in terms of patency and postsurgical weight loss.

Animals↗
PubMed1983

Beta-endorphin immunoreactivity in the plasma of patients with the Prader-Labhart-Willi syndrome and their normal siblings.

No significant difference was found in the range or mean values of ir-beta-endorphin in the plasma of 6 patients with the Prader-Labhart-Willi syndrome compared to 7 of their normal siblings. The hypothesis that some of the symptoms of the P-L-W syndrome are due to excessive opioid activity is not supported by measurement of peripheral levels of ir-beta-endorphin.

Adolescent↗
PubMed1983

Plasma immunoreactive beta-endorphin levels in depression. Effect of electroconvulsive therapy.

Immunoreactive (ir) plasma beta-endorphin level was assayed in ten symptomatic patients with a unipolar major depressive disorder and in 16 psychiatrically normal controls matched for age and sex. Plasma ir-beta-endorphin level in depressed patients was similar to that in controls. All depressed patients was similar to that in controls. All depressed patients had a transient, approximately threefold increase in ir-beta-endorphin after each use of electroconvulsive therapy (ECT). The increase of plasma ir-beta-endorphin level after ECT parallels the transient elevation of adrenocorticotropic hormone level reported by others and probably reflects a hypothalamic response to ECT.

Adrenocorticotropic Hormone↗
PubMed1983

Methadyl acetate (LAAM) in the treatment of heroin addicts. II. Double-blind comparison of gradual and abrupt detoxification.

One hundred nineteen patients were admitted to a six-month (26-week) prenaltrexone detoxification program comparing abrupt and gradual withdrawal from methadyl acetate (LAAM) therapy. All patients were brought to a maintenance level of 50, 50, and 65 mg (Monday, Wednesday, and Friday). Patients randomly assigned to the gradual group (group G) began 4-mg/wk reduction the Monday of week 9 and reached zero dosage (placebo) the Monday of week 23; patients in the abrupt group (group A) continued to receive 50, 50, and 65 mg until the Monday of week 23, when their dosage was dropped to zero (placebo). All patients were given placebo for four weeks. This study showed the superiority of abrupt withdrawal over this gradual-withdrawal schedule. Forty-six percent of group P compared with 28% of group G made the transition to naltrexone treatment. Severity of withdrawal problems was in no case significantly greater in group A.

Adolescent↗
PubMed1983

Central nervous system excitatory effects of meperidine in cancer patients.

The analgesic meperidine has been reported to produce signs of central nervous system excitation in human beings. To determine the relationship between signs and symptoms of central nervous system excitation and plasma levels of meperidine and normeperidine, we studied 67 patients receiving meperidine for the relief of postoperative or chronic pain. In 48 patients, excitatory effects ranging from mild nervousness to tremors, twitches, multifocal myoclonus, and seizures were directly correlated with accumulation of normeperidine in plasma. Evidence of compromised renal function occurred in only 14 of the 48 symptomatic patients, suggesting that renal dysfunction may contribute to but is not the sole factor in the accumulation of normeperidine or its relation to adverse neurological signs. In a second study we surveyed mood alterations in 47 patients receiving meperidine and 29 receiving other narcotic analgesics for postoperative pain. The repeated administration of meperidine was associated with adverse alterations in various elements of mood (e.g., apprehension, sadness, restlessness).

Adolescent↗
PubMed1983

Evidence from opiate binding studies that heroin acts through its metabolites.

The relative affinity to opiate receptors of heroin, 6-acetylmorphine and morphine was estimated by determining their ability to displace specifically bound 3H-naltrexone from rat brain opiate binding sites. In vitro hydrolysis of heroin to 6-acetylmorphine was monitored in the binding assay filtrate by use of a quantitative HPLC procedure. The rate of heroin hydrolysis was significantly slower at 0 degrees C than at 37 degrees C. The displacement of 1 nM 3H-naltrexone by unlabeled ligand at concentrations ranging from 7 to 500 nM was measured at 0 degrees C for 120 minutes, yielding IC50 values of heroin = 483 nM, 6-acetylmorphine = 73 nM and morphine = 53 nM. When the binding data for heroin were recalculated to include the displacement that could be attributed to the 6-acetylmorphine derived from heroin degradation during the incubation, all of the apparent heroin binding was accounted for by the 6-acetylmorphine. These results are consistent with previous reports of the low binding affinity of morphine congeners (e.g., codeine) that lack a free phenolic 3-hydroxyl group and support the view that heroin is a prodrug which serves to determine the distribution of its intrinsically active metabolites, 6-acetylmorphine and morphine.

Animals↗
PubMed1983

Effects of eight-hour naloxone infusions on human subjects.

Twelve normal male volunteers received saline control, low-dose naloxone, and high-dose naloxone infusions during three weekly sessions. The sessions were 16 hr long: 1 hr for predrug assessments, 8 hr during which either naloxone or saline was infused in a double-blind procedure, and a 7-hr postdrug observation period. The 8-hr infusions of naloxone had no effect on experimental ischemic arm pain. In addition, the ischemic arm pain procedure did not significantly increase either plasma levels of cortisol or immunoreactive beta-endorphin, suggesting that the procedure was not stressful. The high-dose naloxone infusion resulted in a slightly aversive mood state and prevented the normal circadian decrease in cortisol levels. Both doses of naloxone increased systolic blood pressure and prevented the normal diurnal increase in temperature. The 8-hr infusions of naloxone did not result in changes in pain, mood, or physiological indices beyond what was present within a few hours after starting the infusion.

Adult↗
PubMed1982

Determination of heroin and its metabolites by high-performance liquid chromatography.

A method is described for the simultaneous determination of heroin (3,6-diacetylmorphine, DAM) and its two active metabolites 6-acetylmorphine and morphine in blood by high-performance liquid chromatography using a normal-phase column and a UV detector at 218 nm. The compounds are stabilized in blood by rapid freezing and recovered by a multistep liquid--liquid extraction. The mobile phase is acetonitrile--methanol (75:25, v/v) buffered to apparent pH 7 with ammonium hydroxide and acetic acid. Using l-alpha-acetylmethadol as an internal standard, UV detection and a 1-ml biofluid sample, the lower limit of sensitivity is 12.5 ng/ml. Commonly used narcotic analgesics including codeine, propoxyphene, meperidine, methadone and levorphanol do not interfere with the analysis. The method has been applied to blood samples from humans and rats. Extracts of blood from a patient who had received an intravenous dose of 14 mg of DAM contained DAM and both of its active metabolites.

Animals↗
PubMed1982

Heroin: analgesia, toxicity and disposition in the mouse.

The acute toxicity of heroin (3,6-diacetylmorphine, DAM) and its metabolites 6-acetylmorphine (AM) and morphine (M) following intravenous (i.v.) and intracerebroventricular (i.c.v.) administration and their tailflick-test analgesic activity following i.c.v. administration were studied in mice. After i.c.v. administration, M was 2.5-3 times more potent as a naloxone-reversible analgesic than either DAM or AM. DAM and AM provoked a naloxone-sensitive respiratory depressant lethality (i.c.v.) while M (i.c.v.), and all three drugs given i.v., caused convulsions prior to death. The dose-response and naloxone antagonism studies suggest that the receptor mechanisms which may subserve opiate convulsions differ from those mediating either analgesia or depressant lethality. Studies of DAM's disposition in vivo and in vitro suggest that unhydrolyzed DAM may contribute to its own pharmacodynamic profile after i.v., but not subcutaneous (s.c.) administration to mice.

Analgesia↗
PubMed1982

Narcotic drugs.

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Analgesics, Opioid↗
PubMed1982

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.

Adult↗
PubMed1982

Antinociceptive activity and toxicity of meperidine and normeperidine in mice.

The antinociceptive (radiant heat tail-flick), convulsant and lethal activities of meperidine (MEP) and normeperidine (NMEP) were studied after s.c. and i.c.v. administration to mice. Both compounds s.c. exhibited naloxone-reversible antinociceptive activity. MEP (ED50 = 23 mg/kg) was 2.5 to 5 times more potent, on a molar basis, than NMEP (ED50 = 72 mg/kg). NMEP was a convulsant [ED50 = 105 mg/kg (s.c.) and 64 micrograms/mouse (i.c.v.)], with a small therapeutic index relative to analgesia whose activity was potentiated by naloxone and antagonized by pentobarbital or morphine, s.c. Death due to s.c. MEP was preceded by convulsions, whereas i.c.v. MEP provoked a primarily depressant lethality. Naloxone antagonized death due to i.c.v. MEP while unmasking its convulsant activity. It is concluded that NMEP is the principal mediator of MEPs central nervous system excitation, that convulsions are mediated by a different population of receptors than either analgesia or respiratory depression and that naloxone exacerbates the convulsant activity of MEP and NMEP.

Analgesics↗