PubMed Health⌕ Search

Biomedical subjects

C E Inturrisi

Publications and source records attributed to C E Inturrisi.

At least 127 records · Page 7Linked to original sources
PubMed1981

Determination of acetylmethadol and metabolites by use of high-performance liquid chromatography.

A method is described for the simultaneous determination of 1, alpha-acetylmethadol (LAAM) and five active metabolites--noracetylmethadol, dinoracetylmethadol, methadol, normethadol, and dinormethadol--in biofluids by high-performance liquid chromatography using a normal-phase column and a UV detector at 218 nm. The compounds are recovered from biofluids by a multistep liquid--liquid extraction. The mobile phase is methanol--acetonitrile (70:30, v/v) containing 0.015% ammonium hydroxide as the modifier. Retention times can be varied by adjusting the composition of the mobile phase to maximize peak height for quantitation using l-propranolol as the internal standard or peak separation for the collection of fractions. Using a UV detector the lower limit of sensitivity is 10 ng/ml of biofluid. Using fraction collection of radiolabeled drug and metabolites followed by liquid scintillation counting the lower limit of sensitivity is 1.0 ng/ml. Commonly used or abused narcotics including morphine, heroin, meperidine, methadone and propoxyphene do not interfere with the analysis. The method has been applied to plasma and urine samples from humans, sheep and rats. Extracts of urine from patients receiving maintenance treatment with LAAM contain LAAM and each of the five active metabolites.

Animals↗
PubMed1981

Methadone: radioimmunoassay and pharmacokinetics in the rat.

A radioimmunoassay for the quantitation of methadone in biofluids is described. The antiserum was prepared by using an albumin conjugate of N-methyl-N-(1-methyl-3,3-diphenyl-4-oxohexyl)aminoethanol succinate. By employing tritium-labeled dl-methadone as the radioligand and a sample volume of 0.05 ml, the method has a lower limit of sensitivity of 3 ng/ml. The ability of the antiserum to detect methadone was not influenced by the presence of the metabolites of methadone or members of the methadol series. Morphine, codeine, levorphanol, meperidine, l, alpha-acetylmethadol and d-propoxyphene do not cross-react. After the i.v. administration of 0.90 or 1.5 mg/kg of methadone to male rats, plasma methadone levels decline biexponentially and elimination is independent of dose. The mean volume of distribution is 7.58 +/- 0.87 liters/kg; the mean elimination T 1/2 is 88.6 +/- 1.9 min and the plasma clearance is 59.3 +/- 1.4 ml/min/kg. These results demonstrate that methadone is eliminated by the rat much more rapidly than previously suspected.

Animals↗
PubMed1981

Pharmacodynamics of subcutaneously administered diacetylmorphine, 6-acetylmorphine and morphine in mice.

Diacetylmorphine (DAM) and 6-acetylmorphine (AM) exhibit virtually identical dose-response and time-action profiles in studies in antinociceptive, excitatory, antidiarrheal and antidiuretic activity after subcutaneous administration to mice. In antinociceptive (Haffner tail clip, phenylquinone writhing and hot plate) and excitatory (Straub tail) tests, both drugs are 3 to 10 times more potent than morphine (M) and reach their peak effect more rapidly than M. Analysis of these data by graded and quantal methods establishes the comparability of the results obtained, while confirming the greater efficiency of the graded method. The durations of action of DAM and AM are shorter than that of M, yielding significant differences in potency estimates based upon peak vs. total effect. DAM and AM are only twice as potent as M in the suppression of prostaglandin E2-induced diarrhea and in antidiuretic activity. These pharmacodynamic studies, along with prior dispositional studies, suggest that the ability of DAM and AM to rapidly cross the blood-brain barrier determines their potency and time-action differences from M in centrally mediated bioassays. In contrast, DAM and AM are only slightly more potent than M in th antidiarrheal and antidiuretic test. These studies support the concept that the pharmacological effects of DAM are mediated principally by metabolically formed AM.

Analgesics↗
PubMed1980

Brain uptake of meperidine in the fetal lamb.

The uptake of meperidine by the brain of the fetal lamb was investigated by determining the concentration of meperidine in the fetal brachiocephalic artery and sagittal vein after intravenous and intramuscular administration to the mother. A positive arteriovenous gradient across the fetal brain existed for 10 minutes after intravenous administration, and for 20 to 25 minutes after intramuscular administration, thus indicating the uptake of meperidine by the fetal brain. The peak concentration of unbound meperidine in the fetal brain, as estimated from the plasma concentration of free meperidine at equilibrium, was three to four times greater after intravenous administration than after intramuscular administration. The findings suggest that, during labor, the route of administration of meperidine will determine the time course of meperidine in the fetal brain and, consequently, the time action of effects seen in the neonate. The lag time required for plasma-brain equilibration may explain the lack of correlation between the incidence of neonatal respiratory depression and the levels of meperidine in the cord after intramuscular administration.

Animals↗
PubMed1980

Analgesic activity of the naturally occurring heptapeptide [Met]enkephalin-Arg6-Phe7.

[Met]Enkephalin-Arg6-Phe7 is an opiate-like peptide normally found in the the adrenal gland and brain that has analgesic (antinociceptive) activity when administered directly into the cerebral ventricles of mice. On a molar basis, [Met]-enkephalin-Arg6-Phe7, with a median effective dose (ED50) of 38.5 nmol/mouse, is 8 times more potent than [Met]enkephalin. As with [Met]enkephalin, analgesic activity is blocked by naloxone and intravenous administration does not produce characteristic opiate effects in tests for analgesic, antidiuretic, or antidiarrheal activity. These findings suggest that [Met]enkephalin-Arg6-Phe7 may be at least as important as the enkephalins in the postulated enkephalin system mediating pain and analgesia.

Analgesics↗
PubMed1980

Renal tubular secretion of meperidine by the fetal lamb.

We have determined the renal clearance of meperidine and inulin simultaneously under steady-state conditions by using the chronic fetal lamb preparation. Meperidine was infused at a constant rate of 3.2 mg/min into the maternal vena cava, and [14C]inulin was infused at a constant rate of 0.22 muCi/min into the fetal vena cava. Total fetal urine output was collected for three consecutive 15-min intervals, and fetal blood was sampled at the midpoint of each urine collection. The mean meperidine clearance in 12 studies was 12.04 +/- 2.90 (S.E.) ml/min, whereas mean inulin clearance was 2.48 +/- 0.35 (S.E.) ml/min. In all but one animal, the ratio of meperidine clearance to inulin clearance is greater than one, indicating tubular secretion of meperidine. The results show that there is a negative relationship between meperidine clearance and urine pH, but there is no relationship between meperidine clearance and gestational age or urine flow rate. These results suggest that meperidine is secreted across the renal tubules by "ion trapping."

Animals↗
PubMed1979

beta-Endorphin: analgesic and hormonal effects in humans.

The pharmacokinetics and the hormonal, analgesic, and behavioral effects of several doses of human beta-endorphin were evaluated after intravenous administration to three patients and intracerebroventricular administration to one patient with pain caused by cancer. These effects were compared to the hormonal effects of intravenously administered morphine sulfate in two patients and an enkephalin analog in two baboons. The mean terminal half-life after intravenous administration of 5 or 10 mg of human beta-endorphin to three patients was 37 min; the mean volume of distribution was 178 ml/kg, and the metabolic clearance rate was 3.2 (ml/min)/kg. The half-life of beta-endorphin in cerebrospinal fluid after intracerebroventricular administration was 93 min, and the volume of distribution was 0.74 ml/kg. A rapid rise in plasma prolactin followed both intravenous and intracerebroventricular beta-endorphin. Intravenous administration did not affect plasma growth hormone, but intracerebroventricular administration suppressed plasma growth hormone. No significant change in plasma growth hormone was noted after intravenous administration of morphine to humans, but plasma growth hormone decreased in one baboon after administration of the enkephalin analog. beta-Endorphin-stimulated release of prolactin occurred at doses lower than those required to produce analgesic and other behavioral effects. When both hormonal and analgesic effects were observed (after 7.5 mg were given intracerebroventricularly), the onset of the hormonal response slightly preceded the analgesic and behavioral responses. These studies suggest that the hormonal effects of beta-endorphin are species dependent and are similar to those of morphine. Hormonal and analgesic effects of beta-endorphin appear to result from the activation of opiate receptors that differ in their locations and characteristics.

Adult↗
PubMed1979

Urinary excretion of meperidine by the fetal lamb.

The renal excretion of meperidine by the fetus was determined in five chronic, unanesthesized fetal lamb preparations. Chronic indwelling catheters were implanted in the maternal aorta and vena cava, the fetal aorta, amniotic sac and allantoic sac. Via laparotomy, two catheters were implanted in the fetal bladder; the urachus and urethra were ligated. After intravenous administration of 2.5 mg/kg to the mother, meperidine rapidly appears in fetal urine. Approximately 0.02 to 0.05% of the maternal dose was excreted into fetal urine as unchanged meperidine in 300 min. The elimination half-life of meperidine in the fetus is 32.6 +/- 3.7 min when calculated from the urinary excretion rates, and 28.6 +/- 3.9 min when estimated from the plasma decay curve. The renal clearance of meperidine by the fetus ranged from 2.8 to 16.7 ml/min. Although the urachus and urethra were ligated, meperidine is found in samples of amniotic and allantoic fluid, indicating that the drug can diffuse across the placental membranes from the mother into these fluids. We have demonstrated that renal elimination of meperidine is a route of drug elimination by the fetus. These data support a pharmacokinetic model that describes the disposition of meperidine in the maternal-fetal unit by use of a two-compartment open model with elimination from both maternal and fetal compartments.

Animals↗
PubMed1978

Amniotic fluid transfer of meperidine from maternal plasma in early pregnancy.

Concurrent samples of maternal plasma and amniotic fluid were collected from 40 subjects during the second trimester of pregnancy following a single intramuscular dose of meperidine (100 mg). Maternal meperidine plasma levels were highest in samples collected from 15 to 50 minutes after drug administration. Thereafter the level declined during the next 2 hours. Meperidine was not detected in amniotic fluid until 30 minutes after the intramuscular dose. We estimated that an apparent equilibrium was reached between plasma and amniotic fluid at 120 to 155 minutes after the drug was given to the mother. Normeperidine was not detected in either maternal plasma or amniotic fluid during the time course of this study.

Amniotic Fluid↗
PubMed1977

Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer.

Concentrations of meperidine and its active metabolite, normeperidine, were measured in plasma of patients receiving the drug for analgesia. Meperidine levels in cancer patients were 0.10 to 0.55 microng/ml 1 h after a dose and were 0.05 to 0.14 in patients in the oliguric period after renal transplantation. Normeperidine levels were 0.05 to 0.28 microng/ml in the cancer patients and 0.13 to 0.36 in the renal failure patients. The ratio of normeperidine to meperidine levels was always higher in the renal failure patients than in the cancer patients. Additionally, two patients receiving multiple doses of meperidine had high normeperidine levels and very high normeperidine/meperidine ratios when they showed signs of central nervous system excitation. These data indicate that normeperidine can contribute to the excitatory effects seen after multiple doses of meperidine and suggest that patients with renal failure are particularly susceptible to this problem.

Acute Kidney Injury↗
PubMed1976

Effects of acetylmethadol on plasma testosterone.

Plasma testosterone levels were measured in a group of 13 men maintained on acetylmethadol for treatment of opiate dependence. Prior to acetylmethadol administration, plasma testosterone levels were within normal adult ranges. Four hours following ingestion of acetylmethadol, plasma testosterone levels were significantly depressed and continued to fall 7-9 hr after drug administration. Plasma testosterone levels remained low 24-25 hr after the drug was taken, but, 48 hr following drug, plasma testosterone levels rose to values approximating those prior to drug. Depression of plasma testosterone levels following acetylmethadol ingestion was not only statistically but also biologically significant, since in many patients the levels were below the normal range for adult males.

Adult↗
PubMed1976

Simultaneous determination of meperidine and normeperidine in biofluids.

A method employing solvent extraction and gas-liquid chromatography has been developed for the simultaneous determination of meperidine and its N-demethylated metabolite, normeperidine, in biofluids. Normeperidine is analyzed as the heptafluorobutyryl derivative. Using a flame ionization detector, the lower limit of sensitivity of the method is 0.02 mug/ml of biofluid for both compounds. Samples of plasma obtained from obstetrical patients, following a single therapeutic dose, were found to contain higher levels of meperidine than concurrent samples of amniotic fluid. Normeperidine could not be detected in either biofluid after a single dose. There is, however, a gradual accumulation of normeperidine in plasma after repeated doses as determined in samples from cancer patients. The method can also be used to determine the disposition of merperidine and the accumulation of normeperidine in the cat.

Amniotic Fluid↗