Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.

Hypothyroxinemia affects 35-50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers' organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

Oral morphine in cancer pain: influences on morphine and metabolite concentration.

One hundred fifty-one patients with chronic cancer pain were studied during chronic treatment with oral morphine. Plasma concentrations of morphine and metabolites (M3G and M6G) were measured. The ratio of plasma morphine to metabolites was not affected by dose. Generalized linear interactive modeling analysis using morphine dose, age, sex, renal and hepatic dysfunction, and concomitant medication as explanatory variables accounted for 70% of the variance in plasma concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Increasing morphine dose was a significant factor for increased plasma concentrations of morphine, M3G, and M6G. Other significant factors were: age greater than 70 years (increased M3G and M6G plasma concentrations), plasma creatinine greater than 150 mumol/L (increased M3G and M6G plasma concentrations), male sex (decreased morphine and M6G plasma concentrations), raised creatinine plus coadministration of tricyclic antidepressants (increased M3G plasma concentrations), ranitidine (increased morphine plasma concentrations), and raised creatinine plus coadministration of ranitidine (increased M6G plasma concentrations).

Rodent strain differences in the NPFF1 and NPFF2 receptor distribution and density in the central nervous system.

The present study evaluates the putative differences between NPFF1 and NPFF2 receptor distribution and density throughout the central nervous system between rat and mouse strains by using in vitro quantitative autoradiography. The binding of [125I]YVP ([125I]YVPNLPQRF-NH2) and [125I]EYF ([125I]EYWSLAAPQRF-NH2), used to label NPFF1 and NPFF2 receptors, respectively, was compared between Sprague-Dawley and Wistar rats and between Swiss and C57BL/6-SV129 mice. In contrast to Wistar, Sprague-Dawley brains contained NPFF1 binding sites in the cortical and spinal cord areas, the accumbens nucleus, the anterodorsal thalamic nucleus, the parafascicular thalamic nucleus, the inferior colliculus and the nucleus of the solitary tract. The distribution of NPFF2 binding sites was also different between the two strains of rats. As compared to Swiss, C57BL/6-SV129 mice showed higher basal NPFF2 receptor levels in cortical areas, telencephalon and some other regions. In contrast, they showed lower amounts in thalamic structures, except the reuniens nucleus, and in mesencephalic and rhombencephalic regions. In the cervical spinal cord the levels of NPFF2 receptors were similar. The NPFF1 binding levels were nearly the same in telencephalic structures while distinct in the forebrain. Differences in amount of NPFF receptor subtypes among these strains of rats or mice could lead to differences in NPFF control of opioid nociception.

Genetic variability in morphine sensitivity and tolerance between different strains of rats.

The development of tolerance, the sensitivity to morphine and the effective morphine plasma concentrations have been studied in Sprague-Dawley (SD-U) and Wistar (W) rats. Daily administration of morphine (10 mg/kg/12 h for 9 days) in W rats produced a reduction in morphine antinociception from day 1 (12+/-0 s) to day 9 (6.7+/-1. 9 s). Morphine antinociception in the SD-U rats did not change over the period of treatment. Naloxone abolished the antinociception of morphine in both opiate naive and chronically treated SD-U rats. The pharmacokinetic parameters of morphine and morphine-3-glucuronide did not differ significantly between strains. Both naive and chronically treated SD-U rats required smaller doses of morphine than W rats to obtain a maximum antinociceptive effect. Plasma concentrations following administration of the same dose of morphine, did not differ between strains or days of treatment. The range of morphine concentrations required to obtain a maximum effect were lower in SD-U rats, both on day 1 and day 8 when compared to W rats. These results show differences between the two strains with regard to both morphine sensitivity and development of tolerance, whilst also suggesting that the differences do not have a kinetic basis.

Morphine-3-glucuronide prevents tolerance to morphine-6-glucuronide in mice.

Daily subcutaneous (s.c.) pretreatment with morphine-3-glucuronide (6 mg/kg) was found to reduce morphine-6-glucuronide (4 mg/kg s.c.)-induced antinociception, with no decrease in the effect over 5 days. Morphine-6-glucuronide administration (4 mg/kg s.c.) on Day 6, without morphine-3-glucorinide pretreatment, results in a significant increase in antinociception (from 24% on Day 5 to 70%; p< or =0.05). Morphine-3-glucuronide may prevent tolerance to morphine-6-glucuronide by reducing morphine-6-glucuronide-induced antinociception.

Morphine and morphine-6-glucuronide plasma concentrations and effect in cancer pain.

The relationships between plasma morphine and metabolite (M3G and M6G) concentrations and analgesic efficacy were investigated in an open study of 39 cancer pain patients receiving chronic oral morphine therapy with either morphine sulfate solution or controlled-release morphine tablets. There were no differences in morphine, metabolite kinetics, or analgesic efficacy between equivalent doses of conventional or controlled-release formulations. The increase in morphine plasma concentration after a dose (1 hr for normal release, 2 hr for controlled release) was correlated significantly with the dose of morphine (r = 0.914, P < 0.001). There was a significant reduction in pain intensity (P < 0.05) and increase in pain relief (P < 0.001) after the dose of morphine administration, when compared with the predose score. One-half of the patients had mild and tolerable adverse effects. Patients were classified by mean pain relief between doses as having optimal, moderate, or poor pain control. No simple relationship was found between morphine plasma concentration and pain control. Morphine plus M6G concentrations in the "optimal control" group (751.2 +/- 194 nmol/L), however, were more than twice those found in the "moderate control" group (276.9 +/- 41.9 nmol/L) (P < 0.05), and no patient in the moderate control group had a morphine plus M6G concentration greater than 405 nmol/L. These results support the importance of M6G in morphine analgesia. For these hospitalized patients, there appeared to be a therapeutic range of morphine plus M6G plasma concentrations for optimal pain control with a lower limit of 400 nmol/L predose.

Peak plasma concentrations after oral morphine: a systematic review.

We performed a systematic review of 69 studies with information on 2146 subjects (454 patients and 1692 healthy volunteers) to examine the maximum plasma concentration (Cmax) and the time taken to reach maximum concentration (Tmax) for different oral morphine formulations, and to clarify factors contributing to variability. Data from healthy volunteers reflected that seen for patients but was less variable. There was minimal difference between single and multiple doses, suggesting no accumulation of morphine. For immediate-release morphine there was no difference in either dose-corrected Cmax or Tmax between solution and tablets, or between different salts. For controlled-release formulations, little difference was observed between brands. Only for once-daily formulations was there any difference in absorption between fed and fasted, with a Tmax for fed subjects considerably longer than for fasted. There was no evidence for any difference between values obtained by radioimmunoassay (RIA) or high-performance liquid chromatography (HPLC).

Single-dose dipyrone for acute postoperative pain.

BACKGROUND: The use of dipyrone as an analgesic is controversial. It is used most commonly to treat postoperative pain, colic pain, cancer pain and migraine, and in many countries, eg, Russia, Spain, Brazil, and in many parts of South-America and Africa, it is the most popular non opioid first line analgesic. In others it has been banned (e.g. USA, UK) because of its association with potentially life-threatening blood dyscrasias such as agranulocytosis. Dipyrone is currently available in Austria, Belgium, France, Germany, Italy, The Netherlands, Spain, Switzerland, South Africa, Latin America, Russia, Israel and India. OBJECTIVES: To assess quantitatively the analgesic efficacy and adverse effects of single-dose dipyrone in randomised trials in moderate to severe postoperative pain. To compare the relative efficacy of dipyrone with other drugs assessed in the same way. SEARCH STRATEGY: Published reports were identified from Medline, Embase, the Cochrane Library (Issue 3 1999), LILACs and the Oxford Pain Relief Database. Additional studies were identified from bibliographies of retrieved reports. Date of the most recent search: December 1999. SELECTION CRITERIA: The following inclusion criteria were used: full journal publication, clinical trial, random allocation of patients to treatment groups, double-blind design, adult patients, pain of moderate to severe intensity at the baseline assessment, postoperative administration of study drugs, treatment arms which included dipyrone and placebo or active control and oral, rectal, intramuscular or intravenous administration of study drugs. DATA COLLECTION AND ANALYSIS: Summed pain intensity and pain relief data over 4-6 hours were extracted and converted into dichotomous information to yield the number of patients who obtained at least 50% pain relief. This was used to calculate the proportion of patients with, and number-needed-to-treat for, at least 50% pain relief over 4-6 hours. Single-dose adverse effect data were collected. MAIN RESULTS: Fifteen studies were included; eight used placebo and seven used an active control (oral dexketoprofen 12.5 mg or 25 mg, oral ketorolac 10 mg, intramuscular pethidine 100 mg or ketorolac 30 mg, intravenous tramadol 100 mg or rectal suprofen 300 mg). In five trials (288 patients) the mean response rate (proportion of patients with at least 50% pain relief) for single dose oral dipyrone 500 mg was 73% (range 54% to 87%) and with placebo it was 32% (19% to 41%) in moderate to severe postoperative pain over 4-6 hours. In two studies (113 patients) the response rate with oral dipyrone 1 g was 69% (61% and 77%) and with placebo it was 20% (11% and 25%). In one study (70 patients) the response rate with intramuscular dipyrone 2 g was 74% and with placebo it was 46%. No analyses could be conducted for adverse effects. The response rates in the active controlled trials were similar to those reported in the placebo controlled trials. REVIEWER'S CONCLUSIONS: Single-dose dipyrone appears to be of similar efficacy to ibuprofen 400 mg and other analgesics frequently used in the treatment of moderate to severe postoperative pain. The commonest adverse effects were somnolence, gastric discomfort and nausea.

Sensitivity to µ-opioid receptor-mediated anti-nociception is determined by cross-regulation between µ- and δ-opioid receptors at supraspinal level.

BACKGROUND AND PURPOSE: The perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter-individual variability in the sensitivity to µ-opioid receptor agonists. EXPERIMENTAL APPROACH: Anti-nociceptive tests, radioligand binding, stimulation of [(35) S]GTP-γ-S binding, inhibition of cAMP production and co-immunoprecipitation experiments were performed in two strains of rat (Sprague-Dawley bred at our university - SDU - and Wistar) that differ in their sensitivity to opioids. KEY RESULTS: The increased anti-nociceptive potency of µ-opioid receptor agonists in SDU rats was reversed by the δ-opioid receptor antagonist, naltrindole. Inhibition of the binding of [(3) H] naltrindole by µ-opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ-opioid receptor ligands on the binding of [(35) S]GTP-γ-S stimulated by µ-opioid receptors agonists. No strain-related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co-immunoprecipitation experiments demonstrated that δ-opioid receptors were associated with µ-opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats. CONCLUSIONS AND IMPLICATIONS: There was increased supraspinal cross-talk between µ and δ-opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti-nociception induced by µ-opioid receptor agonists.

Monitoring serum levels of gentamicin to develop a new regimen for gentamicin dosage in newborns.

The newborns studied had gestational ages ranging between 23-44 weeks, weights ranging between 725-4510 g, and were treated with standard doses of gentamicin (5.2 +/- 1.0 mg/kg/day). The gentamicin serum peak and trough levels were unrelated to administered doses, and a large proportion of patients had low (peak less than 4 micrograms/ml in 12%) or potentially toxic concentrations (trough greater than 2 micrograms/ml in 55%). The pharmacokinetic parameters (t1/2e, 8.2 +/- 4.8 h and Vd, 0.64 +/- 0.22 L/kg) varied markedly between patients. The newborn's weight, age, gestational age, and serum creatinine were factors of importance for the variability of gentamicin serum levels. The newborns were divided into four groups: gestational period less or more than 37 weeks and age below or above 7 days. These groups had different gentamicin serum levels and pharmacokinetic parameters. The results suggest that a gentamicin dosage regimen based on the division of newborn patients into subgroups or calculated from individual pharmacokinetic characteristics would decrease the risk of obtaining potentially toxic or subtherapeutic gentamicin concentrations after the use of standard doses.

Changes in gentamicin serum levels and pharmacokinetic parameters in the newborn in the course of treatment with aminoglycoside.

Gentamicin serum levels were determined in an unselected group of newborns treated with standard doses of the drug to study the changes in pharmacokinetic parameters (trough and peak serum levels/dose ratio, serum level increases/dose ratio, elimination half-life, and distribution volume) 48, 96, and 144 h after commencing treatment. However, no significant changes in the pharmacokinetic parameters were found in different groups of neonates, classified according to gestational age and days of life during the study period. It appears that the dose of gentamicin once it has been individually established does not have to be changed, at least during the first week of treatment.