Influence of ranitidine on the morphine-3-glucuronide to morphine-6-glucuronide ratio after oral administration of morphine in humans

Hypophosphatemia in malnourished children during nutritional recovery (refeeding hypophosphatemia) is recognized as a cause of morbidity and mortality in adolescents with anorexia nervosa but has been only rarely reported to occur in younger children with other diagnoses. Over a 6-year period, we encountered three cases of refeeding hypophosphatemia in malnourished children admitted to a pediatric rehabilitation hospital. Two children had neurologic dysphagia and one had been starved by an abusive parent. The one patient who was symptomatic had obtundation, hemolytic anemia, rhabdomyolysis, and hepatocellular injury that began during refeeding and resolved with treatment. The signs and symptoms, pathophysiology, and treatment of refeeding hypophosphatemia are reviewed.     

Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration

PURPOSE: To develop and assess an automated image cytometric method of apoptotic cell classification for use under conditions in which apoptosis is a rare event (e.g. fibroblastoid cell lines or low-dose irradiation). METHOD: Image acquisition software was adapted to gather double-stained cell images from slides prepared using cell fixation and staining methods that emphasized apoptotic morphology. Chinese hamster ovary cells (CHO) were classified individually by discriminant analysis of morphological and nuclear texture features calculated for each image. Discriminant functions were constructed from a manually classified set of over 60000 cell images categorized as 'normal', 'apoptotic', 'cell doublets' or 'debris' and all subsequent cell images collected were classified using these functions. RESULTS: Application of this technique resulted in a 99.8% accuracy in classification of the normal cell population, and 81.7% classification accuracy for apoptotic cells. This method was then applied to study the time course of the apoptotic response of CHO cells following X-irradiation. Following irradiation with 5 Gy no increase above control levels of apoptosis was noted until 18 h post-irradiation, which corresponded with the release of the G2 block as determined by DNA-content analysis. Apoptotic frequency increased to a peak level of 12.1 +/- 4.6% at 42 h post-irradiation. CONCLUSIONS: Automated image cytometry provides an efficient and consistent method of apoptosis measurement. This study represents the first detailed characterization of the time course and the role of cell division in CHO cell apoptosis.     

Improved one-step solid-phase extraction method for morphine, morphine-3-glucuronide, and morphine-6-glucuronide from plasma and quantitation using high-performance liquid chromatography with electrochemical detection

OBJECTIVE: The purpose of this survey was to study the sensation of oral dryness and its underlying factors in the 55-year-old population of Oulu (a medium-sized Finnish town), 780 of whom (77%) participated. METHOD: In addition to the examination of oral health status and salivary flow rate measurements, depressive symptoms were determined on the basis of the Zung Self-Rating Depression Scale (ZSDS). The participants were also interviewed about their health, medication, physical health, physical activity, smoking habits, alcohol consumption, and factors related to their work. RESULTS: The prevalence of subjective sensations of dry mouth was 25.8% among men and 33.3% among women (p = 0.025). A statistically significant association was found between a subjective sensation of dry mouth and a low unstimulated flow rate, regular smoking, xerogenic medication, and the presence of at least one illness connected with dry mouth. Those who had a sensation of dry mouth also thought their physical condition and their health to be poorer and more often had a high rate of depressive symptoms. After the confounding factors had been added stepwise into the logistic regression model, depressive symptoms were still significantly associated with the sensation of oral dryness. CONCLUSIONS: When evaluating the causes of the sensation of dry mouth, the possibility of depression as an underlying factor should be considered.     

Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers

Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers. With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg.kg-1.hr-1 for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg.kg-1.hr-1 for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G. In addition, metabolite kinetics of M-6-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.     

Delayed neuropathy and inhibition of soluble neuropathy target esterase following the administration of organophosphorus compounds to hens

BACKGROUND: Disulfide exchange reactions are catalyzed by thiol/disulfide oxidoreductases. These enzymes possess a thioredoxin fold and contain a catalytic disulfide with the sequence Cys-X-X-Cys at the N terminus of an alpha helix. Despite these similarities, the various members differ strongly in their redox potentials (-122 mV to -270 mV). Using the strong oxidant DsbA from Escherichia coli as a model system, we investigated whether the redox properties of these enzymes can be modulated rationally by exchange of the X-X dipeptide. RESULTS: The X-X dipeptide of DsbA (Cys30-Pro31-His32-Cys33) was exchanged by the dipeptides of eukaryotic protein disulfide isomerase (PDI; Gly-His), glutaredoxin (Pro-Tyr), and thioredoxin (Gly-Pro) from E. coli. All variants were less oxidizing than wild-type DsbA and their redox potentials were in the order of the related natural enzymes (DsbA > PDI > glutaredoxin > thioredoxin). The equilibrium constant between glutathione and the thioredoxin-like variant increased 1200-fold compared with wild-type DsbA. The variants also showed a strong increase in the pKa of the nucleophilic cysteine (Cys30). As for glutaredoxin and thioredoxin, the catalytic disulfide stabilized the corresponding variants while destabilizing wild-type DsbA and the PDI-like variant. CONCLUSIONS: The X-X dipeptide in the active site of thiol/disulfide oxidoreductases appears to be the main determinant of the redox properties of these enzymes. This empirical finding should be very useful for the design of new thiol/disulfide oxidoreductases with altered redox potentials and for studying the function of these enzymes in vivo.     

Intrathecal administration of p-hydroxymercuribenzoate or phosphoramidon/bestatin-combined induces antinociceptive effects through different opioid mechanisms

BACKGROUND: House dust mite is an important cause of bronchial asthma. Seasonal variation of environmental house dust mite allergen levels and the specific IgE antibody to house dust mite have been reported. OBJECTIVE: We studied the changes in IgG subclass antibodies to house dust mite associated with seasonal variation of house dust mite allergen levels in houses of mite-sensitive asthmatic patients. METHODS: In 14 mite-sensitive asthmatic patients, house dust mite allergen (Der f 1) contents in bedding were measured monthly, and IgG subclass antibodies to house dust mite, Dermatophagoides farinae (D. farinae), were determined by enzyme-linked immunosorbent assay (ELISA) every 3 months from July to December. RESULTS: The concentration of Der f 1 in dust from bedding reached maximum levels in August and September, and significantly decreased in November and December compared with August and September (P < .05). Levels of D. farinae-specific IgG4 antibodies significantly decreased in December compared with September (P < .05) with no statistically significant change between September and June (P > .05). Levels of D. farinae-specific IgG2 antibodies decreased significantly in December compared with June (P < .05). The levels of IgG1 and IgG3 antibodies to D. farinae showed no significant differences during the study period. CONCLUSION: These findings suggest that seasonal changes in natural exposure to house dust mite allergen might lead to concurrent changes in specific IgG4 antibodies to house dust mite in mite-sensitive asthmatic patients and each IgG subclass antibodies to house dust mite might have a different kinetics.     

Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of diclofenac in the rat

The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the pain-induced functional impairment model in the rat. Male Wistar rats were injected with uric acid in the knee joint of the right hind limb, which induced its dysfunction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the antinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinociceptive effect was delayed with respect to blood concentrations. Moreover, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac blood concentration, an anticlockwise hysteresis loop was observed for all doses. Hysteresis collapse was achieved using the effect-compartment model, and the plot of functionality index against diclofenac concentration in the effect-compartment data was well fitted by the sigmoidal Emax model. Our data suggest slow equilibrium kinetics between diclofenac concentration in blood and at its site of action, which leads to a delayed onset of the antinociceptive effect as well as a longer duration of the response resulting from drug accumulation in synovial fluid.     

Pharmacokinetic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect

The in vivo concentration-anticonvulsant effect relationships of six benzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazepam and clobazam were quantified in individual rats and correlated with the affinity to the GABAA-benzodiazepine receptor complex. Furthermore the interaction between midazolam and the benzodiazepine antagonist flumazenil was characterized. All benzodiazepines exhibited a nonlinear relationship between concentration and anticonvulsant effect without ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC250, between 0.067 +/- 0.01 mg. l-1 for midazolam and 0.21 +/- 0.03 mg. l-1 for diazepam. The EC250,u of clobazam was 2.8 +/- 0.9 mg. l-1. These values were considerably larger than the Ki for binding at the GABAA-benzodiazepine receptor complex. No correlation was observed between EC250,u and Ki. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentration-anticonvulsant effect relationship. Analysis of these data on basis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effect at low midazolam concentration was characterized on basis of the sigmoid E maximal effect pharmacodynamic model. The value of the EC50,u was 0.0086 +/- 0.0013 mg. l-1 which is similar to the Ki for binding at the GABAA-benzodiazepine receptor complex. The second more pronounced anticonvulsant effect occurred at higher concentration and was described by an exponential function. The findings of this study indicate that the effect of benzodiazepines against seizures induced by cortical stimulation in vivo cannot be fully accounted for by an interaction at the GABAA-benzodiazepine receptor complex.     

Brain sites involved in the antinociceptive effect of bradykinin in rats

The localization of brain sites where bradykinin (BK) induces its antinociceptive effect in rats, was studied using as index the threshold for the jaw-opening reflex elicited by the dental pulp electrical stimulation test (DPEST). The microinjection of BK into the lateral or fourth cerebral ventricles induced an antinociceptive effect, with Index of Antinociception (IA) of 0.51+/-0.03 and 0.68+/-0.05, respectively. However, microinjections of the peptide into the third ventricle induced a less marked antinociception (IA = 0.28+/-0.08). The brain sites where the microinjection of BK caused an antinociceptive effect were: locus coeruleus, principal nucleus, oral part of the spinal sensorial trigeminal nucleus, and the sensory root of the trigeminal nerve. The antinociceptive effect was more intense when BK (4-16 nmol) was injected into the locus coeruleus. Microinjection of BK (4 nmol) into the fourth ventricle, but not into the locus coeruleus, induced an increase in blood pressure. The microinjection of the peptide into the nucleus tractus solitarius, a site that is also involved in the pressor effect of BK, did not induce an antinociceptive effect. These results indicate that the antinociceptive effect of BK is not related to blood pressure changes. The microinjection of BK into some of the sites involved in the mechanisms of analgaesia, including the periaqueductal gray matter (dorsal, lateral and ventrolateral) and the dorsal raphe nucleus did not induce an antinociceptive effect. The results suggest that the most likely brain sites involved in the antinociceptive effect of BK are the locus coeruleus and the principal sensory trigeminal nucleus. The present results did not exclude the involvement of other brain sites surrounding the lateral and the third ventricles.     

Tolerance to the antinociceptive effect of morphine in spinally transected rats.

Examined the effect of a spinal transection (ST) on morphine (MOR)-induced tolerance in rats with the tail withdrawal reflex (tail flick; TF), elicited by noxious thermal stimulation. Intact Ss became tolerant to sc MOR injections if they were tested on the TF after each injection. MOR administration alone did not produce tolerance; TF tests alone did, although not always to a significant extent. However, when MOR only, TF tests only, or both were administered prior to ST (acute spinal Ss), all groups were tolerant when tested 1 day after spinalization. When the same treatments were administered to Ss 3 wks after ST (chronic spinal Ss), neither MOR nor TF tests alone produced tolerance. Chronic spinal Ss became tolerant only if they were tested after each injection. Results suggest that tolerance develops at the spinal cord as a result of either chronic opiate exposure or performance of the nociceptive response, but in intact Ss, tolerance is inhibited or suppressed by a supraspinal action of MOR. Results also suggest that such tolerance is mediated by descending input or that ST produced intrinsic changes in the spinal cord that preclude the development of tolerance induced only by opiate or behavioral stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delayed cytokine expression in rat brain following experimental contusion

Proinflammatory cytokines mediate brain injury in experimental studies. This study was undertaken to analyze the production of proinflammatory cytokines in experimental contusion. A brain contusion causing delayed edema was mimicked experimentally in rats using a weight-drop model. Intracerebral expression of the cytokines interleukin (IL)-1 beta, tumor necrosis factor-alpha (TNF alpha), IL-6, and interferon-gamma (IFN gamma) was studied by in situ hybridization and immunohistochemistry. The animals were killed at 6 hours or 1, 2, 4, 6, 8, or 16 days postinjury. In the injured area, no messenger (m)RNA expression was seen during the first 2 days after the trauma. On Days 4 to 6 posttrauma, however, strong IL-1 beta, TNF alpha, and IL-6 mRNA expression was detected in mononuclear cells surrounding the contusion. Expression of IFN gamma was not detected. Immunohistochemical double labeling confirmed the in situ hybridization results and demonstrated that mononuclear phagocytes and astrocytes produced IL-1 beta and that mainly astrocytes produced TNF alpha. The findings showed, somewhat unexpectedly, a late peak of intracerebral cytokine production in the injured area and in the contralateral corpus callosum, allowing for both local and global effects on the brain. An unexpected difference in the cellular sources of TNF alpha and IL-1 beta was detected. The cytokine pattern differs from that seen in other central nervous system inflammatory diseases and trauma models, suggesting that the intracerebral immune response is not a uniform event. The dominance of late cytokine production indicates that many cytokine effects are late events in an experimental contusion: Different pathogenic mechanisms may thus be operative at different times after brain injury.     

Systemic levels of 6-keto-prostaglandin F1 alpha following administration of inhaled aerosolized prostacyclin

Tinnitus is sometimes suppressed by cochlear implantation. Tinnitus conditions were examined in 60 adult patients who underwent cochlear implantation in 1990 or later. Before surgery, 90% of these patients reported some type of tinnitus. The patients completed a questionnaire evaluating the loudness and duration of the tinnitus, immediately after the first electrical stimulation and 2 months later. The loudness of tinnitus was suppressed in 65% of the patients at first evaluation. Two months later, the tinnitus was suppressed in 93% of the patients. As for the duration of tinnitus, at first evaluation the tinnitus duration was suppressed in 41% of the patients. Two months later, the duration of tinnitus was suppressed in 61% of the patients.     

Cutaneous toxicity following the administration of dactinomycin

The author describes a patient who has a successful coronary artery bypass. Six weeks later, after a physical examination of the chest, she had unbearable sharp, stabbing pain around the incision which was not responding to nerve blocks, analgesics, nonsteroidal anti inflammatory agents, and epidural blocks. The pain was responsive to mexilitine and disappeared after three weeks of treatment.     

Differential effects of localized lesions of n. accumbens on morphine- and amphetamine-induced locomotor hyperactivity in the C57BL/6J mouse.

In 2 experiments with 46 C57BL/6J mice, it was found that Ss became hyperactive to increasing doses of morphine sulfate. This response was similar to locomotor hyperactivity induced by amphetamine. Lesions and chemical blockade of posterior nucleus accumbens abolished amphetamine-induced hyperactivity and reduced but did not abolish the morphine response. Results demonstrate that response to the drugs is mediated by overlapping but noncongruent neural systems. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Study of the antinociceptive effect of tetrahydro-papaveroline derivatives. Interaction with opioids

The antinociceptive effect of racemic tetrahydropapaveroline (THP), of its two R(+)- and S(-) enantiomers, of 1-2-dehydro-THP and of 1-carboxy-THP was assessed using different pain tests in mice. None of these drugs possessed a significant activity in the hot-plate and tail-flick tests. However, after i.p. injection, they reduced the number of abdominal writhes induced by phenylbenzoquinone, with ED50 values of 51 +/- 7, 73 +/- 9 and 79 +/- 7 mg/kg for the most potent compounds: 1,2-dehydro-THP, +/- THP and -THP, respectively. This activity was not antagonized by naloxone (1 mg/kg, s.c.). However combination of inactive doses of these three compounds (32 mg/kg, i.p.) and of morphine (0.5 mg/kg, s.c.) led to a significant antinociceptive effect (83 to 85% of reduction of the number of writhes). This synergistic potentiation confirmed with the combination of +/- THP (16 mg/kg, i.p.) and morphine (0.5 mg/kg, s.c.) was totally inhibited by naloxone (1 mg/kg, s.c.). These results, although excluding a direct agonistic effect of THP derivatives on opiate receptors, suggest an indirect interaction of these drugs with the endogenous opioid system.     

Enhanced frustrative nonreward effect following 6-hydroxydopamine lesions of the lateral septum in the rat.

Tested the effect of local injections of 6-hydroxydopamine (6-OHDA [3 μg/1 μl]) into the lateral septum in a paradigm that leads to an energizing behavior, through a possible frustrative effect, induced by partial or total omission of reward in hungry adult male Sprague-Dawley rats. Biochemical assays in the septum showed that 6-OHDA reduced endogenous dopamine and, to a lesser extent, noradrenaline concentrations and left intact noncatecholaminergic neurons such as serotoninergic terminals. In a double straight alley, Ss were exposed to an acquisition phase, a partially reinforced phase, and an extinction phase. Ss with lesions ran faster for food than controls in the partial reinforcement or extinction situation. The 2 groups also behaved similarly after the 1st 6 trials of the extinction phase. When Ss were tested in a leverpress conditioning task, lesioned and control Ss learned this task equally well, both with respect to the number of leverpresses and the time to obtain a fixed number of food pellets. In the 1st 5 min following the omission of reward, the number of leverpresses increased more for the lesioned Ss than for controls, a difference that disappeared in the later stages of the test. Results indicate that the loss of septal dopaminergic innervation produces behavioral effects similar to those obtained after total destruction of the same areas by electrocoagulation. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vasoactive intestinal polypeptide induces analgesia and impairs the antinociceptive effect of morphine in mice

OBJECTIVE: To explore the use of sun protection behaviours and the experience of sunburn in a sample of parents and their children in New Zealand. METHODOLOGY: Information was collected from 887 parents using postal questionnaires at the beginning of and during the summer. RESULTS: Thirty per cent of the parents believed their child looked healthier with a suntan, and 40% intended to let their child get a suntan during the summer. Predictors of intention to tan included level of parental education, the child's age, the child's sensitivity to burning and experience of sunburn in the parent. At the end of the summer period, 29% of the children were reported as being sunburned. Predictors of sunburn in the child were the age of the child, experience of sunburn in the parent and use of sunscreen SPF15+ by the parent. CONCLUSION: Despite intense media coverage of the dangers of overexposure to the sun, it is clear that a significant proportion of children are still getting sunburned.     

Intratesticular testosterone concentration following intratunical administration in the hypogonadal animal

The serum and intratesticular testosterone concentration (ITC) after testosterone administration in the tunica vaginalis (TV) sac compared to parenteral administration was studied in 20 dogs that were rendered hypogonadal by gonadotropin-releasing hormone antagonist ('Nal-Glu' GnRH antagonist) in a daily dose of 80 micrograms for 15 days. The 20 dogs were divided into two equal groups. Twenty milligrams of testosterone propionate were administered in the TV cavity in the TV group and intramuscularly (IM) in the IM group. In addition four dogs acted as controls and another four as sham controls. Serum and ITC were determined in all the dogs 1, 2, and 15 days after testosterone administration. Biopsies from TV were taken 3 weeks after testosterone injection for histologic examination. Serum and ITC were significantly reduced (P < 0.01) 15 days after GnRH antagonist. They increased after intratunical testosterone administration to reach the pre-GnRH antagonist level (P > 0.05). After IM testosterone injection, the serum testosterone increased to the pre-GnRH antagonist level (P > 0.05), while the ITC did not. The TV did not show histopathologic abnormalities apart from submesothelial infiltration with inflammatory cells in one dog. In conclusion, TV testosterone administration delivers a major dose of testosterone to the testicle without exposing other tissues to high testosterone levels. The method is safe and may be used as an office treatment. It may be tried in the treatment of patients who are infertile due to a low ITC.