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Repeated Administration (repeated + administration)
Selected AbstractsContrasting Effects of Zonisamide and Acetazolamide on Amygdaloid Kindling in RatsEPILEPSIA, Issue 11 2001Koichi Hamada Summary: ,Purpose: Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy. Methods: Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18. Results: ZNS (10,40 mg/kg; n = 6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25,200 mg/kg; n = 7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50,200 mg/kg; n = 6). ZNS, 25 or 40 mg/kg (n = 8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50,200 mg/kg (n = 6), also retarded seizure development, with 14.0,14.8 stimulations required. Conclusions: ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs. [source] The effects of dexamethasone and prednisolone on pituitary and ovarian function in the mareEQUINE VETERINARY JOURNAL, Issue 5 2010R. A. FERRIS Summary Reasons for performing study: Persistent mating induced endometritis is among the most common causes of infertility in the mare. Recently, improved pregnancy rates have been reported when corticosteroids were administered to ,problem mares' specifically, to modulate the post mating inflammatory response; however, the effect of treatment on pituitary and ovarian function requires further study. Objectives: To evaluate the effects of prolonged treatment with glucocorticoids on pituitary and ovarian function. Methods: Eighteen cycling Quarter Horse mares in early oestrus were assigned randomly to one of 3 treatment groups: dexamethasone 0.05 mg/kg bwt i.v. twice a day, prednisolone 0.5 mg/kg per os twice a day, or placebo for 5 days. Mares were examined by ultrasound daily to evaluate reproductive function. Blood samples were collected daily to measure luteinising hormone (LH), progesterone and cortisol levels. Results: Dexamethasone treatment caused greater (P<0.05) suppression of endogenous cortisol concentration (9.4 ± 1.1 ng/ml) compared to prednisolone- (41.9 ± 4.0 ng/ml) or placebo-treated mares (32.4 ± 3.8 ng/ml). After 24 h, mares treated with dexamethasone exhibited lower uterine oedema scores than prednisolone- or placebo-treated mares. An ovulation rate of 40% was observed in dexamethasone-treated mares (2/5) compared to 83% for prednisolone (5/6) and 100% for placebo-treated (6/6) mares. An absence of a LH surge was noted in 3 of 5 dexamethasone-treated mares and one of 6 prednisolone-treated mares. Conclusions: Repeated administration of dexamethasone to mares in oestrus is associated with decreased uterine oedema, suppression of LH and a high rate of ovulation failure. It is recommended that dexamethasone treatment is limited to only 1 or 2 days and that a lower dose is considered in the management of persistent mating induced endometritis to avoid potential adverse affects on reproductive function. [source] Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcoholEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2001D. N. Stephens Abstract Repeated experience of withdrawal from chronic alcohol treatment increases sensitivity to seizures. It has been argued by analogy that negative affective consequences of withdrawal also sensitize, but repeated experience of withdrawal from another sedative-hypnotic drug, diazepam, results in amelioration of withdrawal anxiety and aversiveness. We tested whether giving rats repeated experience of withdrawal from alcohol altered their ability to acquire a conditioned emotional response (CER). Male Hooded Lister rats were fed a nutritionally complete liquid diet as their only food source. Different groups received control diet, or diet containing 7% ethanol. Rats receiving ethanol diet were fed for either 24 days (Single withdrawal, SWD), or 30 days, with two periods of 3 days, starting at day 11, and 21, in which they received control diet (Repeated withdrawal, RWD). All rats were fed lab chow at the end of their liquid diet feeding period. Starting 12 days after the final withdrawal, groups of Control, SWD and RWD rats were given pentylenetetrazole (PTZ; 30 mg/kg, i.p.) three times a week, and scored for seizures. The occurrence of two successive Stage 5 seizures was taken as the criterion for full PTZ kindling. Other groups of control, SWD and RWD rats were trained to operate levers to obtain food, and were then exposed, in a fully counterbalanced design, to light and tone stimuli which predicted unavoidable footshock (CS+), or which had no consequences (CS,). Rats consumed approximately 17.5 g/kg/day of ethanol, resulting in blood alcohol levels of approximately 100 mg/dL. Repeated administration of PTZ resulted in increasing seizure scores. RWD rats achieved kindling criterion faster than either Control or SWD rats. No differences were seen in the groups in flinch threshold to footshock (0.3 mA). At a shock intensity of 0.35 mA, Control, but not RWD or SWD rats showed significant suppression to the CS+ CS, presentation did not affect response rates. The three groups differed in their response to pairing the CS+ with increasing shock levels, the Controls remaining more sensitive to the CS+. SWD rats showed significant suppression of lever pressing during CS+ presentations only at 0.45 and 0.5 mA, and RWD rats only at 0.5 mA. Giving rats repeated experience of withdrawal from chronic ethanol results in increased sensitivity to PTZ kindling, but reduces their ability to acquire a CER. Withdrawal kindling of sensitivity to anxiogenic events does not seem to occur under circumstances which give rise to kindling of seizure sensitivity. [source] Oral administration of diphenyl diselenide potentiates hepatotoxicity induced by carbon tetrachloride in ratsJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2009Cristina W. Nogueira Abstract Carbon tetrachloride (CCl4) is a model for studying free radical-induced liver injury and screening hepato-protective drugs. Numerous studies have reported the involvement of oxidative stress in CCl4 -induced liver damage and the hepato-protective effects mediated by different antioxidants. The present study examined the effects of diphenyl diselenide, (PhSe)2, on hepatotoxicity induced by CCl4 in rats. To this end, male Wistar rats received (PhSe)2 by oral route at the dosage of 31.2 mg/kg for one or two days. After the second day of treatment, rats received CCl4 orally in a single dose. The liver and kidney were utilized for determination of histopathology, biochemical [aspartate (ALT) and alanine (AST) aminotransferases, alkaline phosphatase (ALP), total bilirrubin (TB) and gamaglutamyl transferase (GGT)] and toxicological parameters [thiobarbituric reactive species (TBARS) levels, catalase activity, ascorbic acid, nonprotein thiols (NPSH) and aminolevulinate dehydratase (, -ALA-D) activity]. Repeated administration of (PhSe)2 caused a marked potentiation of hepatotoxicity induced by CCl4 exposure, as manifested by an increase in biochemical parameters (AST, ALT, ALP, GGT and BT) and severe alteration in histopathology. This study also demonstrated a potentiation of TBARS levels and a consequent depletion of important antioxidant defenses including catalase and ascorbic acid. Pre-treatment with a single dose of (PhSe)2 prevented the effect of strychnine, a substrate for CYPs, abolishing lethality in mice. This result indicates that (PhSe)2 prevented animal death, suggesting an activator action of (PhSe)2 in CYPs. This study clearly indicates that (PhSe)2 potentiated acute hepatic damage induced by CCl4. Copyright © 2008 John Wiley & Sons, Ltd. [source] ,-Opioid receptor knockout mice are insensitive to methamphetamine-induced behavioral sensitizationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2010Xine Shen Abstract Repeated administration of psychostimulants to rodents can lead to behavioral sensitization. Previous studies, using nonspecific opioid receptor (OR) antagonists, revealed that ORs were involved in modulation of behavioral sensitization to methamphetamine (METH). However, the contribution of OR subtypes remains unclear. In the present study, using ,-OR knockout mice, we examined the role of ,-OR in the development of METH sensitization. Mice received daily intraperitoneal injection of drug or saline for 7 consecutive days to initiate sensitization. To express sensitization, animals received one injection of drug (the same as for initiation) or saline on day 11. Animal locomotor activity and stereotypy were monitored during the periods of initiation and expression of sensitization. Also, the concentrations of METH and its active metabolite amphetamine in the blood were measured after single and repeated administrations of METH. METH promoted significant locomotor hyperactivity at low doses and stereotyped behaviors at relative high doses (2.5 mg/kg and above). Repeated administration of METH led to the initiation and expression of behavioral sensitization in wild-type mice. METH-induced behavioral responses were attenuated in the ,-OR knockout mice. Haloperidol (a dopamine receptor antagonist) showed a more potent effect in counteracting METH-induced stereotypy in the ,-OR knockout mice. Saline did not induce behavioral sensitization in either genotype. No significant difference was observed in disposition of METH and amphetamine between the two genotypes. Our study indicated that the ,-opioid system is involved in modulating the development of behavioral sensitization to METH. © 2010 Wiley-Liss, Inc. [source] Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbensJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2006José Antonio Fuentealba Abstract Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16,0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K+ -stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K+ compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K+ -stimulated DA levels in control rats, it did not decrease significantly either basal or K+ -stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc. © 2006 Wiley-Liss, Inc. [source] Influence of endotoxin on the disposition kinetics and dosage regimens of oxytetracycline in calvesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2003R. Kumar The influence of endotoxin on the disposition kinetics of oxytetracycline (OTC) (10 mg/kg) was investigated in five healthy ruminating male crossbred calves. The serum concentration-time data of OTC before and after endotoxin challenge were best described by a two-compartment open model. Repeated administration of Escherichia coli endotoxin (1 ,g/kg, i.v.) at an interval of 12 h up to 48 h produced a clear rise in the body temperature and an increase in the pulse and respiration rates. Endotoxin caused a significant reduction in mean transit time in tissue compartment (MTTT) (P , 0.05), mean residence time in the peripheral tissue compartment (MRTT) (P , 0.05), mean residence time in the body (MRTB) (P , 0.05), elimination half-life (t1/2,2) (P , 0.05) and distribution space in tissues (VT) (P , 0.01) and at steady-state (Vd(ss)) (P , 0.01). Endotoxin had no effect on the distribution clearance (ClD), systemic clearance (Cl) and distribution half-life of OTC, while the values of first order rate constant of transfer of drug from tissue to central compartment (K21) and the zero time intercept at terminal phase (C2) were significantly high. The drug dosage regimens to maintain serum OTC concentrations of 0.5, 1, 2, 4, 6 and 8 ,g/mL were also determined in febrile and clinically healthy animals. [source] Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naďve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposureMOVEMENT DISORDERS, Issue 5 2003Lance A. Smith MSc Abstract Levodopa (L -dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L -dopa dose and frequency of administration on dyskinesia initiation in drug-naďve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L -dopa with the peripheral catechol- O -methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0,7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L -dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L -dopa for 26 days to drug-naďve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L -dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L -dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L -dopa alone, but with no obvious change in duration of L -dopa's effect. However, combining entacapone with L -dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L -dopa alone. Importantly, increasing pulsatile exposure of brain to L -dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society [source] Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004S M Gardiner The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. CsA (5.9 mg kg,1 bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. Pretreatment with the angiotensin (AT1) receptor antagonist, losartan, and the endothelin (ETA and ETB) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the , -adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. Tacrolimus (450 ,g kg,1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. Sirolimus (450 ,g kg,1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects. British Journal of Pharmacology (2004) 141, 634,643. doi:10.1038/sj.bjp.0705659 [source] The pharmacology of cilostazolDIABETES OBESITY & METABOLISM, Issue 2002Karsten Schrör Cilostazol (6-[4-(1-cyclohexyl- 1H -tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone; OPC-13013) is a 2-oxo-quinoline derivative with antithrombotic, vasodilator, antimitogenic and cardiotonic properties. The compound is a potent inhibitor of phosphodiesterase (PDE) 3A, the isoform of PDE 3 in the cardiovascular system (IC50: 0.2 µm). In addition, there is inhibition of adenosine uptake, eventually resulting in changes in cAMP levels, dependent on the type of adenosine receptors (A1 or A2). Cilostazol inhibits platelet aggregation and has considerable antithrombotic effects in vivo. The compound relaxes vascular smooth muscle and inhibits mitogenesis and migration of vascular smooth muscle cells. In the heart, cilostazol causes positive inotropic and chronotropic effects. Most, if not all, of these actions are cAMP-mediated, including the modification of cAMP-controlled gene expression. Cilostazol decreases levels of serum triglycerides and causes some increase in HDL-cholesterol levels. The compound has a number of additional effects which might contribute to its overall clinical efficacy. Cilostazol undergoes intensive and finally complete hepatic metabolism via the cytochrome P450 systems. This might result in some drug interaction, i.e. with erythromycin and omeprazole. The half-life is approximately 10 h, resulting in about 2-fold accumulation of the drug during repeated administration. [source] Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic DrugsEPILEPSIA, Issue 8 2006Wolfgang Löscher Summary:, Development of tolerance (i.e., the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception. Tolerance develops to some drug effects much more rapidly than to others. The extent of tolerance depends on the drug and individual (genetic?) factors. Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment. Different experimental approaches are used to study tolerance in laboratory animals. Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs. Two major types of tolerance are known. Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage. Pharmacodynamic (functional) tolerance is due to "adaptation" of AED targets (e.g., by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment. Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs. Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent. Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response. After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response. Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment. Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists. [source] Adaptative response of antioxidant enzymes in different areas of rat brain after repeated d -amphetamine administrationADDICTION BIOLOGY, Issue 3 2001Félix Carvalho d-Amphetamine has been shown to be a potential brain neurotoxic agent, particularly to dopaminergic neurones. Reactive oxygen species indirectly generated by this drug have been indicated as an important factor in the appearance of neuronal damage but little is known about the adaptations of brain antioxidant systems to its chronic administration. In this study, the activities of several antioxidant enzymes in different areas of rat brain were measured after repeated administration of d-amphetamine sulphate (sc, 20 mg/kg/day, for 14 days), namely glutathione-S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GRed), catalase, and superoxide dismutase (SOD). When compared to a pair-fed control group, d-amphetamine treatment enhanced the activity of GST in hypothalamus to 167%, GPx in striatum to 127%, in nucleus accumbens to 192%, and in medial prefrontal cortex to 139%, GRed in hypothalamus to 139%, as well as catalase in medial prefrontal cortex to 153%. However, the same comparison revealed a decrease in the activity of GRed in medial pre-frontal cortex by 35%. Food restriction itself reduced GRed activity by 49% and enhanced catalase activity to 271% in nucleus accumbens. The modifications observed for the measured antioxidant enzymes reveal that oxidative stress probably plays a role in the deleterious effects of this drug in CNS and that, in general, the brain areas studied underwent adaptations which provided protection against the continuous administration of the drug. [source] Cocaine-induced locomotor activity and Fos expression in nucleus accumbens are sensitized for 6 months after repeated cocaine administration outside the home cageEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Bruce T. Hope Abstract Induction of the immediate early gene protein product Fos has been used extensively to assess neural activation in the striatum after repeated cocaine administration to rats in their home cages but rarely after repeated administration outside the home cage, which produces more robust locomotor sensitization. In the present study, we found cocaine-induced Fos expression in nucleus accumbens, but not caudate-putamen, was enhanced 1 and 6 months after repeated drug administration in locomotor activity chambers. Double-labelling of Fos protein and enkephalin mRNA indicated that Fos expression in nucleus accumbens was enhanced in enkephalin-positive, but not enkephalin-negative, medium spiny neurons. In contrast, cocaine-induced Fos expression was absent altogether in nucleus accumbens and unaltered in caudate-putamen 1 month after repeated cocaine administration in the home cage. As cocaine-induced locomotor activity was also enhanced 1 and 6 months after repeated cocaine administration in locomotor activity chambers, we wanted to confirm that neuronal activity in nucleus accumbens mediates cocaine-induced locomotor activity using our particular treatment regimen. Bilateral infusions of the GABA agonists baclofen and muscimol (1 µg/side) into nucleus accumbens of sensitized rats blocked cocaine-induced Fos expression and locomotor activity. Thus, while neuronal activity in both D1- and D2-type neurons in nucleus accumbens can mediate acute cocaine-induced locomotor activity, the enhanced activation of enkephalinergic D2-type neurons suggests that these latter neurons mediate the enhancement of cocaine-induced locomotor activity for up to 6 months after repeated drug administration outside the home cage. [source] Simultaneous administration of a low-dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long-term survival of cardiac allograft in ratsIMMUNOLOGY, Issue 2 2003Yongzhu Jin Summary T-cell costimulatory blockade combined with donor bone marrow transfusion may induce mixed chimerism, rendering robust tolerance in transplanted organs and cells. However, most protocols entail high doses of donor bone marrow cells (BMCs) or repeated administration of costly agents that block costimulatory pathways, thus delaying clinical development. To circumvent these shortcomings, we developed a strategy in which the dosage of donor BMCs was reduced but compensated by donor splenocytes (SPLCs). Furthermore, repeated administration of costly agents was replaced with a single injection of adenovirus expressing a gene of interest. In rat cardiac transplantation models, cardiac allografts from DA (RT-1a) rats were transplanted heterotopically into the abdomen of LEW (RT-11) recipient rats. Immediately after cardiac transplantation, an adenovirus vector (AdCTLA4Ig; 5 × 109 plaque-forming units) containing the gene for CTLA4Ig was administered to recipients (n = 6) simultaneously with a low dose of donor BMCs (1 × 108/rat) and SPLCs (5 × 107/rat) via the portal vein. The treated LEW recipient rats developed long-lasting mixed chimerism (>10% at >100 days) and exhibited long-term cardiac allografts (mean survival time of > 200 days) compared with control recipients. Moreover, recipients displaying long-lasting mixed chimerism accepted subsequent donor skin allografts while promptly rejecting third-party skin allografts. These results suggest that blockade of the CD28-B7 pathway, using adenovirus-mediated CTLA4Ig gene transfer, in concert with a low dosage of donor BMCs and SPLCs, may represent a feasible strategy to induce stable mixed chimerism and permit long-term survival of cardiac allografts. [source] Hereditary angioedema: an update on available therapeutic optionsJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 9 2010Marcus Maurer Summary There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short-term prophylaxis before surgery, and long-term prophylaxis for those with frequent and severe attacks. In Germany, C1-INH concentrate and icatibant are licensed for acute therapy. C1-INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1-INH activity. This therapy, which has been available for decades, is effective and well-tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well-tolerated, even on repeated administration. An additional human C1-inhibitor, a recombinant human C1-inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long- and short-term prophylaxis. Androgen derivatives are established in long-term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy. [source] Haematological, hepatic and renal alterations after repeated oral and intraperitoneal administration of monoisoamyl DMSA.JOURNAL OF APPLIED TOXICOLOGY, Issue 2 2003Abstract We recently reported the effects of repeated administration of the monoisoamyl ester of dimercaptosuccinic acid (MiADMSA) on a few selected biochemical variables indicative of haematopoietic, liver, kidney and brain toxicity, oxidative stress and essential metal status in male rats. The present investigation studies similar changes in female rats to ,nd out if the changes are independent of gender. The results suggest signi,cant and pronounced toxic effects of MiADMSA on haem biosynthesis, liver and kidneys in female rats exposed to higher doses of orally (p.o.) or intraperitoneally (i.p.) administered MiADMSA, compared with the effects in male rats. No effects on brain tissues were seen. A pronounced depletion of copper was noted in the blood and liver of MiADMSA administered rats, irrespective of route of exposure. It can be concluded that the administration of MiADMSA in female rats is confounded with side-effects and may require caution during its use and further exploration. Copyright © 2003 John Wiley & Sons, Ltd. [source] Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA.JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2002Abstract Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is gaining recognition recently as a better chelator than meso 2,3-dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues because of its lipophilic character. There is, however, little information available on the toxicological properties of this chelator after repeated administration in animals. In the present study, we investigated the dose-dependent effect of MiADMSA on various biochemical parameters suggestive of alterations in haem biosynthesis and hepatic, renal and brain oxidative stress after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to rats. The concentration of essential metals in blood and soft tissues was determined along with histopathological observations of hepatic and renal tissues. The results suggest that MiADMSA administration had no effect on blood ,-aminolevulinic acid dehydratase activity. However, an increase in zinc protoporphyrin and a decrease in haemoglobin levels were noted in animals given MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild hepatotoxicity at the highest dose (100 mg kg,1, i.p.). This was confirmed by histopathological examinations, which identified basophilic stippling, granulation of the cytoplasm, haemorrhage and congestion. At the highest dose, levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione were increased above those of control values. Levels of hepatic reduced glutathione were decreased. Taken together, these observations point to oxidative stress. In animals administered MiADMSA i.p. there was an increase in the brain malondialdehyde levels at the two higher doses (50 and 100 mg kg,1). Essential metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood zinc while significantly decreasing the kidney zinc level. The most significant adverse effect of MiADMSA was on copper concentration, which showed significant depletion from almost all major organs. Magnesium levels in blood decreased but increased in liver of MiADMSA-administered rats. Histopathological observations of liver and kidneys suggest few moderate lesions. It can be concluded that repeated administration of MiADMSA is compromised with some mild toxic effect, particularly the loss of copper. The effects during oral administration are comparatively less pronounced than by the i.p. route. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of Cadmium and Aluminum Intake on the Antioxidant Status and Lipid Peroxidation in Rat TissuesJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2001Shohda A. El-Maraghy Abstract This work aimed to study the relationship between the accumulation of cadmium (Cd) or aluminum (Al) in certain tissues and the levels of lipid peroxides as well as tissue antioxidants. To carry out such investigations, CdCl2 was given to rats in two dose levels; 0.5 or 2.0 mg/kg i.p for 1 day or daily repeated doses for 2 weeks. Al was given as AlCl3 either in a single dose of 100 mg/kg or daily repeated doses of 20 mg/kg for 2 and 4 weeks. The measured parameters were tissue malondialdehyde (MDA, index of lipid peroxidation) and reduced glutathione (GSH) levels as well as the activities of glutathione peroxidase (GSH-PX), glutathione reductase (GSSG-R), and glucose-6-phosphate dehydrogenase (G-6-PDH) enzymes. Liver and kidney functions were assessed by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities as well as serum urea and creatinine concentrations. Cd and Al concentrations in the studied tissues were also measured. Results indicated that tissue Cd was significantly increased after administration of either Cd doses. After a single dose of 0.5 or 2.0 mg/kg CdCl2, the increase in tissue Cd levels were accompanied by an increase in MDA and a decrease in GSH levels. On the other hand, after repeated administration of Cd, tissue Cd accumulation was accompanied by increased hepatic and renal GSH levels with decrease in MDA content and a decrease in GSH-PX activity in liver. Liver function was affected at all dose regimens, whereas kidney function was affected only after 2 weeks administration of the higher dose. In Al treated rats, Al concentration was shown to be increased in liver much more than in brain. This was accompanied by a slight decrease in hepatic GSH level after 2 weeks and a decrease in GSH-PX activity after 4 weeks. Liver function was affected only after repeated injection of Al for 2 or 4 weeks. In general, Al administration exhibited safer pattern than Cd. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:207,214, 2001 [source] Ovarian follicular development stimulated by leuprorelin acetate plus human menopausal gonadotropin in chimpanzeesJOURNAL OF MEDICAL PRIMATOLOGY, Issue 2 2005Nobuhiko Yoshimoto Abstract:, We attempted ovarian stimulation using gonadotropins in 14 chimpanzees. Subjects were given a single administration of leuprorelin acetate, followed by repeated administration of human menopausal gonadotropin (hMG) for 16,21 days. During the dosing period, the ovarian follicle diameter and count were measured by transvaginal ultrasonography. The hormone administration induced the development of multiple follicles, and multiple oocytes were subsequently retrieved. However, the follicle count was decreased, suggesting atresia, in some subjects. Statistically, the final follicle diameter was dependent on the dosing duration and the hMG dose in the late stage, while the maximum follicle count during hMG administration was dependent on age and the hMG dose in the early stage. Five subjects showed mild ovarian hyperstimulation syndrome (OHSS)-like symptoms with a high serum estradiol (E2) concentration. These results suggest that leuprorelin acetate plus hMG administration successfully stimulates the development of multiple ovarian follicles for oocyte retrieval and that the serum E2 concentration is predictive of OHSS-like symptoms in chimpanzees. [source] Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbensJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2006José Antonio Fuentealba Abstract Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16,0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K+ -stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K+ compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K+ -stimulated DA levels in control rats, it did not decrease significantly either basal or K+ -stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc. © 2006 Wiley-Liss, Inc. [source] Alternate delivery route for amifostine as a radio-/chemo-protecting agentJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2008Natalie P. Praetorius Amifostine (ethiofos, WR-2721) is an organic thiophosphate prodrug that serves as an antineoplastic adjunct and cytoprotective agent useful in cancer chemotherapy and radiotherapy. The selective protection of certain tissues of the body is believed to be due to higher alkaline phosphatase activity, higher pH and vascular permeation of normal tissues. Amifostine is conventionally administered intravenously before chemotherapy or radiotherapy. It is approved by the Food and Drug Administration (FDA) to reduce cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. It was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer although this indication was withdrawn in 2005. Amifostine is also FDA approved for patients with head and neck cancer to reduce the incidence of moderate to severe xerostomia in patients who are undergoing postoperative radiation treatment where the radiation port includes a substantial portion of the parotid glands. The potential of amifostine as a cytoprotective agent is unlikely to be fully realized if the method of administration is restricted to intravenous administration. Attempts have been made to develop non-invasive methods of delivery such as transdermal patches, pulmonary inhalers, and oral sustained-release microspheres. It is the goal of this article to explore non-intravenous routes of administration associated with better efficacy of the drug. This review will primarily focus on the variety of more recently studied (2002 and later) alternative modes for amifostine administration, including subcutaneous, intrarectal and oral routes. [source] Behavioral Consequences of Repeated Nicotine During Adolescence in Alcohol-Preferring AA and Alcohol-Avoiding ANA RatsALCOHOLISM, Issue 2 2009Heidi Kemppainen Background:, Epidemiological studies suggest that exposure to nicotine at adolescent age is associated with increased potential to use alcohol and that genetic predisposition may further increase the risk. The present study addressed adolescent vulnerability to repeated nicotine exposure and its influence on subsequent ethanol self-administration by investigating interactions between nicotine-induced behavioral sensitization and voluntary ethanol consumption in alcohol preferring AA (Alko Alcohol) and alcohol nonpreferring ANA (Alko Non-Alcohol) rat lines selected for differential ethanol intake. Methods:, Adolescent and adult rats received 10 injections of nicotine (0.5 mg/kg s.c.), given every second day from postnatal day (Pnd) 27 and 75, respectively. Nicotine-induced (0.5 mg/kg) locomotor activity was measured acutely after the first injection, and after the repeated treatment with nicotine on Pnds 52 and 86 in the adolescent groups and on Pnd 99 in the adult groups. After this, acquisition of voluntary ethanol (10% v/v) consumption as well as nicotine-induced (0.5 mg/kg) ethanol intake was measured in the AA rats. Results:, Adolescent AA rats were more sensitive than adolescent ANA rats to the locomotor effects of nicotine. They were also stimulated more than adult AA rats, but such a difference was not found among ANA rats. Adolescent and adult rats did not differ in their susceptibility to nicotine-induced behavioral sensitization. Genetic predisposition to ethanol self-administration did not interact with development of behavioral sensitization in either adolescents or adults. Acquisition of ethanol intake was enhanced in the adolescent groups relative to the adult groups in a manner that was independent of the nicotine treatment. An increase in ethanol intake was found after challenging animals with nicotine, and this effect was enhanced in the nicotine-treated adolescent group. Conclusions:, These findings provide no or little support for the views that adolescent animals are more sensitive to the neurobehavioral effects of repeated exposure to nicotine and that exposure to nicotine in adolescence may contribute to enhanced vulnerability to ethanol abuse. Furthermore, genetic predisposition to high or low ethanol self-administration does not seem to be a factor that influences individual vulnerability to the neurobehavioral effects of repeated administration of nicotine. [source] The effects of one night of sleep deprivation on known-risk and ambiguous-risk decisionsJOURNAL OF SLEEP RESEARCH, Issue 3 2007BENJAMIN S. MCKENNA Summary Sleep deprivation has been shown to alter decision-making abilities. The majority of research has utilized fairly complex tasks with the goal of emulating 'real-life' scenarios. Here, we use a Lottery Choice Task (LCT) which assesses risk and ambiguity preference for both decisions involving potential gains and those involving potential losses. We hypothesized that one night of sleep deprivation would make subjects more risk seeking in both gains and losses. Both a control group and an experimental group took the LCT on two consecutive days, with an intervening night of either sleep or sleep deprivation. The control group demonstrated that there was no effect of repeated administration of the LCT. For the experimental group, results showed significant interactions of night (normal sleep versus total sleep deprivation, TSD) by frame (gains versus losses), which demonstrate that following as little as 23 h of TSD, the prototypical response to decisions involving risk is altered. Following TSD, subjects were willing to take more risk than they ordinarily would when they were considering a gain, but less risk than they ordinarily would when they were considering a loss. For ambiguity preferences, there seems to be no direct effect of TSD. These findings suggest that, overall, risk preference is moderated by TSD, but whether an individual is willing to take more or less risk than when well-rested depends on whether the decision is framed in terms of gains or losses. [source] The pharmacokinetics and safety of porfimer after repeated administration 30,45 days apart to patients undergoing photodynamic therapyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010S. P. Pereira Summary Background, Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus. Aim, To assess the pharmacokinetics as well as the safety profiles of porfimer after a first and a second dose administered 30,45 days apart in patients undergoing photodynamic therapy. Methods, Nineteen patients (16 with cholangiocarcinoma) were enrolled. Porfimer sodium was administered by i.v. injection over 3,5 min. Blood samples were collected prior to starting i.v. drug injection and postdose at different time points after the first and second administrations. Results, Porfimer exposure values after the second administration were statistically higher than those observed after the first administration, suggesting a slight accumulation of porfimer following repeated administration. The apparent mean elimination half-life of porfimer increased from 410 h after the first administration to 725 h after the second administration. The safety profiles of porfimer after a first and a second administration were similar and did not raise additional concern. Eight patients experienced nine serious adverse events. Only photosensitivity was deemed study-drug related. Conclusion, Porfimer appears to display a safe and tolerable profile when used in patients requiring a second photodynamic therapy within 45 days. [source] Lack of effect of repeated administration of tripelennamine on antipyrine disposition in camelsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000I. A. WASFI First page of article [source] Longitudinal mapping of mouse cerebral blood volume with MRINMR IN BIOMEDICINE, Issue 5 2006Herman Moreno Abstract MRI estimations of cerebral blood volume (CBV), useful in mapping brain dysfunction, typically require intravenous (IV) injections of contrast agents. Transgenically engineered mice have emerged as the dominant animal model with which to investigate disorders of the brain and novel therapeutic agents. The difficulty in gaining IV access in mice prohibits repeated administration of contrast in the same animal, limiting the ability to map CBV changes over time. Here we address this limitation by first optimizing an approach for estimating CBV that relies on intraperitoneal (IP) rather than IV injections of the contrast agent gadodiamide. Next, we show that CBV maps generated with IP or IV injections are quantitatively comparable. Finally, we show that CBV maps generated with IP gadodiamide can be acquired repeatedly, reliably and safely over time. Although this approach has certain limitations, estimating CBV with IP injections is well-suited for mapping the spatiotemporal pattern of brain dysfunction in mice models of disease, and for testing pharmacological agents. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failureBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2003J. Barré Abstract Objectives , To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily. Methods, Study 1: Twelve healthy elderly subjects (CLcreat 72±8 ml/min, 72±4 years mean±SD) and eight young volunteers (CLcreat 134±18 ml/min, 25±8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CLcreat. 17±5 ml/min, 54±10 years), five patients with moderate renal failure (CLcreat. 39±6 ml/min, 54±15 years) and eight volunteers (CLcreat. 104±17 ml/min, 53±9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods. Results, Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC0,24) was significantly increased and renal clearance (CLR) was significantly decreased. Significant correlations were observed between CLcreat and CLR (r=0.94) and between CLcreat and AUC0,24 (r=,0.94). Conclusion , With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CLcreat is directly related to a decrease in CLR and results in an increase in exposure to TMZ. Copyright © 2003 John Wiley & Sons, Ltd. [source] Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Zeruesenay Desta Aims, To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. Methods, The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac -cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. Results, This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 ± 13.6 ng ml,1; P = 0.0008) and AUC(0, ,) (201 ± 161 ng ml,1 h; P = 0.029) of (,)-cisapride were significantly higher than the Cmax (10.5 ± 3.4 ng ml,1) and AUC(0, ,) (70 ± 51.5 ng ml,1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (,)-cisapride (4.7 ± 2.7 h) and (+)-cisapride (4.8 ± 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (,)-cisapride from 30 ± 13.6,55.5 ± 18 ng ml,1 (95% CI on mean difference, ,33, ,17; P = 0.00005) and of (+)-cisapride from 10.5 ± 3.4 to 18.4 ± 6.2 ng ml,1 (95% CI on mean difference, ,11.8, ,3.9, P = 0.00015). The mean AUC(0, ,) of (,)-cisapride was increased from 201 ± 161 to 521.6 ± 303 ng ml,1 h (95% CI on mean difference, ,439, ,202; P = 0.0002) and that of (+)-cisapride from 70 ± 51.5 to 170 ± 91 ng ml,1 h (95% CI on mean difference, ,143, ,53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (,)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t˝ of (,)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. Conclusions, The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (,)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride. [source] Hepatic proliferation in Gunn rats transplanted with hepatocytes: effect of retrorsine and tri-iodothyronineCELL PROLIFERATION, Issue 3 2005F. J. Cubero However, a major problem in most transplantation studies to date has been the limited growth of transplanted cells in the recipient organ. We performed a strategy for selective proliferation of transplanted cells by interfering with the proliferative capacity of resident hepatocytes, using the pyrrolizidine alkaloid retrorsine and then transplanting liver cells in conjunction with repeated administration of triiodothyronine, an inducer of hepatocyte proliferation in rats. In the present study, foetal and adult syngeneic hepatocyte transplantation into spleen was performed in retrorsine-treated hyperbilirubinemic Gunn rats. In parallel, repeated injections of triiodothyronine were given to recipients. Rats were sacrificed at 1, 7, 30 and 90 days after transplantation and blood and bile samples were taken to assess the functionality of transplanted cells. The proliferative activity of transplanted hepatocytes was evaluated using proliferating cell nuclear antigen labelling index. In summary, both adult and foetal hepatocyte transplantation were effective in correcting a metabolic abnormality in Gunn rats for as long as 3 months. The RS/T3 model, as a measure to increase graft function, could represent an important advance to future clinical application of hepatocyte transplantation. [source] Molecular basis of opioid dependence: role of signal regulation by G-proteinsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2003Prudence H Tso Summary 1.,Morphine and opiate narcotics are potent analgesics that have a high propensity to induce tolerance and physical dependence following their repeated administration. 2.,The molecular basis of opiate dependence has not been completely elucidated, although the participation of opioid receptors is a prerequisite. Cellular dependence on opioids is believed to result from the chronic stimulation of opioid-regulated signalling networks. 3.,As G-protein-coupled receptors, the opioid receptors must rely on heterotrimeric G-proteins for signal transduction. Recent advances in our understanding of G-protein signalling have unveiled novel signalling molecules and mechanisms, some of which may be intricately involved in the manifestation of opiate dependence. 4.,In the present review, we will attempt to trace chronic opioid signals along elaborate G-protein-regulated pathways. [source] | |||||||||||||||||||||||||||||||