Levels and distribution of central nervous system amines in normal and morphine-dependent monkeys

The distribution of norepinephrine, dopamine and 5-hydroxytryptamine in various areas of the CNS of the normal monkey has been presented.The central levels and distribution of norepinephrine, dopamine and 5-hydroxytryptamine were determined after single doses of morphine, during maintenance of physical dependence and following withdrawal from chronic administration of morphine. Small and non-stressful doses of morphine were employed to induce experimental physical dependence.Alpha-methyl-DOPA did not qualitatively or quantitatively alter the abstinence syndrome.Pretreatment with iproniazid did not prevent depression produced by single doses of morphine in the non-tolerant monkey.The data observed in this study offer no support for the view that gross behavioral changes in the monkey produced by morphine or by its withdrawal after the development of physical dependence are induced by or may be correlated with changes in amine levels in the CNS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34146/1/0000431.pd

The natural history of primary sclerosing cholangitis in 781 children. A multicenter, international collaboration

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes

Self-administration of psychoactive substances by the monkey

A method has been developed which permits monkeys to self-administer drug solutions, at will, through indwelling intravenous catheters. Psychological dependence on the effects of a drug occurs when a naive monkey voluntarily initiates and maintains self-administration of the drug. If, in addition to psychological dependence, the drug also produces psychotoxicity, either directly or upon abrupt withdrawal, it has a potential abuse liability.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46354/1/213_2004_Article_BF00405254.pd

Psychomotor stimulant self administration as a function of dosage per injection in the Rhesus monkey

The relationships between drug dosage per injection and response rate, and drug dosage per injection and total daily drug intake were ascertained in Rhesus monkeys which self-administered cocaine, pipradrol, methylphenidate and phenmetrazine intravenously. The study demonstrated the monkeys would self-administer all of these compounds over a wide range of dosages. Furthermore, the magnitude of reinforcement, i.e., dosage per injection, and the rate of responding in self-administering these compounds were inversely related. However, total daily drug intake was independent of the dosage per injection over a wide range of dosages. The results indicate that either the subjects can compensate for large changes in unit dosage so that daily drug intake remains stable or that a direct effect of these compounds functions in limiting their self-administration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46379/1/213_2004_Article_BF00401789.pd

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis : Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course

Objective To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. Study design We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level >= 50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level Results We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. Conclusions Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.Peer reviewe

Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children : An International Observational Study

Background and Aims Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children. Approach and Results We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05). Conclusions The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population.Peer reviewe

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children

Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.Peer reviewe

Effect of ethanol and of noise on reaction time in the monkey: Variation with stimulus level

To determine whether the latency-increasing effects of ethanol were differential with respect to the intensity of the stimulus that initiated the response, three rhesus monkeys were trained on a behavioral task in which the latency of a simple motor response was measured following the onset of a pure tone stimulus. Following training, the animals were tested at a number of different tone intensities and functions relating latency to tone intensity were constructed. When these were stable, the animals were given ethanol in doses of 1.0–2.5 g/kg and the effects on response latencies to different tone intensities were determined. It was found that, for all except the lowest stimulus levels, the effect of ethanol was dose-related, while for a given dose the effect was equal across intensity. These results indicate that the effects of ethanol in this situation are on response execution rather than stimulus detection. The effects of ethanol were compared to those of exposure to high intensity noise. This treatment, which affects primarily the inner ear, resulted in substantial increases in latency to low intensity tones, but little, if any, shift at high intensities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46413/1/213_2004_Article_BF00426520.pd

Behavior maintained by intravenous injection of codeine, cocaine, and etorphine in the rhesus macaque and the pigtail macaque

Lever-pressing behavior of two species of macaque, the rhesus macaque ( M. mulatta ) and the pigtail macaque ( M. nemestrina ) was maintained by intravenous injection of codeine, etorphine, or cocaine. Monkeys responded under a fixed-ratio 30 timeout 600 s schedule of drug injection during two daily experimental sessions. Drug-maintained behavior was studied under two access conditions. Under the first condition, selected doses of codeine or cocaine were available for ten consecutive sessions. Under the second condition, responding was maintained by 0.32 mg/kg codeine or 0.32 mg/kg cocaine, and saline and selected doses of codeine, etorphine, and cocaine were substituted during single experimental sessions. Performance varied with drug and injection dose, access condition, and macaque species. For all three drugs, response rate increased and then decreased as injection dose increased. Maximal rates were maintained by 0.10–0.32 mg/kg codeine, 0.0003–0.001 mg/kg etorphine, and 0.10–0.32 mg/kg cocaine. A cocaine dose of 0.32 mg/kg maintained higher rates than any dose of codeine or etorphine, and maintained higher rates when available during consecutive sessions than when substituted for codeine for a single session. Codeine maintained similar rates under all access conditions. The pigtail macaques had short catheter lives, did not readily acquire codeine-maintained responding, and displayed lower rates of drug-maintained lever pressing than the rhesus macaques.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46415/1/213_2004_Article_BF00427883.pd

The effects of ethanol, phenobarbital, and baclofen on ethanol withdrawal in the rhesus monkey

Physical dependence on ethanol was produced in four rhesus monkeys by IV ethanol administration every 8 h. Ethanol was administered on each occasion until the eyeblink reflex was lost. Evidence of physical dependence development, in the form of tremoring 8 h after an infusion, appeared on day 8 of chronic administration. Abrupt cessation of ethanol administration following 16 days of chronic administration was accompanied by moderate to severe tremoring, retching, vomiting, and one or more convulsions. Peak withdrawal occurred between 12 and 32 h after abrupt discontinuation of ethanol administration, and decreased over a period of 64–204 h. Ethanol dependence was then reinstated. Once every 3–4 days, ethanol was withheld for 16 h. Withdrawal signs were scored for the first 12 h of this period, and then a test dose of ethanol, phenobarbital, or baclofen was administered. Withdrawal or intoxication signs were scored over the next 4 h, at which time ethanol administration was resumed. Both ethanol and phenobarbital suppressed ethanol withdrawal sign in a dose-related manner, and produced dose-related intoxication. Baclofen was largely ineffective in reducing withdrawal-induced tremors, although it was capable of producing sedation of a different type than that produced by phenobarbital and ethanol.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46414/1/213_2004_Article_BF00435315.pd