A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism

OBJECTIVE: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. METHOD: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. RESULTS: The dose of olanzapine given after a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. CONCLUSION: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population.     

Ten years of experience with the modified Ross procedure

BACKGROUND: Abnormal performance on the antisaccade task suggests that patients with schizophrenia have difficulty with the inhibition of reflexive attentional shifts. The aim of the study was to investigate whether deficits in the inhibition of reflexive attentional shifts were specific to the oculomotor modality or whether they could also occur when attentional shifts were made without eye movements (e.g. covert attentional shifts). METHODS: Fifteen medicated patients with chronic schizophrenia and 15 matched controls performed the antisaccade task and the covert orientating task (COVAT) where the probability of targets appearing at the same location of a peripheral cue was varied so that voluntary and reflexive orientating systems had the same goal (80% probability of target and cued condition) or opposite goals (20% probability of target at cued location). A condition where only reflexive orientating was initiated was also included (50% probability of target at cued location). For each of these conditions the stimulus onset asynchrony (SOA) varied between 150 and 350 ms. RESULTS: Patients with schizophrenia showed normal latency and accuracy for visually guided saccades but increased error rates and latency on the antisaccade task. For the COVAT, patients with schizophrenia were unable to use voluntary orientating strategies to inhibit reflexive shifts of covert attention. On conditions where only reflexive orientating was required or when the goals of the reflexive and voluntary orientating systems were the same, patients with schizophrenia showed normal performance. CONCLUSIONS: These results suggest the reflexive orientating mode is normal in patients with chronic schizophrenia. However, these patients have a reduced ability to utilize the voluntary orientating mode to control or inhibit reflexive orientating. This impairment of voluntary control is evident for both overt and covert attentional shifts.     

Annelid cytochrome P-450

Both classes of Annelida--Polychaeta and Clitellata--have been shown to contain cytochrome P-450. The metabolism of a number of aromatic hydrocarbons, drugs and pesticides by annelids required oxygen and NADPH, and was inhibited by a variety of cytochrome P-450 inhibitors. A number of types I and II substrates bound to the cytochrome P-450 in polychaete microsomes to give typical types I and II binding spectra. These results suggest that xenobiotics in annelids are metabolized by a typical cytochrome P-450 mixed function oxygenase. In addition to xenobiotics, annelid cytochrome P-450 systems are likely to function in the biosynthesis and metabolism of sterols and hormones found in annelids, such as cholesterol, ecdysteroids and eicosanoids. The primary source of cytochrome P-450 isolated to date from annelids has been intestinal microsomes. Cytochrome P-450 concentrations in these microsomes varied from 8 to 580 pmol mg-1 of protein. The only cytochrome P-450s purified from annelids were the three isomers isolated from microsomes of the oligochaete, Lumbricus terrestris, whose molecular masses were 48,000, 51,000 and 53,000 Da. Work on the induction of cytochrome P-450 in polychaetes by exposure to polycyclic aromatic hydrocarbons or polychlorinated biphenyls has given conflicting results, since some groups found induction after such exposure, but others found no induction. One possible explanation may be exposure to natural soil and sediments inducers, e.g. plant alkaloids, during feeding. Since gene and protein sequences have yet to be carried out on the cytochrome P-450 of any annelid, the relationship of annelid cytochrome P-450s to the 74 families of P-450 so far found, remains to be carried out.     

Variability in the interpretation of dimercaptosuccinic acid scintigraphy after urinary tract infection in children

Technetium-99m-dimercaptosuccinic acid (DMSA) scintigraphy is a frequently used diagnostic test in pediatric practice to assess the presence and severity of renal damage. Most commonly it is performed after urinary tract infection. The aim of this study was to investigate the variability in the interpretation of DMSA scans by pediatric nuclear medicine physicians in this clinical setting. METHODS: We selected all 441 scans from children with first-time urinary tract infection who presented between 1993 and 1995 to a pediatric casualty department and who are participants in a prospective cohort study. Two hundred and ninety-four scans were performed at a median time of 7 days after diagnosis, and 147 scans were from children who were free from further infection over a 1-yr follow-up period. Two experienced nuclear medicine physicians independently interpreted the 441 scans according to whether renal damage was present or absent and using the modified 4-level grading system for DMSA abnormality of Goldraich. Apart from being informed that urinary tract infection was the indication for DMSA scintigraphy, no other clinical information was given to the nuclear medicine physicians. The indices of variability used were the percentage of agreement and the kappa statistic. For the grading scale used, both measures were weighted with integers representing the number of categories from perfect agreement. Disagreement was analyzed for children, kidneys and kidney zones. RESULTS: There was agreement in 86% (kappa = 69%) for the normal-abnormal DMSA scan dichotomy, and the weighted agreement was 94% (weighted kappa = 82%) for the grading of abnormality. Disagreement of DMSA scan interpretation of > or =2 grades was present in three cases (0.7%). The same high level of agreement was present for patient, kidney and kidney zone comparisons. Agreement was not influenced by age or timing of scintigraphy after urinary tract infection. CONCLUSION: Two experienced nuclear medicine physicians showed good agreement in the interpretation of DMSA scintigraphy in children after urinary tract infection and using the grading system of Goldraich.     

Deficient major histocompatibility complex class II antigen presentation in a subset of Hodgkin's disease tumor cells

Hodgkin's disease is a common malignancy of the lymphoid system. Although the scarce Hodgkin and Reed-Sternberg (HRS) tumor cells in involved tissue synthesize major histocompatibility complex (MHC) class II and costimulatory molecules such as CD40 or CD86, it is unclear whether these tumor cells are operational antigen-presenting cells (APC). We developed an immunofluorescence-based assay to determine the number of MHC class II molecules present on the surface of single living HRS cells. We found that in fresh Hodgkin's disease lymph node biopsies, a subset of HRS cells express a substantial number of surface MHC class II molecules that are occupied by MHC class II-associated invariant chain peptides (CLIP), indicating deficient loading of MHC class II molecules with antigenic peptides. Cultured Hodgkin's disease-derived (HD) cell lines, however, were found to express few MHC class II molecules carrying CLIP peptides on the cell surface and were shown to generate sodium dodecyl sulphate (SDS)-stable MHC class II alphabeta dimers. In addition to showing deficient MHC class II antigen presentation in a subset of HRS cells, our results show that the widely used HD-cell lines are not ideal in vitro models for the disease. The disruption of MHC class II-restricted antigen presentation in HRS cells could represent a key mechanism by which these tumor cells escape immune surveillance.     

Novel inhibitors of fungal protein synthesis produced by a strain of Graphium putredinis. Isolation, characterisation and biological properties

The isolation and structure determination of 6 analogues of the fungal protein synthesis inhibitor GR135402, from Graphium putredinis, is described. The relative potencies of the compounds as protein synthesis inhibitors and as in vitro antifungal agents provide interesting insights into the structure-activity relationships in this series.     

Surgical and nonsurgical management of primary and metastatic liver tumors

The medical records of 267 patients who had liver tumors, primary and metastatic, from 1988 to 1995 were retrospectively reviewed. Two hundred thirteen patients (80%) had metastatic disease, and 54 patients (20%) had primary liver disease. Their clinical manifestations and laboratory values were evaluated as factors predictive of diagnosis and survival. There was a significant increase in the occurrence of upper abdominal pain, weight loss, extrahepatic symptoms due to the metastatic origin, and hepatomegaly. Metastases from colorectal primary lesions were synchronous in 34 patients and metachronous in 31 patients. Stomach, lung, and pancreatic primaries were more commonly synchronous. Breast metastases were more commonly metachronous. Elevated serum glutamic-oxaloecetic transaminase and alkaline phosphatase and decreased albumin were the most common liver test abnormalities at diagnosis. Carcinoembryonic antigen values were elevated in the majority of colon cancer patients. Eighty-one percent of patients with primary liver cancer had elevated levels of alpha-fetoprotein, 40 per cent were seropositive for hepatitis B, and 23 per cent were seropositive for hepatitis C. Seventy-nine patients (30%) underwent surgery for their cancer, 37 (47%) had resections, 38 (48%) were unresectable, and 4 (5%) underwent liver transplantation. The patients who underwent surgery had a 32 per cent 5-year survival rate compared to a 0 per cent 5-year survival in the patients who did not have surgery (p = 0.0001). The patients who had resections had a better survival rate than those deemed unresectable at surgery (62% versus 0% at 5-years with p = 0.0008). The perioperative morbidity rate was 16 per cent, with lobectomies having the best rate and trisegmentectomies having the worst. Perioperative mortality rate was zero for all liver resections. Hepatic resection and, in selected patients, liver transplantation are the only two available therapeutic modalities that produce long-term survival with a possible cure in patients with primary and metastatic liver tumor.