Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu _b )on steady state total (C _b )and unbound (Cu _b )blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL _int ).For a substance of very low CL _int ,if fu _b changes, C _t will change and Cu _b will remain constant, whereas if CL _int isvery high, Cu _b will change and C _b will remain constant.The present study defines the effects of a change in fu _b on C _b and Cu _b over the whole CL _int range. Computer simulations were undertaken which predicted that, for a given change in fu _b ,absolute and relative changes in C _b would decreasenonlinearly with increasing CL _{int, twhile the relative change in} Cu _{b would} increasewith CL _int .The absolute change in Cu_b would be independent of CL _int .Significant changes in C_b and Cu _{b would be observed at intermediate values of} CL _{int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in} fu _{b of sodium taurocholate a substance with intermediate} CL _int (such that at fu _b =0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24- ¹⁴ C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu _{b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate} C _{b of 22.7% and a relative decrease in} Cu _{b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance}.This study was supported by the National Health and Medical Research Council of Australia.     

Practice guidelines and outcomes. Where are we headed?

Major forces are at work within the health care system that drive the development of clinical standards or guidelines. This process must be tied in a "feedback-loop" system to a more accurate assessment of patient outcomes. There is a major controversy at the foundation of the process that is pitting the opinions from consensus panels of experts against the inability of individual physicians to accurately estimate the outcomes of different options through implicit systems. In many instances, the quality of medical evidence is poor. Many groups within organized medicine are attempting to write guidelines, and at least four major challenges must be confronted before guidelines are widely adopted by clinicians. A new federal agency may provide the necessary resources to focus the debate on guidelines. Guidelines may eventually enhance the quality of medical care.     

Ganyphilia : etiologic and psychotherapeutic concepts

The author describes a role for psychotherapy in ganyphilia, the homoerotic interest by adult males in adolescents. This paraphilia, which is commonly pandered to by street hustlers, often comes to light when the subject is arrested. When ganyphilia is embedded within a framework of disordered narcissism, the personality disorder itself can be effectively treated by a psychoanalytic psychotherapy informed by contemporary self psychology. After locating ganyphilia in a historical/mythological context, the author presents aspects of the psychotherapy of a court-mandated case to demonstrate both etiologic forces and the treatment process.     

Glycosaminoglycan mimetics (RGTA) modulate adult skeletal muscle satellite cell proliferation in vitro

Confocal Raman microspectroscopy (CRM) provides an important and novel means of analyzing the chemical composition of the adhesive/dentin (a/d) interface. The purpose of this study was to develop a method for quantitative determination of the degree of adhesive penetration at the a/d interface using CRM. Three commercial dentin adhesive systems [Scotchbond Multipurpose Plus (SBMP+), Single Bond (SB), and Primer Bond NT (PBNT)] based on the total etch and "wet" bonding technique were examined in this study. Human dentin specimens treated with these adhesives were analyzed with CRM mapping across the a/d interface. Also, Raman spectra were collected on model mixtures of adhesive and type I collagen, and the ratios of the relative intensities of the Raman bands corresponding to adhesive and collagen were used for the construction of calibration curves. By comparing the Raman band ratios of interface specimens to the calibration curves, the percent of adhesive as a function of spatial position across the a/d interface was determined. The results show that there is a gradual decrease in penetration as a function of position for all three adhesive systems while the adhesive concentration gradient decreases in the order of SBMP+ > SB > PBNT. These differences in penetration of the three adhesives at the a/d interface also are discussed relative to the composition and phase segregation in adhesives. Additionally, our results indicate that confocal Raman microspectroscopy is a reliable in situ analytical technique for simple and rapid quantitative determination of adhesive penetration at its interface with prepared dentin.     

Monoclonal antibodies against carcinoembryonic antigen (CEA) used in a solid-phase enzyme immunoassay. First clinical results

A solid-phase enzyme immunoassay using both mouse monoclonal and goat polyclonal antibodies against carcinoembryonic antigen (CEA) was developed. The assay detects 0.6 to 1.2 ng of CEA per ml of serum and has 3 incubation steps which can be performed in 1 day. Polystyrene balls coated with polyclonal goat anti-CEA antibodies are first incubated with heat-extracted serum samples. Bound CEA is then detected by addition of mouse monoclonal antibodies, followed by goat IgG anti-mouse IgG1 coupled to alkaline phosphatase. Results with this enzyme immunoassay using monoclonal antibodiies (M-EIA) have been compared with those obtained by the conventional inhibition radioimmunoassay (RIA) using goat antiserum. Three hundred and eighty serum samples from 167 patients with malignant or non-malignant diseases and from 134 normal individuals with or without heavy smoking habits were analyzed by the 2 assays. Excellent correlation between the results of the 2 assays was obtained, but the M-EIA, using monoclonal antibodies from a single hybridoma, did not discriminate better than the conventional RIA between CEA produced by different types of carcinoma and between CEA associated with malignant or non-malignant diseases. Follow-up studies of several patients by sequential CEA determinations with the 2 assays showed that the M-EIA was as accurate as the RIA for the detection of tumor recurrences.     

Expression of CDX2 and MUC2 in Barrett's mucosa

Barrett's mucosa is a risk factor for esophageal adenocarcinoma and should be detected at an early stage. It is defined by the presence of columnar epithelium with goblet cells in the lower esophagus, but histologic diagnosis can be uncertain in the absence of distinct goblet cells. We investigated 55 biopsies from 48 patients with endoscopically plain Barrett's esophagus and performed immunohistochemistry for CDX2 and MUC2. In addition, alcian blue (pH 2,5)/PAS staining was done. In histologically unequivocal Barrett's mucosa, nuclear expression of CDX2 in goblet cells and many columnar cells, as well as cytoplasmic positivity for MUC2 in goblet cells, could be observed. Alcian blue (pH 2,5)/PAS stained acidic mucins in goblet cells and in some non-goblet columnar cells. In six cases, no definite Barrett's mucosa was present, and no expression of MUC2 could be observed. In these biopsies, there was granular cytoplasmic and/or focal nuclear staining for CDX2 in non-goblet columnar epithelial cells, indicating their intestinal differentiation. We suggest that this peculiar mucosa is the precursor of unequivocal Barrett's mucosa and would designate it early Barrett's mucosa. Alcian blue for acidic mucins is inconsistent in this epithelium and does not reliably indicate early intestinal differentiation.     

Retinal projections to the lateral posterior-pulvinar complex in intact and early visual cortex lesioned cats

In intact cats, it is generally considered that the lateral posterior-pulvinar complex (LP-pulvinar) does not receive direct retinal terminals, with the exception of the retino-recipient zone known as the geniculate wing. There is, however, some evidence that early lesions of the visual cortex can occasionally induce the formation of novel retinal projections to the LP nucleus. Given the importance of knowing the connectivity pattern of the LP-pulvinar complex in intact and lesioned animals, we used the B fragment of cholera toxin, a sensitive anterograde tracer, to reinvestigate the retinal projections to the LP-pulvinar in normal cats and in cats with early unilateral lesions of the visual cortex (areas 17 and 18). Immunohistochemical localization of the toxin was performed to show the distribution and morphology of retinofugal terminals. A direct bilateral but predominantly contralateral retinal projection reached the caudal portion of LPl and LPm in the form of patches located mainly along its dorsomedial surface and many scattered terminals. The distribution of retinal projections to LP-pulvinar in intact and operated cats did not differ. Contrary to what had been previously reported, we found no evidence for lesion-induced sprouting of retinal axons in these higher-order thalamic nuclei. Retinal input to the LP-pulvinar might modulate visual responses driven by primary visual cortex or superior colliculus.     

Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations

We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. The hypoglycemia is deemed to be due to cortisol deficiency. This report represents the second published case of cortisol deficiency in the CS. A brief review of the endocrine disturbances in the syndrome is provided. We highlight the need for careful endocrinological evaluation of individuals with CS.     

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P相似文献