The relative bioavailability of metoprolol following oral and rectal administration to volunteers and patients

The pharmacokinetics, efficacy and safety of metoprolol tartrate 25 mg fatty suppositories were studied in 5 healthy volunteers and in 8 patients suffering from instable angina pectoris. Metoprolol 25 mg capsules were used as a control oral dosage form. Metoprolol showed a considerable rectal bioavailability (AUC, C max) and was absorbed quickly from the rectum (T max). In both groups rectal bioavailability was comparable. However, oral bioavailability was much lower in the volunteer group than in the patient group. Furthermore, ratios of metoprolol/aOHmetoprolol concentrations in plasma and urine gave an indication for a partial avoidance of the first pass effect after rectal administration. Further research is necessary to define an exact rectal dosage of metoprolol. In all patients, a substantial drop in heart rate, systolic and diastolic blood pressure was seen after administration of the first suppository. Metoprolol suppositories appear to be an effective, safe and suitable alternative for patients who are in need for beta blocking medication and who are unable to take oral medication for a certain amount of time.     

Hepatic scintigraphy in management of infants and children with liver disease

Scintiscans of liver and spleen using technetium 99m sulphur colloid in 15 infants with extrahepatic biliary atresia and 11 infants with severe obstructive jaundice (7 with genetic deficiency of alpha 1-antitrypsin) showed similar hepatic size, pattern of isotope uptake, and splenic abnormality with no distinguishing features. In 37 older children with a variety of liver disorders, the scan was invaluable in showing filling defects in five instances. Selenomethionine was taken up not only by the two filling defects due to hepatoblastoma but also in a haemangioendothelioma. In the remaining patiens liver scanning confirmed hepatic abnormality and the necessity for more specific invasive diagnostic investigations.     

Trifluoperazine: a rynodine receptor agonist

Trifluoperazine (TFP), a phenothiazine, is a commonly used antipsychotic drug whose therapeutic effects are attributed to its central anti-adrenergic and anti-dopaminergic actions. However, TFP is also a calmodulin (CaM) antagonist and alters the Ca²⁺ binding properties of calsequestrin (CSQ). The CaM and CSQ proteins are known modulators of sarcoplasmic reticulum (SR) Ca²⁺ release in ventricular myocytes. We explored TFP actions on cardiac SR Ca²⁺ release in cells and single type-2 ryanodine receptor (RyR2) channel activity in bilayers. In intact and permeabilized ventricular myocytes, TFP produced an initial activation of RyR2-mediated SR Ca²⁺ release and over time depleted SR Ca²⁺ content. At the single channel level, TFP or nortryptiline (NRT; a tricyclic antidepressant also known to modify CSQ Ca²⁺ binding) increased the open probability (Po) of CSQ-free channels with an EC₅₀ of 5.2 μM or 8.9 μM (respectively). This Po increase was due to elevated open event frequency at low drug concentrations while longer mean open events sustained Po at higher drug concentrations. Activation of RyR2 by TFP occurred in the presence or absence of CaM. TFP may also inhibit SR Ca uptake as well as increase RyR2 opening. Our results suggest TFP and NRT can alter RyR2 function by interacting with the channel protein directly, independent of its actions on CSQ or CaM. This direct action may contribute to the clinical adverse cardiac side effects associated with these drugs.     

Advanced glycation end products in hemodialyzed patients with diabetes mellitus correlate with leptin and leptin/body fat ratio

Advanced glycation end products (AGEs) and other carbonyl and oxidative stress compounds are supposed to play a critical role in the pathogenesis of several diseases and their complications, i.e., diabetes mellitus, diabetic retinopathy, atherosclerosis, and chronic renal failure. In the present investigation, we were interested in the relationship of AGEs in plasma to other prominent factors in the patients on chronic hemodialysis treatment-27 patients with diabetes mellitus, 35 patients without diabetes mellitus. AGE-group reactivity was estimated using a spectrofluorometric method (excitation 350 nm, emission 430 nm) and is expressed in arbitrary units (AU). We found significantly higher AGEs levels in diabetics than in non-diabetics on regular hemodialysis treatment both before (2.7 +/- 0.7 x 10(4) AU vs. 2.2 +/- 0.6 x 10(4) AU, p < 0.001) and after the dialysis session (2.3 +/- 0.5 x 10(4) AU vs. 1.8 +/- 0.7 x 10(4) AU, p < 0.005). AGEs were significantly reduced during hemodialysis in both groups of patients--by 15.4% in the diabetic go (p < 0.001) and by 17.3% in non-diabetics (p < 0.005). In the patients with diabetes mellitus, AGEs did not correlate with parameters of the glucose metabolism correction (blood glucose, HbA1c). We observed a significant correlation between AGEs and leptin (r = 0.48, p < 0.05) as well as the leptin/body fat ratio (r = 0.56, p < 0.05) only in hemodialyzed patients with diabetes mellitus. These findings suggest more detailed studies to identify the molecular links between carbonyl stress, i.e., advanced glycation end products, and leptin metabolism, sign of microinflammation and hypertension.     

Bile duct obstruction: radiologic evaluation of level, cause, and tumor resectability

In a prospective study of 65 patients with bile duct obstruction, various radiologic modalities were compared for their capability to demonstrate the level and cause of obstruction and to indicate accurately tumor resectability. Ultrasound (US) was performed in 65 patients, computed tomography (CT) in 51, direct cholangiography (DC) in 57, and angiography in 35. The level of obstruction was correctly indicated by US in 95% of patients and by CT in 90%, and the cause was correctly indicated by US in 88%, by CT in 63%, and by DC in 89%. In predicting tumor resectability, US was correct in 71% of patients, compared with 42% for CT, 58% for DC, and 25% for angiography. US therefore appears to be the single most useful modality in the evaluation bile duct obstruction.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Comparison of different immunoassays for CA 19-9.

We compared six routinely employed immunoassay kits: Architect i2000 and AxSYM, Abbott Laboratories; Elecsys 2010, Roche Diagnostics; ELSA, CIS-BioInternational; Immulite 1, Diagnostic Products Corporation; and IRMA-mat, Byk-Sangtec Diagnostica. Using all analytical systems, we measured identical groups of clinical samples completed with selected control samples. The repeatability of measurements (coefficient of variation) ranged from 2.1% (Elecsys 2010) to 6.7% (ELSA). The parameters of Passing-Bablok regression show significant systematic differences among analytical systems. Data from a Bland-Altman diagram suggest that these differences project onto other, still more significant individual differences among individual samples. Though the cut-off values differ between various systems, no similar clinical efficacy appears to be attained. The behavior of individual systems is quite different for identical control materials and does not necessarily duplicate the calibration for biological samples. The results of determining CA 19-9 cannot be extrapolated from one analytical technique to another, even in cases where the same monoclonal antibody is used. Standardization of CA 19-9 measurement systems is necessary to allow use of the results for the purposes of evidence-based medicine.