Sensitivity of normal and neoplastic human renal tubular epithelium to hyperthermia

Comparison of the intrinsic thermosensitivity of malignant and normal homologous cells are important in evaluating the therapeutic role of hyperthermia in cancer. However, such comparisons had problems with establishing the origin of cells grown in culture. Using monoclonal antibodies we have shown that human kidney cancer lines, Caki-1 and Caki-2, and a normal human renal epithelium line, NHK-4, originated from proximal convoluted tubular epithelium. The observed order of thermosensitivity was Caki-2 greater than Caki-1 greater than NHK-4.     

Thyrotrophin augmentation after commencing thyroxine replacement in primary hypothyroidism

Prospective measurements of serum thyrotrophin and thyroxine concentrations were made in six patients with primary hypothyroidism treated consecutively with an incremental regimen of oral thyroxine. A fall in thyrotrophin occurred over several months, accompanied by a concurrent slow rise in serum thyroxine. Those patients with the highest initial values for thyrotrophin showed the typical curvilinear decline in thyrotrophin, whereas the remaining patients disclosed a transient rise in thyrotrophin for the first 3 months. This paradoxical rise was not associated with depression of cardiac output or glomerular filtration rate. The significance of thyrotrophin augmentation is uncertain, but it may be more common than generally appreciated. It did not occur in those patients with the most severe degrees of thyroid deficiency. Thyroxine exerts a dual action, and augmentation of thyrotrophin may reflect a dominant effect of increased protein synthesis, in contrast to negative feedback inhibition which suppresses thyrotrophin. These opposing actions are in competition at different dose levels of thyroxine, and may contribute not only to augmentation or suppression of thyrotrophin, but also to the curvi-linear pattern of fall. Such variations impair the utility of thyrotrophin as an index of euthyroidism.     

Tolerance and side-effects of paroxetine in elderly depressed patients

Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, is considered to have fewer side-effects than a typical tricyclic antidepressant. As the elderly frequently suffer from adverse effects of psychotropic drugs, safeties and tolerance of paroxetine and their relationship with dose were studied in a double-blind study. Sixteen nondashhospitalised depressed patients, aged 72-86 years, were recruited but 12 patients completed the study. Patients were randomly selected to receive either 15 mg or 30 mg paroxetine daily for 42 days in a double-blind study. A trained nurse made weekly home visits to monitor their medication and general conditions. Patients were assessed at the hospital on days 1, 7, 14, 28 and 42. There were four drop-outs during the first week of study due to lack of motivation, skin rash and upper gastrointestinal symptoms (n=2). Plasma levels of paroxetine showed a dose-related increase in concentrations and indicated a good compliance. At the dosages used, no changes in blood pressure, heart rate, salivary volume, visual choice reaction time, critical flicker fusion threshold and short-term memory were observed in these patients. However, there was a significant improvement in their subjective symptoms (as assessed by a symptom check list and Hamilton Rating Scale) in the 30 mg group, indicating a feeling of well-being.     

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

Introduction: Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment.

Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted.

Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.     

Association between berry characters and Solasodine content of solanum khasianum

Correlation between number, grren weight, dry weight and solasodine percent of berry of the treated and control plant progenies in second generation raised from X-rayed (5 KR, 7.5 KR, 10 KR, 12.5 KR and 15 KR), EMS-treated (0.5%, 0.75% and 1% solution in PO (4)-buffer) and untreated dry seeds of Solanum khasianum Clarke revealed that only the numbers of large and small berries had significant correlation with solasodine percent. Correlation between induced variations (CV%) in these characters indicated that selection on berry characters through M (1) and M (2) generations was effective. Dispersion (due to mutagenesis) in the three berry characters have created the base for progressive selection for high solasodine yielders.     

Hydrolysis of methotrexate-immunoglobulin conjugates by liver homogenates and characterization of catabolites

Summary Methotrexate (MTX) linked to antitumor antibodies inhibits tumor growth better than free MTX, free antibody, or MTX linked to normal rabbit IgG (NRG), in spite of the less effective inhibition of the target enzyme dihydrofolate reductase (DHFR) by conjugated MTX. In addition to the demonstrated higher uptake of MTX linked to antitumor antibodies (compared with the uptake of free MTX or nonspecific IgG conjugates), a contributory factor to the superior tumor inhibitory action of MTX-IgG conjugates may be the prolonged release of active drug from the internalized conjugate. Therefore, we have investigated whether an MTX-IgG conjugate could be hydrolyzed to release free MTX or fully active MTX-containing fragments after incubation with liver homogenates and have characterized the catabolites according to the presence of free MTX and their capacity to inhibit DHFR. Catabolism was optimal at pH 4.6, activated by dithiothreitol, and inhibited by antipain and N--p-tosyl-l-lysine chloromethyl ketone, thus implicating lysosomal enzymes. Liver homogenates produced an MTX-containing, lowmolecular-weight fraction that was isolated by gel filtration. Further purification of this fraction by DEAE-cellulose chromatography gave two MTX-containing peaks, neither of which migrated as free MTX on thin-layer chromatography or inhibited DHFR more effectively than the parent conjugate. However, the presence of amino acid residues in these catabolites could contribute to their observed prolonged intracellular retention and superior antitumor action.Supported by grants [MA 9725 and MA 10008] from the Medical Research Council of Canada     

A new computer-based Farnsworth Munsell 100-hue test for evaluation of color vision

To evaluate a computer-based Farnsworth-Munsell (FM) 100-hue test and compare it with a manual FM 100-hue test in normal and congenital color-deficient individuals. Fifty color defective subjects and 200 normal subjects with a best-corrected visual acuity ≥6/12 were compared using a standard manual FM 100-hue test and a computer-based FM 100-hue test under standard operating conditions as recommended by the manufacturer after initial trial testing. Parameters evaluated were total error scores (TES), type of defect and testing time. Pearson’s correlation coefficient was used to determine the relationship between the test scores. Cohen’s kappa was used to assess agreement of color defect classification between the two tests. A receiver operating characteristic curve was used to determine the optimal cut-off score for the computer-based FM 100-hue test. The mean time was 16 ± 1.5 (range 6–20) min for the manual FM 100-hue test and 7.4 ± 1.4 (range 5–13) min for the computer-based FM 100-hue test, thus reducing testing time to <50 % (p < 0.05). For grading color discrimination, Pearson’s correlation coefficient for TES between the two tests was 0.91 (p < 0.001). For color defect classification, Cohen’s agreement coefficient was 0.98 (p < 0.01). The computer-based FM 100-hue is an effective and rapid method for detecting, classifying and grading color vision anomalies.