Folic Acid‐Conjugated 4‐Amino‐Phenylboronate,a Boron‐Containing Compound Designed for Boron Neutron Capture Therapy,is an Unexpected Agonist for Human Neutrophils and Platelets

Boron neutron capture therapy (BNCT) is an anticancer treatment based on the accumulation in the tumor cells of ¹⁰B‐containing molecules and subsequent irradiation with low‐energy neutrons, which bring about the decay of ¹⁰B to very toxic ⁷Li³⁺ and ⁴He²⁺ ions. The effectiveness of BNCT is limited by the low delivery and accumulation of the used ¹⁰B‐containing compounds. Here, we report the development of folic acid‐conjugated 4‐amino‐phenylboronate as a novel possible compound for the selective delivery of ¹⁰B in BNCT. An extensive analysis about its biocompatibility to mature blood cells and platelet progenitors revealed that the compound markedly supports platelet aggregation, neutrophil oxidative burst, and inhibition of megakaryocyte development, while it does not have any manifest effect on red blood cells.     

Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters

Background

Pediatric medications may possess a high erosive potential to dental tissues due to the existence of acid components in their formulations. The purpose was to determine the erosive and cariogenic potential of pediatric oral liquid medications through the analysis of their physicochemical properties in vitro.

Methods

A total of 59 substances were selected from the drug reference list of the National Health Surveillance Agency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory, corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsants and antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the Total Titratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pH was neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brix scale and the analysis of Total Sugar Content was performed according to Fehling’s method. In addition, it was analyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid and sweetener added to the formulations.

Results

All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61?±?0.08). There was a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents were identified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose was added in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%).

Conclusion

The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic and erosive potential on dental tissues. Competent bodies’ strategies should be implemented in order to broaden the knowledge of health professionals, drug manufacturers and general consuming public about the risks from the consumption of medicines potentially harmful to dental tissues.

     

Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging

Clinical observations indicate that elderly people are prone to severe, often lethal infectious diseases induced by novel pathogens. Since the ability to mount primary immune responses relies on the availability of naive T cells, the circulating naive T-cell reservoir was evaluated throughout the human life span. Naive T cells were identified as CD95(-) T lymphocytes for their phenotypic and functional features. Indeed, the lack of CD95 marker is sufficient to identify a population of naive T cells, as defined by coincidence with previously characterized CD45RA(+) CD62L(+) T cells. Naive CD95(-) T cells, as expected, require a costimulatory signal, such as CD28, to optimally proliferate after anti-CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120 healthy subjects ranging in age from 18 to 105 years revealed that naive T cells decreased sharply with age. The younger subjects had a naive T-lymphocyte count of 825 +/- 48 cells/microL, and the centenarians had a naive T-lymphocyte count of 177 +/- 28 cells/microL. Surprisingly, the naive T-cell count was lower in CD8(+) than in CD4(+) subsets at any age, and the oldest individuals were almost completely depleted of circulating naive CD8(+) T cells (13 +/- 4 cells/microL). Concomitantly, a progressive expansion of CD28(-) T cells occurs with age, which can be interpreted as a compensatory mechanism. These data provide new insights into age-related T-cell-mediated immunodeficiency and reveal some analogies of T-cell dynamics between advanced aging and human immunodeficiency virus (HIV) infection. In conclusion, the exhaustion of the naive CD8(+) T-cell reservoir, which has never been reported before, suggests that this T-cell pool is a major target of the aging process and may define a parameter possibly related to the life span of humans. (Blood. 2000;95:2860-2868)     

Oxytocin response to insulin-induced hypoglycemia in obese subjects before and after weight loss

The response of plasma oxytocin to an iv bolus injection of crystalline insulin (0.15 U/kg) was evaluated in 14 normal weight [mean body mass index (BMI) = 23] and in 9 obese (mean BMI = 42) men. Similar blood glucose decrements after insulin injection were observed in the two groups. Obese and normal weight subjects presented similar basal oxytocin levels. In both groups, oxytocin rose significantly during the insulin tolerance test (ITT); however, the peak oxytocin response in the obese men was significantly lower than in the normal weight subjects. Obese men were restudied after substantial weight loss. Basal oxytocin levels and glucose response to insulin did not change after weight reduction. The oxytocin response to the ITT was significantly higher than before slimming and did not differ from that observed in the normal weight subjects. A significant negative correlation between BMI values and oxytocin peak levels during ITT was observed in the lean controls and obese subjects (r = 0.516, p less than 0.02). These results demonstrate that in obese subjects the oxytocin secretory response during an insulin tolerance test is reduced, suggesting the existence of a hypothalamic-pituitary disorder in obesity.     

High glucocorticoid receptor content of leukemic blasts is a favorable prognostic factor in childhood acute lymphoblastic leukemia

We have previously shown that the number of glucocorticoid receptors (GR) per cell in malignant lymphoblasts from children with newly diagnosed pre-B- and early pre-B-cell acute lymphoblastic leukemia (ALL) has a positive correlation with the probability of successful remission induction (Quddus et al, Cancer Res, 45:6482, 1985). We report now on the long-term outcome for these patients treated on a single protocol with 3 different treatment arms, all of which included glucocorticoid pulses during maintenance therapy. GR were quantitated in leukemic cells from 546 children with ALL at the time of diagnosis. Immunophenotyping studies were performed on all specimens. Prior studies showed that in pre-B- and early pre-B-cell ALL, successful remission induction was associated with a median GR number of 9,900 sites/cell, whereas induction failure was associated with a median receptor number of 4,800 sites/cell. Long-term follow-up of these patients shows an association between higher GR number and improved prognosis. The 5-year event-free survival of 61.0% (SE 2.8%) for patients whose leukemic cells had greater than 8,000 receptors/cell and 47.3% (SE 3.3%) for those with less than 8,000 receptors/cell is significantly different (P < .001). This difference remains significant when adjusted multivariately for blast immunophenotype and clinical risk factors (P < .001) or for treatment type (P < .001). We conclude that GR number greater than 8,000 sites/leukemic cell is a favorable prognostic marker for children with acute lymphocytic leukemia. This finding offers deeper insights into molecular mechanisms of anti- leukemia therapy and suggests that manipulation of steroid receptor number might augment the antitumor response, thus opening new avenues for basic and clinical research.     

Decreases in pain at rest and movement-related pain during zoledronic acid treatment in patients with bone metastases due to breast or prostate cancer: a pilot study

Background In patients with bone metastases, pain may be absent or moderate at rest, but may be exacerbated by different movements or positions. No study has evaluated separately pain at rest and on movement in patients with bone metastases undergoing treatment with zoledronic acid (ZA). Aim The aim of this prospective observational study was to evaluate the reduction in intensity of pain at rest and in movement-related pain after treatment with up to six infusions of ZA 4 mg every 28 days in patients with painful bone metastases due to breast or prostate cancer cared for at the Oncological Units and Pain Therapy and Palliative Care Unit of the NCI of Milano. Materials and methods Pain was assessed by a six-level verbal rating scale (0–5 score) at baseline and on each infusion as well as at follow-up visits (2 weeks after every infusion). The two main endpoints (estimated reduction in pain and movement-related pain) were defined as the difference between the baseline score and the average of all the post-treatment scores for each patient. To allow for the potential confounding effect of analgesic consumption, patients without any increase in analgesic consumption during zoledronic acid treatment were also analyzed as a separate subgroup. Results Forty-eight patients with breast (34) or prostate cancer (14) were enrolled. At baseline, 100% of the patients had pain on movement, in 65% of them, the intensity ranged from moderate to very severe, in 61% of the patients, the intensity of pain on movement was higher than the intensity of pain at rest (average difference 0.89; 95% CI, 0.5–1.30). The estimated mean intensity reduction of pain at rest and on movement was: (a) 0.62 (95% CI, 0.28–0.98) and 0.79 (95% CI, 0.43–1.14), respectively, during the first 90 days of ZA treatment; (b) 0.59 (95% CI, 0.23–0.96) and 0.86 (95% CI, 0.49–1.23), respectively, during the entire treatment and follow-up period. Analgesic consumption decreased or was stable on average in 31 and 27%, respectively, of available follow-up data. In the 14 patients with decreased or stable analgesic consumption, pain reduction was 0.61 and 1.01, respectively. Conclusions In this study, at baseline, all the patients with painful bone metastases experience movement-related pain, and during zoledronic acid treatment, a decrease for both pain at rest and on movement was obtained.     

The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins

A case regarding a newborn infant with severe Rh haemolytic disease, who presented with the bronze baby syndrome and eventually died, is reported. The postmortem examination showed marked extramedullary haematopoiesis in the liver and spleen, heavy hepatic haemosiderosis and mild intralobular cholestasis. The porphyrin content, which was assayed in different tissues. was very high in the liver, suggesting that the increased erythropoiesis seen in Rh haemolytic disease leads to an increased synthesis of porphyrins as by-products of haem synthesis. Phototherapy causes photodestruction, sensitized by bilirubin, of porphyrins (mainly copper porphyrins), yielding brown photoproducts.