A phase I and pharmacokinetic study of sunitinib administered daily for 2 weeks, followed by a 1-week off period

Purpose Sunitinib, an oral multitargeted tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, FLT3, KIT, and RET, is currently approved for the treatment of imatinib-refractory GIST and advanced renal cell carcinoma at a dose of 50 mg daily for 4 weeks followed by a 2-week off period (4/2 schedule). This trial was performed to investigate the safety, tolerability, and pharmacokinetics of sunitinib 50 mg daily for 2 weeks followed by a 1-week off period (2/1 schedule). Experimental design Twelve patients with advanced refractory malignancies were treated with sunitinib on the 2/1 schedule. Intensive safety monitoring included serial measurements of left ventricular ejection fraction (LVEF). Extensive pharmacokinetic sampling was performed on days 1 and 14 of course 1, and on day 14 of courses 2 and 3 to evaluate sunitinib and the SU12662 metabolite. Results Twelve patients received a total of 50 courses with an average (±SD) off-drug period of 11.5 ± 5.7 days. Two patients experienced DLT: one patient had asymptomatic grade 4 elevations in lipase and amylase, and another patient had an asymptomatic grade 2 decline in LVEF in course 1. In total, five patients demonstrated asymptomatic grade 2 declines in LVEF. Other principal effects were similar to previous experience with sunitinib, including fatigue, myelosuppression, skin discoloration, and gastrointestinal effects. Pharmacokinetic studies revealed no significant accumulation of sunitinib or SU12662. One patient with papillary thyroid cancer developed a partial response, and was on study for 16 courses, followed by an additional 18 courses on a continuation protocol. Conclusions The 2/1 schedule of sunitinib 50 mg was tolerable, and no significant drug accumulation was demonstrated. The safety profile on this schedule was consistent with the safety profile of sunitinib when administered on a 4-week on, 2-week off schedule. Grant Support: National Cancer Institute/Avon Foundation Progress for Patients Award (Carolyn Britten), Stop Cancer Career Development Award (Carolyn Britten).     

Polymorphism of the h allele and the population frequency of sporadic nonfunctional alleles

BACKGROUND: Current polymerase chain reaction-based strategies for phenotype prediction often fail when sporadic nonfunctional alleles are encountered. The population frequency of such mutations was not known for any gene under low selection pressure and may be best examined in blood groups systems lacking prevalent nonfunctional alleles. The frequency of the very rare Bombay blood group (Oh, genotype hh sese) was recently determined in a systematic survey of more than 600,000 white individuals. STUDY DESIGN AND METHODS: With this survey used in conjunction with additional blood samples, the population frequency of nonfunctional alleles of the gene encoding the alpha (1,2)fucosyltransferase (H or FUT1) was determined. RESULTS: Seven different h alleles were found in five unrelated individuals, three of whom were homozygous for unique alleles. There was no prevalent h allele. Five missense and one frameshift mutations were observed, that were the presumptive causes of the null phenotype; the coding sequence of one h allele was identical to the H sequence. The average inbreeding factor alpha was 0.00116. The frequency of nonfunctional alleles at the H gene locus was calculated as 1 in 347 in a large white population (95% CI: 1:185-1:824). CONCLUSION: The Bombay blood group phenotype in white is due to diverse, sporadic, nonfunctional alleles without any prevalent allele. Assuming similar rates of nonfunctional alleles in glycosyltransferase genes like ABO, current genotyping strategies may fail as often as once in about 300 individuals of blood group O. Sporadic neutral alleles may also pose a serious obstacle for population-wide screening of many disease-associated genes.     

Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study

BackgroundBevacizumab prolongs overall and progression-free survival when added to fluorouracil-based chemotherapy in patients with metastatic colorectal cancer in randomised controlled trials (RCTs). However, gastrointestinal perforation (GIP) occurs in 1–2% of treated patients. We sought to describe the incidence, temporal pattern, outcomes and potential risk factors for GIP in a large, community-based observational cohort study of patients treated with bevacizumab.Patients and methodsBaseline patient and tumour characteristics, including potential GIP risk factors, were collected at study entry. Treatment, targeted adverse events, progression events and survival data were recorded every 3 months. Detailed clinical information was collected for all patients experiencing a GIP event. Effects of baseline risk factors on GIP risk were investigated using Cox proportional hazards regression.ResultsOf 1953 evaluable patients followed for a median of 20.1 months, 37 (1.9%) experienced GIP. Most GIP events were surgically managed with successful outcomes; four events were fatal. The majority of GIP events (26/37) occurred ⩽6 months after starting bevacizumab (median, 3.35 months). Univariate and multivariate analyses showed that age ⩾65 years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6 months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure.ConclusionThe observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention.     

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.     

Structural Requirements in the Fc Region of Rabbit IgG Antibodies Necessary to Induce Cytotoxicity by Human Lymphocytes

Rabbit IgG anti-chicken erythrocyte antibodies were compared with the Fab/c or Facb fragments of IgG and with partially reduced and alkylated IgG for the capacity to induce cytotoxicity by normal human lymphocytes. The Fab/c antibody fragment, which lacks one Fab region, was still able to induce cytotoxicity. In contrast, the Facb antibody fragment, which lacks the Cγ3 domains, was nearly ineffective in activating the effector cells, whereas intact antibody activity was demonstrated by its ability to inhibit the cytotoxicity induced by unsplit IgG. Similarly, partial reduction and alkylation of the IgG antibodies, under conditions affecting the interchain disulphide bonds only, greatly diminished their ability to induce cytotoxicity, although they effectively inhibited the cytotoxicity induced by untreated IgG. On the basis of these results and previous data, we suggest that the reaction of the Fc region of IgG with the effector cell depends on the integrity of the Cγ² domain in the native, divalent state or on the interaction between the Cγ² and Cγ³ domains.     

Spinal,epidural or propofol anaesthesia for out–patient knee arthroscopy?

Background : We have compared three different methods of anaesthesia for out–patient knee arthroscopy in terms of perioperative conditions, postoperative pain, time taken and economy.
Methods : 91 ASA I–II patients scheduled for elective knee arthroscopy were included. After premedication with diazepam 10 mg and naproxene 500 mg orally, they were randomly assigned into one of three groups: Group S (n=32) received spinal anaesthesia with lidocaine 50 mg/ml 1.5–2 ml in 7.5% glucose through a 27–G Quincke needle, Group E (n=29) received epidural anaesthesia with mepivacaine 20 mg/ml and epinephrine 5 μg/ml, 15–20 ml, and Group P (n=30) received propofol anaesthesia with a bolus induction of 2 mg/kg followed by infusion.
Results : The time from start of anaesthesia until start of operation was significantly less in Group P than in the two other Groups: 7.45.4 min as compared to 23.04.8 min in Group S and 31.09.1 min in Group E (meanSD, P<0.05). After end of surgery, the duration of the postoperative regional block was 7528 min in Group S and 125 79 min in Group E (P<0.05). In Group S and Group E the postoperative pain was significantly less than in Group P at admission to the recovery unit and 60, 120 and 180 min later (P<0.05). The overall incidence of postoperative nausea or vomiting was less than 5% with no differences between the groups. One patient in Group E had block failure and one patient in Group S had a post–spinal headache. The perioperative costs of drugs and disposables were highest in Group P (30 USD) and lowest in Group S (6.5 USD).
Conclusion : Propofol anaesthesia results in the shortest stay in the operation theatre but a higher degree of postoperative pain and a higher cost of drugs and disposables.     

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.