Phenelzine in urine: assay and relation to acetylator status

1 Phenelzine cannot be extracted as such from biological fluids.

2 Formation of the acetonide derivative prior to extraction allows phenelzine to be extracted and assayed by gas chromatography at levels down to 0.5 μg/ml.

3 At this sensitivity the drug can be detected in urine but not in plasma, after therapeutic doses.

4 Persons typed as slow acetylators of sulphadimidine excreted approximately twice as much unmetabolized phenelzine in urine compared to fast acetylators.

     

Phase I/II clinical study of pulsed paclitaxel radiosensitization for thoracic malignancy: a therapeutic approach on the basis of preclinical research of human cancer cell lines.

PURPOSE: A Phase I/II clinical study using pulsed low-dose paclitaxel and radiation for thoracic malignancy was conducted. The study was based on preclinical research of the effects of paclitaxel on apoptosis and the cell cycle in human cancer cell lines. EXPERIMENTAL DESIGN: Three human epithelial cancer cell lines were investigated for preclinical study. Cells were analyzed for apoptosis and cell cycle characteristics after paclitaxel treatment. The Phase I/II clinical trial for non-small cell lung cancer used pulsed low-dose paclitaxel three times/week with the starting dose of 15 mg/m(2). Daily thoracic radiotherapy was delivered in 1.8 Gy/fraction to 60-65 Gy for gross disease and to 45-58 Gy for microscopic disease. Timing of radiotherapy was delayed to allow for a minimum of 4 h for cell cycle progression. RESULTS: Forty-one patients have enrolled and 33 completed treatments. Seventeen patients completed the Phase I study, with an average primary tumor shrinkage of 83 +/- 8% (95% confidence interval). Tumor response rate was 100% for the Phase I study. Overall local control was 98%, and the survival rate was 46% at 1 year, 33% at 2 years, and 18% at 3 years. Toxicity was low with 3 of 18 patients having grade 3 pneumonitis and 3 of 18 patients having grade 3 esophagitis. There was no grade 4 pneumonitis, esophagitis, or hematological toxicity. CONCLUSIONS: Pulsed low-dose paclitaxel radiosensitization for non-small cell lung cancer resulted in a superior local control rate and comparable survival rate when compared with chemoradiation regimens using systemic dose chemotherapy. The regimen is associated with low toxicity and deserves additional investigation, particularly in patients with poor performance or older age, who cannot tolerate standard chemoradiation regimens.     

Formal retrospective case review and sudden infant death

A review of 24 consecutive sudden infant deaths was undertaken to evaluate the importance of the various stages in the postmortem assessment of such cases. Death in three cases was caused by obvious trauma. Of the remainder, 16 were attributed to sudden infant death syndrome (SIDS), 4 to accidental asphyxia (identified by death scene examination and/or formal case review) and 1 to a lingual thyroglossal duct cyst. Three (14%) of 21 deaths thought to be SIDS after postmortem examination were attributed to asphyxia following subsequent formal case review.     

Effect of the viable-yellow (A(vy)) agouti allele on skin tumorigenesis and humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice

We previously reported that papillomas can arise from the follicular epithelium of v-Ha-ras transgenic TGxAC mice. Since the viable-yellow mutation (A(vy)) of the mouse agouti gene which regulates coat color pigmentation by acting within the micro-environment of the hair follicle has been shown to function as a tumor promoter in the liver, we hypothesized that it may also play a role in TGxAC skin tumorigenesis. Endogenous agouti protein product was detected in the outer root sheath of anagen hair follicles following plucking of the hair shaft, but not in the interfollicular epithelium, in TGxAC mice on an FVB/N genetic background. It was also detected in papillomas from these mice produced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment or plucking. Expression of the A(vy) allele in the v-Ha-ras transgenic TGxAC mouse line results in an approximately 2-fold increase in papilloma development compared with controls which did not carry the A(vy) allele following twice-weekly treatment with 1.25, 2.5 or 5.0 microg TPA. In addition, TPA-treated, papilloma-bearing F1 mice which carried the A(vy) allele, but not F1 mice which did not carry the A(vy) allele, exhibited a syndrome of humoral hypercalcemia mediated by parathyroid hormone-related protein (PTHrP) that led to weight loss, hypercalcemia and hypophosphatemia. Thus, we conclude that the A(vy) allele can influence the development of skin tumors and PTHrP-mediated humoral hypercalcemia in v-Ha-ras transgenic TGxAC mice.      

Antipsychotic drug use patterns and the cost of treating schizophrenia

This study investigated the relationships between antipsychotic drug use patterns and direct costs for 3,321 Medi-Cal patients with schizophrenia. Ordinary least-squares regression models were used to estimate the impact on costs of receiving antipsychotic drug treatment, delays in treatment, changes in therapy, and continuous therapy. Average costs were $25,940 per year per patient. Having used an antipsychotic drug was correlated with lower psychiatric hospital costs ($2,846 less) but higher nursing home costs. Completing one year of uninterrupted drug therapy was correlated with higher nursing home costs. Delayed drug treatment and changes in therapy increased the cost by $9,418 and $9,719, respectively.     

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults,Canada, 2015–2019

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.     

Combination anti-CD137 and anti-CD40 antibody therapy in murine myc-driven hematological cancers

In order to stimulate antigen presentation and T cell activity against cancer, we treated three different tumor models in mice with the monoclonal antibodies anti-CD40 plus anti-CD137 (BiMab). In a subcutaneous transplantable MC38 colon cancer model, there was significant enhancement in the survival of mice following BiMab treatment. Anti-CD40 has shown considerable success against lymphoma in previous studies by other investigators, and we also showed in this study that, in a model of Eμ-Myc lymphoma, there was a statistically significant enhancement of survival of mice following BiMab treatment. Following the success of the BiMab treatment in the previous two models, we wished to determine if it would be successful in a mouse model of multiple myeloma. Firstly, we tested a transplantable model of disease in which multiple myeloma cells derived from Vk*MYC mice were injected intravenously. A minor proportion of anti-CD137 and BiMab treated mice experienced prolongation of life beyond 250 days. Then we tested the therapy in a spontaneously occurring multiple myeloma model, in Vk*MYC transgenic mice. The majority of mice treated survived longer than control mice, although statistical significance was not demonstrated.