Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues

Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen- and growth factor-mediated intracellular free Ca²⁺ ([Ca²⁺]_i) signalling in mammalian cells. Methods and Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca²⁺]_i signalling in Swiss 3T3 fibroblasts with IC₅₀ values of 14, 16 and 18 μM, respectively. ⁴⁵Ca²⁺ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC₅₀ of 34 μM. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC₅₀ of 8 μM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC₅₀ values in the range 3 to 22 μM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca²⁺]_i signalling and inhibition of the growth of HT-29 human colon cancer cells (P=0.001) and of CCRF-CEM human leukemia cells (P=0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 μM and of its major metabolite N-depropyl oryzalin was 53 μM. Conclusion: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations. Received: 24 December 1996 / Accepted: 20 March 1997     

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.     

Demonstration of ATP-Dependent,Transcellular Transport of Lipid Across the Lymphatic Endothelium Using an In Vitro Model of the Lacteal

Pharmaceutical Research - The lymphatic system plays crucial roles in tissue fluid balance, trafficking of immune cells, and the uptake of dietary lipid from the intestine. Given these roles there...     

Pediatric Perioperative DNR Orders: A Case Series in a Children's Hospital

Context

Do-not-resuscitate (DNR) orders are common among children receiving palliative care, who may nevertheless benefit from surgery and other procedures. Although anesthesia, surgery, and pediatric guidelines recommend systematic reconsideration of DNR orders in the perioperative period, data regarding how clinicians evaluate and manage DNR orders in the perioperative period are limited.

Philippine Academy of Rehabilitation Medicine emergency basic relief and medical aid mission project (November 2013–February 2014): the role of physiatrists in Super Typhoon Haiyan

Background: Physiatrists have provided humanitarian assistance in recent large-scale global natural disasters. Super Typhoon Haiyan, the deadliest and most costly typhoon in modern Philippine history, made landfall on 8 November 2013 resulting in significant humanitarian needs.

Methods: Philippine Academy of Rehabilitation Medicine physiatrists conducted a project of 23 emergency basic relief and medical aid missions in response to Super Typhoon Haiyan from November 2013 to February 2014. The final mission was a medical aid mission to the inland rural community of Burauen, Leyte. Summary data were collected, collated, and tabulated; project and mission evaluation was performed.

Results: During the humanitarian assistance project, 31,254 basic relief kits containing a variety of food and non-food items were distributed and medical services including consultation, treatment, and medicines were provided to 7255 patients. Of the 344 conditions evaluated in the medical aid mission to Burauen, Leyte 85 (59%) were physical and rehabilitation medicine conditions comprised of musculoskeletal (62 [73%]), neurological (17 [20%]), and dermatological (6 [7%]) diagnoses. Post-mission and project analysis resulted in recommendations and programmatic changes to strengthen response in future disasters. Physiatrists functioned as medical providers, mission team leaders, community advocates, and in other roles.

Conclusions: This physiatrist-led humanitarian assistance project met critical basic relief and medical aid needs of persons impacted by Super Typhoon Haiyan, demonstrating significant roles performed by physiatrists in response to a large-scale natural disaster. Resulting disaster programing changes and recommendations may inform a more effective response by PARM mission teams in the Philippines as well as by other South-Eastern Asia teams comprising rehabilitation professionals to large-scale, regional natural disasters.

• Implications for rehabilitation

• Large-scale natural disasters including tropical cyclones can have a catastrophic impact on the affected population.

• In response to Super Typhoon Haiyan, physiatrists representing the Philippine Academy of Rehabilitation Medicine conducted a project of 23 emergency basic relief and medical aid missions from November 2013 to February 2014.

• Project analysis indicates that medical mission teams responding in similar settings may expect to evaluate a significant number of physical medicine and rehabilitation conditions.

• Medical rehabilitation with participation by rehabilitation professionals including rehabilitation doctors is essential to the emergency medical response in large-scale natural disasters.

     

Septic arthritis

This chapter describes a rational approach to septic arthritis based on sound principles of pathology and therapeutics. Early diagnosis and prompt treatment are essential if normal function of the infected joint is to be restored. In any acute joint disease, infection must be suspected, and if present, detected. It is important to identify causative bacteria in order to administer the correct antibiotic. The clinical features are different in neonates, children and adults. Diagnosis is not usually difficult and may be aided by diagnostic ultrasound and arthrocentesis. Both antibiotics and joint lavage are essential parts of management. Successful outcome is based on effective treatment and results in normal joint function. Ineffective or delayed treatment may be crippling.