Novel agents in development for the treatment of melanoma

In 2005, melanoma is estimated to affect 55,000 Americans. Of these, 7700 are estimated to die from the disease. Immunological approaches have yielded the only newly FDA-approved agents for melanoma in 30 years, which includes high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma. A survival advantage was shown in two of three randomised clinical trials with high-dose IFN-alpha2b in the high-risk adjuvant setting. However, both agents are associated with high cost and toxicity rates. A number of novel therapeutic agents are undergoing active clinical investigation. The more promising of these will be discussed in this review, including bcl-2 antisense therapy, v-raf murine sarcoma viral oncogene homologue B1 inhibition, heat-shock proteins, anti-alphavbeta3 integrin monoclonal antibody, thalidomide and newer immunomodulatory drugs, and anti-cytotoxic T lymphocyte-associated protein-4 monoclonal antibody.     

Effects of malathion subchronic exposure on rat skeletal muscle glucose metabolism

Regarding the widespread use of organophosphorous pesticides (OP) especially malathion in environment and reported cases of muscle disturbances in human and animal, the present work was undertaken to explore effects of malathion subchronic exposure on rat leg skeletal muscle glucose metabolism by measuring key enzymes of glycogenolysis and glycolysis. Malathion was administered through food for 4 weeks at concentrations of 100, 200, and 400ppm to rats. Activities of enzymes including glycogen phosphorylase (GP), hexokinase (HK), and phosphofructokinase-1 (PFK) were measured in skeletal muscle homogenate of exposed rats. Levels of glucose and insulin were measured in blood. Four weeks administration of malathion at doses of 200 and 400ppm increased blood glucose concentrations to 44.4 and 60.6% of control, respectively. Malathion at doses of 200 and 400ppm increased blood insulin concentration to 36.6 and 143.2% of control, respectively. Malathion at doses of 100, 200, and 400ppm increased muscle PFK activity to 40.4, 53.5, and 83.1% of control, respectively. Malathion at doses of 400ppm increased skeletal muscle GP to 91.6% of control. Skeletal muscle HK was not influenced by malathion treatment. It is concluded that malathion influences muscle glycogenolysis and glycolysis as well as secretion of insulin from pancreas which all may explain diabetic potential of malathion.     

Interleukin-2 for the treatment of melanoma

Current therapeutic options for the treatment of advanced melanoma are inadequate. Chemotherapy with dacarbazine remains a 'gold standard' despite no evidence of improved survival or durable remissions. Interleukin (IL)-2 is an immunotherapeutic agent that, when administered in a high-dose bolus schedule, produces a small number of durable remissions in patients with metastatic melanoma, and on this basis it was approved for use in the US in 1998. In randomized clinical trials, IL-2, administered as a continuous infusion either alone or in combination with chemotherapy (biochemotherapy), has not improved response rates over chemotherapy alone. Low-dose IL-2, while less toxic and more convenient, produces low response rates and appears to be ineffective in metastatic melanoma. Newer, innovative approaches such as IL-2 gene therapy and strategies to ameliorate the toxicity of this agent are now being explored in clinical trials.     

PREOS NPS (Allelix/Nycomed)

NPS Allelix and Nycomed are developing PREOS, an injectable recombinant human parathyroid hormone, for the potential treatment of osteoporosis. In May 2005, NPS filed a market authorization application for PREOS in the US which was accepted for review in July 2005.     

The effect of cyclosporine on the development and expression of cannabinoid tolerance in mice

Cyclosporine, beside its immunosuppressive action, has several effects on different neuronal functions, such as modulation of neurotransmitter release, the inhibition of nitric oxide synthesis and release, the reduction of cAMP production and inhibition of morphine-induced tolerance. In the present study, the effect of cyclosporine on the expression and development of tolerance to WIN 55,212-2, a cannabinoid receptor agonist, was studied. Intra peritoneal (i.p.) injection of WIN 55,212-2 (2-6 mg/kg) induced time-dependent and dose-dependent analgesia and catalepsy in mice. Administration of cyclosporine (20 mg/kg i.p.), 30 min before WIN 55,212-2 (6 mg/kg i.p.), did not change the analgesic and cataleptic effects of WIN 55,212-2. When WIN 55,212-2 (6 mg/kg i.p.) was injected once a day, animals became completely tolerant to the analgesic and cataleptic effects within five and nine days respectively. Cyclosporine (20 mg/kg i.p.) injected once daily, 30 min before WIN 55,212-2, attenuated the development of tolerance to the analgesic and cataleptic effects of WIN 55,212-2 but did not affect the expression of tolerance. Since cyclosporine given chronically by itself did not alter the analgesia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest cyclosporine may act with some selectivity on the mechanisms involved in development of cannabinoid tolerance.     

Inhibition of erythrocyte “apoptosis” by catecholamines

Osmotic shock, oxidative stress and Cl⁻ removal activate a non-selective Ca²⁺-permeable cation conductance in human erythrocytes. The entry of Ca²⁺ leads to activation of a scramblase with subsequent exposure of phosphatidylserine at the cell surface. Phosphatidylserine mediates binding to phosphatidylserine receptors on macrophages which engulf and degrade phosphatidylserine exposing cells. Moreover, phosphatidylserine exposure may lead to adherence of erythrocytes to the vascular wall. In the present study, we explored whether activation of the non-selective cation conductance and subsequent phosphatidylserine exposure might be influenced by catecholamines. Phosphatidylserine exposure has been determined by FITC-annexin V binding while cell volume was estimated from forward scatter in FACS analysis. Removal of Cl⁻ enhanced annexin binding and decreased forward scatter, an effect significantly blunted by the β agonist isoproterenol (IC₅₀ approx. 1 μM). Fluo-3 fluorescence measurements revealed an increase of cytosolic Ca²⁺ activity following Cl⁻ removal, an effect again significantly blunted by isoproterenol exposure (10 μM). Whole-cell patch-clamp experiments performed in Cl⁻ free bath solution indeed disclosed a time-dependent inactivation of a non-selective cation conductance following isoproterenol exposure (10 μM). Phenylephrine (IC₅₀<10 μM), dobutamine (IC₅₀ approx. 1 μM) and dopamine (IC₅₀ approx. 3 μM) similarly inhibited the effect of Cl⁻ removal on annexin binding and forward scatter. In conclusion, several catecholamines inhibit the Cl⁻ removal-activated Ca²⁺ entry into erythrocytes, thus preventing increase of cytosolic Ca²⁺ activity, subsequent cell shrinkage and activation of erythrocyte scramblase. The catecholamines thus counteract erythrocyte phosphatidylserine exposure and subsequent clearance of erythrocytes from circulating blood.     

Field evaluation of a recombinant glutathione S-transferase-based pyrethroid quantification assay

A recombinant glutathione S-transferase (GST)-based pyrethroid quantification assay was field-tested in Ifakara, Tanzania. Initial laboratory tests suggested that all reagents used in the assay should be sufficiently stable for field use, provided that domestic refrigeration facilities were available. Insecticide-impregnated bednets were collected from a region where a social marketing programme was in progress. A total of 100 bednets were collected and the assay plus standard HPLC analysis was performed on the residues extracted from four replicate areas of each net. Insecticide residue estimations for assays performed on white and pale green bednet samples were accurate when compared with residue analysis by HPLC. However, for dark green or blue bednets, there was no correlation between the GST-based assay and HPLC pyrethroid quantification results. The assay failure with the dark coloured nets was caused by the extraction of the dyes along with the insecticide, which subsequently interfered with the GST assay. When the same samples were analysed by HPLC, the dyes were separated from the insecticide by reverse phase column chromatography and hence did not affect the results.     

Angiographic embolization of a traumatic pulmonary pseudoaneurysm

We present a case report of a 50-year-old male who sustained a gunshot wound to the right chest. The initial thoracotomy demonstrated a nonbleeding gunshot wound in the middle lobe and was otherwise unremarkable. Later that day, after continued resuscitation, his chest tube output dramatically increased and he was taken back for redo thoracotomy. An injury to the lateral branch of the middle lobe pulmonary artery was encountered and suture ligated. The patient presented several weeks later with hemoptysis. Computed tomography of the chest demonstrated pooling of contrast in the middle lobe. Angiography confirmed the diagnosis of a pulmonary artery pseudoaneurysm and was coil embolized without difficulty. This report represents a case of coil embolization of traumatic pulmonary artery pseudoaneurysm.     

Preventing the withdrawal response associated with rocuronium injection: a comparison of fentanyl with lidocaine

We compared the efficacy of IV fentanyl with IV lidocaine as pretreatment for the prevention of withdrawal response after rocuronium injection. For this prospective, randomized, placebo-controlled, double-blind study we recruited 90 patients aged between 18 and 65 yr, ASA physical status I or II, who had undergone elective surgery requiring general anesthesia and positive pressure ventilation. Patients were randomly allocated to 1 of 3 groups: group F received 2 mL IV fentanyl 50 microg/mL (100 microg), group L received 2 mL of preservative-free lidocaine 2% (40 mg), and group P (placebo) received 2 mL of normal saline. The incidence of withdrawal response after rocuronium was 57%, 30%, and 7% in the placebo, lidocaine, and fentanyl groups, respectively. We found a significant reduction in incidence of withdrawal response in both the fentanyl and lidocaine groups when compared with the placebo group (P < 0.05), with the fentanyl group being most effective (P < 0.05). In conclusion, both fentanyl and lidocaine are effective clinical treatments to alleviate the withdrawal response associated with rocuronium injection, with fentanyl being more effective.     

A 2-year follow-up of orphans' competence, socioemotional problems and post-traumatic stress symptoms in traditional foster care and orphanages in Iraqi Kurdistan

BACKGROUND: This paper aims to compare orphans' development in two different care systems. METHODS: Based on age, sex, psychological trauma scores, competence and psychological problem scores, two comparable samples were found representing orphans in the traditional foster care (n = 94) and the orphanages (n = 48) in a middle-large city in Iraqi Kurdistan. At an index interview, Child Behaviour Checklist (CBCL), Harvard-Uppsala Trauma Questionnaire for Children and Post-traumatic Stress Symptoms for Children (PTSS-C) were administered to the caregivers. After 1 year the CBCL, and after 2 years both the CBCL and the PTSS-C, were-re-administered, consecutively. RESULTS: Although both samples revealed significant decrease in the means of total competence and problem scores over time, the improvement in activity scale, externalizing problem scores and post-traumatic stress disorder-related symptoms proved to be more significant in the foster care than in the orphanages. While the activity scale improved in the foster care, the school competence deteriorated in both samples, particularly among the girls in the orphanages. The improvement of boys' activity scores in the foster care, and deterioration of girls' school competence in the orphanages were the most significant gender differences between samples over time. CONCLUSIONS: Even if the two orphan care systems showed more similarities than differences, the foster care revealed better outcomes over time. The results are discussed in relation to gender, age, socio-economic situation, cultural values and the characteristics of each care system.