Deep venous thrombosis prophylaxis: Are guidelines being followed?

Introduction: The purposes of the present study were to determine whether patients in The Canberra Hospital are receiving appropriate Deep Venous Thrombosis (DVT) prophylaxis, and to ascertain the awareness of appropriate treatment by clinicians. Methods: Part 1 of the present study comprised of a point prevalence study of The Canberra Hospital inpatients. Patients were assessed for the risk of their developing DVT. The prophylaxis they were receiving was documented. In Part 2 of the present study, clinicians at The Canberra Hospital filled out a questionnaire that outlined three case scenarios. They were required to identify the risk group and appropriate prophylaxis for each group. Consultants, registrars and junior medical officers were assessed separately. Results: The results of Part 1 of the present study showed that the majority of inpatients in The Canberra Hospital are not receiving appropriate prophylaxes according to international guidelines. Graduated compression stockings are rarely used, and often ineffectively applied. All groups performed poorly in Part 2 of the present study. Participants were frequently unable to identify the risk group for a particular scenario. There was also confusion regarding the appropriate prophylaxis for a particular risk group. Discussion: Deep Venous Thrombosis is a major problem among hospitalized patients. However, despite its importance, there is a lack of appropriate prophylaxes being instituted. This, together with the poor performance of the participating clinicians in Part 2 of the present study, indicate that there are significant problems in The Canberra Hospital regarding DVT prophylaxes and that steps need to be taken to overcome these problems.     

Serum immunoglobulin levels in neoplastic disorder of breast

Serum IgG, IgA and IgM were estimated in 42 cases of carcinoma and 12 cases of fibroadenoma of breast. The results were compared with 20 healthy female controls. Results showed increased levels of serum IgA in carcinoma breast cases. This increase was statistically significant (p = 0.001) when compared with healthy controls while IgG and IgM values were found to be insignificant. Values of IgG, IgA and IgM in cases of fibroadenoma breast when compared with the controls were found to be insignificant. Statistically significant increased value of IgA was also observed in medullary carcinoma and non-metastasizing tumours when viewed separately, suggestive of good prognostic index of serum IgA level estimation in the case of carcinoma breast.     

Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat.

Deltamethrin (DLT) is a type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based pharmacokinetic (PBPK) model for DLT was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapidly perfused tissues) and diffusion-limited (fat, blood/plasma, and slowly perfused tissues) rate equations. The blood was divided into plasma and erythrocytes. Cytochrome P450-mediated metabolism was accounted for in the liver and carboxylesterase (CaE)-mediated metabolism in plasma and liver. Serial blood, brain, and fat samples were taken for DLT analysis for up to 48 h after adult rats received 2 or 10 mg DLT/kg po. Hepatic biotransformation accounted for approximately 78% of these administered doses. Plasma CaEs accounted for biotransformation of approximately 8% of each dosage. Refined PBPK model forecasts compared favorably to the 2- and 10-mg/kg po blood, plasma, brain, and fat DLT profiles, as well as profiles subsequently obtained from adult rats given 1 mg/kg iv. DLT kinetic profiles extracted from published reports of oral and iv experiments were also used for verification of the model's simulations. There was generally good agreement in most instances between predicted and the limited amount of empirical data. It became clear from our modeling efforts that there is considerably more to be learned about processes that govern GI absorption and exsorption, transport, binding, brain uptake and egress, fat deposition, and systemic elimination of DLT and other pyrethroids. The current model can serve as a foundation for construction of models for other pyrethroids and can be improved as more definitive information on DLT kinetic processes becomes available.     

pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat ECD.

The objective of this study was to develop a rupturable, capsule-based pulsatile drug delivery system with pH-independent properties prepared using aqueous coating. The drug release is induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating. Croscarmellose sodium (AcDiSol) is a preferable superdisintegrant compared to low substituted hydroxypropylcellulose (L-HPC) and sodium starch glycolate (Explotab), because of controlled lag time, followed by a quick and complete drug release. However, due to its anionic character, AcDiSol showed pH-dependent swelling characteristics (pH 7.4 > 0.1N HCl) resulting in a pH-dependent lag time. The pH dependency could be eliminated by the addition of fumaric acid to the swelling layer, which allowed to keep an acidic micro-environment. Formation of the rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose (Aquacoat) ECD), whereby sufficient drying during the coating was needed to avoid swelling of the AcDiSol layer. A higher coating level was required, when aqueous dispersion was used, compared to organic coatings. However, an advantageous aspect of the aqueous coating was the lower sensitivity of the lag time to a deviation in the coating level.     

Gefitinib inhibits the growth and invasion of urothelial carcinoma cell lines in which Akt and MAPK activation is dependent on constitutive epidermal growth factor receptor activation.

PURPOSE: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. EXPERIMENTAL DESIGN: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. RESULTS: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. CONCLUSIONS: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.     

Primary osteosarcoma of the skull

Primary osteogenic sarcoma of the skull is an exceedingly rare condition. An adult male patient is described, who had a painless swelling in the right forehead that had rapidly enlarged in the previous 6 months. Radiological investigations showed a large destructive mass lesion involving the right side of the frontal bone with extension into the frontal sinus, causing marked extradural compression of brain parenchyma. Histopathological examination confirmed the lesion to be primary osteogenic sarcoma.     

Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer.

BACKGROUND: With its potent inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways. This study is designed to combine sorafenib and gemcitabine due to their compatibility in preclinical models and nonoverlapping clinical toxicities. EXPERIMENTAL DESIGN: An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks. RESULTS: Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine. CONCLUSIONS: Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.     

Seasonality of first admissions for schizophrenia in the Southern Hemisphere

Northern Hemisphere studies of first admissions for schizophrenia have shown an excess of summer admissions (June, July and August) compared to other times of the year. The within-year fluctuations in first admissions could be related to meteorological factors that fluctuate between seasons (e.g. temperature, photoperiod) and/or social factors (e.g. holidays, religious events). If meteorological factors were primarily responsible for the fluctuation, then Southern Hemisphere studies should find excess first admissions in December, January and February. This paper presents the first season of first admission study of schizophrenia in the Southern Hemisphere. The month and year of first admission for schizophrenia (ICD 8/9) for 4487 male and 3252 female, Australian-born individuals were extracted from a Queensland mental health register. Spectral analysis showed a strong annual periodicity of first admissions for males with the peak in August (Southern Hemisphere winter) and a trough in the summer months (December to February). The pattern for females also displayed annual periodicity. These results correspond to the Northern Hemisphere reports of excess of schizophrenia first admissions in terms of the month of the year but not the season of excess. Further work is needed in order to clarify the impact of latitude and meteorological factors on the month of first admission for schizophrenia.     

辣椒辣素对大鼠膀胱逼尿肌作用的实验研究

目的　探讨辣椒辣素 (capsaicin ,CAP)对大鼠膀胱功能的影响及其作用机制。 方法　将 2 5只Wistar大鼠分为 5组 ,分别用 0 .9mmol/L、1.8mmol/L、3.6mmol/L、7.2mmol/LCAP作用于大鼠膀胱 ,用生理盐水作对照。观察用药前后膀胱内压力变化、膀胱容量及残余尿量。另取大鼠膀胱三角区组织用PAP法进行免疫组化染色 ,观察P物质 (SP) ,根据免疫组化SP阳性神经纤维的密度和染色强度分为 4级 ,即可疑 (± )、轻度阳性 (+) 2～ 4个阳性纤维 ,染色差 ;中度阳性 (++) 5～ 6阳性纤维 ,染色较强 ;强阳性 (+++) 7～ 9阳性纤维 ,染色很强。结果　①低浓度组 0 .9mmol/LCAP组和 1.8mmol/LCAP组与对照组比较 ,其膀胱内压、膀胱容量和残余尿量均无显著性差异 ;SP分布也无明显差异 (P >0 .0 5 )。②高浓度组 (3.6mmol/LCAP组和 7.2mmol/LCAP组 )膀胱内压明显降低 ,残余尿量增加 (P <0 .0 1) ;③高浓度组膀胱组织内SP阳性神经纤维明显减少 ,染色明显减弱 (P<0 .0 1)。结论　高浓度辣椒辣素可抑制膀胱逼尿肌收缩 ,抑制排尿 ;另外高浓度CAP能耗竭膀胱内感觉神经末梢肽类介质SP。说明CAP通过消耗膀胱内的SP抑制感觉信号的传递 ,使逼尿肌不能正常收缩而抑制排尿