Compatibility and stability of bryostatin 1 in infusion devices

Bryostatin 1 is currently in phase II clinical trial sponsored by the National Cancer Institute as an anticancer chemotherapeutic agent. Bryostatin 1 for injection was supplied in a dual pack containing a drug vial and a diluent vial and was manufactured by Ben Venue Laboratories, Inc (Bedford, OH). The stability and compatibility of the bryostatin 1-PET formulation, diluted to 1 and 10 ug/mL in saline and benzyl alcohol preserved saline, with polypropylene (PP) and polyvinyl chloride (PVC) bags at room temperature (27°C) were studied. All experiments were conducted in triplicate and analyses were performed using a validated, stability-indicating, high performance liquid chromatography (HPLC) assay.Bryostatin 1 solutions were compatible with PP bags. At both concentrations and with both salines, the bryostatin content remained unchanged during the 28-day storage period, benzyl alcohol concentration in the preserved saline solutions also remained relatively constant. In PVC bags, however, a decrease in bryostatin 1 concentrations without generation of decomposition products was observed at both dilutions and with both salines during the 28-day storage. A decrease in benzyl alcohol concentration in the preserved saline was also observed. While no diethylhexylphthalate (DEHP) leakage into the solution was observed in PP bags, DEHP leakage in PVC infusion bags was observed on day 2 of storage which increased with storage time and leveled off on day 6. The amount of DEHP leached into drug solution is dependent on the drug concentration. This study suggests bryostatin-PET formulation diluted with preserved saline can be used for long-term (4 week) intravenous administration using PP infusion bags, but not with PVC bags.     

Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in the reversible metabolism of carbon dioxide to carbonic acid and, hence, in physiological pH regulation. It also participates in cellular differentiation and proliferation, its expression being absent in most normal tissues. It has been recently postulated that the hypoxia-inducible factor (HIF-1) pathway up-regulated by hypoxia accounts for CAIX overexpression in most human tumors. In the present study, we examined the expression of this enzyme in diffuse gliomas of astrocytic origin in relation to vascular endothelial growth factor (VEGF) and HIF-1alpha expression, proliferation rate (as assessed with Ki-67 antigen), microvessel morphology, and survival. Of 84 cases analyzed, 61 cases (72.6%) displayed strong membrane and/or cytoplasmic expression of CAIX and were grouped as positive. Immunoreactivity tended to have a perinecrotic distribution and increased in parallel with the extent of necrosis (P < .001) and histologic grade (P < .001). A positive correlation was also noted with HIF-1alpha and VEGF expression (P < .001), proliferation rate (P = .010), microvessel density (P = .004), and microvessel caliber parameters (P = .014-.038). In univariate survival analysis, increased CAIX expression was associated with shortened survival in the entire cohort (P < .0001), along with VEGF (P = .0205) and HIF-1alpha levels (P = .0190). Multivariate analysis selected the interaction model of CAIX, with grade and age as the only parameters independently affecting survival. CAIX expression was also the only significant parameter for the survival of patients with grades II/III. We conclude that CAIX may be used as a prognostic indicator in diffuse astrocytomas to refine the information provided by grade. Given the role of CAIX in the acidification of tumor environment and its up-regulation by hypoxia, it is thought that CAIX expression may be linked to resistance of tumor cells to radiotherapy by allowing them to acclimatize to a hypoxic and acidic microenvironment.     

Gestational Diabetes and Hypertensive Disorders of Pregnancy as Vascular Risk Signals: An Overview and Grading of the Evidence

The occurrence of common pregnancy-related medical disorders identifies women at high risk of developing future vascular disease. Systematic reviews of cohort studies demonstrate that gestational diabetes confers a 7-fold risk increase for type 2 diabetes, and preeclampsia confers a 1.8-fold risk increase for type 2 diabetes and 3.4-fold risk increase for hypertension. Gestational diabetes and hypertensive disorders of pregnancy (HDP) increase the risk of premature vascular disease, but the 2-fold risk increase associated with preeclampsia is only partially explained by the development of traditional vascular risk factors. Despite the compelling evidence for gestational diabetes and HDP as vascular risk indicators, there are no published Canadian vascular prevention guidelines that recognize these postpartum women. In contrast, the 2011 American Heart Association guidelines on cardiovascular disease in women include gestational diabetes and HDP in their vascular risk assessment. Studies indicate that the importance surveillance of vascular risk factors in these women after pregnancy is underappreciated by the women themselves and their physicians. Although a prudent diet and physically active lifestyle were demonstrated to reduce diabetes risk in women with a gestational diabetes history in the American Diabetes Prevention Program trial, adoption of these health behaviours is low; qualitative studies confirm a need for tailored strategies that address barriers and provide social support. Further research is also needed on approaches to reduce vascular risk in women with a history of gestational diabetes and HDP. Otherwise, an early window of opportunity for chronic disease prevention in young, high-risk women will be missed.     

Convulsive status epilepticus following abrupt high-dose benzodiazepine discontinuation

The misuse of benzodiazepines (BNZ)s may result in serious side effects. Three cases of convulsive status epilepticus (CSE) following abrupt discontinuation of long-term use of 25 mg of lorazepam in one patient and more than 20 mg of flunitrazepam in two patients are presented; they were non-epileptics and free of other high-risk factors for seizures. A favorable outcome for all three cases was noted. They remain free of seizures without antiepileptic treatment. Nevertheless, because of the extensive use of benzodiazepines, such rare high-risk side effects must be emphasized.     

Assessment of proliferating-cell nuclear antigen immunostaining in soft-tissue tumours: Relationship to histological grade and mitotic activity

The proliferative activity in 70 cases of soft-tissue tumours was estimated immunohistochemically using the monoclonal antibody PC-10, which recognizes proliferating-cell nuclear antigen (PCNA) in paraffin sections. The PCNA index (i.e. the percentage of positive neoplastic nuclei) and to a lesser degree the PCNA count (i.e. the number of positive neoplastic nuclei per ten high-power fields) positively correlated with the malignancy grade (PCNA index:P<0.001; PCNA count:P<0.01). However, the range of values of PCNA index and PCNA count was similar between benign and grade I tumours. A statistically significant positive correlation was also established between PCNA index and PCNA count on the one hand and mitotic count on the other, but the correlation coefficient was low (r=0.351,P<0.01, andr=0.290,P<0.05 respectively). These results indicate that PCNA immunostaining may successfully be used as an adjunct to the conventional histopathological parameters in assessing the malignancy grade in soft-tissue tumours although it is of limited value in distinguishing between benign and grade I tumours.Abbreviations PCNA proliferating-cell nuclear antigen - HPF high-power field     

Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia

Beyond allopurinol and the well-established uricosuric drugs, several other agents can decrease serum uric acid (SUA) levels, such as losartan, fenofibrate and some non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs increase renal urate excretion. Hyperuricaemia and gout are common problems (at least 1% of Western men are affected by gout). Raised SUA levels increase the incidence of acute gout and renal calculi. Hyperuricaemia may also predict an increased risk of vascular events. Therefore, lowering SUA levels is of clinical relevance. In this review we consider the effect on SUA levels of drugs that are prescribed for indications other than treating hyperuricaemia. These drugs may obviate the need for specific treatment (e.g. allopurinol) aimed at lowering SUA levels. Furthermore, because hyperuricaemic patients may already be on several drugs (e.g. due to associated dyslipidaemia, hypertension and/or arthritis) compliance may be improved by avoiding additional medication. The potential for adverse effects associated with polypharmacy would also be decreased.     

Effect of statins and aspirin alone and in combination on clinical outcome in dyslipidaemic patients with coronary heart disease. A subgroup analysis of the GREACE study

DECLARATION OF INTEREST: The GREACE study was conducted independently; no Company or Institution has supported it financially. Some of the authors have attended conferences and participated in other trials sponsored by various pharmaceutical companies.We assessed the possible 'synergy' of statins and aspirin (ASA) in reducing vascular events in patients with coronary heart disease, in a post hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. All patients (n = 1600) were divided into four groups according to long-term treatment: Group A (n = 787; statin + ASA), B (n = 93; statin - no ASA), C (n = 599; no statin - on ASA) and D (n = 121; no statin - no ASA). From all patients 692 were either on a statin or ASA monotherapy (Groups B + C). Relative risk reductions (RRRs) in 'all events' (primary endpoint) between groups were assessed. During the 3-year follow-up there were 292 cardiovascular events; 92 (12% of patients) in Group A, 14 (15%) in group B, 144 in Group C (24%) and 42 events in Group D (35%). The total number of events in Group B + C was 158 (23%). The RRRs in the primary endpoint were: Group A versus B 24% (P = 0.1912), A versus C 51% (P < 0.0001), A versus B + C 49% (P < 0.0001) and A versus D 71% (P < 0.0001). The RRRs in Group B versus C was 36% (P = 0.0431) and B versus D 57% (P = 0.0012), while in C versus D 33% (P = 0.0084). Our findings show that statins and ASA have an additive effect in reducing cardiovascular events. Aggressive statin use in the absence of ASA also substantially reduced cardiovascular events. Treatment with ASA in the absence of statin use reduced clinical events in comparison to patients not treated with either drug.     

Low molecular weight heparins: the optimal treatment for venous thromboembolism

Venous thromboembolism (VTE) is a common vascular complication that requires immediate as well as long-term treatment. Unfractionated heparin (UFH), followed by oral anticoagulants (OAs), is of proved efficacy in the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). However, low molecular weight heparins (LMWHs) have successfully replaced UFH both in the prevention and in the initial treatment of DVT and PE. Recent trials evaluated the efficacy and safety of LMWH therapy as an alternative to vitamin K antagonists in long-term VTE secondary prophylaxis for all patients and in specific subgroups. LMWHs differ considerably from each other. These agents were studied separately, administered according to various protocols, in various doses and for different duration of treatment. Results from prospective randomized trials, conducted during the last decade, indicate that LMWHs are at least as effective and yet safer than OAs in the long-term treatment of VTE. In this brief overview, we consider the potential advantages of treatment with LMWH in patients with VTE.