Factors Affecting the In Vivo Lactone Stability and Systemic Clearance of the Lipophilic Camptothecin Analogue AR-67

Purpose  

The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3^rd generation camptothecin analogue.     

Consequences of "conservative" conventional management of axillary vein thrombosis

To evaluate the long-term effects of "conservative" management (heparin initially then Coumadin for 3 months) on patients with axillary vein thrombosis, the authors studied 20 patients (average age 44 years) who presented at the Wellesley Hospital in Toronto between 1975 and 1984. The diagnosis of axillary vein thrombosis was made from history, findings on physical examination and Doppler studies. In 12 patients, the diagnosis was confirmed by venography. Three patients subsequently underwent a first-rib resection for thoracic outlet syndrome. The average follow-up was 42 months. The cause of the thrombosis in 3 patients was an intravenous-line catheter, in 7 it was effort thrombosis and in 10 the cause was unknown. Two patients had had a previous deep venous thrombosis in the lower limb. Results of conservative treatment showed that only five patients had residual minimal swelling and two had minor discomfort. These symptoms did not interfere with either leisure or work activities in any of the patients. Fifteen patients were asymptomatic. One patient had nonfatal pulmonary embolism. The conservative management of axillary vein thrombosis is safe, effective, relatively inexpensive and gives excellent long-term results. The prognosis is good, irrespective of the cause of the thrombosis and, in view of this, a more aggressive approach, using either streptokinase therapy or thrombectomy, does not appear to be justified.     

Native valve right sided infective endocarditis

Right-sided infective endocarditis (RSIE) accounts for 5–10% of all cases of infective endocarditis (IE), and is predominantly encountered in the injecting drug user (IDU) population, where HIV and HCV coinfections often coexist. Staphylococcus aureus is the most common pathogen. The pathogenesis of RSIE is still not well understood. RSIE usually presents as a persistent fever with respiratory symptoms whilst signs of systemic embolisation as seen in left-sided IE are notably absent. The prompt diagnosis of RSIE thus requires a high index of suspicion. Transthoracic echocardiography (TTE) can detect the majority of RSIE, whilst transoesophageal echocardiography (TOE) can increase sensitivity. Virulence of the causative organism and vegetation size are the major determinants of prognosis. Most cases of RSIE resolve with appropriate antibiotic administration.     

Preliminary noise reduction efforts in a medical intensive care unit

Noise is a significant contributor to sleep disruption in the intensive care unit (ICU) that may result in increased patient morbidity such as delirium and prolonged length of stay in ICU. We conducted a pre-post intervention study in a 24-bed tertiary care academic medical ICU to reduce the mean noise levels. Baseline dosimeter recordings of ICU noise levels demonstrated a mean noise level of 54.2 A-weighted decibels (dBA) and peak noise levels of 109.9 dBA, well above the Environmental Protection Agency’s recommended levels. There were 1735 episodes of “defects” (maximum noise levels > 60 dBA). Following implementation of multipronged interventions, although the mean noise levels did not change significantly between pre- and post-intervention (54.2 vs 53.8 dBA; p = 0.96), there was a significant reduction in the number of “defects” post-intervention (1735 vs 1289, p ≤ 0.000), and the providers felt that the patients were sleeping longer in the ICU post-intervention.     

Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II‐infused rats

Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II‐dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague–Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II‐induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II‐mediated increase in plasma and heart aldosterone 2.3‐ and 1.8‐fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1‐mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4‐hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress‐associated cardiovascular damage in Ang II‐dependent hypertension.     

Angiotensin receptor blockade increases pancreatic insulin secretion and decreases glucose intolerance during glucose supplementation in a model of metabolic syndrome

Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT?) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT? protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT? activation and increased GLP-1 signaling.     

Global mental health and development: a thematic series

Background

A political movement towards building alternatives to long-term hospitalization of psychiatric patients in Korea has gained momentum. We aimed to provide sturdy foundation needed to formulate the most rational policy by review of caregiver’s opinion to the political alternatives under discussion for facilitating discharge of long-term stayed psychiatric patients in Korea.

Discussion

Caregivers in Korea, whose family members had been hospitalized longer than 6 months and all of whom applied to the Mental Health Review Board (MHRB) for an examination required for extended stay, have shown reluctance to take their patients back home. Especially, a half of them answered that if MHRB would order compulsory discharge, they would take their patients to another hospital instead of living together. Despite of those pessimistic attitudes, one of the promising solutions might be residential care as an alternative to the long-term hospital care, which is most preferred by caregivers.

Conclusion

After all, the issue of who should take an accountability of the psychiatric patients is essential in establishing mental health policy. Korean government should analyze and reform mental health delivery systems such as residential service system, community-based case management programs and hospital treatment systems including payment program which can facilitate reasonable decision by professionals as well as caregivers for the appropriate admission rather than longer term hospitalizations.     

Aprotinin reduces oxidative stress induced by pneumoperitoneum in rats

Background

Ischemia–reperfusion injury induced by pneumoperitoneum is a well-studied entity, which increases oxidative stress during laparoscopic operations. The reported anti-inflammatory action of aprotinin was measured in a pneumoperitoneum model in rats for the first time in this study.

Materials and methods

A total of 60 male Albino Wistar rats were used in our protocol. Prolonged pneumoperitoneum (4 h) was applied, causing splanchnic ischemia and a period of reperfusion with a duration of 60 or 180 min followed. Several cytokines and markers of oxidative stress were measured in liver, small intestine, and lungs to compare the aprotinin group with the control group. Tissue inflammation was also evaluated and compared between groups using a five-scaled histopathologic score.

Results

In aprotinin group values of biochemical markers (tumor necrosis factor α, interleukin 6, endothelin 1, C reactive protein, pro-oxidant–antioxidant balance, and carbonyl proteins) were lower in all tissues studied. Statistical significance was greater in liver and lungs (P < 0.05). Histopathologic examination revealed significant difference between control and aprotinin groups in all tissues examined. Aprotinin groups showed mild to moderate lesions, while in control groups severe to very severe inflammation was present. Aprotinin subgroup with prolonged reperfusion period (180 min) showed milder lesions in all tissues than the rest of the groups.

Conclusions

Aprotinin reduced inflammatory response and oxidative stress induced by pneumoperitoneum in liver, small intestine, and lungs.