PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anti-cancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.     

Effects of leptin on biliary lipids: potential consequences for gallstone formation and therapy in obesity

Gallstone disease is exceptionally common, occurring especially in Western populations, with cholesterol gallstones predominating. Currently, it is believed that obesity is the most consistent and important risk factor for the development of cholesterol gallstones. Obesity has been shown to be associated with the supersaturation of bile with cholesterol because of increased hepatic secretion of the sterol. In accord with current information from experimental studies, leptin appears to be involved in biliary cholesterol secretion and cholesterol gallstone formation in humans. This review summarizes the current information on the role of obesity in biliary lipid secretion as well as the effect of leptin and its potential consequences for gallstone formation and therapy in the obese.     

Quantitative relationship between bile acid structure and biliary lipid secretion in rats

A series of unconjugated and taurine conjugated bile acids (BAs) differing in water solubility (SWo), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 mumol/min/kg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids secretions, and bile flow. The BAs studied differ in the number (2-3), position (-3, -6, -7, -12), and orientation of the hydroxyls (alpha/beta); the side chain structure was modified by shortening (C-23, nor-BA) and by lengthening (C-25, homo-BA), while maintaining the same structure of nuclear hydroxyls (3 alpha 7 beta). At a "tracer" dose, all C-24 natural BAs are efficiently recovered in bile when administered in both unconjugated and taurine conjugated forms. At a "high dose", all taurine conjugated BAs are efficiently recovered in bile (80-100%). However, a variable recovery was observed among unconjugated BAs: trihydroxy BAs are efficiently recovered (85-100%), while dihydroxy BAs are only partially recovered (25-40%). The side chain-modified BAs [i.e., C-23 nor and C-25 homo analogs of ursodeoxycholic acid (UDCA)] are partially recovered at a tracer dose (20-30%), but less at a high dose (10-20%) when administered in the unconjugated form. In contrast, the corresponding taurine conjugates are more efficiently recovered in bile (60-80%). Conjugation with taurine increases total recovery of unconjugated BAs in bile by not more than 30-40%. Highly hydrophilic and water-soluble BAs, such as ursocholic acid (SWo = 1.67 mM) and cholic acid (SWo = 0.27 mM), can also be secreted as unconjugates, and this accounts for their complete recovery. The conjugation step is rate limiting for poorly soluble BAs such as ursodeoxycholic acid (SWo = 0.009 mM) when administered at a high dose, and critical for nor and homo analogs which are poorly soluble and whose side chain modification partially suppresses their conjugation with taurine or glycine and thereby induces alternative pathways such as glucuronidation or sulfation. The induced bile flow is directly related to the hydrophilicity of the natural C-24 bile acid.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacological manipulation of biliary water and lipids: potential consequences for prevention of acute biliary pancreatitis

Acute biliary pancreatitis, caused by macroscopic cholesterol gallstones or microlithiasis, is often a severe disease with considerable morbidity and mortality. Formation of cholesterol gallstones and microlithiasis is caused by cholesterol crystallization from cholesterol supersaturated gallbladder bile. Particularly patients with fast and extensive crystallization, due to highly concentrated bile, low biliary phospholipid contents and gallbladder mucin hypersecretion seem at risk for pancreatitis. Patients who suffered from acute biliary pancreatitis should undergo cholecystectomy as secondary prevention strategy. For patients at high surgical risk, endoscopic sphincterotomy may be an appropriate alternative. Pharmacological manipulation of biliary lipids by the hydrophilic bile salt ursodeoxycholic acid is reserved for patients with recurrent pancreatitis despite previous cholecystectomy or sphincterotomy, or with contraindications to surgical and endoscopic treatment. Maintenance therapy with ursodeoxycholic acid is however a very effective secondary prevention strategy. Potentially, secondary prevention of acute biliary pancreatitis could also be achieved through decreasing biliary mucin contents by UDCA, NSAIDs or N-acetylcystein, or through achieving bile dilution (currently not feasible).     

Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention

Importance of the field: Antipsychotic medications are the cornerstone of treatment in schizophrenia, and a large body of data confirms the value of ongoing and continuous antipsychotic pharmacotherapy in controlling symptoms and preventing relapse. However, nonadherence with antipsychotic treatment is a significant issue, with estimates as high as 90%.

Areas covered in this review: This review focuses on long-acting injectable (LAI) antipsychotics and their role in the treatment of schizophrenia. The existing literature, with an emphasis on clinical evidence, is assessed. This includes both reviews and specific trials that examine LAIs and compare them with oral agents, with measures ranging from relapse and rehospitalization to adherence. Both advantages and limitations (e.g., challenges in terms of dose titration and time to steady state) are examined.

What the reader will gain: This overview serves as an update for clinicians wishing to understand LAIs better, including the newer second-generation antipsychotics (SGAs) with this formulation available, and their potential role in the long-term treatment of individuals with schizophrenia.

Take home message: Despite identified advantages, LAIs are not used as widely as might be expected. It would seem that clinicians are at least partly responsible for this, influenced by our own misperceptions (e.g., that LAIs are not acceptable to patients) and, perhaps, misinformation (e.g., increased side effect risk). As clinicians, we may well be shortchanging LAIs if we position them as a treatment of last resort for the multi-episode, nonadherent, ‘revolving door’ patient, especially given recent evidence underscoring their potential benefits in first-episode patients. The search for new and more effective antipsychotics will continue, but we are reminded that suboptimal outcomes may have as much to do with nonadherence as inadequate treatments. Evidence has established that LAI antipsychotics demonstrate distinct benefits in this regard, and we would be remiss if we did not exploit this already available strategy. As well as additional research, we need to rethink how we position these agents in our treatment algorithms if we are to maximize their potential.     

残余胆囊的诊治及预防

目的：探讨胆囊切除术后残余胆囊的病因诊断及防治方法。方法：回顾分析2002年6月～2009年6月收治的18例残余胆囊患者的临床资料。结果：18例患者中初次手术行经典胆囊切除术7例,小切口胆囊切除术6例,腹腔镜胆囊切除术5例,患者均于1～10年前行过胆囊切除术,术后首次出现症状时间为15d～9年。经B超、CT、ERCP和MRCP等影像学方法诊断残余胆囊,17例再次手术成功,切除残余胆囊,症状消失,痊愈出院,1例并存内科疾病不能耐受手术,经解痉、止痛、抗感染、利胆治疗后缓解。结论：正确选择胆囊切除术的手术时机和手术方式,严格按规程操作,术中解剖清楚胆囊三角,在距胆总管0.3～0.5cm处处理胆囊管是预防残余胆囊的关键,手术切除是治疗该病的有效方法。     

Choleresis and inhibition of biliary lipid secretion induced by piperacillin in the rat

1. The effects of the administration piperacillin on bile flow and biliary lipid secretion were studied in male Wistar rats. 2. Intravenous injection of piperacillin at doses ranging from 0.3 to 3.0 mmol/kg bodyweight led to an increase in its biliary concentration and excretion rate. Maximal biliary excretion was reached at a dose of 2.0 mmol/kg piperacillin. 3. Excretion of the antibiotic into bile was associated with a marked choleresis. A linear relationship was observed between bile flow and piperacillin excretion, 5.7 micro L bile being produced per micro mol piperacillin excreted into the bile. 4. Continuous i.v. infusion of piperacillin at 2.0 mmol/100 g per min did not result in significant changes in bile acid or cholesterol secretion, but biliary phospholipid secretion was markedly reduced. The inhibitory effect on phospholipid secretion was also present when biliary lipid output had been previously increased by an infusion of taurocholate (200 nmol/100 g per min). Addition of taurocholate did not reverse the impairment of phospholipid secretion induced by piperacillin. 5. These results indicate that acute administration of piperacillin in the rat induces a marked choleresis by stimulating bile acid-independent bile flow. The significant impairment in phospholipid secretion suggests a specific effect on intracellular supply and/or translocation across the canalicular membrane.     

Immunophilins: their properties and their potential role in therapeutic drug monitoring

This article reviews recent developments in the immunophilin arena and the current state of knowledge about the biochemical properties of immunophilins. The role of immunophilin-binding assays is also explored with the conclusion that some of these immunosuppressive-drug-binding proteins may provide better assays for sirolimus and tacrolimus than current immunoassays.     

Chalcones and their potential role in inflammation

Chalcones are a group of phenolic compounds which possess a wide variety of cytoprotective and modulatory functions. They have been shown to possess antioxidant, oxygen scavenging and anti-inflammatory properties in a variety of experimental systems and can trigger the intracellular cascade of protective pathways offering a promising stratagem for therapeutic applications. In this research we will review the anti-inflammatory effect of chalcone derivatives and new approaches.     

Inhibition of biliary lipid and protein secretion by cyclosporine A in the rat.

We investigated the effect of cyclosporine A (CyA) administered as a single i.v. dose of 20 and 40 mg/kg body wt, on biliary secretion of cholesterol, phospholipid, bile acid, and lysosomal marker and canalicular plasma membrane marker enzymes in anaesthetized Wistar rats. CyA reduced the concentration and biliary secretion of cholesterol, phospholipid and bile acid to a considerable extent; the inhibitory effect of CyA on the biliary secretion of phospholipid and bile acid was greater than that on cholesterol. The biliary outputs of acid phosphatase (AcP) and gamma-glutamyltransferase (gamma-GT) were also diminished by the drug, all these effects being dose-dependent. Maximum decreases in bile acid secretion were observed 10 min after administration, whereas those of cholesterol and phospholipid were delayed. Bile acid concentrations and secretion returned to pretest values at 30-50 min after CyA injection whereas those of cholesterol and phospholipid remained significantly reduced at this time point. The greater inhibitory effect of CyA on the biliary outputs of phospholipid and bile acid relative to cholesterol secretion together with the asynchronous fall and recovery of bile acid, cholesterol and phospholipid concentrations and secretion alter the cholesterol/bile acid, phospholipid/bile acid and cholesterol/phospholipid molar ratios as well as the lithogenic index, thus suggesting that CyA would uncouple biliary lipid secretion from bile acid secretion. Since under physiological conditions biliary lipid and gamma-GT secretion is related to and dependent upon bile acid secretion, we propose that the CyA-induced inhibition on lipid and gamma-GT secretion is, at least partly, secondary to the fall in bile acid output caused by the drug. However, since CyA inhibits secretory processes independent of the hepatobiliary flux of bile acid, such as the exocytic discharge of AcP, and because it also uncouples biliary lipid from bile acid secretion, other mechanisms and factors involved in lipid and protein secretion (such as intracellular transport, canalicular membrane fluidity and/or intracanalicular events) might also be altered by this drug.     

Metalloproteinases: their role in arthritis and potential as therapeutic targets

Irreversible degradation of articular cartilage is a major feature of the arthritides, and its prevention is a therapeutic goal which has been difficult to achieve. Enzymes from the matrix metalloproteinase and ADAMTS (a disintegrin, a metalloproteinase, and thrombospondin motif) families are key mediators of cartilage extracellular matrix destruction. Inhibition of metalloproteinase activity is therefore a conceptually attractive therapeutic strategy, although clinical efficacy has not yet been demonstrated. This review outlines the biology behind metalloproteinases as drug targets in the arthritides, and poses important questions for the future design of such therapies.     

Effect of thiazide treatment on biliary lipid composition in healthy volunteers

Summary An increased incidence of cholecystitis has been observed in thiazide-treated patients. In order to test the possibility that the therapy might have caused an increase in the cholesterol saturation of gallbladder bile, biliary lipid composition was determined in fasting duodenal bile obtained from 10 healthy individuals after cholecystokinin injection, before and after 3 weeks of treatment with hydrochlorthiazide.The mean relative concentration of cholesterol was increased in 6 subjects, from 4.7 to 5.6 mol%, and the cholesterol saturation of bile was increased in 7, from 69 to 81%. These preliminary results indicate that thiazide treatment may to some extent increase biliary cholesterol saturation, and this may, at least in part, explain the higher prevalence of symptomatic gallbladder disease during such therapy.     

Human papilloma virus vaccines and their role in cancer prevention

The introduction of the human papilloma virus (HPV) vaccine is the single most important advance in the prevention of cervical cancer since the introduction of cervical cytology half a century ago. Vaccination should ideally occur prior to a female's first sexual experience. This article suggests that the HPV vaccine should be publicly funded in New Zealand.