Anti-obesity drugs: use, mechanisms and clinical importance.

The high prevalence of obesity (>20% in industrialized countries) and its serious health risks, cause severe individual and public costs. Pharmacological interventions are available, such as dietary products and drugs acting on the absorption of nutrients, the production of hormones regulating the feeling of hunger and satiety, and the expenditure of energy. The individual benefit of these pharmacological interventions depends on the efficiency of these measures and the side-effects associated with them. The afflicted patient, and very often even the treating physician, are unable to evaluate the risk/benefit ratio of these drugs for the individual patient. This article describes the possibilities and limitations of pharmacological interventions to treat obesity and gives information on the indications for dietary, pharmacological and surgical interventions.     

石家庄地区超广谱β-内酰胺酶产酶菌及其药敏情况

目的：为了解超广谱β－内酰胺酶（ESBLs)分布情况，耐药特性及合理有效使用抗生素，有效控制产ESBLs菌的流行。方法：采用纸片扩散法，对在我区感染患者中分离的312株革兰阴性菌进行了ESBLs检测，及对23种抗生素的敏感性观察，并加以分析。结果：检出51株产ESBLs菌，总检出率16．3％，对头孢他啶、头孢噻肟、头孢泊肟耐药率为16．7％－100％，且交叉耐药极为严重，但对亚胺培南和含β－内酰胺酶抑制剂的抗生素均敏感。结论：治疗ESBLs菌引起的感染应使用亚胺培南、头孢西丁和含β-内酰胺酶抑制剂的复合药物有效。     

To increase power in randomized clinical trials without increasing sample size.

The power of a randomized clinical trial (RCT) depends on two factors: sample size and effect size. Most psychiatric research design strategies focus on increasing sample size, despite major problems in recruiting large numbers of subjects or funding such costly studies. It is possible to increase power in RCTs in a variety of ways without increasing sample size, in essence by increasing effect size by decreasing within-group variance. Such strategies are presented and discussed.     

Drug interactions of clinical importance with antihyperglycaemic agents: an update.

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.     

Drug-antacid interactions: assessment of clinical importance

Antacids and adsorbents are commonly used preparations that are generally considered to be pharmacologically inert and free from adverse effects. They may, however, interact with a diverse range of primary drugs and the sequelae can be disadvantageous to the efficacy of the primary medication. Many such reports in the literature are based on animal experiments, or on single-dose studies in healthy subjects. Some reports are anecdotal and are unconfirmed; others are based solely on in vitro evidence. Potentially important interactions have been suggested for a relatively small group of drugs: tetracyclines, phenytoin, digoxin, chloroquine, cimetidine, quinidine, nonsteroidal antiinflammatory drugs, and beta-blocking agents. The evidence for these has been critically evaluated, as well as for antacid-anticoagulant and antacid-nitrofurantoin interactions that have been wrongly emphasized in the literature. The majority of literature reports on interactions with antacids have been overemphasized; only ferrous sulfate-, isoniazid-, and tetracycline-antacid interactions fall into a category I importance (scale I-III of descending importance). This category is for those interactions with good evidence of actual or potential importance in patients or in relevant studies on normal subjects.     

Strategy for increasing the demand for clinical pharmacists

A strategy for increasing the demand for clinical pharmaceutical services in hospitals is described. The strategy consists of three steps: (1) Show that the overall quality of drug prescribing affects patient outcomes not only in a negative way but also in a positive manner; i.e., appropriate prescribing speeds recovery and minimizes the need for more expensive types of care; (2) show that the pharmacist can detect poor quality prescribing; and (3) show that after detecting poor quality prescribing, the clinical pharmacist can effectively intervene in the prescribing process to reduce inappropriate prescribing and improve patient outcomes.     

Acceptance and importance of clinical pharmacists' LIMM-based recommendations

Objective The objective of this study was to evaluate the quality of the clinical pharmacy service in a Swedish hospital according to the Lund Integrated Medicine Management (LIMM) model, in terms of the acceptance and clinical significance of the recommendations made by clinical pharmacists. Method The clinical significance of the recommendations made by clinical pharmacists was assessed for a random sample of inpatients receiving the clinical pharmacy service in 2007. Two independent physicians retrospectively ranked the recommendations emerging from errors in the patients?? current medication list and actual drug-related problems according to Hatoum, with rankings ranging between 1 (adverse significance) and 6 (extremely significant). Results The random sample comprised 132 patients (out of 800 receiving the service). The clinical significance of 197 recommendations was assessed. The physicians accepted and implemented 178 (90%) of the clinical pharmacists?? recommendations. Most of these recommendations, 170 (83%), were ranked 3 (somewhat significant) or higher. Conclusion This study provides further evidence of the quality of the LIMM model and confirms that the inclusion of clinical pharmacists in a multi-professional team can improve drug therapy for inpatients. The very high level of acceptance by the physicians of the pharmacists?? recommendations further demonstrates the effectiveness of the process.     

The importance of general practitioner information in selection of volunteers for clinical trials.

The safe conduct of phase I volunteer studies requires careful selection and screening of volunteers. We have reviewed the results of the selection procedure in our clinic. The information received from the volunteer's general practitioner revealed clinical problems which had not been disclosed during medical history or examination.     

Physiological and clinical importance of lipoprotein(a)

Lipoprotein(a) is a genetically regulated trait, and its concentration in serum seems to be independent from that of other lipoprotein classes. It can be detected by ultracentrifugation in the d = 1.05-1.12 g/ml density range. Based on epidemiological observations Lp(a) is an independent risk factor for coronary heart disease. Its structure resembles LDL, but contains, in addition to apolipoprotein B 100, the disulphide-linked apoprotein(a). Apoprotein(a) shares a striking homology with plasminogen, consisting multiple repeating domains similar to kringle IV, a single kringle V and an inactive protease segment. The heterogeneity of Lp(a) complex is determined by the apoprotein(a) moiety. It seems so, that atherogenic properties of Lp(a) can be explained by its binding to glycosaminoglycans and inhibition of fibrinolysis. This latter effect is carried out by the kringle domains, which can interact with the plasminogen activators and plasmin binding sites on endothelial surface. The atherogenic properties of Lp(a) are expressed over 30 mg/dL serum concentration. Well-known antilipidemic drugs do not affect its serum level and genetically determined phenotype. Diseases leading to secondary hyperlipoproteinemia may influence the lipoprotein(a) level, too.     

Protein binding displacement interactions and their clinical importance

The binding of drugs to proteins is an important pharmacokinetic parameter. Many methods are available for the study of drug protein binding phenomena and there are also many ways to interpret the binding data. Although much emphasis has been placed on the binding of drugs in the plasma, binding also takes place in the tissues. Displacement interactions involving plasma or tissue binding sites have been implicated as the causative mechanisms in many drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interactions. However, the importance of plasma binding displacement as a mechanism of drug interaction has been overestimated and overstated, being based largely on in vitro data. Because displaced drug can normally distribute out of the plasma compartment, increases of free drug concentrations are usually transient and therefore will not give rise to changed pharmacological effects in the patient. Those clinically important drug interactions formerly considered to be caused via displacement from plasma binding sites usually have another interaction mechanism involved; commonly decreased metabolism or renal elimination also takes place. Plasma binding displacement interactions, however, do become important clinically in certain specific situations, namely, when the displacing drug is administered quickly to the patient by the intravenous route, during therapeutic drug monitoring, and in certain drug disposition studies which involve the use of a heparin lock for blood sampling. Tissue binding displacement interactions have a greater potential to cause adverse effects in the patient as in this case drug will be forced from extravascular sites back into the plasma. The resulting increased drug plasma levels will lead to enhanced pharmacological effects and, possibly, frank toxicity. Displacement of drugs from binding sites simultaneously in both the plasma and in the tissues will combine the effects seen after displacement from the separate areas. Due to decreased binding in both areas, the free drug concentration in the plasma will increase leading to overactivity of the displaced drug.     

Cereblon在多发性骨髓瘤中的研究进展及临床意义

以沙利度胺、来那度胺、泊马度胺为代表的免疫调节药物,对于多发性骨髓瘤患者的治疗反应率及预后产生了重要影响。Cereblon(CRBN),最初发现与常染色体隐性遗传非综合征性智力发育迟缓相关,近年研究已经证明其不仅为沙利度胺致畸作用的靶点,还与免疫调节药物抗骨髓瘤作用的临床反应率及患者的生存时间相关;目前认为,CRBN可能是通过形成DDB1-CUL4-ROC1泛素连接酶复合物介导抗骨髓瘤活性。还需要更多有关CRBN分子机制及临床相关性研究以促进免疫调节药物耐药机制的进一步发展以及更有效、低毒性的药物出现,提高多发性骨髓瘤患者的生存质量。     

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis

ABSTRACT

Background: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-β) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy.

Objective: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS).

Methods: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology.

Results: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2–45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1‐point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 (?p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN‐β therapy. NAb+ patients experience an approximately four-fold increase (?p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01).

Conclusion: The induction of NAbs in IFN‐β treated patients reduce clinical effect and accelerate disease progression.