Chronopharmacology: a new perspective in pharmacology

Vital signs and several constituents of the serum and urine exhibit a circadian rhythm, and the same is true for the onset of several diseases. The rhythmic changes in the blood volume, functions of the liver and kidney, etc., have implications for drug availability, and the circadian changes should be taken into account in pharmacokinetic studies. These changes are the subject of chronopharmacokinetics. In addition to the circadian rhythm in changes in drug absorption, elimination and bioavailability, a rhythm of the intensity of drug effects and side-effects may also be observed: this is the domain of chronopharmacodynamics. Several examples demonstrate that chronopharmacokinetic and chronopharmacodynamic results support the view that the temporal organization of the organism is an important variable influencing the action of drugs.     

Potential drug interactions associated with treatments for type 2 diabetes and its comorbidities: a clinical pharmacology review

Type 2 diabetes is a disease of glucose metabolism that commonly involves multiple comorbidities, including lipid dyscrasias and hypertension. Each concurrent disorder contributes some risk of complications and requires therapeutic intervention. The simultaneous management of so many coexisting illnesses can be complex and commonly results in patients being prescribed multiple medications--referred to as polypharmacy--which may further complicate treatment. To ensure the best patient outcomes, the treating physician must be aware of all the therapeutic agents that a patient is taking to assess possible drug interactions that such a plethora of medications may confer. This article addresses the underlying comorbidites, the drugs commonly used to treat them and the interactions that may arise from concomitant administration.     

Rosiglitazone: a new therapy for Type 2 diabetes

Rosiglitazone (Avandiatrade mark) is a new generation thiazolidinedione used in the treatment of Type 2 diabetes. As with other thiazolidinediones, it binds to the gamma-isoform of the peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor. Subsequent to PPAR-gamma activation, rosiglitazone increases insulin suppression of hepatic glucose output and increases peripheral glucose uptake in the muscles, thereby improving the glycaemic state of the individual. In rodent models of obesity and Type 2 diabetes, rosiglitazone has been shown to have positive effects in the main target organs responsible for the condition, namely the liver, pancreas, skeletal muscle and adipose tissue. These studies also suggest that rosiglitazone may help in preserving renal and pancreatic function that deteriorates in chronic hyperinsulinaemia. In clinical studies, rosiglitazone has been shown to be effective, safe and well-tolerated, not only when used as monotherapy, but also when used in combination with sulphonylureas, metformin or insulin. Unlike troglitazone, rosiglitazone is not metabolised via CYP3A4 and is thus unlikely to be subject to clinically important drug interactions. In addition, no evidence of hepatotoxicity has been associated with rosiglitazone to date. Rosiglitazone should therefore be strongly considered as part of the overall management of Type 2 diabetes.     

Norfloxacin: clinical pharmacology and clinical use

Norfloxacin, a nalidixic acid analog, is the first of the fluorinated quinolinecarboxylic acids to be marketed in the United States. It demonstrates potent antibacterial activity against aerobic, gram-negative bacteria including the Enterobacteriaceae, gentamicin-resistant Pseudomonas aeruginosa, and penicillin-resistant Neisseria gonorrhoeae. Norfloxacin exhibits good activity against methicillin-resistant and -sensitive Staphylococcus aureus, but less activity against most other aerobic, gram-positive organisms. Anaerobic bacteria are resistant to the drug. Resistance to norfloxacin is not plasmid mediated, but is secondary to bacterial mutation, and occurs less frequently than nalidixic acid resistance. Its pharmacokinetic properties after a 400-mg oral dose consist of a peak serum concentration of 1.3-1.58 micrograms/ml, an elimination half-life of 3-7 hours, and good penetration into kidney and prostatic tissues. Renal excretion is the major route of elimination. Norfloxacin is highly effective in the treatment of uncomplicated and complicated urinary tract infections, and gonococcal urethritis. Adverse effects are generally well tolerated and usually do not require discontinuation of therapy.     

Clinical pharmacology of alogliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of Type 2 diabetes

Alogliptin is a new, potent, highly selective, orally available inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme developed for the treatment of Type 2 diabetes mellitus (T2DM). Inhibition of the DPP-4 enzyme, prevents the inactivation of the incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP), both of which have very short half-lives. GLP-1 and GIP are released in response to food ingestion; they enhance nutrient-induced insulin secretion and inhibit postprandial glucagon secretion. The pharmacokinetics and pharmacodynamics of alogliptin are suitable for once-daily dosing. In two Phase I clinical trials, one in healthy subjects and one in early-diagnosed patients with T2DM, alogliptin has been shown to be safe and well tolerated. In a Phase II clinical trial, alogliptin was shown to be safe and demonstrated efficacy in patients with T2DM with a dose-response profile suitable for Phase III dose selection.     

黄芪抗缺氧缺血性损伤实验药理学研究和儿科临床应用进展

黄芪味甘、性温,有补气升阳、固表生肌、托毒排脓和利水消肿等功效,是一种天然的抗氧化剂,其化学成分包括甙类、多糖、氨基酸、微量元素等。近年来对黄芪及其有效成分的实验药理学研究显示其对缺氧缺血性损伤有防护作用。本文就黄芪抗缺氧缺血     

Integrating pharmacology and clinical pharmacology in universities

Continuing development of safe and effective new medicines is critically important for global health, social prosperity and the economy. The drug discovery-development pipeline depends critically on close partnerships between scientists and clinicians and on educational programmes that ensure that the pharmacological workforce, in its broadest sense, is fit for purpose. Here I consider factors that have influenced the development of basic and clinical pharmacology in UK universities over the past 40 years and discuss ways in which basic pharmacologists, clinical pharmacologists and scientists from different disciplines can work together effectively, while retaining their professional identities and fostering developments in their disciplines. Specifically, I propose the establishment of Institutes of Drug Discovery and Development, whose activities could include development and implementation of a translational pharmacology research strategy, drawing on the collective expertise of the membership and the university as whole; provision of a forum for regular seminars and symposia to promote the discipline, encourage collaboration and develop a cohesive community; provision of a research advisory service, covering, for example, data management, applications for ethics permission, clinical trials design, statistics and regulatory affairs; liaison with potential funders and leadership of major funding bids, including funding for doctoral training; provision of advice on intellectual property protection and the commercialization of research; liaison with corporate partners to facilitate collaboration, knowledge transfer and effective translation; and leadership of undergraduate and postgraduate education in basic and clinical pharmacology and related sciences for medical and science students, including continuing professional development and transferable skills.     

Perchlorate clinical pharmacology and human health: a review

Potassium perchlorate has been used at various times during the last 50 years to treat hyperthyroidism. Since World War II ammonium perchlorate has been used as a propellant for rockets. In 1997, the assay sensitivity for perchlorate in water was improved from 0.4 mg/L (ppm) to 4 microg/L (ppb). As a result, public water supplies in Southern California were found to contain perchlorate ions in the range of 5 to 8 ppb, and those in Southern Nevada were found to contain 5 to 24 ppb. Research programs have been developed to assess the safety or risk from these exposures and to assist state and regulatory agencies in setting a reasonable safe level for perchlorate in drinking water. This report reviews the evidence on the human health effects of perchlorate exposure. Perchlorate is a competitive inhibitor of iodine uptake. All of its pharmacologic effects at current therapeutic levels or lower are associated with inhibition of the sodium-iodide symporter (NIS) on the thyroid follicular cell membrane. A review of the medical and occupational studies has been undertaken to identify perchlorate exposure levels at which thyroid hormone levels may be reduced or thyrotropin levels increased. This exposure level may begin in the 35 to 100 mg/d range. Volunteer studies have been designed to determine the exposure levels at which perchlorate begins to affect iodine uptake in humans. Such effects may begin at levels of approximately 1 mg/d. Environmental studies have assessed the thyroidal health of newborns and adults at current environmental exposures to perchlorate and have concluded that the present levels appear to be safe. Whereas additional studies are underway both in laboratory animals and in the field, it appears that a safe level can be established for perchlorate in water and that regulatory agencies and others are now trying to determine that level.     

2型糖尿病伴发消化性溃疡愈合质量及其复发的临床分析

目的：探讨2型糖尿病（type 2 diabetes mellitus,T2DM）伴发消化性溃疡（peptic ulcer,Pu）愈合质量及复发的临床特点。方法：选择2013年3月～2014年5月来我院住院的2型糖尿病伴发消化性溃疡患者156例为观察组,收集同期住院的非糖尿病消化性溃疡患者142例为对照组,治疗结束后1个月随访两组溃疡愈合质量及溃疡分布情况,并于治疗结束后12个月随访溃疡复发率。结果：治疗结束后1个月随访发现,观察组有98例溃疡愈合达S期,愈合率64.1％;65例达Sc期愈合,愈合率41.7%;对照组125例溃疡愈合达S期,愈合率88.0％;92例达Sc期愈合,愈合率64.8%,观察组S期、Sc期溃疡愈合率低于对照组,差异有统计学意义。结论：T2DM患者存在微血管病变,胃黏膜血流量明显降低,导致容易发生PU,溃疡愈合质量差,复发率高,需定期复查,提高溃疡愈合质量。     

Activated T lymphocytes in Type 2 diabetes: implications from in vitro studies

The number of subjects with Type 2 diabetes (DM2) has risen significantly in the last ten years. Obtaining sufficient human tissue to study this disease process as well as many other diseases is generally difficult. T lymphocytes offer a unique opportunity for these studies. Although resting human peripheral T-lymphocytes are devoid of insulin receptors, these receptors emerge upon activation of cells by specific antigens or mitogens. Concomitant with the insulin receptors, two other growth factor receptors (IGF-1 and IL-2) also emerge on the T lymphocyte cell surface along with intracellular signal transduction mechanisms and insulin degrading enzyme (IDE). After binding to its receptor, insulin has been shown to exert its classical effects on carbohydrate metabolism in the stimulated T- cell; thereby, validating the use of activated T-lymphocytes for studying the pathogenesis of metabolic and immune disorders and the mechanism(s) by which insulin exerts its effects. In activated T-lymphocytes, insulin stimulates glucose uptake, glucose oxidation, pyruvate flux and pyruvate dehydrogenase activity, amino acid transport, lipid metabolism and protein synthesis. Through its ability to enhance nutrient uptake and raise the levels of intermediary cellular metabolism, insulin is believed to maintain the allo-activated state of lymphocytes, enhance T-Lymphocyte responsiveness, and support or possibly promote the actions of immuno-derived regulatory growth and differential factors. Since insulin enhances energy requirements and protein synthesis necessary for appropriate T-cell functions, defects in insulin action may lead to inappropriate immunoresponses in various metabolic states such as in diabetes. Studies from our lab have found insulin binding, processing, and responsiveness in phytohemagglutinin(PHA)-activated T-cells are reflective of the donor's glycemic status and ambient insulin levels in subjects with Type 1 and Type 2 diabetes (DM2) and other insulin resistant states. Our studies show that patients with diabetic ketoacidosis and hyperglycemia have increased proinflammatory cytokines and activated CD4+ and CD8+ T lymphocytes. The diabetic state, where effective insulin concentrations are low and both glucose and free fatty acids are high, provides an environment of oxidative stress and activation of the inflammatory pathways. The mechanisms underlying insulin action, in general, or in the CD4+ and CD8+ T-lymphocytes, in particular, have not been clearly elucidated. Due to the accessibility of obtaining these cells from patients, activated T-lymphocytes offer the potential of studying diabetes and other disease in human subjects.     

Type 2 diabetes in youth from the Western Pacific region: glycaemic control, diabetes care and complications

OBJECTIVE: To describe the glycaemic control, diabetes care and prevalence of complications in youth with type 2 diabetes from the Western Pacific Region. RESEARCH DESIGN AND METHODS: Cross-sectional, clinic-based audit of 331 patients aged < 18 years from 56 centres in Australia, China-Beijing, China-Shanghai, China-Hong Kong, Indonesia, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan and Thailand. Clinical and management data were recorded along with glycated haemoglobin (HbA(1c)), lipids and complication rates. MAIN OUTCOME MEASURES: Glycaemic control, complications, diabetes management. RESULTS: Median age was 14.9 years (interquartile range 13.2-16.4 years) and median diabetes duration 2.3 years (1.4-3.6 years). Median HbA(1c) was 7% (5.9-9.9%) and HbA(1c) was > 7.5% in 40% of patients. In multiple regression analysis, glycaemic control varied significantly between countries (p = 0.02); higher HbA(1c) was associated with fewer home blood glucose measurements (p = 0.005) and higher insulin dose/kg (p < 0.0001). Blood glucose monitoring was performed by 65% of patients (range 33-96% by country). In 25% of patients, management consisted of diet alone or no treatment (range 0-53% by country); oral anti-diabetic drugs alone were used in 49%, insulin alone in 11% and both in 15%. Microalbuminuria was found in 8% and hypertension in 24%. The risk of hypertension increased with higher BMI (OR 1.16, 95% CI 1.09-1.24, p < 0.0001); antihypertensive agents were used in 4% of patients. CONCLUSIONS: The management of type 2 diabetes in youth from the Western Pacific Region varies widely. Hypertension and microalbuminuria were frequent, but not commonly treated. Further investigation into the natural history and risk factors for complications in youth with type 2 diabetes is required to assist in developing evidence based management guidelines.     

Integrating pharmacology and clinical pharmacology in pharmaceutical companies

Integration of clinical and preclinical pharmacology in pharmaceutical companies could be improved by several key recommendations: Companies should ensure that there is an adequate pool of trained clinical pharmacologists and preclinical pharmacologists. Training should include topics that allow clinical pharmacologists to be cognizant of the methods, issues and challenges faced by the preclinical pharmacologists and vice versa. Companies should incentivize such integration internally by aligning objectives and metrics/incentives. In academic medicine and the NHS there should be support for involvement of clinical pharmacologists in basic academic research and industrial R & D and new ways of facilitating and incentivizing preclinical pharmacologists and clinical pharmacologists to move between these various environments should be sought.     

The clinical pharmacology of the medical treatment for overactive bladder in adults

ABSTRACT

Introduction

Overactive bladder is a prevalent symptom complex that affects the patient’s quality of life. Any disruption between the neuronal micturition pathway can lead to bladder overactivity. Neurogenic causes, myogenic causes, aging, bladder outlet obstruction, sex, and psychological factors are some of the factors contributing to bladder overactivity. The complaint of any symptoms of OAB, which is highly prevalent and affects overall QOL, often needs therapeutic interventions. When conservative therapy methods fail, the addition of medications is recommended. The most commonly used agents for the treatment of OAB are antimuscarinic drugs. New classes of drugs, such as beta-3 agonists, have enriched our pharmacologic armamentarium.