Current Clinical Pharmacology - Volume 8, Issue 2, 2013

Simply put, there is no cure for obesity. Pharmaceuticals that induce weight loss of extent of at least 5% from baseline are applied and tested as the weight loosing drugs. Available guidelines include recommendations that pharmacologic treatment of obesity may be offered to patients with BMI > 30 kg/m2; or BMI >27 kg/m2 and obesity related comorbidity. Both categories cumulatively include essential boundary condition of failing to achieve clinically significant weight loss through diet and exercise alone. In despite the exceedingly growing number of investigations and approaches, overall achievements in pharmacological treatments of obesity are limited. Antiobesity drugs are typically burdened with issues concerning the sustainability of lost weight, besides limitations in short term efficiency. Another important problem lays in the fact that the drug induced weight loss could be annihilated or reversed if patient does not adhere to personal lifestyle changes. Later include adjustments in behaviour sphere, dietary habits and physical activity. Recently, focus of clinical interests came to prevention of obesity epidemic through optimization of chronic pharmacotherapies, especially ones associated with weight gain side-effect. This review presents the most important representatives of antiobesity drugs and essential principles that ought to be taken in to count in order to treat obesity more successfully.

Iodine is an essential trace element for life. Its biological effects are a consequence of its incorporation to the thyroid hormones, which play a crucial role in fetal organogenesis, and in particular in brain development. This takes place during early gestation and involves delicate targeting throughout the central nervous system, including adequate neuronal growth, migration and myelinization at different sites, such as the cerebral cortex and neocortex, visual and auditory cortex, hippocampus and cerebellum. Pregnancy is characterized by an increased demand of thyroid hormones by the feto-placental unit in order to fulfill the necessary requirements of thyroid hormone action for normal fetal development. Up until week 20, the fetal thyroid is not fully active and therefore is completely dependent on the maternal thyroxine supply. Thus, the maternal thyroid has to adapt to this situation by producing about 1.5 fold more thyroxine. This requires that enzymatic gland machinery works normally as well as an adequate iodine intake, the principal substrate for thyroid hormone synthesis. Biological consequences of iodine related maternal hypothyroxinemia are currently very well known, by both experimental models and by clinical and epidemiological evidences. The associated disturbances parallel the degree of maternal thyroxine deficiency, ranging from increased neonatal morbi-mortality and severe mental dysfunction, to hyperactivity, attention disorders and a substantial decrease of IQ of an irreversible nature in the progeny of mothers suffering a deprivation of iodine during pregnancy. As a consequence, iodine deficiency is the leading preventable cause of mental impaired function in the world, affecting as many as 2 billion people (35.2% of the entire population). Prevention of fetal iodine deficiency – a problem of pandemic proportions- is feasible, provided that an iodine supply of 200-300 μg/day to the mother is ensured, before and throughout gestation as well as during the lactating period.

Background: The concept of drug titration emerged recently for intraoperative fluid administration during Fast-Track colonic surgery to avoid hypovolemia as well as excessive crystalloid administration. The Pleth Variability Index (PVI) is an oximeter-derived parameter. It allows a continuous monitoring of the respiratory variation of the perfusion index. Objective: To investigate if applying the concept of fluid titration with PVI-guided colloid administration conjointly with restricted crystalloids administration changes the amount of fluid administered. Design, settings and patients: Twenty one ASA 2 patients scheduled for Fast-Track colonic surgery were randomized in two groups: the PVI-guided the fluid management group and the the control group. Intervention and main outcome measures: After the induction of general anesthesia, the PVI group received a 10 mL.kg- 1.h-1 infusion of crystalloid during the first hour, reduced to 2 mL.kg-1.h-1 thereafter. Colloids 250 mL were administered if necessary to maintain a PVI value of 10 to 13%. In the control group, a 10 mL.kg-1.h-1 infusion of crystalloid during the first hour was followed by a 5 mL.kg-1.h-1 infusion. Boluses of 250 mL of colloids were administered if required to maintain the mean arterial pressure above 65 mmHg. Results: Intraoperative crystalloids infused volume were significantly lower in the PVI group (925+/-262 mL vs 1129+/- 160 mL; P=0.04). In contrast, the infused amounts of colloids was higher in the PVI group (725+/-521 mL vs 250+/-224 mL; P=0.01). Interestingly, total fluid amount infused intra- ant postoperatively were similar between the groups (1650+/- 807 mL vs 1379+/-186 mL; P=0.21). Conclusion: PVI-guided fluid management in Fast-Track colonic surgery is not necessarily associated with different total volume infused.

The last decade has witnessed a greater transparency in clinical research with the advent of clinical trial registries. The aim of the study was to describe the trends in the globalization of clinical trials in the last five years. We performed an internet search using the WHO International clinical trials registry platform (WHO ICTRP) to identify the clinical trials conducted from January 2007 to December 31, 2011 among 25 countries. Among the 25 countries, the United States, Japan and Germany occupy the top positions in the total number of clinical trials conducted. Clinical trials in the US (36312) constituted 31.5% of the total number of trials performed during this period. However over a period of five years both US and Western Europe appear to show a decline, while the emerging countries show a rise in clinical trials registered. Among the emerging countries China, India and Republic of Korea are most active regions involved in clinical trials. Cancer, diabetes and respiratory diseases were most widely researched areas overall. Although the study confirms the transition in the clinical trials research towards emerging countries, the developed regions of the world still contribute to more than 70% of the trials registered worldwide.

Purpose: Bone antiresorptive treatment is associated with osteonecrosis of the jaws. Interventions used to treat this complication are diverse, controversial, and largely empirical but certain risk factors could help in its avoidance. The aim of this evidence-based review is to elucidate any interventions that are effective in reducing the risk for development of ONJ in cancer patients receiving bone antiresorptive therapy and to quantify the effectiveness of such interventions. Materials & Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2012. We selected randomized controlled trials (RCTs). Cohort studies were included only as long as there are no RCTs on the same modality. Results: Twelve studies were included in the systematic review while nine studies contributed to the various comparisons. Prescribing denosumab (DSB) instead of zoledronic acid (ZA) may not be expected to reduce risk ONJ (RR:0.71 [99% CI: 0.41-1.24], I2=0%). Prescribing clodronate (RR:10.15 [99% CI: 2.43-42.35], I2=0%) or pamidronate (RR:4.41 [99% CI: 1.90-10.24], I2=16%) instead of ZA may reduce risk for ONJ. Dental extractions remain the most potent risk factor for ONJ (RR:14.04, [99% CI: 10.36-19.03], I2=0%) and their avoidance can be considered an effective risk-reductive intervention. ONJ risk can be reduced by dental prophylactic measures (RR:0.45, [99% CI: 0.23-0.85], I2=7%). Conclusions: DSB and ZA might cause ONJ more frequently compared with chlodornate or pamidronate. Prescription pamidronate and clodronate helps avoid the complication. Reducing the administered dose for denosumab and zoledronic acid might reduce risk for ONJ as well. More randomized clinical trials comparing reduced doses of these regimens against those currently approved are needed.

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women's health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer. The search for the ‘ideal’ SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained. In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.

Obesity is among the greatest health problems worldwide. However, there is a certain lack in regard to objective evidence-based clinical therapeutic algorithms. The conservative therapy (lifestyle changes, pharmacotherapy) often fails to attain clinically significant weight lost. For this reason, more effective forms of treatment were developed (for example bariatric surgery or newly emerging field of endoscopic gastroenterological devices). The implementation of surgical therapy is marked with relatively narrowly stated indication parameters. The endoscopic methods showed promising results in weight loss, within satisfying safety profiles, although there are no clear defined positions of endoscopic devices in the treatment of obesity. Endoscopic treatment seems to be especially interesting as an alternative to surgery, because of significant surgical risk reduction. This review presents an analysis of the position of invasive treatments of obesity.

A higher prevalence of coronary heart disease, cardiac and overall mortality is associated with obesity. The development of obesity appears in different adaptations in the morphology of cardiac structure and function. Obesity causes eccentric hypertrophy and changes in diastolic function of left ventricle. A systolic on diastolic heart dysfunction results from the breakdown of compensatory pace to raised wall stress and dilatation of chambers. Obesity does not possess primary cause and effect relationship with cardiovascular disease, such as LDL cholesterol. It is regarded as a means of facilitating factors such as hypertension, diabetes or cigarette smoking. Adipose tissue in this manner works as the hormone generating tissue, secreting various peptides and secondary messengers and inflammatory cytokines. Pharmacotherapy can be a useful component in the global fight against obesity. Besides repeating re-evaluations of weight loosing drug treatment with respect to efficiency or safety for continuous use, one must not underappreciate the pretreatment risk-assessments and expected benefits of treatment, along with impact on the patient's quality of life and motivation. Pharmacotherapy of obesity is reserved for obese people with body mass index (BMI) ≥ 30 kg/m2 but also in individuals with BMI 27 .0 and 29 .9 kg/m2 and obesity related comorbidities as obstructive sleep apnea, hypertension, dyslipidemias, diabetes and metabolic syndrome. Although connections between obesity and cardiovascular diseases (CVD) are acknowledged for over dozen of years, there is still a lack of scientific research into the field and it is a challenge for future studies.

The decision to administer antidote after paracetamol overdose is based on the extent of drug exposure, and this often relies on the reported dose. Few data exist concerning the validity of this approach in children. The present observational study sought to examine the relationship between the reported dose and paracetamol concentrations in patients aged ≤18 years admitted to York Hospital between October 2008 and November 2010 inclusive. There were 77 cases and casenotes were evaluable in 61, with median age 14 years (IQR 3-15 years), and weight 54.0 kg (18.2-63.5 kg), including 47 females (71%). Paracetamol dose was 83 mg/kg (57-148 mg/kg), and interval between ingestion and serum concentration was 4.5 hours (4.0-5.4 hours). There was a positive correlation between dose and equivalent 4-hour paracetamol concentration: Spearman's rho=0.57, 95% CI 0.36-0.73, P<0.0001. These findings support the importance of reported dose as part of initial risk assessment, especially in situations where laboratory determination is unhelpful, such as after a staggered ingestion.

Bacterial intestinal overgrowth syndrome (SIBO) treatment is based on antibiotics. Probiotics have been shown to give similar results, whilst no study is available about prebiotics. This study evaluated the addition of probiotics or prebiotics to antibiotics on SIBO symptoms in a 6-month follow-up. We enrolled 40 patients (14 males and 26 females) reporting abdominal compliant without gastrointestinal diseases/alarm symptoms. SIBO was diagnosed by the agreement of lactulose and glucose breath tests. Patients were randomly divided into two groups homogeneous for sex and age: group 1 received Rifaximin 400 mg/day for 7 days/month followed by Lactobacillus casei for 7 days more and group 2 antibiotic followed by short chain fructo-oligosaccharides. All patients recorded a questionnaire for subjective symptom evaluation according to Rome III criteria and Bristol scale for stool characters before the study and after 6 months. Statistics: Student's t and Fisher's exact tests. In group 1, a significant improvement was obtained in 5 out of 6 symptoms, whilst in group 2 in 4 out of 6 symptoms (nausea and number of bowel movements failed to improve). Despite we observed a trend of probiotics to be more effective than prebiotics, the difference in the percentage of improved symptoms was not significant (83,3% vs 66.6%; p= 0.57). Our preliminary data show a good outcome with sequential antibioticprobiotic/ prebiotic administration in patients with SIBO.