Current Clinical Pharmacology - Volume 4, Issue 3, 2009

In this paper errors in variables methods for fitting straight lines to data are reviewed. In these methods the x and y variables are both assumed to be subject to measurement error and not, as in simple least squares linear regression, just one of them. The methods are described in a unified context using the statistical principle of the method of moments. Guidance is given on the choice of an appropriate method of estimating the slope and intercept of the fitted line. Formulas for the approximate standard errors of the estimators are provided in a technical appendix. A numerical example from biochemical studies is included to illustrate the methodology.

Normal pregnancy is associated with significant hemodynamic changes in the cardiovascular system in order to meet the metabolic demands of mother and fetus. These changes include increased cardiac output, decreased vascular resistance, and vascular remodeling in the uterine and systemic circulation. Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria and hypertension. Several risk factors have been implicated in the pathogenesis of PE including genetic and dietary factors. Ca2+ is an essential dietary element and an important regulator of many cellular processes including vascular function. The importance of adequate dietary Ca2+ intake during pregnancy is supported by many studies. Pregnancy-associated changes in Ca2+ metabolism and plasma Ca2+ have been observed. During pregnancy, changes in intracellular free Ca2+ concentration ([Ca2+]i) have been described in red blood cells, platelets and immune cells. Also, during pregnancy, an increase in [Ca2+]i in endothelial cells (EC) stimulates the production of vasodilator substances such as nitric oxide and prostacyclin. Normal pregnancy is also associated with decreased vascular smooth muscle (VSM) [Ca2+]i and possibly the Ca2+-sensitization pathways of VSM contraction including protein kinase C, Rho-kinase, and mitogen-activated protein kinase. Ca2+-dependent matrix metalloproteinases could also promote extracellular matrix degradation and vascular remodeling during pregnancy. Disruption in the balance between dietary, plasma and vascular cell Ca2+ may be responsible for some of the manifestations of PE including procoagulation, decreased vasodilation, and increased vasoconstriction and vascular resistance. The potential benefits of Ca2+ supplements during pregnancy, and the use of modulators of vascular Ca2+ to reduce the manifestations of PE in susceptible women remain an important area for experimental and clinical research.

This review presents the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of fluoroquinolones pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug-drug interactions) is also discussed.

The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological pharmacotherapeutic instead of pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun Nterminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the “stress-sensor“ protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.

Drug discovery is the main flag ship of the pharmaceutical industry in order to ensure that innovations constantly occur in the identification and development of novel therapeutic options for the management of diseases. Recently, research trends that take advantage of the safety and efficacy of marketed products by combining such products with other agents to influence certain clinical pharmacology attribute(s) have emerged. The focus of the review is to evaluate ongoing research trends that have considered leveraging on certain clinical pharmacology attributes in the areas of viral infection (HIV and influenza) and oncology. Case studies discussed in this review include: a) the use of probenecid to block the organic anion renal transport of oseltamivir carboxylate (a key active metabolite of oseltamivir phosphate) to reduce the oral dose of oseltamivir phosphate; b) the use of rifampicin to induce the CYP2C19 enzyme and thereby, promote the formation of a potent active metabolite M8 (nelfinavir hydroxyl-t-butylamide) and achieve sustained blood levels to combat HIV infection along with ritonavir; c) the use of CYP3A4 inhibitors such as ketoconazole, cyclosporin A, ritonavir etc to overcome the extensive presystemic metabolism of docetaxel and enhance the oral bioavailability of docetaxel. Along with the case studies, several hurdles for drug development such as dose selection, frequency of dosing, and duration of the clinical studies, picking the right surrogate(s) for efficacy, evaluation of drug-drug interaction potential with other cosubstrates have been discussed in line with the current day requirements for a sound clinical and regulatory strategy. In summary, based on the collated information, a pragmatic approach would render feasibility for a balanced therapy management using combined clinical pharmacology attributes of drugs.

Aim: Impact of gender on aminoglycoside induced nephrotoxicity is still controversial and inconclusive. The objective of this study was to investigate the nephrotoxic potential of amikacin (AK) and gentamicin (GM) in male and female hospitalized patients. Methodology: A one-year, non-interventional prospective study of patients administered either GM or AK. The study was carried out at the internal medicine department of Al-Watani governmental hospital. Nephrotoxicity was defined as a blood creatinine (Cr) increase of ≥ 0.5 mg/ dL from the basal (normal) Cr level. Data were entered and analyzed using SPSS 16. Results: A total of 94 patients were identified (GM, n = 45 and AK, n = 49). Male and female patients on GM had comparable characteristics except that males had significantly higher number of co-existing chronic diseases. No gender differences were observed in gentamicin induced nephrotoxicity (37% in males versus 33.3% in females, P = 0.8). Male and female patients on AK were also comparable in demographic and clinical characteristics. However, significant differences in gender susceptibility were observed with AK induced nephrotoxicity (31.6% in females versus 6.7% in males, P = 0.043). Pattern of serum creatinine changes in patients on GM were comparable between males and females. However, in females on AK, s.cr levels were rising sharply after the fourth day compared with that in male patients on AK. Conclusion: Gender differences in aminoglycoside induced nephrotoxicty were seen with AK where females were more vulnerable to nephrotoxicity. Such gender differences did not exist with GM.

Objectives: To assess the prevalence of the metabolic syndrome (MetS) in overweight/obese children and adolescents of an out-patient clinic, and to compare two definitions of MetS in adolescents. Methods: In total, 528 overweight/obese children (3-16 years), of multi-ethnic origin, underwent an oral glucose tolerance test, blood collections and anthropometric measurements. In children <10 years, MetS was assessed according to childspecific cut-off values (MetS-child). In adolescents, MetS-child and MetS-adolescent (the recommendation of the International Diabetes Federation for adolescents) were compared. Results: The prevalence of MetS-child within the cohort (median age 11.3, range 3.1-16.4 years) was 18.6% (children <10 years vs. adolescents: 14.1% vs. 20.7%, P=0.073). Insulin resistance was present in 47.7% (children <10 years vs. adolescents: 21.8% vs. 60.1%, P<0.001). MetS-child was highly prevalent, and not statistically significant between age groups. In adolescents, the prevalence of MetS-adolescent was higher than MetS-child (33.2% vs. 20.7%, P<0.001). The agreement between the MetS definitions was moderate (κ=0.51), with the agreement for the MetS-criteria for abnormal lipid levels being substantial to very good (κ=0.71 to 0.80). Conclusions: MetS-child was highly prevalent in overweight/obese children and adolescents. A higher prevalence of MetS according to adolescent- as compared to child-specific criteria was found.

Recent Adcances and Developments in Treatment Strategies Against Pancreatic Cancer. Rosemary A. Fryer, Christine Galustian and Angus G. Dalgleish. Original Citation: Curr Clin Pharm 2009; 4(2): 102-112. During the preparation of the manuscript, on the title page, the last author's surname was misspelled. The correct author's name appears above.