N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity

Any clinical intervention (e.g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010 (1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)-5-([2-(3,4-dimethoxyphenyl)ethyl]-methylamino)-2-isopropylpentyl)-amide), a pyrroline modification of verapamil (2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylmethyl-amino]-2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery (expressed as a percentage of preischemic baseline) in contractile function (left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 microM (51.0 +/- 6.4%) as well as at 50 microM (75.1 +/- 7.4%) as compared with verapamil at 5 microM (32.2 +/- 3.7%) or untreated control hearts (18.1 +/- 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 (45.7 +/- 4.5 U/liter) as compared with untreated controls (131.5 +/- 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H-3010 group (11.7 +/- 1.6%) compared with verapamil (25.1 +/- 2.9%) and control (41.3 +/- 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H-3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.     

Cardioprotection by sulfaphenazole, a cytochrome p450 inhibitor: mitigation of ischemia-reperfusion injury by scavenging of reactive oxygen species

Cytochrome P450 (P450) enzymes play a significant role in promoting myocardial ischemia-reperfusion (I/R) injury. CYP2C9, an isoform of P450, is known to generate superoxide radicals in the reperfused heart. Sulfaphenazole (SPZ), a CYP2C9 inhibitor, has been shown to decrease I/R injury; however, the mechanism of cardioprotection by SPZ is not well elucidated. The objective of this study was to test whether SPZ mitigates myocardial I/R injury by scavenging reactive oxygen species (ROS). Isolated rat hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts were perfused with SPZ and/or N(omega)-nitro-L-arginine methylester (L-NAME). Coronary flow (CF), left-ventricular developed pressure (LVDP), and rate-pressure product (RPP) were monitored. Superoxide and nitric oxide (NO) generation in the reperfused tissue was determined using fluorescence methods. Myocardial infarct size was measured using triphenyltetrazolium chloride staining. The SPZ-treated group showed a significant recovery of cardiac function compared with the untreated I/R group (CF, 53 versus 45%; LVDP, 48 versus 22%; RPP, 51 versus 20%). The infarct size was significantly reduced in the SPZ-treated group (15%) compared with the I/R control (42%). Coadministration of L-NAME with SPZ significantly attenuated the beneficial effects of SPZ. In addition, SPZ treatment showed significantly decreased superoxide levels and enhanced NO bioavailability in the reperfused heart. In conclusion, the protective effect of SPZ against I/R-mediated myocardial damage appears to be due to a reduction in the superoxide level caused by its inhibition of CYP2C9, as well as scavenging of oxygen free radicals generated in the reperfused heart.     

Isolation and identification of Enterococcus faecalis from necrotic root canals using multiplex PCR

This study was designed to survey the incidence of Enterococcus faecalis infection in symptomatic and asymptomatic root canals of necrotic teeth using PCR and to isolate the bacterium for further screening. Sixty patients categorized according to their clinical symptoms were used for sampling by insertion of paper points into the root canals and absorbing all the fluids present within them. The samples were incubated in 1.0 ml 2xYT (containing 16 g bacto tryptone, 10 g yeast extract and 5.0 g NaCl per liter) for 24 h at 37 degrees C without aeration prior to multiplex PCR analysis. To assist the isolation of E. faecalis, sub-samples were further grown in the same medium supplemented with 6.5% NaCl and back-inoculated into bile esculin. Using multiple cultivation-dependent and PCR analyses, 6 cases (10%) of E. faecalis were identified. Four isolates were obtained from asymptomatic cases of chronic apical periodontitis, and the other two were associated with phoenix abscess and acute apical abscess, respectively. No E. faecalis infection was found in 5 patients with acute apical periodontitis or in 9 with chronic suppurative periodontitis. Our results indicate that there is no significant difference in the incidence of E. faecalis between symptomatic and asymptomatic necrotic dental root canals (P > 0.05).     

Misconceptions and issues regarding allometric scaling during the drug development process

Introduction: Allometry is the study of size and its consequences. The simple hypothesis of allometric scaling is that all physiological parameters are proportional to body size or body mass. This review examines the development of theory-based allometry or fixed exponents (0.75 and 1.0 for basal metabolic rate and volume, respectively) and the evidence for or against the theory. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the concept of theory-based allometry in biology, physiology, and pharmacokinetics.

Areas covered: In this review, the history of the development of theoretical allometry and the strong evidence against theory-based allometry demonstrated by experimental data is provided. During drug development, allometry is applied to both inter-species (from animals to humans) and intra-species (adults to children) scaling. These two forms of allometric scaling in the context of theory-based allometry are discussed and provide insight on scientific progress that refute theory-based allometry.

Expert opinion: Theory-based allometry is a mere theory and experimental data and real-life observations strongly negate the existence of such a theory. Pharmacostatistical and physiological models based on theory-based allometry can be misleading and incorrect because the theory-based allometric exponent 0.75 is not universal. The exponents of allometry are data dependent and are not fixed in the universe.     

Anthropometric Determinations of Umbilical Position in Iraqi Adults

Introduction  Umbilicus is an important surface landmark on the anterior abdominal wall in addition to its aesthetic and psychological effect. Objectives  The objective of the study is to determine the position of umbilicus in Iraqi adults to provide a guide for the neoumbilicus in abdominoplasty. Subjects and Methods  This is an observational study performed on 100 volunteers with no abdominal wall abnormality. Measurements included weight, height, body mass index (BMI), distance from xiphoid to umbilicus, distance from xiphoid process to pubic symphysis, distance from xiphoid process to both anterior superior iliac spine (ASIS), distance from pubic symphysis to umbilicus and from pubic symphysis to xiphisternum, distance of umbilicus to both ASIS, and distance of umbilicus to interspinous line and to inter-anterior hypochondrium line. Results  The study included 100 volunteers, with 50% male and 50% female whose age ranges between 18 to 60 years. The results were a follows: distance from xiphoid process to umbilicus and distance from xiphoid process to pubic symphysis were 18.03 ± 3.25 cm and 32.21 ± 4.64 cm, respectively; distances from xiphoid process to right ASIS and left ASIS were 25.95 ± 5.72 cm and 25.84 ± 6.02 cm, respectively; distance from pubic symphysis to umbilicus was 17.66 ± 3.12 cm; distance of umbilicus to interspinous line was 9.25 ± 1.84 cm. The distance from umbilicus to inter anterior hypochondrium line was 9.905 ± 2.19 cm. Conclusion  These measurements can determine the neoumbilicus position, reduce practical mistakes, and improve postsurgical outcomes.     

Overview of non-invasive factors (low level laser and low intensity pulsed ultrasound) accelerating tooth movement during orthodontic treatment

The need for orthodontic treatment is increasing all the time. As the treatment is time consuming ranging from a year to several years, any method of reducing the period of treatment and increasing the quality of the tissue will be beneficial to patients. The use of non-invasive techniques such as low level laser therapy and low intensity pulsed ultasound in accelerating orthodontic tooth movement are promising. Thus, this overview study will help to generate more understanding about the background information and the possible applications of them in daily orthodontics, depending on previous literature searching for reviews and original research articles.