Adv Drug Deliv Rev. 2009 Apr 28;61(4):290-302. Epub 2009 Feb 26.

Therapeutic strategies by modulating oxygen stress in cancer and inflammation.

Fang J, Seki T, Maeda H.

Source

Department of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. fangjun@ph.sojo-u.ac.jp

Abstract

Oxygen is the essential molecule for all aerobic organisms, and plays predominant role in ATP generation, namely, oxidative phosphorylation. During this process, reactive oxygen species (ROS) including superoxide anion (O(2)(-)) and hydrogen peroxide (H(2)O(2)) are produced as by-products, while it seems indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, during times of environmental stress ROS levels may increase dramatically, resulting in significant damage to cell structure and functions. This cumulated situation of ROS is known as oxidative stress, which may, however, be utilized for eradicating cancer cells. It is well known that oxidative stress, namely over-production of ROS, involves in the initiation and progression of many diseases and disorders, including cardiovascular diseases, inflammation, ischemia-reperfusion (I/R) injury, viral pathogenesis, drug-induced tissue injury, hypertension, formation of drug resistant mutant, etc. Thus, it is reasonable to counter balance of ROS and to treat such ROS-related diseases by inhibiting ROS production. Such therapeutic strategies are described in this article, that includes polymeric superoxide dismutase (SOD) (e.g., pyran copolymer-SOD), xanthine oxidase (XO) inhibitor as we developed water soluble form of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP), heme oxygenase-1 (HO-1) inducers (e.g., hemin and its polymeric form), and other antioxidants or radical scavengers (e.g., canolol). On the contrary, because of its highly cytotoxic nature, ROS can also be used to kill cancer cells if one can modulate its generation selectively in cancer. To achieve this goal, a unique therapeutic strategy was developed named as "oxidation therapy", by delivering cytotoxic ROS directly to the solid tumor, or alternatively inhibiting the antioxidative enzyme system, such as HO-1 in tumor. This anticancer strategy was examined by use of O(2)(-) or H(2)O(2)-generating enzymes (i.e., XO and d-amino acid oxidase [DAO] respectively), and by discovering the inhibitor of HO-1 (i.e., zinc protoporphyrin [ZnPP] and its polymeric derivatives). Further for the objective of tumor targeting and thus reducing side effects, polymer conjugates or micellar drugs were prepared by use of poly(ethylene glycol) (PEG) or styrene maleic acid copolymer (SMA), which utilize EPR (enhanced permeability and retention) effect for tumor-selective delivery. These macromolecular drugs further showed superior pharmacokinetics including much longer in vivo half-life, particularly tumor targeted accumulation, and thus remarkable antitumor effects. The present review concerns primarily our own works, in the direction of "Controlling oxidative stress: Therapeutic and delivery strategy" of this volume

Am J Cardiol. 1996 Apr 1;77(9):739-44.

Influence of obesity on the diagnostic value of electrocardiographic criteria for detecting left ventricular hypertrophy.

Abergel E, Tase M, Menard J, Chatellier G.

Source

Centre d'Investigations Cliniques, and the Service d'Informatique Medicale, Hôpital Broussais, Paris, France.

Abstract

Easily applicable, clinically relevant electrocardiographic criteria are needed to screen large populations for left ventricular (LV) hypertrophy. The aim of this study was to evaluate, in a population of 380 hypertensive patients of both sexes, whether obesity modified the diagnostic performance of Sokolow-Lyon and Cornell voltage criteria by comparing them with echocardiographic evaluations using different indexation methods for LV mass presentation (body surface area and various powers of the height variable). For the population as a whole, Cornell voltage was better correlated to LV mass than was Sokolow-Lyon voltage (r = 0.48 and 0.36, respectively). The poorest performance of Sokolow-Lyon voltage was observed among obese patients (best r = 0.1 and 0.21 in obese women and men, respectively). Sensitivities were assessed at a 95% specificity level. In nonobese patients, using sex-adjusted voltage values (43 and 36 mm in men and women, respectively, for Sokolow-Lyon voltage, and 28 and 25 mm for Cornell voltage), the sensitivities of Cornell voltage and Sokolow-Lyon voltage were similar in men and women (near 22% and 36%, respectively), whatever the indexation method used for LV mass. In obese patients, Cornell voltage sensitivity was similar to that of nonobese patients, whereas Sokolow-Lyon voltage had a much poorer sensitivity (<10%). For simple LV hypertrophy detection criteria, Sokolow-Lyon voltage should be avoided in obese hypertensive patients and replaced by the Cornell voltage criteria, which are not influenced by the presence of obesity.

Hypertension. 2004 Aug;44(2):175-9. Epub 2004 Jun 28.

New gender-specific partition values for ECG criteria of left ventricular hypertrophy: recalibration against cardiac MRI.

Alfakih K, Walters K, Jones T, Ridgway J, Hall AS, Sivananthan M.

Source

British Heart Foundation Cardiac MRI Unit, Leeds General Infirmary, Leeds, UK.

Abstract

ECG criteria for left ventricular hypertrophy (LVH) were mostly validated using left ventricular mass (LVM) as measured by M-mode echocardiography. LVM as measured by cardiac MRI has been demonstrated to be much more accurate and reproducible. We reevaluated the sensitivity and specificity of 4 ECG criteria of LVH against LVM as measured by cardiac MRI. Patients with systemic hypertension (n=288) and 60 normal volunteers had their LVM measured using a 1.5-Tesla MRI system. A 12-lead ECG was recorded, and 4 ECG criteria were evaluated: Sokolow-Lyon voltage, Cornell voltage, Cornell product, and Sokolow-Lyon product. Based on a cardiac MRI normal range, 39.9% of the hypertensive males and 36.7% of the hypertensive females had elevated LVM index. At a specificity of 95%, the Sokolow-Lyon product criterion had the highest sensitivity in females (26.2%), the Cornell criterion had the highest sensitivity in males (26.2%), and the Cornell product criteria had a relatively high sensitivity in both males and females (25.0% and 23.8%). Receiver operating characteristic curves showed the Cornell and Cornell product criteria to be superior for males whereas the Sokolow-Lyon product criterion was superior for females. Comparing the mean LVM index values of the subjects who were ECG LVH positive to the normal volunteers indicated that the ECG LVH criteria detect individuals with an LVM index substantially above the normal range. We have redefined the partition values for 4 different ECG LVH criteria, according to gender, and found that they detect subjects with markedly elevated LVM index

J Hypertens. 2012 May;30(5):990-6.

ECG detection of left ventricular hypertrophy: the simpler, the better?

Gosse P, Jan E, Coulon P, Cremer A, Papaioannou G, Yeim S.

Source

Cardiology-Hypertension Department, Hôpital Saint André, University Hospital of Bordeaux, Bordeaux, France. philippe.gosse@chu-bordeaux.fr

Abstract

OBJECTIVE:

ECG is commonly employed to identify left ventricular hypertrophy (LVH) and a high risk of cardiovascular events (CVE) in hypertensive patients. However, the multiplicity of the existing criteria does not simplify interpretation of the data. We compared a number of common criteria in hypertensive patients by taking as references left ventricular mass (LVM) measured by echocardiography and prediction of incident CVE.

METHODS:

The population was a cohort of 958 hypertensive patients (mean age 48 years) recruited before any treatment and having benefited from an ECG and an echocardiography. We evaluated their outcomes at regular intervals. We examined the relationships between several ECG criteria of LVH and LVM as well the occurrence of CVE.

RESULTS:

Among the various parameters tested (Sokoloff, Cornell, Cornell product) the simple measurement of the RaVL wave offered the best correlations to LVM and the best prediction of the existence of an echocardiographic LVH (receiver-operating characteristic curves). Its alterations were best correlated with the changes in LVM during the follow-up period. Moreover, this simple measurement offered the best performance for the prediction of the occurrence of CVE (123 events after a mean lapse of 12 years).

CONCLUSION:

In the interpretation of an ECG in the hypertensive patient, the single measurement of the R wave in aVL gives results at least as good as those of more complicated indices, which do not appear to contribute further to the diagnosis of LVH and the prediction of cardiovascular risk