Hoda A. El-Bahrawy

Human Recombinant Erythropoietin in Asphyxia Neonatorum: Pilot Trial

OBJECTIVE: The goal was to examine biochemical, neurophysiologic, anatomic, and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: We conducted a prospective case-control study with 45 neonates in 3 groups, a normal healthy group (N = 15), a HIE-erythropoietin group (N = 15; infants with mild/moderate HIE who received human recombinant erythropoietin, 2500 IU/kg, subcutaneously, daily for 5 days), and a HIE-control group (N = 15; did not receive erythropoietin). Serum concentrations of nitric oxide (NO) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups. The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks. Brain MRI was performed at 3 weeks. Neurologic evaluations and Denver Developmental Screening Test II assessments were performed at 6 months. RESULTS: Compared with normal healthy neonates, the 2 HIE groups had greater blood NO concentrations (P < .001). At enrollment, the 2 HIE groups did not differ in clinical severity, seizure incidence, NO concentrations, or electroencephalographic findings. At 2 weeks of age, electroencephalographic backgrounds improved significantly (P = .01) and NO concentrations decreased (P < .001) in the HIE-erythropoietin group, compared with the HIE-control group; MRI findings did not differ between groups. At 6 months of age, infants in the HIE-erythropoietin group had fewer neurologic (P = .03) and developmental (P = .03) abnormalities. CONCLUSION: This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE, to protect against encephalopathy.

Green Tea Attenuates Benzene-Induced Oxidative Stress in Pump Workers

Workers exposed to benzene frequently suffer from toxicities of the bone marrow as well as the central nervous, immune, and reproductive systems. This toxicity most likely is a result of the oxidative metabolism of benzene to reactive products. As green tea possesses antioxidant effects, the objective of this study was to examine any amelioration of benzene-induced oxidative stress in pump workers drinking 6 cups (150 ml/cup) of freshly prepared tea daily. Sixty male non-smoking subjects, divided into four groups: no benzene exposure/no green tea; no exposure/tea; exposure/no tea; and, exposure/tea, were monitored after a 6 mo period. On the final day of the study, urine samples were collected for analyses of benzene, trans-trans muconic acid, and phenol. Blood was also collected at this time; plasma was assayed for total antioxidant activity, malondialdehyde (MDA), and glutathione (GSH) while erythrocytes were analyzed for activity of antioxidant enzymes glutathione peroxidase (GSHPX), superoxide dismutase (SOD), and catalase. The results demonstrated that urinary levels of benzene, trans-trans muconic acid, and phenol were elevated in all pump workers, and that this elevation was mitigated by consumption of green tea. The benzene exposures also led to significant reductions in plasma GSH levels and erythrocyte antioxidant enzyme activities; these effects were abrogated (to near-control levels) by the tea. Interestingly, among control subjects, tea ingestion itself caused significant increases in both GSHPX and catalase activities. Unlike with the other plasma parameters, while the benzene exposures also significantly increased plasma MDA levels and decreased total antioxidant activity, tea ingestion did not cause a near-total reversion to control values; the effects on these two endpoints were more like those noted with the urine parameters (mitigation, not abrogation). These studies demonstrate that drinking green tea during benzene exposure can reduce several parameters indicative of oxidative stress. As such, as a dietary supplement, green tea could represent a potential therapeutic agent in reducing certain aspects of benzene-induced toxicity.

Modulation of bone turnover in orchidectomized rats treated with raloxifene and risedronate

Osteoporosis is a reduction in bone mineral density (BMD). It develops less often in men than in women. This study aimed to evaluate the bone protective effects of raloxifene (RAL), risedronate (RIS), and their combination on osteoporotic male rats. Forty male Wister rats (12 weeks) were randomly divided into five groups: sham‐operated group (n = 8), orchidectomized (ORX) group (n = 7), RAL group (n = 9), RIS group (n = 7) and RAL + RIS group (n = 7). RAL was orally administered at 3 mg/kg three times/week, and RIS was given subcutaneously at 5 μg/kg, twice weekly. After 6 weeks of treatment, serum cathepsin‐K, alkaline (ALP) and acid phosphatase activities, serum osteocalcin, serum Ca2+, and Pi were determined. Urinary Ca2+ and deoxypyridinoline levels, BMD, and Ca2+ content of femur ash were estimated. Histochemical localization of ALP activity of tibia and histomorphometry was examined. As compared to sham, ORX rats showed a significant increase in bone turnover markers, and histochemical activity of ALP was increased markedly in proximal tibia of ORX rats, whereas BMD and Ca2+ content of femur ash were reduced after ORX. These changes were modulated after treatment with RAL and RIS or both to ORX rats; BMD of femur was improved by each treatment, and bone turnover markers were reduced as compared to ORX vehicle group. We concluded that orchidectomy induced osteoporosis and increased bone turnover in male rats because of withdrawal of sex hormones. Both RAL and RIS could treat osteoporosis in ORX rats; they reduced bone turnover markers and maintained BMD.

Antifibrotic effect of AT‐1 blocker and statin in rats with hepatic fibrosis

Hepatic fibrosis is an outcome of chronic liver injury. Angiotensin II (ANG II) may play a role in the pathogenesis of hepatic fibrosis. Certain drugs such as ACE inhibitors, ANG II antagonists, and even statins could interfere with the renin angiotensin system and modulate its deleterious effects. This study was carried out to investigate the possible role of losartan and atorvastatin in liver fibrosis. Liver fibrosis was induced in rats by i.p. injection of 50% CCl4 twice per week for 8 weeks. The rats intoxicated with CCl4 were divided into four groups: fibrosis control; losartan group; atorvastatin group; and co‐treated group. A fifth group of normal healthy rats served as a control group. The results showed that losartan and atorvastatin, either alone or in combination, significantly decreased ALT, AST, hyaluronic acid and hydroxyproline levels in their groups compared to those of the fibrosis control group. A significant decrease in TGF‐β was found in the losartan and co‐treated groups but not in the atorvastatin group. These biochemical data were supported by liver histopathology and α‐SMA. The results indicate that the combined treatment with both losartan and atorvastatin produced a greater effect than either drug alone and proved a beneficial role in inhibiting or reversing liver fibrosis.

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway

Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

Chemopreventive effect of omega-3 polyunsaturated fatty acids and atorvastatin in rats with bladder cancer

Bladder cancer remains a huge concern for the medical community because of its incidence and prevalence rates, as well as high percentage of recurrence and progression. Omega-3 polyunsaturated fatty acids and atorvastatin proved anti-inflammatory effects through peroxisome proliferator-activated receptor gamma mechanism. However, their chemopreventive effect still remained to be examined and clarified. In this study, bladder cancer was induced in rats by the chemical carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid: 2:3 w/w; 1200 mg/kg) and/or atorvastatin (6 mg/kg) were given orally daily to rats for eight consecutive weeks concomitantly with N-butyl-N-(4-hydroxybutyl)nitrosamine and continued for further 4 weeks after cessation of N-butyl-N-(4-hydroxybutyl)nitrosamine administration. The histopathological examination of rat bladder revealed the presence of tumors and the absence of apoptotic bodies in sections from N-butyl-N-(4-hydroxybutyl)nitrosamine group, while tumors were absent and apoptotic bodies were clearly observed in sections from rat groups treated with omega-3 polyunsaturated fatty acids, atorvastatin, or both drugs. The study of the molecular mechanisms illustrated downregulation of COX-2 and P53 (mutant) genes and suppression of transforming growth factor beta-1 and the lipid peroxidation product malondialdehyde in serum of rats of the three treated groups. This chemopreventive effect was confirmed by and associated with lower level of bladder tumor antigen in urine. However, the combined treatment with both drugs exhibited the major protective effect and nearly corrected the dyslipidemia that has been induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. Collectively, omega-3 polyunsaturated fatty acids and atorvastatin, besides having anti-inflammatory properties, proved a chemopreventive effect against bladder cancer, which nominates them to be used as adjuvant therapy with other chemotherapeutics.

Nebivolol prevents indomethacin-induced gastric ulcer in rats

Abstract Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-α and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFα and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients.

A comparative study of variants of pegylated interferon alpha in treatment of chronic HCV patients.

HCV infection presents a vast burden in the regions of high prevalence such as Egypt, where most HCV isolates are genotype 4b. Combined treatment of three variants of pegylated interferon and ribavirin is still the standard of care in Egypt. However, no conclusive data confirming their efficacy are available. Here, 60 chronic HCV patients were randomized for ribavirin plus Peg Intron (PEG‐IFNα‐2b), Pegasys (PEG‐IFNα‐2a) or Reiveron Retard (PEG‐IFNα‐2a). Serum interferon and antibody (Ab) levels were measured, and responses and costs were compared. Serum interferon levels were higher in Pegasys group (1625.1 ng/mL) followed by Reiveron Retard (1076.5 ng/mL), and Peg Intron group (857.72 ng/mL). Moreover, Ab levels were the lowest in Reiveron Retard group (318.4 ng/mL), followed by Peg Intron (439.93 ng/mL), and Pegasys cases (610.83 ng/mL). The best 24‐week response rates were detected in the Pegasys group (73.3%), followed by Peg Intron (66.67%), and Reiveron Retard (40%). Treatment with both Pegasys and Peg Intron were most cost‐effective. Furthermore, Pegasys was superior in both 6‐month response and serum interferon, despite having higher Ab levels (more antigenicity). Our data have notable clinical implications and suggest that Pegasys may be a superior choice of interferon therapy for chronic HCV under low socioeconomic conditions.

L- Carnitine Decreases Her-2/neu in Breast Cancer Patients Treated with Tamoxifen

Background: The crosstalk between the estrogen receptor (ER) and the growth factor receptor pathways is implicated in breast cancer cell growth. L-carnitine as complementary medicine may help reducing therapy-associated toxicity or improving cancer-related symptoms. The possible role of L-carnitine to modulate IGF-1 and Her-2/neu in breast cancer patients maintained on tamoxifen, was investigated. Patients & Methods: Two groups of postmenopausal breast cancer patients were studied: Control group received no treatment (n=20) and Tamoxifen (TAM)-treated group (n=40). Blood samples were withdrawn at the start of study and then TAM group were supplemented with L-carnitine (L-CAR) for 6 months, after which blood samples were collected. Results: TAM group before L-CAR administration showed significant decrease in serum CEA, CA15.3, Her-2/neu and IGF-1 levels compared to breast cancer control group. After L-CAR administration, a significant decrease in Her-2/neu was obtained compared to that before L-CAR, whereas the lowering effects of TAM on tumor markers and IGF-1 were preserved. Estradiol showed no significant difference between groups. Conclusion: L-carnitine as add-on therapy to TAM produced a further decrease in Her-2/neu and thus, may offer a better cancer prognosis, which may be a prospective trial to overcome TAM resistance.

Roflumilast, type 4 phosphodiesterase inhibitor, attenuates inflammation in rats with ulcerative colitis via down-regulation of iNOS and elevation of cAMP

Background: Roflumilast (Rof), a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be an effective agent in inflammatory diseases and marketed for chronic obstructive pulmonary disease. Objective: This study was conducted to examine the potential anti‐inflammatory effects of Rof in dextran sulphate sodium (DSS)–induced ulcerative colitis (UC) in rats and to investigate the molecular mechanisms underlying these effects. Methods: Forty male Wistar rats were divided into four groups: normal control, colitis group (rats received 5% DSS in their drinking water continuously for 7 days), Rof group, and sulfasalazine (SLZ) group. The Rof (5 mg/kg) and SLZ (500 mg/kg) groups underwent pretreatment with DSS one week ahead of DSS challenge and parallel with DSS. Colitis was determined by assessing colon length, weight loss, histologic colon score, quantifying the concentration of tumor necrosis factor alpha (TNF‐&agr;), nitric oxide (NO), cyclic adenosine monophosphate (cAMP), myeloperoxidase (MPO) activity and inducible nitric oxide synthase (iNOS) gene expression in colon tissue. Results: Rof attenuated the severity of colitis as evidenced by increased colon length, prevention of body weight loss, and improved colon histologic score compared to DSS group. Rof also suppressed the inflammatory response induced in DSS colitis group by decreasing colon concentration of TNF‐&agr;, NO and MPO activity and down‐ regulation of iNOS gene expression. The level of cAMP was increased by Rof compared to DSS group. The obtained results of Rof were comparable to those exerted by SLZ. Conclusion: These findings revealed the beneficial effects of Rof in alleviating inflammation in DSS colitis.