Postmarketing Safety of Biosimilars: Current Status, Challenges, and Opportunities in the Spontaneous Reporting System.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

Identification of heterotic groups in South-Asian-bred hybrid parents of pearl millet.

KEY MESSAGE: Pearl millet breeding programs can use this heterotic group information on seed and restorer parents to generate new series of pearl millet hybrids having higher yields than the existing hybrids. Five hundred and eighty hybrid parents, 320 R- and 260 B-lines, derived from 6 pearl millet breeding programs in India, genotyped following RAD-GBS (about 0.9 million SNPs) clustered into 12 R- and 7 B-line groups. With few exceptions, hybrid parents of all the breeding programs were found distributed across all the marker-based groups suggesting good diversity in these programs. Three hundred and twenty hybrids generated using 37 (22 R and 15 B) representative parents, evaluated for grain yield at four locations in India, showed significant differences in yield, heterosis, and combining ability. Across all the hybrids, mean mid- and better-parent heterosis for grain yield was 84.0% and 60.5%, respectively. Groups G12 B × G12 R and G10 B × G12 R had highest heterosis of about 10% over best check hybrid Pioneer 86M86. The parents involved in heterotic hybrids were mainly from the groups G4R, G10B, G12B, G12R, and G13B. Based on the heterotic performance and combining ability of groups, 2 B-line (HGB-1 and HGB-2) and 2 R-line (HGR-1 and HGR-2) heterotic groups were identified. Hybrids from HGB-1 × HGR-1 and HGB-2 × HGR-1 showed grain yield heterosis of 10.6 and 9.3%, respectively, over best hybrid check. Results indicated that parental groups can be formed first by molecular markers, which may not predict the best hybrid combination, but it can reveal a practical value of assigning existing and new hybrid pearl millet parental lines into heterotic groups to develop high-yielding hybrids from the different heterotic groups.

Postmarketing Safety of Biosimilars: Current Status, Challenges, and Opportunities in the Spontaneous Reporting System.

Recombinant drug products successfully treat many life-threatening and chronic diseases. The high cost of these drugs makes them inaccessible to the patients particularly in developing countries. Patent expiration of innovator recombinant drug products has led to the development of biosimilars or similar biologics by several manufacturers. Unlike generics, these are not identical to their innovator products because of the differences in the manufacturing process; however, they are similar in quality characteristics, biological activity, safety, and efficacy. The regulatory procedures used for generic drugs cannot be applied for biosimilars as they are large complex structures produced from living cells and can produce potential risk of immune-based adverse reactions. Out of several safety issues related to biosimilars, two main safety concerns are variable potency and immunogenicity, for which a robust long-term pharmacovigilance system is needed. Various guidelines have been issued for the regulatory approval and pharmacovigilance of biosimilars by USFDA, EU, and pharma-emerging countries like China and India. The article includes the pharmacovigilance plan of biosimilars in these countries, discusses the challenges and opportunities in pharmacovigilance through spontaneous reporting systems, and suggests amendments in the existing suspected adverse event reporting form of the Pharmacovigilance Programme of India.

Tomato facultative parthenocarpy results from SlAGAMOUS-LIKE 6 loss of function.

The extreme sensitivity of the microsporogenesis process to moderately high or low temperatures is a major hindrance for tomato (Solanum lycopersicum) sexual reproduction and hence year-round cropping. Consequently, breeding for parthenocarpy, namely, fertilization-independent fruit set, is considered a valuable goal especially for maintaining sustainable agriculture in the face of global warming. A mutant capable of setting high-quality seedless (parthenocarpic) fruit was found following a screen of EMS-mutagenized tomato population for yielding under heat stress. Next-generation sequencing followed by marker-assisted mapping and CRISPR/Cas9 gene knockout confirmed that a mutation in SlAGAMOUS-LIKE 6 (SlAGL6) was responsible for the parthenocarpic phenotype. The mutant is capable of fruit production under heat stress conditions that severely hamper fertilization-dependent fruit set. Different from other tomato recessive monogenic mutants for parthenocarpy, Slagl6 mutations impose no homeotic changes, the seedless fruits are of normal weight and shape, pollen viability is unaffected, and sexual reproduction capacity is maintained, thus making Slagl6 an attractive gene for facultative parthenocarpy. The characteristics of the analysed mutant combined with the gene's mode of expression imply SlAGL6 as a key regulator of the transition between the state of 'ovary arrest' imposed towards anthesis and the fertilization-triggered fruit set.

Peripheral T-cell lymphoma, not otherwise specified.

The peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) belongs to a heterogeneous class of aggressive neoplasms. Although several morphologic subtypes of this tumor have been described, no particular genetic, immunological, or distinct clinical features define this disease. Patients can experience night sweats, fever, lymphadenopathy, weight loss, splenomegaly, and/or skin changes. Common laboratory tests reveal that patients have anemia, thrombocytosis, lymphocytosis, eosinophilia, hypergammaglobulinemia, or increased lactate dehydrogenase. In this case study, a patient presented with massive lymphadenopathy and right lower limb swelling, which he developed over 6 weeks. A tissue biopsy and supporting investigations confirmed the diagnosis of PTCL, NOS.

Nitric Oxide Overproduction in Tomato shr Mutant Shifts Metabolic Profiles and Suppresses Fruit Growth and Ripening.

Nitric oxide (NO) plays a pivotal role in growth and disease resistance in plants. It also acts as a secondary messenger in signaling pathways for several plant hormones. Despite its clear role in regulating plant development, its role in fruit development is not known. In an earlier study, we described a short root (shr) mutant of tomato, whose phenotype results from hyperaccumulation of NO. The molecular mapping localized shr locus in 2.5 Mb region of chromosome 9. The shr mutant showed sluggish growth, with smaller leaves, flowers and was less fertile than wild type. The shr mutant also showed reduced fruit size and slower ripening of the fruits post-mature green stage to the red ripe stage. Comparison of the metabolite profiles of shr fruits with wild-type fruits during ripening revealed a significant shift in the patterns. In shr fruits intermediates of the tricarboxylic acid (TCA) cycle were differentially regulated than WT indicating NO affected the regulation of TCA cycle. The accumulation of several amino acids, particularly tyrosine, was higher, whereas most fatty acids were downregulated in shr fruits. Among the plant hormones at one or more stages of ripening, ethylene, Indole-3-acetic acid and Indole-3-butyric acid increased in shr, whereas abscisic acid declined. Our analyses indicate that the retardation of fruit growth and ripening in shr mutant likely results from the influence of NO on central carbon metabolism and endogenous phytohormones levels.

Zingiber officinale attenuates retinal microvascular changes in diabetic rats via anti-inflammatory and antiangiogenic mechanisms.

PURPOSE: Diabetic retinopathy is a common microvascular complication of long-standing diabetes. Several complex interconnecting biochemical pathways are activated in response to hyperglycemia. These pathways culminate into proinflammatory and angiogenic effects that bring about structural and functional damage to the retinal vasculature. Since Zingiber officinale (ginger) is known for its anti-inflammatory and antiangiogenic properties, we investigated the effects of its extract standardized to 5% 6-gingerol, the major active constituent of ginger, in attenuating retinal microvascular changes in rats with streptozotocin-induced diabetes. METHODS: Diabetic rats were treated orally with the vehicle or the ginger extract (75 mg/kg/day) over a period of 24 weeks along with regular monitoring of bodyweight and blood glucose and weekly fundus photography. At the end of the 24-week treatment, the retinas were isolated for histopathological examination under a light microscope, transmission electron microscopy, and determination of the retinal tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and vascular endothelial growth factor (VEGF) levels. RESULTS: Oral administration of the ginger extract resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and vascular basement membrane thickness. Improvement in the architecture of the retinal vasculature was associated with significantly reduced expression of NF-κB and reduced activity of TNF-α and VEGF in the retinal tissue in the ginger extract-treated group compared to the vehicle-treated group. CONCLUSIONS: The current study showed that ginger extract containing 5% of 6-gingerol attenuates the retinal microvascular changes in rats with streptozotocin-induced diabetes through anti-inflammatory and antiangiogenic actions. Although precise molecular targets remain to be determined, 6-gingerol seems to be a potential candidate for further investigation.

Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats.

The present study was undertaken to evaluate the protective effects of genistein against cardiac inflammation and oxidative stress in streptozotocin (STZ) (45 mg/kg body weight)-induced diabetic rats. genistein (300 mg/kg/day) was administered orally for 24 weeks to STZ-induced diabetic rats. The effects of genistein on blood glucose, % glycosylated hemoglobin (HbA1c), C-reactive protein, tumor necrosis factor (TNF- α), transforming growth factor (TGF-ß1), and total antioxidant were studied. Ultrastructural and histopathological assessment of injury were also undertaken using transmission electron microscope. STZ-induced diabetes resulted in significant increase in the levels of blood glucose, HbA1c, C-reactive protein, TNF- α and TGF-ß1, and a decline in total antioxidant reserve of the myocardium. Administration of genistein to diabetic rats resulted in a decrease in blood glucose (p < 0.001), % HbA1c (p < 0.0001), C-reactive protein (p < 0.001), and expression of TNF- α (p < 0.001) and TGF-ß1 (p < 0.0001) proteins. In addition, genistein treatment results in augmentation of total antioxidant (p < 0.01) reserve of the hearts. The above findings were supported by histological as well as immunohistochemical localization of NF-κB (p65) in the heart. Genistein treatment ameliorated the ultrastructural degenerative changes in the cardiac tissues as compared to the diabetic control. The result demonstrates that genistein restored the integrity of the diabetic myocardium by virtue of its anti-inflammatory and antioxidant effects.

Prevention and management of diabetic retinopathy in STZ diabetic rats by Tinospora cordifolia and its molecular mechanisms.

We investigated the potential of Tinospora cordifolia (TC) in treatment of diabetic retinopathy in STZ-induced rats due to its antihyperglycemic, angiogenic, antiinflammatory and antioxidant effects. The diabetic rats, treated for 24 weeks with TC extract (250 mg/kg), were evaluated for lenticular and fundus changes. Biochemical parameters were estimated and histopathological studies performed. TC significantly reduced blood glucose and glycated hemoglobin in treated rats. It prevented cataract development in treated group. Angiogenic markers VEGF and PKC increased in diabetic retina, which reduced significantly with TC. Anti-inflammatory parameters TNF-α and IL-1ß elevated in diabetic group unlike that in treated group. TC also provided defense against depletion of antioxidant enzymes- glutathione and catalase. Histopathological studies revealed thickening of basement membrane of the retinal and glomerular vasculature of diabetic rat, but no basement membrane widening was seen in treated animals. Destruction of pancreatic islet structure was observed in diabetic group, but not in treated. Thus, TC reduces blood glucose and inhibits overexpression of angiogenic and inflammatory mediators, which are distinct markers of diabetic retinopathy. It also prevents retinal oxidative stress and restores antioxidant enzyme levels. These data provide evidence for the safety and potential effect of TC in the management of experimental diabetic retinopathy.

The brain MR Image segmentation techniques and use of diagnostic packages.

RATIONALE AND OBJECTIVES: This article provides a survey of segmentation methods for medical images. Usually, classification of segmentation methods is done based on the approaches adopted and the domain of application. MATERIALS AND METHODS: This survey is conducted on the recent segmentation methods used in biomedical image processing and explores the methods useful for better segmentation. A critical appraisal of the current status of semiautomated and automated methods is made for the segmentation of anatomical medical images emphasizing the advantages and disadvantages. Computer-aided diagnosis (CAD) used by radiologists as a second opinion has become one of the major research areas in medical imaging and diagnostic radiology. A picture archiving communication system (PACS) is an integrated workflow system for managing images and related data that is designed to streamline operations throughout the whole patient care delivery process. RESULTS: By using PACS, the medical image interpretation may be changed from conventional hard-copy images to soft-copy studies viewed on the systems workstations. CONCLUSION: The automatic segmentations assist the doctors in making quick diagnosis. The CAD need not be comparable to that of physicians, but is surely complementary.

Trigonella foenum-graecum (Fenugreek) protects against selenite-induced oxidative stress in experimental cataractogenesis.

Cataract is the opacification in eye lens and leads to 50% of blindness worldwide. The present study was undertaken to evaluate the anticataract potential of Trigonella foenum-graecum Linn seeds (fenugreek) in selenite-induced in vitro and in vivo cataract. In vitro enucleated rat lenses were maintained in organ culture containing Dulbecco's modified Eagles medium (DMEM) alone or in addition with 100 microM selenite and served as the normal and control groups, respectively. For the test group, the medium was supplemented with selenite and T. foenum-graecum aqueous extract. The lenses were incubated for 24 h at 37 degrees C. After incubation, the lenses were processed for the estimation of reduced glutathione (GSH), lipid peroxidation product (malondialdehyde), and the antioxidant enzymes. In vivo selenite cataract was induced in 9-day-old rats by subcutaneous injection of sodium selenite (25 micromol/kg body weight). Animals in the test group were injected with different doses of aqueous extract of T. foenum-graecum 4 h before the selenite challenge. A fall in GSH and a rise in malondialdehyde levels were observed in control as compared to normal lenses. T. foenum-graecum significantly (P < 0.01) restored glutathione and decreased malondialdehyde levels. A significant restoration in the activities of antioxidant enzymes such as superoxide dismutase (P < 0.01), catalase, (P < 0.01), glutathione peroxidase (P < 0.01), and glutathione-S-transferase (P < 0.01) was observed in the T. foenum-graecum supplemented group as compared to control. In vivo, none of the eyes was found with nuclear cataract in treated group as opposed to 72.5% in the control group. T. foenum-graecum protects against experimental cataract by virtue of its antioxidant properties. Further studies are warranted to explore its role in human cataract.

Current concepts in the pathophysiology of glaucoma.

Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized. The literature available in the National Medical Library and online Pubmed search engine was used for literature review.

Anti-tumor studies with extracts of Calotropis procera (Ait.) R.Br. root employing Hep2 cells and their possible mechanism of action.

Anti-tumor potential of root extracts of Calotropis procera: methanolic extract (CM), hexane extract (CH), aqueous extract (CW) and ethylacetate extract (CE) and its possible mechanism against Hep2 cancer cells has been investigated. Cellular proliferation activities were assayed by tetrazolium bromide (MTT) colorimetry. Morphological changes of cancer cells were observed under inverted microscope and cell cycle parameters were determined by flow cytometry following propidium iodide staining. Treatment with the extracts at various doses of 1, 5, 10 and 25 microg/ml revealed that CM, CH and CE possessed cytotoxicity, whereas CW did not have cytotoxic effect. CE (10 microg/ml) showed strongest cytotoxic effect (96.3%) on Hep2 at 48 hr following treatment, whereas CM and CH showed cytotoxicity of 72.7 and 60.5%, respectively. Extract-treated cells exhibited typical morphological changes of apoptosis. Results of flow cytometric analysis clearly demonstrated that root extracts initiated apoptosis of Hep2 cells through cell cycle arrest at S phase, thus preventing cells from entering G2/M phase. Results of the study indicate that the root extracts of C. procera inhibit the proliferation of Hep2 cells via apoptotic and cell cycle disruption based mechanisms.

Comparison of effect of daily versus weekly iron supplementation during pregnancy on lipid peroxidation.

OBJECTIVES: To compare the effect of daily versus weekly iron supplementation on lipid peroxidation, hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women. METHODS: Of 109 women randomly allocated into three groups, 90 completed the study. Group I (n = 30) received daily iron folic acid; Group II (n = 30) received weekly iron folic acid; Group III (n = 30) received daily iron (III)-hydroxide polymaltose complex. Hemoglobin levels, hematological indices, thiobarbituric acid reactive substances (TBARS) and glutathione levels were measured at baseline (14-16 weeks) and at 30-34 weeks. Statistical analysis was done using the anova test. RESULTS: Group I had a highly significant increase in TBARS level (0.61 +/- 0.26 micromol/L, P = 0.000) compared to groups II and III in which the change in TBARS was not significant (0.02 +/- 0.06 and 0.007 +/- 0.06 micromol/L, respectively). There was an insignificant fall in glutathione levels in all groups. There was no significant difference in the mean period of gestation, pregnancy complications and neonatal outcome between the three groups. Among 22.2% of women who were non-compliant, Group I had significantly higher incidence of non-compliance (P = 0.016) and side-effects (P = 0.001). Final hemoglobin was higher in Group I than II (11.9 +/- 1.2, 11.3 +/- 0.9, respectively, P = 0.041). The TBARS level was not statistically different between preterm and term deliveries. Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia. The final TBARS level was significantly higher in these women (P = 0.000). CONCLUSIONS: Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation, the latter is comparable with daily iron (III)-hydroxide polymaltose complex. Lipid peroxidation levels are significantly higher in preeclampsia.

Inhibition of benzopyrene-diol-epoxide (BPDE)-induced bax and caspase-9 by cadmium: role of mitogen activated protein kinase.

Cadmium, a major metal constituent of tobacco smoke, elicits synergistic enhancement of cell transformation when combined with benzo[a]pyrene (BP) or other polynuclear aromatic hydrocarbons (PAHs). The mechanism underlying this synergism is not clearly understood. Present study demonstrates that (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), an ultimate carcinogen of BP, induces apoptosis in human leukemic HL-60 cells and others, and cadmium at non-cytotoxic concentration inhibits BPDE-induced apoptosis. We observed that BPDE treatment also activates all three MAP kinases e.g. ERK1/2, p38 and JNK in HL-60 cells, and inhibition of BPDE-induced apoptosis by cadmium is associated with down-regulation of pro-apoptotic bax induction/caspase-9 activation and up-regulation of ERK phosphorylation, whereas p38 MAP kinase and c-Jun phosphorylation (indicative of JNK activation) remain unaffected. Inhibition of ERKs by prior treatment of cells with 10muM U0126 relieves cadmium-mediated inhibition of apoptosis/bax induction/caspase-9 activation. Our results suggest that cadmium inhibits BPDE-induced apoptosis by modulating apoptotic signaling through up-regulation of ERK, which is known to promote cell survival.

Outcome of very large superficial bladder tumours: a 10-year experience.

OBJECTIVES: To determine the biological behaviour of very large superficial bladder tumours (pTa, pT1) and evaluate the impact of the initial tumour weight on long-term prognosis. MATERIAL AND METHODS: Of 1569 patients who presented with bladder tumours over a 10-year period, 1070 of the tumours were superficial. Fifty-nine patients had very large tumours (resected weight >or= 15 g). Case notes were analysed to determine recurrence, progression and survival. Median follow-up was 60 months (range 1-156 months). Histological slides were reviewed for all tumours initially reported as pT1 to determine the presence of uninvolved muscle. Statistical analysis was performed using the Kaplan-Meier method to calculate progression and survival estimates. RESULTS: The overall progression and recurrence rates for very large superficial bladder tumours were 18% and 68%, respectively. The progression rates for Ta, T1, G1, G2 and G3 tumours were 4%, 28%, 0%, 20% and 50%, respectively, with highest progression rates being seen for pT1G2 and pT1G3 tumours. The progression rate was significantly influenced by initial stage (p=0.01) and grade (p=0.03). Tumour weight did not affect either recurrence, progression or cause-specific survival. There were no differences in progression and survival rates in patients with tumour weights of 15-30 and >30 g (p=0.80 and 0.07, respectively). The review of histology slides of T1 tumours showed that 7/10 cases (70%) with progression had no muscle or an inadequate amount of muscle for definitive staging. Upper urinary tract tumours were seen in only two patients (3.4%). CONCLUSIONS: Large size is not an adverse prognostic factor for patients with a superficial bladder tumour. However, these cases are difficult to stage. In view of the high rates of progression and disease-specific mortality, we recommend that very large pT1G2 bladder tumours should be considered as high-risk tumours and targeted for aggressive treatment, including early re-resection, to rule out any occult invasive disease.

Inhibition of benzopyrene diol epoxide-induced apoptosis by cadmium(II) is AP-1-independent: role of extracelluler signal related kinase.

Cadmium, a major metal constituent of tobacco smoke, elicits synergistic enhancement of cell transformation when combined with benzo[a]pyrene (BP) or other PAHs. The mechanism underlying this synergism is not clearly understood. We observed that (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), an ultimate carcinogen of BP, induces apoptosis in promotion sensitive mouse epidermal JB6 Cl41 cells at non-cytotoxic concentrations. BPDE also activates AP-1 several folds in AP-1 reporter JB6 cells. Cadmium at non-cytotoxic concentrations inhibits both AP-1 activation and apoptosis in response to BPDE. Since AP-1 is known to be involved in stress-induced apoptosis we investigated whether inhibition of AP-1 by cadmium has any role in the inhibition of BPDE-induced apoptosis. MAP kinases (particularly ERKs, p38 and JNKs) are known to have important role in DNA damage-induced AP-1 activation. We observed that ERK and JNK, but not p38 MAP kinase, are involved in BPDE-induced AP-1 activation. Effect of cadmium on MAP kinases and the effect of inhibition of above three MAP kinases on BPDE-induced AP-1 activation and apoptosis indicate that AP-1 is probably not involved in BPDE-induced apoptosis. Cadmium up-regulates BPDE-activated ERKs and ERK inhibition by U0126 relieves cadmium-mediated inhibition of BPDE-induced apoptosis. We suggest that cadmium inhibits BPDE-induced apoptosis not involving AP-1 but probably through a different mechanism by up-regulating ERK which is known to promote cell survival.

Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease.

Several studies have revealed varying degrees of changes in sarcoplasmic reticular and myofibrillar activities, protein content, gene expression and intracellular Ca-handling during cardiac dysfunction due to ischemia-reperfusion (I/R); however, relatively little is known about the sarcolemmal and mitochondrial alterations, as well as their mechanisms in the I/R hearts. Because I/R is associated with oxidative stress and intracellular Ca-overload, it has been indicated that changes in subcellular activities, protein content and gene expression due to I/R are related to both oxidative stress and Ca-overload. Intracellular Ca-overload appears to induce changes in subcellular activities, protein contents and gene expression (subcellular remodeling) by activation of proteases and phospholipases, as well as by affecting the genetic apparatus, whereas oxidative stress is considered to cause oxidation of functional groups of different subcellular proteins in addition to modifying the genetic machinery. Ischemic preconditioning, which is known to depress the development of both intracellular Ca-overload and oxidative stress due to I/R, was observed to attenuate the I/R-induced subcellular remodeling and improve cardiac performance. It is suggested that a combination therapy with antioxidants and interventions, which reduce the development of intracellular Ca-overload, may improve cardiac function by preventing or attenuating the occurrence of subcellular remodeling due to ischemic heart disease. It is proposed that defects in the activities of subcellular organelles may serve as underlying mechanisms for I/R-induced cardiac dysfunction under acute conditions, whereas subcellular remodeling due to alterations in gene expression may explain the impaired cardiac performance under chronic conditions of I/R.

LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial.

AIM: Menopause is a pro-atherogenic state with a sharp rise in the incidence of coronary artery disease. This pilot study was designed as an equivalence randomized clinical trial to explore the potential of LycoRed (containing 2000 microg lycopene) as an alternative to hormone replacement therapy (HRT) for the prevention of coronary artery disease in postmenopausal women. METHODS: Forty-one healthy postmenopausal women were randomly allocated to receive either continuous combined HRT (n = 21) or LycoRed (n = 20) for six months. Serum lipid profile, marker of lipid peroxidation (malondialdehyde), and the level of endogenous antioxidant (glutathione) were measured at the baseline, and 3 and 6 months after the intervention in both groups. RESULTS: At 6 months, HRT resulted in a significant decrease in total cholesterol (TC) level by 23.5%, low-density lipoproteins (LDL) by 19.6%, and an increase in high-density lipoproteins (HDL) by 38.9%. The LycoRed group showed similar changes in TC (-24.2%), LDL (-14.9%) and HDL (+26.1%). Triglyceride levels showed a smaller though significant increase at 6 months, but not at 3 months, in both groups. There was no significant change in the very LDL (VLDL) level in either group. Malondialdehyde levels decreased significantly by 16.3% and 13.3%, whereas glutathione levels increased significantly by 5.9% and 12.5% in HRT and LycoRed groups, respectively. CONCLUSION: Both HRT and LycoRed had a favorable effect on serum lipids and oxidative stress markers which were comparable. LycoRed can be used as an alternative to HRT to reduce the risk of atherosclerosis in postmenopausal women.